A proper infection control program in the Ministry of Health's hospitals-Jeddah, Saudi Arabia has never been applied based on focused and aimed scientific plans. The objective of this study was to monitor the enforcement of a scientifically based infection prevention and control program via continuous auditing.A standardization and continuous auditing program was implemented in the year 2009 in twelve hospitals. Three auditing visits were conducted throughout this year to estimate hospital-wide compliance of the required procedures and strategies using auditing sheets based on that year's target aims.The first compliance rate for the first visit in the first year was 42% which increased to 66% during the second visit and to 78% during the third visit. During the first audit there were deficiencies in: general measures in infection control (43%), surveillance (31%), monitoring of infection control guidelines (81%), isolation practice (64%), infection control committee performance (66%) and education (46%). These deficiencies improved during the second audit as follows: (37%), (24%), (39%), (21%), (49%) and (25%) respectfully. During the third audit, deficiencies were as follows: (32%), (22%), (22%), (14%), (34%) and (9%) respectfully.A standardized infection control program for ongoing monitoring led to a significant improvement in infection control practices in all twelve hospitals in Jeddah. Consequently, these results might suggest that such a program can be applied to other Ministry of Health hospitals in the Kingdom.None declared.


The inherited periodic fever syndromes are single gene disorders of innate immunity which have provided invaluable insights into the regulation of inflammation. They are all extremely rare but are clinically important as they cause very significant day to day symptoms and carry a high risk of early death due to AA amyloidosis. With the exception of familial Mediterranean fever treatment was essentially ineffective until this century.The discovery in 2002 that specific IL-1 blockade completely prevented all symptoms in cryopyrin associated periodic syndrome (CAPS) transformed treatment of this rare genetic disease. Isolation of the responsible gene, NLRP3, followed by rapid advances in molecular biology and identification of the inflammasome has made it clear that CAPS is purely a disease of IL-1 dysregulation. These discoveries combined with the availability of specific anti IL-1 agents have resulted in new insights into the regulation of IL-1 beta production in humans and its long term consequences.IL-1 is now recognised to be an important mediator of inflammation in other inherited autoinflammatory diseases such as Familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), deficiency of IL-1 receptor antagonist (DIRA) and mevalonate kinase deficiency and has transformed patient prognosis and quality of life. In addition the recognition that IL-1 blockade provides complete disease control in acquired diseases of uncertain aetiology particularly Schnitzler’s syndrome and systemic onset juvenile chronic arthritis (SoJIA), adult onset Stills disease and recurrent idiopathic pericarditis has made it clear that these too are autoinflammatory disorders. One of the most striking features of these diseases is that IL-1 blocking agents have been used for prolonged periods as monotherapy without serious side effects or breakthrough of inflammatory activity thus differentiating them from the commoner autoimmune disorders such as rheumatoid arthritis and vasculitis.


Occult hepatitis B (OHB) is not a new entity and there are many reports of patients with hepatitis B virus (HBV) evidence replication in the absence of detectable hepatitis B surface antigen (HBsAg) and occasionally other HBV serologic markers . After iEgypt has the highest prevalence of HCV infection in the world . HoweverEnd-stage renal disease (ESRD) is a significant problem in almost all countries and the prevalence has increased considerably in developing countries especially in Middle East countries. The prevalence of HCV infection among hemodialysis patients differs in different parts of Middle East countries which is 48% in Egypt . The pre


Agnotecous, a cricket genus endemic to New Caledonia showing a generalized pattern of sympatry between species making sympatric speciation plausible. We obtained five mitochondrial and five nuclear markers (6.8 kb) from 37 taxa corresponding to 17 of the 21 known extant species of Agnotecous, and including several localities per species, and we conducted phylogenetic and dating analyses. Our results suggest that the diversification of Agnotecous occurred mostly through allopatric speciation in the last 10 Myr. Highly microendemic species are the most recent ones (<2 Myr) and current sympatry is due to secondary range expansion after allopatric speciation. Species distribution should then be viewed as a highly dynamic process and extreme microendemism only as a temporary situation. We discuss these results considering the influence of climatic changes combined with intricate soil diversity and mountain topography. A complex interplay between these factors could have permitted repeated speciation events and range expansion.Islands are bounded areas where high endemism is explained either by allopatric speciation through the fragmentation of the limited amount of space available, or by sympatric speciation and accumulation of daughter species. Most empirical evidence point out the dominant action of allopatric speciation. We evaluate this general view by looking at a case study where sympatric speciation is suspected. We analyse the mode, tempo and geography of speciation in  Diversity hotspots in islands are characterized by very high specific richness and endemism resulting from local diversification of groups which are “trapped” in very limited spatial areas Empirical case studies showed or suggested that diversifications in islands most often result from repeated events of local allopatric speciation and subsequent establishment of microendemism New Caledonia, one of most diverse island biodiversity hotspots AgnotecousHere we analyse the mode, tempo and geography of speciation in the microendemic species of the cricket genus We use a dated species-level phylogeny, analyses of diversification time-course, and age-range correlation methods to investigate the mode of speciation and causes of microendemism. We aim at discriminating between two alternative scenarios:Under a scenario of dominant allopatric speciation, the observed pattern of sympatry is caused by secondary sympatry with post-speciational movements.Under a scenario of dominant sympatric speciation, the observed pattern of sympatry results directly from recent sympatric speciation, with little or no post-speciational movements.According to the dominant mode of speciation, we will compare and discuss the pattern of microendemism and tempo of species diversification in New Caledonia with respect to the influence of climatic changes combined with intricate soil distribution and mountain topography. This study will allow us understanding the origin of microendemic distributions in an evolutionary and biogeographical perspective.Agnotecous. Each species is represented by specimens known from 1–7 localities (mean = 1.8). Three species from different eneopterine tribes  and one species belonging to another cricket subfamily  were used as outgroups The molecular sampling consists of 37 individuals corresponding to 17 out of the 21 known extant species of Agnotecous, we generated a consensus sequence per Agnotecous species using IUPAC ambiguity codes under BIOEDIT v 7.0.9.0 DNA sequences were aligned under Muscle with default parameters Agnotecous at 10.5 Myr ago, and its divergence with L. santoensis at 15 Myr ago, with standard deviations of 1 Myr for each calibration point Likelihood-ratio test Agnotecous phylogeny using the software SymmeTREE , which implements a whole-tree topological approach to the study of diversification rates. Diversification rate variation within the phylogeny is reported by a range of test statistics that vary in their sensitivity to nodal depth scales Lineage Through Time (LTT) plot derived from the BEAST MCC tree was used to visualise the time-course of diversification. We tested the null hypothesis of equal diversification rates across the Agnotecous data set and using the estimated pure speciation value.We also compare the fit of rate-variable models to the null hypothesis of constant diversification by using likelihood methods based on birth-death models and model-fitting approach (BDL) implemented in the R package LASER A. petchekara is close to A. azurensis, A. humboldti and A. nekando are close to A. chopardi, and A. novaecaledoniae is close to A. sarramea (within clade B2).To compare diversification rates, we used APE Data on geographic distribution of the species were obtained from the collections of the following institutions: Muséum national d’Histoire naturelle (Paris), Natural History Museum (London), Queensland Museum (Brisbane), Osaka Museum of Natural History (Osaka), Naturhistorisches Museum (Vienna) and National Museum of Natural History (Leiden). The material examined in previous taxonomic studies of the genus was taken into account Agnotecous azurensis, aimed at generating a continuous distribution area for this species. Considering these range sizes, our sampling covers 70% of Agnotecous main potential habitat (rainforest)  method test Agnotecous is not characterised by high mobility (short-winged species unable to fly), we also computed two modified indicators following Although Finally, we computed the relationship between areas and ages of species to investigate post-speciational range expansion, and test whether microendemism is mostly found in younger clades.Distribution areas and ages of clades were compared with the map of soil diversity using the GIS layers provided by Direction des Infrastructures, de la Topographie et des Transports Terrestres of the Gouvernement de la Nouvelle-Calédonie, and past climatic events with data in Chevillotte et al. Agnotecous (Agnotecous are found around three major recent climatic events (Two main lineages (A and B) of similar age  are recovered within the genus notecous . Each clc events : The genThe species-level LTT plots suggested two minor increases in diversification rates around 3.5 and 2 Myr ago , and a sThese results are not confirmed by BDL analyses: the best rate-constant model (pure birth) had an AIC of 13.16 versus 15.97 for the rate-variable model (yule-2-rate) (ΔAICrc = 3.19) see . AlthougAgnotecous. Only three species belonging to clade B2 are not sympatric with any other  and slope (0.01244>0), thus rejecting a scenario of fully sympatric speciation . Values  species , indicatAgnotecous, a cricket genus characterized by restricted areas of distribution . However, this case of partial sympatry is mostly a consequence of our definition of estimated range sizes, and these species are indeed not syntopic, but were found at different altitudes on the same mountain (Mont Mou: 375 m for A. minoris versus 1010–1140 m for Agnotecous sp.).In se study  and 4, dAgnotecous?All the studies analysing the mode of speciation in New Caledonia have concluded that both the faunal and floral diversity originated from dominant allopatric speciation Recent events may have affected the post-speciational distributions of the species, resulting in secondary contacts between them. This kind of pattern was already found in other microendemic taxa showing lower levels of sympatry. For example, sympatric species occupy different microhabitats as a consequence of character displacement in Australian freshwater snails 2), and younger species show more restricted distributions. This is especially true in the clade B2 (2 (mean = 100 km2), compared to the 122–500 km2 for other species (mean = 253 km2). Highly microendemic species are thus clearly the most recent ones  show a larger distribution Click here for additional data file.Figure S2Topologies obtained in parsimony (a) and Bayesian inference (b) for mitochondrial dataset only.(PDF)Click here for additional data file.Figure S3Comparison between the phylogeny obtained from the 37 specimens  and the phylogeny from the 16 consensus sequences .(PDF)Click here for additional data file.Figure S4Repartition of p-values obtained by the analyses under apTreeshape.(PDF)Click here for additional data file.Table S1Additional information on taxonomic sampling, voucher references (specimen numbers in MNHN collections) and GenBank accession numbers of the specimens included in this study.(PDF)Click here for additional data file.Table S2Primers used in this study.(PDF)Click here for additional data file.Table S3Agnotecous species.Results of the Bayesian test of monophyly for (PDF)Click here for additional data file.Table S4Details of the geographic distribution of species used in the analysis of geographical pattern of speciation.(PDF)Click here for additional data file.Table S5Results of the asymmetry tests conducted under SymmeTREE for seven test statistics.(PDF)Click here for additional data file.Table S6Results of the diversification rate change test conducted under the R package apTreeshape.(PDF)Click here for additional data file.Table S7Results of the BDL analyses and comparison of AIC values from different diversification models.(PDF)Click here for additional data file.Text S1Additional information on sequencing protocols.(PDF)Click here for additional data file.Text S2Characteristics of mitochondrial (a) and nuclear (b) datasets used in this study.(PDF)Click here for additional data file.Text S3Congruence tests between nuclear and mitochondrial data sets.(PDF)Click here for additional data file.Text S4Details about phylogenetic analyses.(PDF)Click here for additional data file.Text S5Additional BEAST parameters and details of calibrations.(PDF)Click here for additional data file.Text S6Details of the rate.estimate function used in GEIGER.(PDF)Click here for additional data file.


Traumatic Brain Injury (TBI) is a contributing factor to approximately one third of all injury-related deaths in USA annually. Updated statistical records for TBI in Egypt are lacking. The current research is aiming for estimating the prevalence of TBI in Egypt in order to develop a comprehensive TBI prevention program.One year period  descriptive epidemiological study of moderate and severe TBI cases admitted to the emergency department, Cairo main university hospital. The Data collection sheet included personal data , incident related data  and both; clinical and radiological findings.Moderate and severe injuries account for 17.2% (844) of all TBI presented cases in the 4 months for the study. Male sex was predominantly affected 79% of cases. 63% of the cases were between 19 and 55 years old and the 2 main causes were fall from height (FFH) and motor vehicle collision (MVC) which account for about 64% of cases. 17% of cases were among pediatric group (1-18 years) and FFH was the leading cause with 34% followed by MVC and stuck by or against events with the same percentages (21%). Causes of moderate and severe TBI among seniors (above 60 years) were FFH (28%), MVC (24%), and Stuck by or against events (15%).Traumatic brain injury is a serious public health problem in Egypt. Further data interpretation over wider periods of time should be conducted for better understanding of TBI prevalence is highly recommended to develop effective injury prevention program. Inefficient recording should raise the concern to establish an optimal system for data recording and interpreting.


Contact electrochemical transfer of silver from a metal-film stamp  or a metal-coated scanning probe  is demonstrated to allow site-selective metallization of monolayer template patterns of any desired shape and size created by constructive nanolithography. The precise nanoscale control of metal delivery to predefined surface sites, achieved as a result of the selective affinity of the monolayer template for electrochemically generated metal ions, provides a versatile synthetic tool en route to the bottom-up assembly of electric nanocircuits. These findings offer direct experimental support to the view that, in electrochemical metal deposition, charge is carried across the electrode–solution interface by ion migration to the electrode rather than by electron transfer to hydrated ions in solution. The quest for a chemical methodology applicable to the bottom-up fabrication of planned electric nanocircuits that can be effectively addressed from the external macroscopic world continues to pose major synthetic challenges. Metal growth or deposition on or within a preformed template structure has been successfully used in the fabrication of various metallic nanoscale objects and periodic nanostructures –12; howe3 groups of a self-assembled OTS/Si monolayer  to –olecules ,16. The olecules –1518,27 ecules 15.contact electrochemical patterning and transfer (CEP–CET), whereby OTSeo features are first printed or inscribed on a target OTS monolayer by using a stamp electrode consisting of a patterned silver film on OTS (Ag/OTS@OTS/Si) or a silver-coated SFM tip electrode, and then in-situ metallized by direct electrochemical transfer of the metal from the patterning electrode itself 30], respAll monolayer nanopatterning (CNL) and serial metallization (CET) operations were carried out in the contact mode , under controlled humidity at 55–65% RH. A SOLVER P47 SFM system (NT-MDT) was used in the fabrication of the OTSeo@OTS nanopatterns in 2C-coated HSC20 contact probes (Team Nanotec) were used in the inscription of the OTSeo lines, (under conditions similar to those mentioned above in relation to The serial CET experiments  were perFile 1Serial CET trial experiments and comparison of imaging results obtained under different SFM imaging conditions.


Occluded Artery Trial (OAT) demonstrated that percutaneous coronary intervention (PCI) with optimal medical therapy does not reduce the frequency of major adverse events compared to optimal medical therapy alone when performed on days 3-28 post ST-elevation myocardial infarction (STEMI) in stable patients. However the assessment of infarct zone (IZ) viability was not used as an inclusion criterion in the this trial. Several studies in patients with stable coronary artery disease have shown that only patients with preserved myocardial viability benefit from revascularization.Therefore we decided to assess the frequency of IZ viability in patients fulfilling the criteria for randomization in the OAT trial.Until now the registry included 16 patients  screened for participation in the Cardiac magnetic resonance for the Occluded infarct-related Artery Treatment (COAT) trial  which is a single center randomized study conducted in the Institute of Cardiology in Warsaw to compare late revascularization with optimal medical therapy alone on days 3-28 post MI in stable patients with preserved IZ viability. Estimated enrollment into the randomized phase is 40 patients. Viability is defined as necrosis transmurality <50% in at least 4 segments of IZ on cardiac magnetic resonance. The primary end-point of the study is a change in systolic wall thickening (SWT) at 6 months. Secondary end-points include change in left ventricular ejection fraction (LVEF), wall motion score index (WMSI), end-diastolic and end-systolic left ventricular volumes .In the studied group 8 patients (50%) did not have preserved viability of the infarct zone. Patients with preserved IZ viability were randomized to late revascularization (4 patients) or optimal therapy alone (4 patients).Lack of preserved IZ viability in 50% of patients fulfilling the criteria for randomization in the OAT trial might have influenced the negative results of this trial regarding late revascularization in STEMI. Hypothesis tested in the ongoing COAT trial assumes that late opening of the occluded infarct-related artery only in patients with preserved myocardial tissue viability may lead to improvement of left ventricular function and/or volumes.


Arabidopsis thaliana ovules initiate within the developing gynoecium from meristematic tissue located along the margins of the floral carpels. When fertilized the ovules will develop into seeds. SEUSS (SEU) and AINTEGUMENTA (ANT) encode transcriptional regulators that are critical for the proper formation of ovules from the carpel margin meristem (CMM). The synergistic loss of ovule initiation observed in the seu ant double mutant suggests that SEU and ANT share overlapping functions during CMM development. However the molecular mechanism underlying this synergistic interaction is unknown. Using the ATH1 transcriptomics platform we identified transcripts that were differentially expressed in seu ant double mutant relative to wild type and single mutant gynoecia. In particular we sought to identify transcripts whose expression was dependent on the coordinated activities of the SEU and ANT gene products. Our analysis identifies a diverse set of transcripts that display altered expression in the seu ant double mutant tissues. The analysis of overrepresented Gene Ontology classifications suggests a preponderance of transcriptional regulators including multiple members of the REPRODUCTIVE MERISTEMS (REM) and GROWTH-REGULATING FACTOR (GRF) families are mis-regulated in the seu ant gynoecia. Our in situ hybridization analyses indicate that many of these genes are preferentially expressed within the developing CMM. This study is the first step toward a detailed description of the transcriptional regulatory hierarchies that control the development of the CMM and ovule initiation. Understanding the regulatory hierarchy controlled by SEU and ANT will clarify the molecular mechanism of the functional redundancy of these two genes and illuminate the developmental and molecular events required for CMM development and ovule initiation.In flowering plants the gynoecium is the female reproductive structure. In  Arabidopsis thaliana, two rows of ovules develop from a ridge of meristematic tissue on the inner surface of the seed pod or gynoecium. Within the developing ovule primordia, much is known about molecular patterning events along the proximal to distal axis and the mechanisms of integument development In both gymnosperms and angiosperms, ovules are critical for reproductive competence. Ovules contain the female gametophyte and thus the egg cell. Additionally, upon fertilization the ovules develop into the seeds that nurture and protect the developing embryos. In Gynoecial development in Arabidopsis initiates at stage 6 of floral development  single mutant is nearly wild type while the aintegumenta (ant) mutant conditions the loss of about 50% of the ovule primordia. Together the loss of both the SEU and ANT activities in the seu ant double results in the complete loss of ovule initiation, indicating a synergistic genetic interaction and suggesting a degree of overlapping function for SEU and ANT during CMM development.A number of genes have been suggested to play a role in the maintenance of meristematic potential in the CMM and for the subsequent initiation of ovule primordia from the flanks of the CMM. While no single mutant has been reported to strongly disrupt ovule initiation, several higher order mutant combinations have been reported to disrupt the initiation of ovule primordia from the CMM SEU and ANT both encode transcriptional regulators ANT encodes an AP2-type DNA binding transcription factor that is expressed in all lateral organ primordia  ANT is expressed throughout the stage 6 gynoecial mound with a higher level of expression within the adaxial core  ANT is strong in the ovule anlagen and early ovule primordia as they arise. ANT activity during primordium development supports organ growth by maintaining the developmental period during which cell growth and cell divisions occur ANT has also been shown to contribute to proper specification of floral organ identity and polarity specification ANT regulation have not yet been published, PHB and cyclinD3 have been shown genetically to be downstream of ANT regulation ANT in organ polarity specification and regulation of cellular proliferation and/or organ growth.SEU encodes a transcriptional adaptor protein that is expressed widely throughout the plant SEU does not have a specific DNA binding activity but rather complexes with sequence specific DNA binding proteins in order to exert its effects on transcriptional regulation AGAMOUS (AG) expression during floral organ identity specification AG transcription through the recruitment of histone deacetylase proteins seu ant mutant is not conditioned simply by a de-repression of AG, but rather that SEU and ANT function to maintain or specify adaxial fate in the gynoecium and that this fate specification is critical for proper CMM development PHABULOSA (PHB) and REVOLUTA (REV) are reduced in the adaxial core of the stage 6 gynoecium in seu ant mutant plants. PHB and REV encode transcriptional regulators of the Homeodomain Leucine Zipper Class III type (HDZip-III) that are known to play a key role in the specification of adaxial identity in lateral organs SEU and ANT activity on HDZip-III expression was due to a direct or indirect regulation of their expression or accumulation. Additionally the defects in ovule and CMM development observed in the seu ant double mutant were not rescued when PHB activity was replaced, suggesting that either that PHB could not substitute for the other HDZip-III family members or that gene functions in addition to HDZip-IIIs are required downstream of SEU and ANT for CMM development ant rev double mutant, but not in ant phb double mutant support the idea of a functional differentiation between the PHB and REV activities within the CMM SEU and ANT that remain to be elucidated.A variety of experimental data suggest that the disruption of CMM development observed in the SEU and ANT are members of gene families whose members have been shown to share redundant function SEUSS-LIKE genes, SLK1, and SLK2 genetically enhance the ant mutant phenotype with respect to ovule initiation defects ANT-LIKE family member, AIL6, shares a critical redundant function with ANT as the ant ail6 double mutants flowers display reduced medial domain development and initiate very few ovule primordia ANT and the YABBY family members YAB1 and YAB3 is suggested by the synergistic disruption of ovule initiation observed in the ant yab1 and ant yab1yab3 mutants ant shatterproof1 (shp1) shatterproof2 (shp2) crabs claw (crc) mutants implicates the SHP MADS domain transcription factors in CMM development. These studies together highlight an important role for ANT function during CMM development and ovule initiation as well as reveal a high degree of functional redundancy within this tissue.Although no single mutant has been identified that eliminates CMM development or ovule initiation, a number of double mutant or higher order mutant combinations condition a severe disruption of the CMM and CMM-derived tissues (e.g. ovules) seu ant double mutant. In particular we sought to identify transcripts whose expression was dependent on the coordinated activities of SEU and ANT gene products. We hoped to both identify novel regulators of CMM development and to examine the molecular mechanism of the functional redundancy of SEU and ANT during CMM development. Our analysis identified a diverse set of transcripts that display altered expression in the seu ant double mutant tissues. Our in situ hybridization analyses indicate that many of these genes are preferentially expressed within the developing CMM. The analysis of overrepresented Gene Ontology classifications suggests a preponderance of transcriptional regulators including multiple members of the REPRODUCTIVE MERISTEMS (REM) and GROWTH-REGULATING FACTOR (GRF) families of transcriptional regulators are mis-regulated in the seu ant gynoecia. This study is the first step toward a detailed description of the transcriptional regulatory hierarchies that control the development of the CMM and ovule initiation.A number of key regulators of CMM development may be difficult to recover with standard forward genetic approaches due to a high degree of redundancy. Identifying genes that have specific patterns of spatial and temporal expression in the CMM would generate a set of candidate genes that could then be analyzed by reverse genetic approaches. In this paper we employ a transcriptomic profiling approach to identify sets of genes that are differentially expressed in the developing carpels of the seu ant double mutant relative to either single mutant. We isolated RNA from staged  and hand-dissected gynoecia to limit the developmental window of the sample to the period just before and then during ovule primordia initiation, the earliest steps of ovule development. This differentiates our work from that of the Gasser and Colombo groups that have focused on later ovule developmental stages when identifying ovule-specific transcripts In an effort to identify novel regulators of CMM development and ovule initiation we identified genes that are preferentially expressed within the CMM within the context of the gynoecium. Additionally we endeavored to prioritize genes whose expression is synergistically disrupted in the seu-3, ant-1, and seu-3 ant-1 double mutant). We first analyzed mRNA accumulation in each single mutant relative to the Col-0 wild type gynoecial samples. To identify transcripts whose steady-state levels were altered in the single mutants relative to wild type, we utilized a 1-way ANOVA and identified probe sets (transcripts) that displayed a statistically significant difference in accumulation by the genotype term. This analysis identified 120 under-expressed and 200 over-expressed transcripts in the seu single mutant and 219 under-expressed and 241 over-expressed transcripts in the ant single mutant (We utilized the Arabidopsis ATH1 Gene Chip (Affymetrix) to compare transcript levels between four different genotypes  over-represented GO terms suggest a role for this gene set in transcriptional regulation and relevant developmental processes, and 2) the reduced accumulation of these transcripts in the seu ant double mutant suggests that they may be preferentially expressed in the CMM in the wild-type gynoecium and, thus, are candidates for novel regulators of CMM development.We focused our attention on the genes that displayed seu ant double mutant we used a second analytical approach (Approach II) comprised of two steps. We first selected probe sets for which the mean expression was significantly lower in the seu or ant single mutant relative to wild type . These include AT1G02800 (ATCEL2), AT3G55560 (AGF2), AT5g57720 (REM15) AT2g46870 (NGA1), AT1G68640 (PAN), AT2G34710 (PHB), AT4G37750 (ANT), AT1G70560 (TAA1), AT5G18000 (VDD), AT3G17010 (REM22), and AT4G31610 (REM34 - previously AtREM1) PHB and TAA1) has been previously shown to be reduced in seu, ant or seu ant mutant gynoecia SEU and ANT have been implicated in the repression of AG in perianth organs, the levels of AG expression were not significantly different from wild type in the seu or ant single mutant gynoecial RNA samples . The Arabidopsis B3 superfamily consists of 118 genes all of which encode proteins containing one or more B3-type DNA binding domains. The B3 superfamily is comprised of four sub-families: REPRODUCTIVE MERISTEM); LAV (LEAFY COTYLEDON2[LEC2]-ABSCISIC ACID INSENSITIVE3 [ABI3]-VAL); ARF(AUXIN RESPONSE FACTOR);REM ( and RELATED TO ABI3RAV( and VP1). Six of the seven B3 regulators that were identified in our transcriptomics approach are from the REM subfamily for which there is little functional data. Four of these genes, AT4G31610 (REM34/AtREM1), AT5G18000 (VDD), At5G57720 (REM15) and AT3G17010 (REM22), have been previously reported to display CMM-enriched expression Surprisingly, seven out of the 31 Approach II candidate genes were members of the  factors  [49],  with experiment number (E-MEXP-3293).Two analyses were run on our data. The first was a simple 1-way ANOVA by genotype. This method identified genes with expression levels that were statically different from that of the mean of the expression values. Class variables were specified as the genotype and the genotype was modeled as a fixed effect. The data was not compared to any baseline, but the LSMeans were run for simple differences of genotype using pFDR for the multiple testing method with an alpha of 0.05. Additionally we required that log2 of the magnitude of the expression level difference between the compared genotype means was greater than 0.35. The fixation method for the data points with large residuals was set as the False Positive Rate and the LSMeans standardization rate was set for Standard Deviation. The second analysis method (Approach II) was directed at detecting genes whose expression was synergistically affected in the enes See . Gene liseu, ant, and seu ant genotypes. Each biological replicate was assayed in triplicate. Results in ADENOSINE PHOSPHORIBOSYL TRANSFERASE1 . Results shown are the average expression normalized to APT1 and the standard error of the mean for four biological replicates. APT1 was shown to be unaffected by genotype in our gynoecial RNA samples by comparison of APT1 expression levels with two other standards  across the four genotypes. Statistical analysis of one way ANOVA was conducted in JMP8  using a Tukey-Kramer HSD test and a p value cutoff of 0.05. Sequences of the oligonucleotides used for qRT-PCR analysis are described in in situ hybridizations were carried out as reported previously http://www4.ncsu.edu/~rgfranks/research/protocols.html.For analysis of transcript abundances, RNA from stage 8–10 gynoecia isolated for microarray analysis (pre-amplification) was used. cDNA synthesis and qRT-PCR were performed as previously described Table S1seu single mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S2Genes over-expressed (increased accumulation) in the seu single mutant via one way ANOVA.(XLS)Click here for additional data file.Table S3ant single mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S4ant single mutant via one way ANOVA.Genes over-expressed (increased accumulation) in the (XLS)Click here for additional data file.Table S5seu single mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S6seu single mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S7ant single mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S8ant single mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S9seu ant double mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S10seu ant double mutant via one way ANOVA.Genes over-expressed in the (XLS)Click here for additional data file.Table S11seu ant double mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S12seu ant double mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S13Sequences of oligonucleotides used for qRT PCR analysis of candidate gene expression.(XLS)Click here for additional data file.Table S14Output from JMP Genomics (SAS) ANOVA analysis with values for estimate builder (non-additivity) model for double mutant.(XLS)Click here for additional data file.


To identify the origin of synchronous and metachronous urothelial carcinoma (UC) of the bladder and upper urinary tract to get a better understanding of the basic mechanism behind the multifocality of UC, which may provide a sound bases for the future development of new strategies for detection, prevention and therapy.Six patients with UC of the bladder and synchronous or metachronous UC of the upper urinary tract were studied. Genetic analysis involving the study of loss of heterozygosity (LOH) has been evaluated on their tumours using well characterised and new markers of UC .Five of the six patients demonstrated informative results. Four of five (80%) of patients had synchronous or metacharonous UC tumour and showed patterns of LOH consistent with tumorigenesis from monoclonal tumour origin. One of five (20%) patients exhibited a LOH consistent with oligoclonal tumorigenesis.These findings suggest that both the monoclonal and field cancerization theory of tumorigenesis may play a role in tumors of the urothelial tract. However, more data is needed. Urothelial carcinoma (UC) of the bladder is the fifth most common solid cancer in the industrialized world  as a measure of clonality   model exposed to known carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine has shown oligoclonal tumour development in 30% of mice, suggesting that the field defect means of tumorigenesis plays a significant role in cancer of urothelial tract  with UC of the UUT and synchronous or metachronous bladder UC that underwent surgical excision of their tumours were identified. These patients underwent nephroureterectomy for their UUT tumour(s) and transurethral resection of their bladder tumour(s). All tumours excised were high grade UC. The patients were not treated with any radiotherapy or chemotherapy prior to their surgical resection. Patients had not received any intravesical chemotherapy or immunotherapy for the bladder tumours. Tissue sample and microdissection: Formalin fixed paraffin embedded archival tissue was cut to 5um sections, and stained with haematoxylin and eosin for microscopic evaluation. Pathological identification of tumours was done with guidance of pathologist. Laser assisted microdissection of neoplastic tissue was performed using the PixCell II Laser-Capture Microdissection® apparatus  was used to amplify genomic DNA at four specific loci on two different chromosomes: 9p21 (D9S171), 9q32 (D9S177), 9q22 (D9S303) and 17p13 (TP53). D9S171 is associated with tumour suppressor gene p16, a well characterized marker of early bladder tumorigenesis  was examined in 6 patients. Of the six patients, five patients showed informative results (83%) in one of the four loci studied. However, no patient showed informative results through all four loci  with informative loci showed a monoclonal pattern of LOH, while only one of five patients (. (20%) showed an oligoclonal pattern of LOH. Unfortunately, the patient with the oligoclonal pattern of LOH was male, and a confirmatory x-inactivation study could not be conducted. These findings are consistent with results seen by Sidranksy et al.  Habuchi   while the overgrowth of one clone in late stages tumorigenesis (high-grade tumours) may result in pseudomonoclonality  or intraepithelial spread. In one of case however, there was evidence for tumour that may arise independently, consistent with the field cancerization model. This suggest that although the single cell theory of tumorigenesis may be the predominate means of UC progression, the field cancerization model may also play a small albeit significant role, which must not be overlooked when considering appropriate treatments modalities, and when using molecular diagnostic techniques to diagnosis and monitor for disease recurrence.


Right heart catheterization (RHC) is required for definitive diagnosis of pulmonary hypertension (PH) and serial echocardiograms or RHC are necessary for long term disease management. However, RHC is invasive, costly and risky for the patient. EchocarTo evaluate the use of Cardiac MR for measuring right ventricular parameters in order to assess Pulmonary Hypertension.23 patients with PH and 12 controls underwent CMR on a 1.5T Siemens Avanto scanner. All patients underwent RHC to diagnose PH within 1 month of CMR study. The CMR protocol included cine SSFP of the whole heart and phase contrast MRI of the pulmonary valve (PV). The following conventional right ventricular (RV) functional parameters were calculated: ejection fraction (EF), end diastolic volume (EDV) and end systolic volume (ESV). Time to peak systole (TPS), an indirect measure of RV strain, was derived from the volume-time curves of the RV. PV flow analysis was performed and the following parameters were calculated: peak velocity, full-width at half maximum (FWHM), acceleration time (AT) and ejection time (ET).The results of RV functional parameters and PV flow values are shown in Tables TPS, calculated by CMR, may be a useful additional quantitative measure for diagnosis of PH and may be of value in long-term non-invasive assessment of treatment efficacy.


Microthrombosis has been demonstrated in early and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Markers of coagulation activation as microparticles (MPs) are an established risk factor for thrombosis. Our hypothesis was that levels of microparticles might correlate with aSAH severity, early cerebral ischemia (ECI) and delayed cerebral ischemia (DCI).Consecutive aSAH patients (age 18 to 80) admitted to our department between November 2011 and September 2012 were enrolled in the study. Total MPs (anxV+), platelet MPs , tissue factor MPs , and endothelial MPs  were assessed in venous blood samples. Measurement of MPs levels were obtained at early (<3 days) and delayed phase (7 to 10 days). Multiparameter MRI  was performed to evaluate ischemic damage and vasospasm at the same time points. Qualitative evaluation of severity of ischemic damage was performed on DWI sequences. Levels of MPs were evaluated comparing different groups in terms of SAH severity , ECI severity and occurrence of delayed complications (vasospasm and DCI).n = 9) when compared with WFNS 1 to 2 (n = 16) patients. Interestingly, patients with most severe ECI and DCI showed the highest values of MPs, but this trend did not reach statistical significance, probably because of the small number of patients included in the study.Twenty-five patients  were included in the analysis. Overall increased levels of MPs were observed at early phase after aSAH when compared with controls. Contrarily to our hypothesis, in the early phase no significant differences of MP level were observed in WFNS 4 to 5 (Microparticles and microthrombosis may increase the severity of early and delayed ischemic damage after aSAH.


Studies report that women with Rheumatoid Arthritis (RA) are not wearing therapeutic footwear. It is likely they are wearing normal retail footwear. Previous research gives limited information on people’s perceptions on the relationships that exist between retail footwear, well-being and quality of life (QOL). This study aimed to explore these perceptions and to identify the factors influencing footwear selection.Eleven women with RA wearing retail footwear were recruited from an out-patient podiatry clinic in the south east of England. Semi-structured interviews were carried out and a hermeneutical approach; interpretative phenomenological analysis of transcripts occurred to identify recurring themes.Six main themes were revealed from the analysis. These included: (1) the nature of foot complaints and deformities, (2) aesthetic appearance and design of footwear, (3) body image, (4) psychosocial aspects, (5) Perceptions of footwear and (6) the therapeutic value of retail shoes.Retail footwear for these women with RA has impacted on their individuality which has been shown to link significantly with their body images. Whilst footwear itself has not impacted solely on the well-being of these women; the disease process has. These consequences have been identified in their quality of life.


Tau pathology is characteristic of Alzheimer’s disease (AD) and related tauopathies including Parkinson’s disease (PD) wherein a significant percentage of PD patients who develop dementia harbor AD-like tau pathology. Tau pathology is characterized by insoluble filamentous aggregates of hyperphosphorylated tau in CNS neurons known as neurofibrillary tangles (NFTs) and neuropil threads (NTs). NFTs and NTs are implicated in mechanisms of neurodegeneration through gains of toxic functions or losses of normal tau functions. Hyperphosphorylation and decreased solubility of tau leads to a loss of the ability of tau to bind to and stabilize microtubules (MTs) which impairs axonal transport and results in neuronal dysfunction and degeneration. This presentation describes the use of MT stabilizing drugs to counteract the loss of tau function and prevent/ameliorate tau mediated neurodegeneration in a transgenic (Tg) mouse model of an AD-like neurodegenerative tauopathy. Briefly, proof of concept prevention and intervention studies of the brain-penetrant MT-stabilizing agent epothilone D (EpoD) are described in young (prevention) and aged (intervention) P301S mutant tau Tg mice (PS 19 mice) with little (young PS 19 mice) or abundant tau pathology and behavioral impairments (aged PS19 mice). In the prevention and intervention studies, EpoD treatment reduced axonal dystrophy and increased axonal MT density which led to improved neuronal integrity and cognitive performance. EpoD treatment also improved fast axonal transport in the aged PS19 Tg mice. Unexpectedly, aged PS19 mice treated with EpoD showed a marked reduction in forebrain tau pathology and increased hippocampal neuronal integrity. There were no dose-limiting side effects in the EpoD treated young and aged PS19 mice. These studies support the view that EpoD and other brain-penetrant MT-stabilizing drugs offset the loss of tau function in neurodegenerative tauopathies and therefore are potential therapeutics for the treatment of AD and related tauopathies. Finally, a new seeded transmission model of tauopathy is presented using injections of preformed tau fibrils into the brains of PS19 mice which presents new opportunities to assess the efficacy of MT stabilizers and other potential passive immunization therapies for AD and related tauopathies.Supported by grants from the NINDS/NIA.


The overall outcome of HIV disease may depend on the host's capacity to maintain dendritic cell (DC) homeostasis at mucosal sites, where DC populations, one of the earliest cell types to be exposed to the virus, present an inherent capacity to modulate the balance between tolerance and protection. DCs may influence mucosal B cell responses against HIV through contact and/or production of B cell growth factors such as B lymphocyte stimulator (BLyS/BAFF), which in turn modulate the outcome of CD4[superscript]+[/superscript] T cell HIV effectors/targets. Recent observations of HIV/SIV infections in non-pathogenic animal models and from mucosal vaccination of nonhuman primates suggest that maintenance of systemic integrity may be achieved through constraining highly efficient immune responses to mucosal sites.B lymphocyte disorders are important consequences of HIV infection  mice Indeed, there is an increasing body of experimental evidence demonstrating the role of B cells in regulating the development, proliferation, and maintenance of CD4+ T cell HIV effectors/targets. Recent observations of HIV/SIV infections in non-pathogenic animal models and from mucosal vaccination of nonhuman primates suggest that maintenance of systemic integrity may be achieved through constraining highly efficient immune responses to mucosal sites.The overall outcome of HIV disease may depend on the host's capacity to maintain dendritic cell (DC) homeostasis at mucosalsites, where DC populations, one of the earliest cell types to be exposed to the virus, present an inherent capacity to modulate the balance between tolerance and protection. DCs may influence mucosal B cell responses against HIV through contact and/or production of B cell growth factors such as B lymphocyte stimulator (BLyS/BAFF), which in turn modulate the outcome of CD4BLyS expression levels correlate with both the extent to which the B cell compartment is compromised and HIV disease progression status. The fact that HIV elite controllers expressed relatively low levels of BLyS suggest that therapeutic blockage of BLyS in HIV progressors may restore balanced effector to regulatory cell ratios to reduce both HIV target cells and systemic immune activation that are the hallmarks of HIV disease progression.


We show that intracerebral injection of such isolates into C57BL/6 mice produces a disease with preservation of PrPres molecular features distinct from BSE.We previously reported that cattle were affected by a prion disorder that differed from bovine spongiform encephalopathy (BSE) by showing distinct molecular features of disease-associated protease-resistant prion protein (PrP Characterization of the infectious agent associated with BSE showed unique features. These include defined incubation periods and distribution of brain lesions after transmission to wild-type mice, not only directly from cattle, but also after natural or experimentally induced cross-species transmission (res) accumulating in the brains of animals and humans with BSE have demonstrated specific molecular features. These include a low molecular mass of unglycosylated PrPres with high proportions of diglycosylated PrPres  and decreased levels of diglycosylated PrPres when compared with BSE isolates  and labeling with P4 monoclonal antibody  C57BL/6 female mice  were injected intracerebrally with 20 μL of 10% (weight/volume) homogenates per mouse prepared from brain stem samples of 3 cattle TSE isolates. Two of the isolates were characterized, as previously described   or Supersignal  and visualized either on film  or directly in an image analysis system . Molecular masses of PrPres glycoforms were determined as the average of the center positions of the bands from at least 3 repeated electrophoretic procedures, as measured by comparison with a biotinylated marker  included on each gel. Immunologic reactivities of antibodies 12B2 and Sha31 were compared in Western blots run in parallel with the same samples with both antibodies.Frozen mouse brain tissues and fixed brain tissues were examined by Western blot analysis and immunohistochemical tests as previously described (res detection among mice analyzed by Western blot are shown in the Table.After intracerebral injection of cattle brain samples into C57BL/6 mice, disease was observed in mice with the 2 H-type isolates, as well as with the BSE sample. Survival periods of mice and results of PrPres from H-type–infected mouse brains in comparison with BSE-infected mice is shown in res glycoforms in mice infected with H-type isolates than in mice infected with a typical BSE agent (1.1- to 1.5-Da difference in the unglycosylated PrPres (res protease cleavage showed that only the PrPres of mice infected with H-type isolates was recognized by antibody 12B2 (Western blot analysis of PrPd PrPres A. Studieody 12B2 B. This fHistopathologic analysis showed vacuolar lesions in the thalamus A that weres molecular signature. This evidence in favor of a new bovine prion strain in cattle suggests that BSE is not the only transmissible prion disease in cattle. The origin of such cases has not been determined (res after infection with the BSE agent. However, based on analysis of molecular features of prion diseases in cattle, this situation is similar to that in humans (Our data show that the recently identified bovine H-type isolates involve an infectious agent that can induce development of a disease across a species barrier, while maintaining the specific associated PrP


Objectives: To investigate cognitive components and mechanisms of learning and memory in primary progressive aphasia (PPA) using a simple clinical measure, the Three Words Three Shapes Test (3W3S).Background: PPA patients can complain of memory loss and may perform poorly in standard tests of memory. The extent to which these signs and symptoms reflect dysfunction of the left hemisphere language versus limbic memory network remains unknown.Methods: 3W3S data from 26 patients with a clinical diagnosis of PPA were compared with previously published data from patients with typical dementia of the Alzheimer type (DAT) and cognitively healthy elders.Results: PPA patients showed two bottlenecks in new learning. First, they were impaired in the effortless (but not effortful) on-line encoding of verbal  items. Second, they were impaired in the retrieval (but not retention) of verbal  items. In contrast, DAT patients had impairments also in effortful on-line encoding and retention of verbal and nonverbal items.Conclusions: PPA selectively interferes with spontaneous on-line encoding and subsequent retrieval of verbal information. This combination may underlie poor memory test performance and is likely to reflect the dysfunction of the left hemisphere language rather than medial temporal memory network.


Research indicates a clear need for easily accessible interventions of different lengths and intensity for individuals with problematic substance use. Internet interventions with therapist support for problematic alcohol use have yielded positive results in prior studies, but have never been investigated in Sweden. This pilot study tested an online structured relapse prevention program with and without therapist support. 80 internet help-seekers from the general population were recruited through a national self-help site and randomized into three groups: 1) therapist support via secure messages (n=20); 2) a choice between therapist support via messages or live chats (n=20); 3) self-help (n=40). Baseline data showed no significant differences between the three groups concerning age, gender, Time Line Follow Back (TLFB), Alcohol Use Disorders Identification Test (AUDIT), Readiness to Change Questionnaire (RTCQ) and Quality of Life (WHOQOL). In the group with a choice between messages and chat, 35% chose chat. All follow-up data for the study have recently been collected, and results will be analyzed for presentation at the conference. This study has the potential to further broaden knowledge about internet-based interventions for problematic alcohol use, and provide information about the significance of therapist support.


Neurons of the striatum receive important glutaminergic input from the cortex and thalamus and massive dopaminergic innervation from midbrain dopamine neurons. The majority (95%) of striatal neurons are medium spiny projection neurons and 5% are aspiny interneurons. The projection neurons are GABAergic and form the direct and indirect striatal output pathways that have been shown to be crucial for normal motor function and appetitively motivated learning. The importance of the medium spiny projection neurons is highlighted by the severe debilitation associated with the loss of their dopaminergic input in Parkinson’s disease or degeneration of these cells in Huntington’s disease . Approximately half of all medium spiny striatal neurons express the dopamine D1A receptor (Drd1a) and these neurons comprise the direct output pathway to the medial globus pallidus and substantia nigra pars reticulata . Early deletion of the Drd1-expressing striatal neurons in mice results in severe motor impairment, eating deficits and reduced striatal volume . In order to separate potential developmental effects from the normal role of the Drd1a-expressing striatal cells in adult mice, we have made a mouse model that allows for the inducible deletion or expression of targeted genes specifically within the Drd1a-expressing striatal neurons using BAC transgenesis.A bacterial artificial chromosome (BAC) designated RP23-47M2 was obtained from BACPAC resources of the Children’s Hospital Oakland Research Institute (CHORI). This BAC contains the Drd1a locus. Using the techniques of bacterial homologous recombination , a cassette containing the reverse tetracycline-controlled transactivator (rtTA) fused to the herpes simplex virus VP16 transactivator was inserted at the ATG start site of the Drd1a locus. Transgenic mice with the modified BAC randomly integrated into their genomes were produced by microinjection of the modified BAC into mouse zygotes at the University of Michigan Transgenic Core. Transgenic mouse lines carrying the rtTA allele were crossed with reporter transgenic mice carrying the allele for tetO-lacZ. In bi-transgenic mice this approach (TET-ON) allows for the activation of the tet operator by rtTA in the presence of doxycycline (DOX). Therefore, during DOX administration, the lacZ gene produces β-galactosidase which can be detected through X-gal staining.Drd1a-rtTA/tetO-lacZ lines were screened and at least one line to date has shown strong expression specifically within the mouse striatum. X-gal staining is present throughout the striatum, with somewhat higher levels in the medial aspects of the structure. We are continuing to screen additional lines and are determining the minimal parameters of DOX administration (dose and duration) necessary for the inducible expression of rtTA/VP16.We have made the first inducible Drd1a TET-ON mouse. This mouse, in conjunction with other transgenic models, will allow for the inducible expression or deletion of target genes specifically within Drd1a-expressing cells and will be highly useful in the study of Parkinson’s and Huntington’s diseases, addiction and the normal role of Drd1a-expressing cells.


Adverse drug reactions (ADR) appear more frequently then what is actually reported and registered. The aim was to establish an intensive monitoring system and to analyze ADR in hospitalized patients.The prospective study covered 200 patients hospitalized in the Cardiology Center, Clinical Center of Montenegro. ADR were recorded in the following way: patients were interviewed on the basis of a symptoms list and any signs which could point to eventual ADR. Secondly, lab tests and other available parameters were monitored.At the time when interviews took place, patients received on average 8.0 ± 2.6 medicines (2–17). In total, 67 patients (33%) had 75 ADR. Twenty one ADR (28%) are classified as serious. Fifty four ADR resulted in the recovery of the patient (72%), eight had as an outcome prolonged hospitalization (11%), another eight were life threatening (11%), while five ADR (6%) were the cause of the hospitalization. The most frequent ADR which had as an outcome admission to hospital were caused by digoxin (40%), prolonged hospital stay by furosemide (38%), while the most frequent registered ADR which were life threatening were caused by streptokinase (50%).Monitoring ADR in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and accompanying diseases. Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions induced by this class of medicinal products seems necessary. Additional educational efforts could affirm the rationalization of the pharmacotherapy.


Background: Recent findings strongly promoted the hypothesis that common pelvic gynecological diseases including endometriosis and ovarian neoplasia may develop de novo from ectopic endometrial-like glands and/or embryonic epithelial remnants. To verify the frequency, the anatomical localization and the phenotype of misplaced endometrial tissue along the fetal female reproductive tract, histological and immunohistochemical analyses of uteri, fallopian tubes, and uterosacral ligaments were performed. Methods: Reproductive organs were collected from seven female fetuses at autopsy, five of them from gestational ages between 18 and 26 weeks and two fetuses with gestational ages of 33 and 36 weeks deceased of placental anomalies. Serial sections from areas containing ectopic glands and embryonic duct residues were analyzed by histological and immunohistochemical procedures. Results: Numerous ectopic endometrial glands and stroma were detected in the myometrium in two fetuses with low levels of expression of estrogen receptor-alpha (ER-α) and progesterone receptors (PR). The embryonic ducts were localized in the uterine broad and ovarian ligaments and under the fallopian tube serosa in six fetuses. Low levels of steroid receptors expression were found in the embryonic residues, whereas the carcino-embryonic antigen (CEA) and the tumor marker Ca 125 were not detected. The embryonic residues stromal component strongly expressed the CD 10 and vimentin proteins. Conclusion: The anatomical and the immunohistochemical features of the ectopic organoid structures identified in fetal female reproductive tract suggest that endometriotic as well as neoplastic disease in adult women may develop on the basis of misplaced endometrial glands and/or embryonic cell remnants. Endometriosis is a heterogeneous gynecological disease clinically characterized by the presence of different anatomo-clinical subtypes Giudice, . The mosIn the present study, we evaluated the incidence and the anatomical location of displaced endometrial tissue in the reproductive tract in seven female fetuses. Serial sectioning of the reproductive organs was realized followed by immunohistochemical analysis of tissue areas containing ectopic glands and embryonic cell rests. It was observed that the anatomical and the phenotypic features of the mislocated tissue components recall some pathological characteristics of both benign and malignant gynecological conditions.Reproductive organs from a series of seven human female fetuses at different gestational ages ranging from 18 to 36 weeks were obtained at autopsy. All together, the causes of fetal death were placental pathology in two samples, cardiac malformations in two cases and voluntary abortions in three. The reproductive organs were carefully dissected, fixed in buffered formaldehyde, and included in paraffin.Between 200 and 400 serial sections with thickness of 5–7 mm from each paraffin block containing uteri, fallopian tubes, ovaries, and uterosacral ligaments were prepared and stained by hematoxylin and eosin (H&E). To ascertain tissue sections containing ectopic endometrial glands and/or embryonic duct remnants, every sixth slide was separately stained and microscopically analyzed.The following antibodies were employed; rabbit anti estrogen receptor-alpha (ER-α), ; monoclonal mouse anti human progesterone receptor, clone PR 636 ; monoclonal anti human CA125, clone M11 CA125 (Dako); monoclonal anti human CD10 clone 56C6 (Dako); monoclonal anti human carcino-embryonic antigen (CEA) clone II-7 (Dako); rabbit anti human alpha-1-foetoprotein (Dako); monoclonal anti human epithelial membrane antigen (EMA) clone E29 (Dako); mouse anti human Cytokeratin 7  and monoclonal mouse anti-vimentin clone VIM 3B (Dako).Five micrometres thick sections were deparaffinized in xylene, rehydrated through graded alcohol series, and washed in PBS. For antigen retrieval, the slides were immerged in citrate buffer (pH = 6.0) during 25 min at 96°C essentially as described , PR (14%), and ER-α (6%) was revealed in the ectopic glandular structures localized in the uterine wall. A strong expression of CD10 (41.3%) but lower level of vimentin specific immunolabeling (20%) was observed in the stromal component surrounding the displaced glands. Representative illustrations of PR expression in orthotopic endometrial cells as well as the expression of PR, ER-α, and CD10 in the uterine ectopic glands and stroma are shown in Figures Concerning the embryonic remnants, consistent EMA immunostaining ranging between 32 and 53% was detected in the duct lining cells, while lower level of expression in duct cells of both ER-α 10–23%) and PR (13–44%) molecules was found in all samples. The stromal-like component surrounding the duct residues contained between 1 and 3% of immunoreactive cells for ER-α and between 4 and 13% of immunoreactive cells for PR. Approximately 2–11% of the ductal cells and 1–3% of the stormal cells expressed cytokeratin 7, while CEA and CA125 molecules were not detected. Using anti alpha-1-fetoprotein antibody, close to 42% of the epithelial and duct surrounding mesenchymal cells were intensely immunoreactive on sections from two fetuses. Representative illustrations of the embryonic duct residues labeled with anti ER-α, anti PR, anti alpha-1-fetoprotein and anti CD10 antibodies are shown in Figures 0–23% andIn this study we show presence of misplaced endometrial glands and embryonic duct-like remnants in the reproductive organs in six of seven examined female fetuses. The phenotypic features of the ectopic glands in the myometrium of two fetuses indicate particularly weak expression of PR and ER-α steroid hormone receptors in comparison to their high level of expression in cells lining the endometrial cavity. In these two cases, moderate level of PR expression was also revealed in the cell nuclei of the stromal component, while ER-α receptors were not found. Overall, the presented findings are in accordance with other studies describing the levels of ER-α and PR in misplaced glands in patients with both endometriosis and adenomyosis (Van der Walt et al., Concerning the foci of embryonic duct remnants observed, moderate expression of PR and low levels of ER-α were uniformly revealed in the epithelial cells in all cases. Histologically, some ducts appeared dysplastic and surrounded by a dense cellular stromal layer consistently expressing vimentin and CD10 molecules. Of interest, these tubular structures in most of the samples did not clearly express cytokeratin 7, and Ca 125 protein molecules. This might be related to particular phenotypic features of coelomic metaplastic cell rests at given gestational age (Batt and Smith, de novo expression of this protein in ovarian malignancy arising from endometriosis (Horiuchi et al., In spite of the limited number of studied cases, the findings of ectopic glands and/or embryonic ducts in the reproductive tract of female fetuses is a remarkable phenomenon that could be referred to the theory of involvement of Müllerian or Wolfian cell rests in the pathogenesis of both endometriosis and particular pelvic malignancies Fujii, . At presIn conclusion, the presented data support the theory that at least some subtypes of endometriotic and gynecological neoplastic lesions may be related to anomalies occurring during the embryogenesis. These data stand in relationship with the embryological origin of certain pelvic malignancies based on the metaplastic potentiality of the secondary Müllerian system. The observed frequency of displaced embryonic structures, also suggests a complex pathogenetic mechanism in the development of endometriosis-associated neoplasms including genetic, hormonal, and/or environmental events. Consequently, further studies of endometriotic and neoplastic lesions should include novel embryonic cellular phenotypic markers, that could provide important diagnostic and predictive information to guide clinical decision making.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Our objective was to investigate the molecular mechanism underlying the processing of proBNP, levels of which are increased in heart failure ,2.Rat neonatal atrial and ventricular myocytes were cultured separately. We examined: (1) the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; (2) levels of corin and furin mRNA in atrial and ventricular myocytes and the effect their knockdown on proBNP processing; (3) molecular forms of BNP in plasma from rats and humans with and without heart failure; (4) the structure of proBNP in humans and rats; (5) the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP expressed in rat myocytes transfected with lentiviral vectors.BNP was the major molecular form secreted by atrial (75±9%) and ventricular (85±9%) myocytes, and was the major intracellular form in atrial myocytes (60±5%). ProBNP was the major intracellular form in ventricular myocytes (58±4%). The relative levels of furin mRNA correlated with those of BNP in atrial and ventricular myocytes, and transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes. BNP was the major molecular form in rat plasma 90±10%), whereas proBNP was the major form in human plasma (72±8%). The relative fraction of human BNP in rat myocytes expressing human proBNP was 60±5%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly (Figure 0%, whereO-glycosylation and cleavage sites in humans.These results suggest that proBNP is processed into BNP and N-terminal proBNP intracellularly, most likely by furin in rat. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the


From a methodological point of view, these results demonstrate the suitability of computing bilateral CoP trajectories regularity for the assessment of lateralized postural control under pathological conditions.The present study was designed to assess the relative contribution of each leg to unperturbed bipedal posture in lower limb amputees. To achieve this goal, eight unilateral traumatic trans-femoral amputees (TFA) were asked to stand as still as possible on a plantar pressure data acquisition system with their eyes closed. Four dependent variables were computed to describe the subject's postural behavior: (1) body weight distribution, (2) amplitude, (3) velocity and (4) regularity of centre of foot pressure (CoP) trajectories under the amputated (A) leg and the non-amputated (NA) leg. Results showed a larger body weight distribution applied to the NA leg than to the A leg and a more regular CoP profiles  with greater amplitude and velocity under the NA leg than under the A leg. Taken together, these findings suggest that the NA leg and the A leg do not equally contribute to the control of unperturbed bipedal posture in TFA. The observation that TFA do  In recent years, a growing number of studies have been designed to explore the dynamical structure of the centre of foot pressure (CoP) trajectories in terms of entropy (regularity/predictability) to provide more insight into mechanisms involved in the control of bipedal unperturbed stance  , with feet parallel separated by 10 cm, and their arms hanging loosely by their sides. This system includes capacitive force sensors arranged in matrix form  body weight (BW) distribution, (2) amplitude (On the one hand, to quantify the amount of postural sway under each leg, the root mean square of the CoP displacements (The means of the three postural measurements recorded were used for statistical analyses. BW distribution,


This review aimed to ascertain the extent to which the issue of departure from treatment protocol (DTP) is reported and addressed in published analyses of RCTs.One hundred publications of RCTs were randomly selected from those published in the BMJ, NEJM, JAMA and Lancet during 2008. Each trial report was reviewed to determine the extent and nature of reporting on DTP and whether statistical methods were used to deal with DTP for both benefit and harms analyses.Even the most basic adherence information was not presented in some trials. Forty-two publications did not state how many patients actually initiated their randomised treatment. Information about treatment discontinuation can be vague and may not allow assessment of the number of patients who completed the treatment protocol.Ninety-eight publications reported at least one form of DTP, including non-receipt of allocated treatment , incomplete treatment in those who initiated allocated treatment (78), switching trial treatments (12), starting disallowed/non-trial treatment (4), starting open label treatment out of trial (7), contamination across groups (3) and other nonadherence to treatment dose or schedule (23). Treatment providers were reported to be nonadherent when delivering treatment in 12 trials.More than half (50 (51%)) of the publications that reported DTP used some method to deal with it, but none were based on randomisation-preserving techniques. The most common method was based on per protocol (PP) analysis (46) (including one instance of using inverse probability of censoring weighting) often labelled as intention to treat (ITT) (18) or modified ITT (5), but missing data techniques (2) and as treated analyses (3) were also implemented. Less than 40% (26) of the 69 trials which presented harms analyses specifically defined harms analysis populations, and the majority of these definitions were based on actual treatment received (18). The majority (31) of the 43 trials that did not explicitly specify harms analysis population appeared to analysed harms outcomes using ITT. Twelve reports explicitly commented on the fact that DTP was likely to have influenced the observed treatment effect.DTP data presented in RCT publications, particularly related to treatment initiation and discontinuation, may be ambiguous or scant. Trialists often attempt to deal with DTP using variations of PP analysis, although they may be labelled as ITT; randomisation-preserving methods are not typically used. There appears to be confusion among trialists over the appropriate analysis population for harms outcomes in the presence of DTP.


Self-transcendence (ST) is one of specific human experiences often related to harmony with nature or feeling oneness with others or the self as an integral part of the whole universe. The Temperament and Character Inventory (TCI) is a widely used personality measure, and ST is one of personality dimensions  and body cooperation indexed by central (CNS) and autonomic (ANS) nervous system interaction (Cahn and Polich, In summary, growing empirical evidences indicate meditation has potential to develop ST—a positive relationship between self and other that transcends self-focused needs and increases prosocial characteristics (Hölzel et al.,


Haemodynamic monitoring is essential for the management of critically ill patients. Currently there are various techniques available in clinical practice to measure cardiac output (CO) in ICUs including pulmonary artery catheter (PAC), oesophageal Doppler, lithium dilution cardiac output (LiDCO) and pulse-induced contour cardiac output (PiCCO) studies. In recent times PAC has been used less with less invasive methods becoming more popular. We conducted a telephone survey of the current CO monitoring practices in adult ICUs in the United Kingdom.All general adult ICUs in the United Kingdom were surveyed via telephone. The nurse-in-charge or the senior physician for the shift was consulted to ascertain which cardiac output monitors (COMs) were available for use, which was their first choice and if they used PAC in the past 12 months.A total of 225 adult ICUs were surveyed and all the replies were recorded on paper (98% response). Two hundred and eleven (96%) units used at least one form of COM while the rest of the 14 units did not use any COM tool. One hundred and two (48%) use more than one form of cardiac output monitoring. Oesphageal Doppler was most popular , followed by LiDCO and PICCO both used in 73/211 (35%) of the units, and pulse contour analysis . Seven out of 211 (3%) units still use PAC as the preferred method of COM, of these two had other COM devices available and five used PAC only. Forty-six out of 211 (22%) units were using PAC at least occasionally. In contrast, a similar survey performed in 2005 [The results show the changes in COM over the past 5 years in comparison with a previous survey in 2005 . There a


National and international guidelines on antiretroviral therapy for HIV infection recently changed to recommend earlier treatment, following the publication during 2009 of two collaborative analyses of HIV cohort studies ,2. These


However, the detection of other genomic variants remains a challenge due to the lack of appropriate tools for heterozygous base-calling fluorescence chromatogram data analysis. In this study, we developed a free web-based program, Mixed Sequence Reader (MSR), which can directly analyze heterozygous base-calling fluorescence chromatogram data in .abi file format using comparisons with reference sequences. The heterozygous sequences are identified as two distinct sequences and aligned with reference sequences. Our results showed that MSR may be used to (i) physically locate indel and STR sequences and determine STR copy number by searching NCBI reference sequences; (ii) predict combinations of microsatellite patterns using the Federal Bureau of Investigation Combined DNA Index System (CODIS); (iii) determine human papilloma virus (HPV) genotypes by searching current viral databases in cases of double infections; (iv) estimate the copy number of paralogous genes, such as β-defensin 4 (DEFB4) and its paralog HSPDP3.The direct sequencing of PCR products generates heterozygous base-calling fluorescence chromatograms that are useful for identifying single-nucleotide polymorphisms (SNPs), insertion-deletions (indels), short tandem repeats (STRs), and paralogous genes. Indels and STRs can be easily detected using the currently available In The detection of genomic variations is important in studying the relationships between causative genes and diseases and the relationships between predisposing genes and complex trait diseases, such as type 2 diabetes, coronary heart disease, and cancers –4. Strucdelligent program uses dynamic programming optimization to decode the heterozygous indels with International Union of Pure and Applied Chemistry DNA code system (IUPAC code)  Another type of “mixed” sequence is represented by viral coinfection in the same specimen. For example, double HPV genotypes within one sample could be analyzed by EasyChip using probes designed to amplify the variable regions that are unique to each HPV genotype . To valiDEFB4 gene, which is well known for its multiple copy number variations. The PCR primers used amplified DEFB4 and its paralog, the pseudogene HSPDP3  and chromosome 8 . The LRi value of each chromatography peak was used to estimate the ratio between DEFB4/HSPDP3 and calculate the DEFB4 copy number  . Second,delligent, which only processes IUPAC code data. Only MSR can map sequence data to a reference database and report the most possible mixed sequence. MSR and CHILD can estimate the ratio of sequences in a mixture. Only PolyScan can process next-generation sequencing data  STR repeat structure and those of plasmid cloning, (B) MSR analyzed results are shown as the IUPAC code and decomposed sequence.Supplementary Figure 2: (A) Chromatography trace of a combined two CODIS D21S11 Locus subtype, (B) there were two 4-bp gaps in the alignment of two subtypes in CODIS D21S11 Locus.Click here for additional data file.


While considerable research has evaluated the effects of joint mobilisation on spinal, pelvic and shoulder biomechanics, there is a paucity of research evaluating the effects of foot mobilisation techniques (FMT) on gait. This pilot study evaluated the immediate effects of FMT on plantar pressures and temporal-spatial gait parameters.Fifteen adults (48±21.4 years) that had no known balance problems or falls history participated. An instrumented treadmill system  was used to measure plantar pressure and temporal-spatial gait parameters. Data were recorded for 30 seconds of steady state walking immediately before and after intervention using a standardised protocol of FMT. Repeated measures ANOVAs were used to assess the effect of FMT on gait parameters at an alpha level of .05.Of the 34 gait parameters measured, only three changed significantly after FMT. Peak pressure beneath the lateral heel (4%) and lateral forefoot (9%) was increased immediately following FMT (p<.05) and was accompanied by a delay (3%) in the time to peak pressure beneath the lateral forefoot (p<.05).Changes in plantar pressure following FMT were small and less than the reported measurement error of the treadmill system. Therefore, in this pilot study the immediate effect of FMT on gait parameters was negligible. Further research evaluating short and long term effects of FMT on specific aspects of the locomotor system are needed.


To the Editor: The recent article by Helms et al. described the distribution of Salmonella enterica serovar Typhimurium definitive page type 104 (DT104) infections in 29 countries from 1992 to 2001 (According to the Colindale scheme for phage typing (Emergence of phage subtype DT104A was identified in June 2004 during an outbreak of salmonellosis in Rome. This subtype had never been previously identified in Italy. All DT104A isolates were susceptible to the Enter-net panel of antimicrobial drugs (The incidence of DT104 in Italy has remained stable from 2002 through 2004. However, emergence of subtype DT104A during a recent outbreak highlights the need for subtyping in identifying communitywide outbreaks and in monitoring changing subtype patterns.


Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-β) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as α smooth muscle actin (α-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders. It is generally accepted that activated mesenchymal cells or myofibroblasts play a crucial role in the pathogenesis of various fibrotic diseases including interstitial pulmonary fibrosis, systemic sclerosis and liver or cardiac fibrosis being responsible for the exaggerated production and accumulation of extracellular matrix proteins in various organs affected by these diseases -4. AlthoThe occurrence of EndoMT in experimentally induced cardiac fibrosis was originally described by Zeisberg et al.  employinin vitro. The treated cells displayed a progressive loss and the eventual disappearance of endothelial-specific cell markers (CD-31 and VE-cadherin) and a parallel acquisition of mesenchymal cell markers including vimentin, collagen I and N-cadherin. These results suggested that intestinal endothelial cells exposed to an inflammatory environment may participate in the intestinal fibrotic process which accompanies intestinal inflammatory diseases. The in vitro observations were confirmed by studies of molecular co-localization in human colonic mucosa [In contrast with the extensive evidence from experimental animal models demonstrating the important participation of EndoMT in the development of tissue fibrosis studies with human endothelial cells are just beginning to appear. One such study  examinedc mucosa .Another study examined the expression of cell surface markers specific for endothelial cells in mesenchymal/fibroblastic cells present in the subendothelial compartment of small vessels in lungs from patients with Systemic Sclerosis-associated pulmonary fibrosis . ConfocaIn contrast to the very extensive studies conducted to unravel the molecular mechanisms and the regulatory pathways that modulate epithelial mesenchymal transition -31, the Besides TGF-β it has been shown that endothelin-1 (ET-1) may also participate in EndoMT. In one study, Widyantoro et al.  showed tAlthough there are numerous studies which have conclusively shown the crucial involvement of members of the TGF-β family of growth factors in initiation of EndoMT, the detailed molecular events and the intracellular cascades activated by TGF-β that result in the remarkable phenotypic change of endothelial cells to mesenchymal cells have not been entirely elucidated. Recent studies in primary cultures of murine pulmonary endothelial cells  and in cde novo mesenchymal phenotypes. These studies identified the c-Abl protein kinase (c-Abl), protein kinase Cδ (PKC-δ), and glycogen synthase kinase 3β (GSK-3β) as important participants and that GSK-3β kinase phosphorylation was a crucial event in this process [Several studies explored the underlying molecular pathways that may cause the significant loss of endothelial-specific markers while inducing strong  process ,42. It i process ,44 as ilIn summary, numerous recent studies have provided strong evidence for the prominent participation of EndoMT in the generation of activated myofibroblasts during the development of experimentally induced tissue fibrosis suggesting that EndoMT plays a crucial role in fibrotic diseases. There is some early experimental evidence providing support and validation for the participation of EndoMT in the development of human intestinal fibrosis and of Systemic Sclerosis-associated pulmonary fibrosis. The firm demonstration of the occurrence of EndoMT in human fibrotic diseases and further understanding of the molecular mechanisms involved may lead to the pharmacologic modulation or abrogation of this pathway in human fibrotic disorders and may represent a novel therapeutic approach for these devastating diseases.The authors declare that they have no competing interests.


It has been shown in in-vitro experiments that "withdrawal" of tamoxifen inhibits growth of tumor cells. However, evidence is scarce when this is extrapolated into clinical context. We report our experience to verify the clinical relevance of "withdrawal therapy".Breast cancer patients since 1998 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: (1) estrogen receptor positive, operable primary breast cancer in elderly (age > 70 years), locally advanced or metastatic breast cancer; (2) disease deemed suitable for treatment by hormonal manipulation; (3) disease assessable by UICC criteria; (4) received "withdrawal" from a prior endocrine agent as a form of therapy; (5) on "withdrawal therapy" for ≥ 6 months unless they progressed prior.Seventeen patients with median age of 84.3 (53.7-92.5) had "withdrawal therapy" as second to tenth line of treatment following prior endocrine therapy using tamoxifen (n = 10), an aromatase inhibitor (n = 5), megestrol acetate (n = 1) or fulvestrant (n = 1). Ten patients (58.8%) had clinical benefit (CB)  with a median duration of Clinical Benefit (DoCB) of 10+ (7-27) months. Two patients remain on "withdrawal therapy" at the time of analysis."Withdrawal therapy" appears to produce sustained CB in a significant proportion of patients. This applies not only to "withdrawal" from tamoxifen, but also from other categories of endocrine agents. "Withdrawal" from endocrine therapy is, therefore, a viable intercalating option between endocrine agents to minimise resistance and provide additional line of therapy. It should be considered as part of the sequencing of endocrine therapy. Estrogen receptor (ER) positive breast cancers after a period of response to anti-estrogens develop resistance and clinically the disease progresses. Besides the predominant role of alternative signalling pathways, domination of partial agonistic activity of tamoxifen over its antagonist activity has been implicated for acquired resistance . RegressCase-notes of the breast cancer patients treated in the Nottingham breast unit since 1998 fulfilling the following criteria were studied retrospectively:• ER positive invasive breast carcinoma proven by histology  • Primary operable cancer in elderly (age > 70 years) (who were frail or refused to undergo surgery), locally advanced or metastatic• Disease deemed suitable for further hormonal manipulation• Disease progressed on a hormonal agent and thus suitable for "withdrawal" from an endocrine agent as a therapeutic option • Assessable lesions were deemed to have shown CB when they either had objective response in the form of complete response (CR) or partial response (PR); or had stable disease (SD) for ≥ 6 months in accordance with UICC criteria ,10• Metastatic lesions were assessed radiologically (CT scan/X-rays/bone scan) every 3 months as routine protocol in the unit• On "withdrawal therapy" for at least 6 months unless disease progressed priorDuration of CB (DoCB) is the duration of therapy in months only in patients who have derived CB and including patient still on treatment. Duration of treatment (DoT) is the duration of therapy in months of all patients (regardless of the type of response) and including patient still on treatmentSeventeen patients with either locally advanced primary (n = 3) or metastatic n = 14) breast cancer had "withdrawal" treatment as 2nd to 10th line of treatment. Patient and tumor characteristics are shown in Table 4 breast Tamoxifen may continue to provide antagonistic activity on ER nuclear signalling activity but may act as an agonist on the ER membrane signalling activity which could explain the loss of continuing CB to some patients on long-term tamoxifen therapy . There iIn an in-vivo study , athymicThe lack of response in the remaining patients on withdrawal of tamoxifen could partly be explained by the growth promoting action of natural estrogen in the body as seen in the above in-vivo study . Therefo-11 M/L or more of estradiol. This is again possible due to activation of cross-talk mechanisms and domination of mitogen-activated protein kinase or growth factors [In our study, as seen in table st 4 years followed by 12 months in year 5)[The above in-vitro concept is being explored further in clinical settings. There is ongoing recruitment to a phase III trial  wherein node positive early stage patients who have completed 4-6 years of prior adjuvant endocrine therapy (a SERM/AI/both) are randomised to receive either 5 years of daily letrozole or receive intermittent letrozole regime (daily for first 9 months of 1n year 5). The ratIn locally advanced and advanced breast cancer, ideally, inhibitors of the alternative pathways would be the subsequent logical therapy following resistance to other endocrine agents. However, if the patient is unfit to receive any further anti-estrogen therapy then it is very likely that they would not be suitable for further growth factor inhibitors or indeed chemotherapeutic agents. In this circumstance, withdrawal of therapy may be the only feasible option or alternating regime of endocrine therapy and withdrawal therapy as is being tested in the adjuvant setting in the SOLE trial.Our data therefore provides some clinical evidence and emphasises the relevance of withdrawal therapy. The concept is being tested in large randomised trials in adjuvant settings. However, larger datasets and results of ongoing adjuvant trials are needed to provide confirmatory evidence for or against the concept and feasibility of withdrawal therapy in locally advanced and metastatic breast cancer.The authors declare that they have no competing interests.KLC conceived this study. Patients were under care of JFR and KLC. AA collected data, performed analysis, drafted, revised and finalised the manuscript. KLC and JFR revised and approved of the contents of the manuscript. All authors read and approved the final manuscript.


Diabetes related foot ulcers (DRFU) frequently require surgical debridement or limb saving, partial foot amputation. The resultant wounds are generally deep and associated with prolonged healing times. Negative pressure wound therapy (NPWT) is increasingly used to facilitate healing of these complex wounds. This retrospective audit provides outcome data on patients with post-surgical wounds managed with NPWT within our High Risk Foot Service (HRFS). There is a paucity of data on clinical outcomes of DRFU treated with this therapy.Data from patients treated for post-surgical wounds within the HRFS was extracted from our electronic data base. A manual review of the patients records treated with NPWT was conducted to determine wound severity (University of Texas grading system), time to healing (from date of surgery), duration of NPWT and complications including new or recurrence of wounds and the need for further surgical management.155 patients with post surgical wounds were managed by the HRFS between September 2006 and November 2010. Many (83%) of these were superficial ulcers (grade 1), the remainder involved tendon and or bone (Grade 2 and 3). Thirty seven patients (37 wounds) were treated with NPWT. Two were superficial (grade 1), 19 were to tendon (grade 2) and 16 were to bone (grade 3). Most (34) were clinically infected at baseline and 13 were ischaemic. Median time to healing (from the date of surgery) was 121 days. Twenty one healed and 5 cases are ongoing. NPWT was used for a median of 30 days. Two required further foot surgery before healing, 14 patients developed new ulcers (unrelated to NPWT), 3 patients who healed required below knee amputation within 2 years and 1 died during the follow-up period.NPWT is often used in our service for the management of complex post surgical wounds with close to 60% achieving complete wound closure and a low rate of major amputation. While many factors may influence this result, the increasing use of NWPT is supported in this setting. Data collection is ongoing and we plan to compare these outcomes to a historical control group and hope that this sets a benchmark for appropriate use of NPWT.


Cancer remains a major health concern in the management of HIV infection in areas of the world with and without access to highly active antiretroviral therapy. In the USA alone, approximately 56,000 people were newly diagnosed with HIV infection in 2006; 53% of these new diagnosis occurred in gay and bisexual men but Black/African American men (45%) ,women (27%) , and Hispanics 17%) were also strongly affected [7% were aAMC-PNs conducted activities that raised awareness in their local communities of AIDS-related malignancies, developed partnerships with local health community organizations and identified areas where further communication was needed. PNs took the lead in developing a PN brochure and in the design of several tailored recruitment strategies. The PN program is making important inroads into behavioral interventions to increase participation of minorities and underserved populations in AMC trials.