Expression of p21 protein predicts clinical outcome in DLBCL patients older than 60 years treated with R-CHOP but not CHOP: a prospective ECOG and Southwest Oncology Group correlative study on E4494.
To prospectively investigate the prognostic significance of p21 and p53 expression in diffuse large B-cell lymphoma in the context of the U.S. Intergroup trial comparing conventional cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy to rituximab-CHOP (R-CHOP) induction, with or without maintenance rituximab. Immunohistochemical staining of 197 paraffin-embedded biopsy specimens was scored by an independent panel of experts. The cyclin-dependent kinase inhibitor, p21, was expressed in 55% of cases examined. In a multivariable analysis adjusting for International Prognostic Index score and BCL2 status, p21 expression was a significant, independent, favorable predictive factor for failure-free survival (relative risk, 0.3; P = 0.001) and overall survival (relative risk, 0.3; P = 0.003) for patients treated with R-CHOP. Expression of p21 was not predictive of outcome for CHOP-treated patients. Only p21-positive cases benefited from the addition of rituximab to CHOP. Among p21-positive patients, treatment with R-CHOP was associated with a higher failure-free survival rate at 5 years compared with CHOP (61% versus 24%; P = 0.01). In contrast, no significant differences were detected in failure-free survival according to treatment arm for p21-negative patients. Expression of p53, alone or in combination with p21, did not predict for outcome in univariable or multivariable analyses. In this study, p21 protein expression emerged as an important independent predictor of a favorable clinical outcome when rituximab was added to CHOP therapy. These data suggest that rituximab-related effects on lymphoma survival pathways may be functionally linked to p21 activity.


Stable and color tunable emission properties based on non-cyclometalated gold(III) complexes.
Stable and emission tunable non-cyclometalated gold(III) triaryl complexes of the type [(L)Au(C6F5)3] [L = 2-(2,4-difluorophenylpyridine) (1), 4-phenylpyridine (2), 2-phenylpyridine (3), 2-phenylisoquinoline (4), 2-thienylpyridine (5)] were synthesized starting from a common precursor complex [(THT)Au(C6F5)3] [THT = tetrahydrothiophene] in good to modest yields. Extensive characterization of the complexes by various nuclear magnetic resonance spectroscopy techniques and elemental analysis further corroborated the single-crystal X-ray diffraction studies. The complexes displayed room temperature phosphorescence in the neat solid and in 2-MeTHF at 77 K. Detailed photophysical investigations of the complexes in the neat solid and at 77 K revealed the successful tuning of the emission maxima with modest quantum yields across the visible part of the electromagnetic spectrum depending on the electronic properties of the heterocyclic ligands. DFT (Density Functional Theory) and TDDFT (Time Dependent Density Functional Theory) calculations were performed to discern the composition of the excited state as well as confirm the obtained relative emission energies upon substitution with electronically different ligands. The obtained diverse emissive behavior of the complexes combined with the ease of synthesis illustrate the generality and applicability of the design approach to obtain emissive gold(iii) complexes devoid of cyclometalation.


NEDD4 E3 ligase inhibits the activity of the Hippo pathway by targeting LATS1 for degradation.
Proper regulation of cell proliferation, cell apoptosis, and cell death are vital for the development and survival of living organisms. Failure or dysfunction of any of these processes can have devastating effects, including cancer. The Hippo pathway, first discovered in Drosophila, has been found to be a major growth-regulatory signaling pathway that controls these crucial processes and has been implicated in cell-progress regulation and organ size determination. Abnormal regulation of this pathway has been found in several cancer types. However, the mechanisms that regulate the pathway and its core members yet have to be elucidated. One of the main core components of this pathway is LATS1, a serine/threonine kinase. Therefore, understanding how LATS1 activity is regulated is expected to shed light on new mechanisms that regulate the Hippo pathway. In the current work, we identified several potential LATS1 regulators and proved that NEDD4 E3 ubiquitin ligase controls LATS1 stability. We demonstrate that NEDD4 directly interacts with LATS1, leading to ubiquitination and decreased levels of LATS1 and, thus, increased YAP localization in the nucleus, which subsequently increases the transcriptional activity of YAP. As such, we show that NEDD4 acts as an additional regulator of the Hippo pathway on the protein level via interactions between WW domain-containing and PPxY motif-containing proteins. These findings might be applied in the development of new therapeutic approaches through the activation of LATS1.


INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence.
The CDKN2A tumour suppressor locus encodes two distinct proteins, p16(INK4a) and p14(ARF), both of which have been implicated in replicative senescence, the state of permanent growth arrest provoked in somatic cells by aberrant proliferative signals or by cumulative population doublings in culture. Here we describe primary fibroblasts from a member of a melanoma-prone family who is homozygous for an intragenic deletion in CDKN2A. Analyses of the resultant gene products imply that the cells are p16(INK4a) deficient but express physiologically relevant levels of a frameshift protein that retains the known functions of p14(ARF). Although they have a finite lifespan, the cells are resistant to arrest by oncogenic RAS. Indeed, ectopic expression of RAS and telomerase (hTERT) results in outgrowth of anchorage-independent colonies that have essentially diploid karyotypes and functional p53. We find that in human fibroblasts, ARF is not induced demonstrably by RAS, pointing to significant differences between the proliferative barriers implemented by the CDKN2A locus in different cell types or species.


Using a knowledge transfer framework to identify factors facilitating implementation of family-based treatment.
To conduct a qualitative study to identify factors that would facilitate the transfer of the research evidence on Family-Based Treatment (FBT) into clinical practice. Fundamental qualitative description guided sampling, data collection, and analytic decisions for this study. Forty therapists who treat children and adolescents under the age of 18 with Anorexia Nervosa (AN) and belong to Ontario's provincial network of specialized eating disorder services completed an in-depth interview focusing on elements proposed by the Lavis knowledge transfer framework. An experienced coder conducted content analysis, with 20% of the interviews double-coded for reliability purposes. Participants requested training in the FBT model, including the provision of research evidence (i.e., journal articles), as well as the specific tenets of the model according to the FBT manual. The suggested audience for implementation included not only therapists themselves, but administrators, physicians, and community members. The development of best practice guidelines was also supported. Local FBT experts were suggested as credible messengers. Infrastructure relating to financial support and time away from clinical duties were reported to be essential for training. Ongoing supervision and mentorship were reported to be important elements of implementation and evaluation processes. Suggestions for moving FBT into practice were consistent with previous research, however, the importance of obtaining the evidence in the form of primary research articles and obtaining team buy-in were remarkable. Developing context-specific training programs and administrative processes for the implementation of FBT are warranted.


Integration of a nationally procured electronic health record system into user work practices.
Evidence suggests that many small- and medium-scale Electronic Health Record (EHR) implementations encounter problems, these often stemming from users' difficulties in accommodating the new technology into their work practices. There is the possibility that these challenges may be exacerbated in the context of the larger-scale, more standardised, implementation strategies now being pursued as part of major national modernisation initiatives. We sought to understand how England's centrally procured and delivered EHR software was integrated within the work practices of users in selected secondary and specialist care settings. We conducted a qualitative longitudinal case study-based investigation drawing on sociotechnical theory in three purposefully selected sites implementing early functionality of a nationally procured EHR system. The complete dataset comprised semi-structured interview data from a total of 66 different participants, 38.5 hours of non-participant observation of use of the software in context, accompanying researcher field notes, and hospital documents (including project initiation and lessons learnt reports). Transcribed data were analysed thematically using a combination of deductive and inductive approaches, and drawing on NVivo8 software to facilitate coding. The nationally led "top-down" implementation and the associated focus on interoperability limited the opportunity to customise software to local needs. Lack of system usability led users to employ a range of workarounds unanticipated by management to compensate for the perceived shortcomings of the system. These had a number of knock-on effects relating to the nature of collaborative work, patterns of communication, the timeliness and availability of records (including paper) and the ability for hospital management to monitor organisational performance. This work has highlighted the importance of addressing potentially adverse unintended consequences of workarounds associated with the introduction of EHRs. This can be achieved with customisation, which is inevitably somewhat restricted in the context of attempts to implement national solutions. The tensions and potential trade-offs between achieving large-scale interoperability and local requirements is likely to be the subject of continuous debate in England and beyond with no easy answers in sight.


Antioxidant potential by arabinoxylan rice bran, MGN-3/biobran, represents a mechanism for its oncostatic effect against murine solid Ehrlich carcinoma.
We have recently examined the oncolytic effect of arabinoxylan rice bran, MGN-3/biobran, against solid Ehrlich carcinoma (SEC)-bearing mice via immune-modulation and apoptosis [N.K. Badr El-din, E. Noaman, M. Ghoneum, In vivo tumor inhibitory effects of nutritional rice bran supplement MGN-3/biobran on Ehrlich carcinoma-bearing mice, Nutr. Cancer 60 (2) (2008) 235-244]. In the present study, we examined the antioxidant system as another possible mechanism through which MGN-3 exerts its oncostatic potential. Female albino mice were inoculated intramuscularly in the right thigh with Ehrlich ascites carcinoma (EAC) cells. MGN-3 (25 mg/kg body weight) was injected intraperitoneally (i.p.) six times a week for 25 days into mice at either day 4 or day 11 post-EAC cell inoculation. Tumor growth, lipid peroxidation (LPx), glutathione (GSH) contents, the activity of the antioxidant scavenger enzymes, and alterations in gene expression were examined. MGN-3 efficiently suppressed the growth of tumors, which was associated with normalization of the LPx levels and augmentation of GSH contents. MGN-3 enhanced the activity of the endogenous antioxidant scavenging enzymes -- superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione-S-transferase (GST) -- in blood, liver, and tumor tissue. Similarly it up-regulated the expression of GPx, SOD1 and CAT mRNA in the liver. The effect of MGN-3 was more pronounced when treated early, at day 4 of tumor cell inoculation, as compared to later treatment at 11 days. In conclusion, MGN-3-induced oncostatic activity by modulating lipid peroxidation, augmenting the antioxidant defense system and protecting against oxidative stress.


Intrascleral Fixation of an Intraocular Lens through the Pars Plana Prevents Corneal Endothelial Damage.
We report two cases of aphakia in whom an intraocular lens (IOL) was intrasclerally fixated through the pars plana to minimize further corneal endothelial damage. A modified lock-and-lead technique was used. A sclerotomy and scleral incision were made 2.5 mm from the limbus. A 24-G catheter needle was used for penetration of the leading haptic, and two ultrathin 30-G needles were used to bury the ends of the haptics. The scleral incision was sutured with 8-0 nylon. Corneal endothelial cells were preserved after surgery. Neither intra- nor postoperative complications were observed. Intrascleral fixation of an IOL through the pars plana effectively minimizes further damage to corneal endothelial cells in select cases.


Phase II study of everolimus (RAD001) in previously treated small cell lung cancer.
Mammalian target of rapamycin (mTOR) is a promising target in small cell lung cancer (SCLC). We designed a phase II study of everolimus, an mTOR inhibitor, in previously treated, relapsed SCLC. Patients were treated with everolimus 10 mg orally daily until disease progression. The primary endpoint was disease control rate (DCR) at 6 weeks. PI3K/Akt signaling pathway biomarkers were evaluated on baseline tumor tissue. A total of 40 patients were treated: 23 had 1 prior regimen/sensitive relapse, 4 had 1 prior regimen/refractory, and 13 had 2 prior regimens. Twenty-eight patients received 2 or more cycles of everolimus, 7 received 1 cycle, and 5 did not complete the first cycle. Best response in 35 evaluable patients: 1 (3%) partial response (in sensitive relapse), 8 (23%) stable disease, and 26 (74%) progression; DCR at 6 weeks was 26% (95% CI = 11-40). Median survival was 6.7 months and median time to progression was 1.3 months. Grade 3 toxicities included thrombocytopenia (n = 2), neutropenia (n = 2), infection (n = 2), pneumonitis (n = 1), fatigue (n = 1), elevated transaminases (n = 1), diarrhea (n = 2), and acute renal failure (n = 1). High phosphorylated AKT expression was modestly associated with overall survival (HR = 2.07; 95% CI = 0.97-4.43). Baseline S6 kinase protein expression was significantly higher in patients with disease control versus patients with progression (P = 0.0093). Everolimus was well tolerated but had limited single-agent antitumor activity in unselected previously treated patients with relapsed SCLC. Further evaluation in combination regimens for patients with sensitive relapse may be considered.


Role of adenosine on ventricular overdrive suppression in isolated guinea pig hearts and Purkinje fibers.
The present study was undertaken to demonstrate and characterize potentiation of ventricular overdrive suppression by adenosine. To substantiate that adenosine has an enhanced effect on overdrive suppression, it would be necessary to demonstrate that adenosine increases pause duration independent of slowing spontaneous pre-drive rate. In isolated perfused guinea pig hearts with surgically induced complete atrioventricular block, the effect of adenosine (2-20 microM) on pause duration was compared to two alternative means of slowing the pre-drive rate, i.e., hypothermia (28.0 degrees C to 34.0 degrees C) and cesium chloride (0.3-1.0 mM). The slope value of the linear regression line describing the relationship between pre-drive cycle length and pause duration for adenosine (15.8) was significantly greater than control (1.7), hypothermia (1.7), and cesium chloride (5.4). The competitive adenosine antagonist, aminophylline (60 microM), when infused at the initiation of overdrive during adenosine administration, significantly reduced the effect of adenosine on pause duration by 72.9 +/- 4.2% (mean +/- SEM). The reduction in pause duration by aminophylline was specific for adenosine and did not occur under control conditions or during cesium chloride administration. During hypoxia, aminophylline and adenosine deaminase, when infused at the initiation of overdrive, caused 72.3 +/- 5.6 and 63.3 +/- 6.1% reductions in pause duration, respectively. Endogenous adenosine levels rose significantly with hypoxia (1,687 +/- 202 vs. 36 +/- 4 pmol/min per g during normoxia) and increased significantly further during hypoxic overdrive (3,004 +/- 323 pmol/min per g). In isolated guinea pig Purkinje fibers (n = 4), adenosine (20 microM) increased pause duration by 73.6 +/- 9.9% while only minimally affecting the pre-drive cycle length (7.6 +/- 3.8%). These fibers, when stimulated at 1.5 Hz, also displayed an adenosine-induced reduction in action potential duration at 90% repolarization (16 +/- 2 msec). In addition, we demonstrated that adenosine had an enhanced effect on pause duration in the presence of ouabain (1 microM)-induced attenuation of overdrive suppression. Thus, in isolated Purkinje fibers, it is unlikely that the potentiating effect of adenosine on pause duration, which is independent of its chronotropic effect, is mediated via an enhancement of sodium potassium adenosine triphosphatase pump activity. The effect of adenosine is likely to be secondary to a direct action on outward potassium conductance.(ABSTRACT TRUNCATED AT 400 WORDS)


On designing multicore-aware simulators for systems biology endowed with OnLine statistics.
The paper arguments are on enabling methodologies for the design of a fully parallel, online, interactive tool aiming to support the bioinformatics scientists .In particular, the features of these methodologies, supported by the FastFlow parallel programming framework, are shown on a simulation tool to perform the modeling, the tuning, and the sensitivity analysis of stochastic biological models. A stochastic simulation needs thousands of independent simulation trajectories turning into big data that should be analysed by statistic and data mining tools. In the considered approach the two stages are pipelined in such a way that the simulation stage streams out the partial results of all simulation trajectories to the analysis stage that immediately produces a partial result. The simulation-analysis workflow is validated for performance and effectiveness of the online analysis in capturing biological systems behavior on a multicore platform and representative proof-of-concept biological systems. The exploited methodologies include pattern-based parallel programming and data streaming that provide key features to the software designers such as performance portability and efficient in-memory (big) data management and movement. Two paradigmatic classes of biological systems exhibiting multistable and oscillatory behavior are used as a testbed.


Zearalenone applied per os provides adverse effects in structure of chosen parts of bitch reproductive system.
Both earlier investigations and complete formulas of pet food for dogs show that professionally prepared pet food is based in 30% on the material of the plant origin. Our own investigations prove that animal feeding stuffs of the plant origin are very often vectors of many undesirable substances (including micotoxins) that are unfavourable for carnivores. Zearalenone is a micotoxin, which frequently occurs among them. It was revealed in pet food in quantities from 5.0-299.5 microg/kg. It is a very dangerous xenobiotic because of its quick and easy absorption in the organism after per os application in monogastric animals. It is also a sterid and despite its plant origin it binds estrogen receptors in the reproductive tract and causes its hypo- and dysfunction. It is clearly visible in young, growing organisms and those during the menopause. In bitches, dysfunctions of the reproduction system, such as: endometritis-pyometra syndrome, prolonged oestrus, ovarian cysts and others are often found. It is supposed that specific for this species hormonal regulation of the reproduction processes based on the long progesterone and prolactin cycles, and on high sensibility to estrogens plays an important role in the etiopathogenesis of these dysfunctions. The application of hormones in bitches in therapeutic and biotechnical (contraception) purposes are the other factors, which should be taken into account in this aspect. There are some suggestions that therapeutic management, unfortunately connected with mistakes in the medical art, is often a cause of pathological condition in a reproductive organ in bitches. However, another reason of these disorders may be that bitches take zearalenone with the commercial pet food. The long-lasting intake of the feed with a low dose of this micotoxin may be the factor, which complicates hormonal regulation of the reproduction processes and is the cause of many disorders. Our own pilotage investigations showed that application of zearalenone at a dose of 200 microg/kg b.w. for 7 days leads to apoptotic-like changes in granule cells in the bitch reproductive system, atresia of follicular cells and oedema and hyperplasia of the oviductal and uterine cells. They could also indicate a follicular phase of the oestrus cycle in bitch. However, it did not take place.


Experimental and computational validation of models of fluorescent and luminescent reporter genes in bacteria.
Fluorescent and luminescent reporter genes have become popular tools for the real-time monitoring of gene expression in living cells. However, mathematical models are necessary for extracting biologically meaningful quantities from the primary data. We present a rigorous method for deriving relative protein synthesis rates (mRNA concentrations) and protein concentrations by means of kinetic models of gene expression. We experimentally and computationally validate this approach in the case of the protein Fis, a global regulator of transcription in Escherichia coli. We show that the mRNA and protein concentration profiles predicted from the models agree quite well with direct measurements obtained by Northern and Western blots, respectively. Moreover, we present computational procedures for taking into account systematic biases like the folding time of the fluorescent reporter protein and differences in the half-lives of reporter and host gene products. The results show that large differences in protein half-lives, more than mRNA half-lives, may be critical for the interpretation of reporter gene data in the analysis of the dynamics of regulatory systems. The paper contributes to the development of sound methods for the interpretation of reporter gene data, notably in the context of the reconstruction and validation of models of regulatory networks. The results have wide applicability for the analysis of gene expression in bacteria and may be extended to higher organisms.


Cardioprotection mechanism of mangiferin on doxorubicin-induced rats: Focus on intracellular calcium regulation.
The molecular mechanism of doxorubicin (DOX) cardiotoxicity involves overproduction of free radicals that leads to intracellular calcium dysregulation and apoptosis. Mangiferin (MGR), a naturally occurring glucosylxanthone, has antioxidant and cardioprotective properties. However, its cardioprotection mechanism has yet to be revealed. This study determines whether the cardioprotective effect of MGR is caused by its effect on intracellular calcium regulation. Male Sprague-Dawley rats were induced by DOX intraperitoneally with a total dose of 15 mg/kg bw. MGR was given orally at the doses of 30 and 60 mg/kg bw/d for seven consecutive weeks. The parameters examined were mRNA expression levels of proinflammatory cytokine gene (TNF-α), calcium regulatory gene (SERCA2a) and proapoptotic genes (caspase-9 and caspase-12), as well as cytosolic and mitochondrial calcium levels. Treatment with MGR at 60 mg/kg bw/d significantly decreased the mRNA expression levels of TNF-α by 44.55% and caspase-9 by 52.79%, as well as the cytosolic calcium level by 24.15% (p < 0.05). SERCA2a and caspase-12 expressions were only slightly affected (27.27% increase and 24.85% decrease for SERCA2a and caspase-12, respectively, p > 0.05). Meanwhile, MGR 30 mg/kg bw/d gave insignificant results in all parameters. MGR protected against DOX-induced cardiac inflammation and apoptosis via down-regulation of proapoptotic and proinflammatory gene expressions, upregulation of SERCA2a gene expression, and normalization of cytosolic calcium level. Thus, the cardioprotective effect of MGR is at least in part due to the regulation of intracellular calcium homeostasis.


Vibrational solvatochromism: towards systematic approach to modeling solvation phenomena.
Vibrational solvatochromic frequency shift of IR probe is an effect of interaction between local electric field and IR probe in condensed phases. Despite prolonged efforts to develop empirical maps for vibrational frequency shifts and transition dipoles of IR probes, a systematic approach to ab initio calculation of vibrational solvatochromic charges and multipoles has not been developed. Here, we report on density functional theory (DFT) calculations of N-methylacetamide (NMA) frequency shifts using implicit and coarse-grained models. The solvatochromic infrared spectral shifts are estimated based on the distributed multipole analysis of electronic densities calculated for gas-phase equilibrium structure of NMA. Thus obtained distributed solvatochromic multipole parameters are used to calculate the amide I vibrational frequency shifts of NMA in water clusters that mimic the instantaneous configurations of the liquid water. Our results indicate that the spectral shifts are primarily electrostatic in nature and can be quantitatively reproduced using the proposed model with semi-quantitative accuracy when compared to the corresponding DFT results.


Effect of coconut cake on the bacterial enzyme activity in 1,2-dimethyl hydrazine induced colon cancer.
Colon cancer is one of the most common forms of malignant tumors in humans, and its incidence is increasing. Since the intestinal microflora is directly in contact with the colonic cells, the enzymes of the bacterial microflora may also play a role in colon carcinogenesis. We studied the activity of bacterial enzymes in experimental colon cancer. Twenty milligrams per kilogram body weight of 1,2-dimethyl hydrazine (DMH) was administered subcutaneously once a week for first 15 weeks and then discontinued. Coconut cake (25%) was mixed in the diet and given to 30 rats to study the diet effect throughout the experimental period. After 30 weeks, the macroscopic findings in the colon as well as the incidence of tumors in 30 rats was recorded in each group and the activity of beta-glucuronidase and mucinase was estimated in the tissues, colon and fecal contents of 10 rats per group. Average number of tumors in the colon as well as the incidence of cancer was significantly increased in DMH-treated rats which was markedly reduced on supplementing coconut cake. DMH injections significantly elevated both the activities of beta-glucuronidase (distal colon, distal intestine, liver and colon contents) and mucinase (colon and fecal contents) as compared to the control rats. The increase in beta-glucuronidase activity may augment the hydrolysis of glucuronide conjugates, liberating the toxins, while the increase in mucinase activity may enhance the hydrolysis of the protective mucins in the colon. Coconut cake supplementation to DMH-treated rats significantly decreased the incidence and number of tumors as well as the activity of beta-glucuronidase and mucinase. Coconut cake has a protective effect against DMH induced colon cancer by virtue of its ability to lower the activities of the microbial enzymes beta-glucuronidase and mucinase.


Provider-based research networks may improve early access to innovative colon cancer treatment for African Americans treated in the community.
African American (AA) patients with colon cancer (CC) experience worse outcomes than whites partly due to differential treatment. The National Cancer Institute's Community Clinical Oncology Program (CCOP), a provider-based research network, adopts and diffuses innovative CC treatments quickly. The authors hypothesized that CCOP participation would lessen racial differences in the receipt of oxaliplatin, an innovative treatment for CC, among patients with stage III CC in the community. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, the authors performed a population-based retrospective cohort study of AA and white individuals aged ≥66 years who were diagnosed with AJCC stage III CC from 2003 through 2005. Generalized estimating equations were used to calculate the odds of receiving an oxaliplatin-containing regimen. Predicted probabilities of oxaliplatin receipt for race-CCOP combinations were calculated. The absolute difference in oxaliplatin receipt between races was estimated using the interaction contrast ratio. Of 2971 included individuals, 36% received oxaliplatin, 29.5% were CCOP-affiliated, and 7.6% were AA. On multivariate analysis, early diffusion of oxaliplatin was not found to be associated with race or CCOP participation. The probability of receiving oxaliplatin for AAs participating in a CCOP (0.46) was nearly double that of AAs who were not participating in a CCOP (0.25; P <.05). For white individuals, the probabilities of receiving oxaliplatin did not differ by CCOP participation. For oxaliplatin receipt, the joint effects assessment suggested a greater benefit of CCOP participation among AAs (interaction contrast ratio, 1.7). Among older patients with stage III CC, there is a differential impact of race on oxaliplatin receipt depending on CCOP participation. AAs treated by CCOPs were more likely to receive oxaliplatin than AAs treated elsewhere. Provider-based research networks may facilitate early access to innovative treatment for AAs with stage III CC.


Type 2 deiodinase at the crossroads of thyroid hormone action.
Thyroid hormone action can be customized on a cell-specific fashion through the controlled action of the deiodinase group of enzymes, which are homodimeric thioredoxin fold containing selenoproteins. Whereas the type II deiodinase (D2) initiates thyroid hormone signaling by activating the pro-hormone thyroxine (T4) to the biologically active T3 molecule, the type III deiodinase (D3) terminates thyroid hormone action by catalyzing the inactivation of both T4 and T3 molecules. Deiodinases play a role in thyroid hormone homeostasis, development, growth and metabolic control by affecting the intracellular levels of T3 and thus gene expression on a cell-specific basis. Whereas both Dio2 and Dio3 are transcriptionally regulated, ubiquitination of D2 is a switch mechanism that controls D2 activity and intracellular T3 production. The hedgehog-inducible WSB-1 and the yeast Doa10 mammalian ortholog TEB4 are two E3 ligases that inactivate D2 via ubiquitination. Inactivation involves disruption of the D2:D2 dimer and can be reversed via two ubiquitin-specific proteases, USP20 and USP33, rescuing catalytic activity and T3 production. The ubiquitin-based switch mechanism that controls D2 activity illustrates how different cell types fine-tune thyroid hormone signaling, making D2 a suitable target for pharmacological intervention. This article reviews the cellular and molecular aspects of D2 regulation and the current models of D2-mediated thyroid hormone signaling.


Implications of spatially heterogeneous vaccination coverage for the risk of congenital rubella syndrome in South Africa.
Rubella is generally a mild childhood disease, but infection during early pregnancy may cause spontaneous abortion or congenital rubella syndrome (CRS), which may entail a variety of birth defects. Since vaccination at levels short of those necessary to achieve eradication may increase the average age of infection, and thus potentially the CRS burden, introduction of the vaccine has been limited to contexts where coverage is high. Recent work suggests that spatial heterogeneity in coverage should also be a focus of concern. Here, we use a detailed dataset from South Africa to explore the implications of heterogeneous vaccination for the burden of CRS, introducing realistic vaccination scenarios based on reported levels of measles vaccine coverage. Our results highlight the potential impact of country-wide reductions of incidence of rubella on the local CRS burdens in districts with small population sizes. However, simulations indicate that if rubella vaccination is introduced with coverage reflecting current estimates for measles coverage in South Africa, the burden of CRS is likely to be reduced overall over a 30 year time horizon by a factor of 3, despite the fact that this coverage is lower than the traditional 80 per cent rule of thumb for vaccine introduction, probably owing to a combination of relatively low birth and transmission rates. We conclude by discussing the likely impact of private-sector vaccination.


Transcatheter mitral valve interventions: current status and future perspective.
With the recent developments in the field of transcatheter aortic valve replacement for aortic stenosis there has been a similar advance in the field of transcatheter mitral valve therapy for mitral regurgitation (MR). Both the anatomy of the mitral apparatus and the spectrum of pathology of MR are more complex than for aortic valve disease, and thus the development of MR therapies has been more complicated and less rapid. The purpose of this review of recent literature is to provide a synopsis of the present technologies under development for percutaneous therapy for MR. Leaflet repair with MitraClip has accrued the largest human experience among the technologies that are under development, having been used to treat over 6,000 patients. MitraClip is currently being used in patients with functional MR and at high risk for conventional surgery. Coronary sinus, or indirect annuloplasty, has the next largest clinical experience, with several hundred patients treated in trials. Other MR therapy devices, including several direct annuloplasty approaches, mitral valve replacement prostheses, and chordal replacement devices, are still in the earlier phases of development. The early technological advances have not only enhanced our understanding of the complex interplay of different components of the mitral valve apparatus but also promise continued refinement in our present modalities of treatment and improved clinical outcomes for future patients.


Immediate effect of specific nostril manipulating yoga breathing practices on autonomic and respiratory variables.
The effect of right, left, and alternate nostril yoga breathing (i.e., RNYB, LNYB, and ANYB, respectively) were compared with breath awareness (BAW) and normal breathing (CTL). Autonomic and respiratory variables were studied in 21 male volunteers with ages between 18 and 45 years and experience in the yoga breathing practices between 3 and 48 months. Subjects were assessed in five experimental sessions on five separate days. The sessions were in fixed possible sequences and subjects were assigned to a sequence randomly. Each session was for 40 min; 30 min for the breathing practice, preceded and followed by 5 min of quiet sitting. Assessments included heart rate variability, skin conductance, finger plethysmogram amplitude, breath rate, and blood pressure. Following RNYB there was a significant increase in systolic, diastolic and mean pressure. In contrast, the systolic and diastolic pressure decreased after ANYB and the systolic and mean pressure were lower after LNYB. Hence, unilateral nostril yoga breathing practices appear to influence the blood pressure in different ways. These effects suggest possible therapeutic applications.


Improved synthetic-heterodyne Michelson interferometer vibrometer using phase and gain control feedback.
Synthetic-heterodyne demodulation is a useful technique for dynamic displacement and velocity measurement using interferometric sensors as it can provide an output signal which is immune to interferometric drift. With the advent of cost effective, high-speed real-time signal processing systems and software, processing of the complex signals encountered in interferometry has become more feasible. In conventional synthetic-heterodyne demodulation schemes, to obtain the dynamic displacement or vibration of the object under test requires knowledge of the interferometer visibility and also the argument of two Bessel functions. In this paper, a new synthetic-heterodyne demodulation method is described leading to an expression for the dynamic displacement and velocity of the object under test that is significantly less sensitive to the received optical power. In addition, the application of two independent phase and gain feedback loops is used to compensate for the nonideal gain and phase response of the anti-aliasing filter required for the signal acquisition of the received wideband interferometer signal. The efficacy of the improved system is demonstrated by measuring the displacement sensitivity frequency response and linearity of a Piezoelectric Mirror-Shifter (PMS) over a range of 200 Hz-9 kHz. In addition, the system is used to measure the response of the PMS to triangular and impulse type stimuli. The experimental results show excellent agreement with measurements taken using two independent industry standard calibration methods.


Uniqueness, intractability and exact algorithms: reflections on level-k phylogenetic networks.
Phylogenetic networks provide a way to describe and visualize evolutionary histories that have undergone so-called reticulate evolutionary events such as recombination, hybridization or horizontal gene transfer. The level k of a network determines how non-treelike the evolution can be, with level-0 networks being trees. We study the problem of constructing level-k phylogenetic networks from triplets, i.e. phylogenetic trees for three leaves (taxa). We give, for each k, a level-k network that is uniquely defined by its triplets. We demonstrate the applicability of this result by using it to prove that (1) for all k > or = 1 it is NP-hard to construct a level-k network consistent with all input triplets, and (2) for all k > or = 0 it is NP-hard to construct a level-k network consistent with a maximum number of input triplets, even when the input is dense. As a response to this intractability, we give an exact algorithm for constructing level-1 networks consistent with a maximum number of input triplets.


Improving the quality of outpatient care for older patients with diabetes: lessons from a comparison of rural and urban communities.
Our goal was to compare the quality of diabetic care received by patients in rural and urban communities. We performed a retrospective analysis of claims data captured by the Medicare program. We included all fee-for-service Medicare patients 65 years and older living in the state of Washington who had 2 or more physician encounters for diabetes care during 1994. The outcomes were the extent to which patients received 3 specific recommended services: glycated hemoglobin determination, cholesterol measurement, and eye examination. A total of 30,589 Medicare patients (8.4%) were considered to have diabetes; 29.1% lived in rural communities. Generalists provided most diabetic care in all locations. Patients living in small rural towns received almost half their outpatient care in larger communities. Patients living in large rural towns remote from metropolitan areas were more likely to have received the recommended tests than patients in all other groups. Patients who saw an endocrinologist at least once during the year were more likely to have received the recommended tests. Large rural towns may provide the best conditions for high-quality care: They are vibrant, rapidly growing communities that serve as regional referral centers and have an adequate-but not excessive-supply of both generalist and specialist physicians. Generalists provide most diabetic care in all settings, and consultation with an endocrinologist may improve adherence to guidelines.


Status of glomerular proteoglycans in aminonucleoside nephrosis.
Status of glomerular proteoglycans (PGs) in puromycin aminonucleoside nephrosis was investigated. Rats were made nephrotic and sacrificed 0, 7, 14, and 21 days later. Maximal proteinuric response was observed between 7 and 14 days. Prior to sacrifice, they received injections of conjugated or unconjugated anti-heparan-sulfate-proteoglycan antibody, directed against its core protein (Mr = 18,000). Their kidneys were processed for direct and indirect immunofluorescence, immunoperoxidase, tannic-acid staining, and tissue autoradiography (ARG). By tannic-acid staining, antibody binding sites identical to the anionic sites described previously were discovered. No qualitative differences were observed by these immunohistochemical techniques. Quantitative tissue ARG did not reveal any statistical differences in the binding of antibody between the control and nephrotic groups. For de novo biosynthetic studies, rats were sacrificed on day 10. Their kidneys were utilized for labeling of basement membrane PGs by employing [35S]-sulfate as the precursor product. Tissue ARG, as well as biochemical studies, were performed on the radiolabeled glomeruli. PGs were extracted with 4 M GuCl and characterized by Sepharose CL-6B and DEAE-Sephacel chromatography. There was an overall increase in the total incorporated radioactivities in the glomerular and media fractions. No differences were observed in the macromolecular size characteristics of intact PGs and glycosaminoglycan chains of either glomerular or media fractions. However, an increase in the charge-density characteristics was observed in PGs of the nephrotic group. By tissue ARG, an increase in the grain densities over the basement membrane and mesangial matrices of the glomerulus was noted. These data indicate that the intact PGs, their chains and core protein do not undergo significant biochemical alterations; however, de novo synthesized PGs have higher charge-density characteristics which may be related to a higher degree of sulfation that occurs during the course of aminonucleoside nephrosis.


Bacteriorhodopsin: the effect of bilayer thickness on 2D-array formation, and the structural re-alignment of retinal through the photocycle.
From our earlier extensive protein-lipid reconstitution studies, the conditions under which bacteriorhodopsin forms organised 2D arrays in large unilamellar vesicles have been established using freeze-fracture electron microscopy. In a background bilayer matrix of phosphatidylcholine (diC(14:0)), the protein can form arrays only when the anionic purple membrane lipid, phosphatidylglycerol phosphate (or the sulphate derivative) is present. Here we have now extended this work to investigate the effect of bilayer thickness on array formation. Phosphatidylcholines with various chain lengths (diC(12:0), diC(14:0) and diC(16:0)) and which form bilayers of well defined bilayer thickness, have been used as the matrix into which bacteriorhodopsin, together with minimal levels (c. 4-10 lipids per bacteriorhodopsin) of diphytanyl phosphatidyl-glycerol phosphate, has been reconstituted. Arrays are formed in all complexes and bhickness appears only to alter the type of array formed, either as an orthogonal or as an hexagonal array. Secondly, we have previously deduced the entire conformation of retinal within the bacteriorhodopsin binding pocket in oriented purple membrane fragments. Using solid state deuterium NMR of the specifically deutero-methylated retinal labelled at each of the methyl positions in the molecule, the C-CD(3) bond vectors of the chromophore have been resolved to +/- 2 degrees . The ring conformation is 6-S-trans, but the polyene chain is slightly curved when in the protein binding site. Here, we describe studies on the protein in both the ground state and the trapped M(412)-state of the photocycle, to show that the orientation of the central methyl group (C(19)) on the polyene chain, which is at 40 degrees +/- 1 degrees with respect to the membrane normal, only changes its orientation by approximately 4 degrees upon 13-cis-isomerization. Thus, it is the Schiff base end of the chromophore which moves upon light incidence acting as a local switch on the protein in the photocycle, whilst the ring end of the chromophore moves rather less.


Mental health in Dutch adolescents: a TRAILS report on prevalence, severity, age of onset, continuity and co-morbidity of DSM disorders.
With psychopathology rising during adolescence and evidence suggesting that adult mental health burden is often due to disorders beginning in youth, it is important to investigate the epidemiology of adolescent mental disorders. We analysed data gathered at ages 11 (baseline) and 19 years from the population-based Dutch TRacking Adolescents' Individual Lives Survey (TRAILS) study. At baseline we administered the Achenbach measures (Child Behavior Checklist, Youth Self-Report) and at age 19 years the World Health Organization's Composite International Diagnostic Interview version 3.0 (CIDI 3.0) to 1584 youths. Lifetime, 12-month and 30-day prevalences of any CIDI-DSM-IV disorder were 45, 31 and 15%, respectively. Half were severe. Anxiety disorders were the most common but the least severe whereas mood and behaviour disorders were less prevalent but more severe. Disorders persisted, mostly by recurrence in mood disorders and chronicity in anxiety disorders. Median onset age varied substantially across disorders. Having one disorder increased subjects' risk of developing another disorder. We found substantial homotypic and heterotypic continuity. Baseline problems predicted the development of diagnosable disorders in adolescence. Non-intact families and low maternal education predicted externalizing disorders. Most morbidity concentrated in 5-10% of the sample, experiencing 34-55% of all severe lifetime disorders. At late adolescence, 22% of youths have experienced a severe episode and 23% only mild episodes. This psychopathology is rather persistent, mostly due to recurrence, showing both monotypic and heterotypic continuity, with family context affecting particularly externalizing disorders. High problem levels at age 11 years are modest precursors of incident adolescent disorders. The burden of mental illness concentrates in 5-10% of the adolescent population.


Habitat structural complexity mediates food web dynamics in a freshwater macrophyte community.
A considerable amount of research has investigated the influence of habitat structure on predator success, yet few studies have explored the implications for community structure and food-web dynamics. The relative importance of macrophyte structure and fish predation on the composition of the macroinvertebrate and periphyton communities in a lowland river was investigated using a multifactorial caging experiment. We hypothesised that: (1) fish predators are less effective in a more structurally complex macrophyte analogue; (2) strong direct and indirect effects of fish predators (e.g. trophic cascades) are less likely to occur in a structurally complex habitat; and (3) the strength of these patterns is influenced by the composition of the prevailing community assemblage. We measured the abundance and composition of the macroinvertebrate and periphyton communities associated with three different-shaped macrophyte analogues, under different fish predator treatments and at different times. Macrophyte analogue architecture had strong, consistent effects on both the macroinvertebrate and periphyton communities; both were most abundant and diverse on the most structurally complex plant analogue. In contrast, the fish predators affected only a subset of the macroinvertebrate community and there was a suggestion of minor indirect effects on periphyton community composition. Contrary to expectations, the fish predators had their strongest effects in the most structurally complex macrophyte analogue. We conclude that in this system, macrophyte shape strongly regulates the associated freshwater assemblage, resulting in a diverse community structure less likely to exhibit strong effects of fish predation.


Consensus clinical recommendations for the management of plasma lipid disorders in the Middle East.
Plasma lipid disorders are key risk factors for the development of atherosclerotic cardiovascular disease (ASCVD) and are prevalent in the Middle East, with rates increasing in recent decades. Despite this, no region-specific guidelines for managing plasma lipids exist and there is a lack of use of guidelines developed in other regions. A multidisciplinary panel of regional experts was convened to develop consensus clinical recommendations for the management of plasma lipids in the Middle East. The panel considered existing international guidelines and regional clinical experience to develop recommendations. The panel's recommendations include plasma lipid screening, ASCVD risk calculation and treatment considerations. The panel recommend that plasma lipid levels should be measured in all at-risk patients and at regular intervals in all adults from the age of 20years. A scoring system should be used to calculate ASCVD risk that includes known lipid and non-lipid risk factors. Primary treatment targets include low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol. Lifestyle modifications should be first-line treatment for all patients; the first-line pharmacological treatment targeting plasma lipids in patients at moderate-to-high risk of ASCVD is statin therapy, with a number of adjunctive or second-line agents available. Guidance is also provided on the management of underlying conditions and special populations; of particular pertinence in the region are familial hypercholesterolaemia, diabetes and metabolic dyslipidaemia. These consensus clinical recommendations provide practicing clinicians with comprehensive, region-specific guidance to improve the detection and management of plasma lipid disorders in patients in the Middle East.


Structural and functional evidence for the denervation of human myometrium during pregnancy.
The neuronal influence of the contractility of the term-pregnant human uterus was studied by pharmacologic and histochemical methods. By the use of adrenergic and cholinergic antagonists or tetrodotoxin it was demonstrated that the contractile response of superfused myometrial strips from the term-pregnant uterus to electrofield stimulation was not influenced by any neuronal factor. Using an indirect immunofluorescence technique with an antiserum to the glial and Schwann cell specific S-100 protein, a marked paucity of nerve fibers was demonstrated in myometrial strips from the term-pregnant uterus as compared with the nonpregnant uterus. It is concluded that the described decrease of nerve fibers within the myometrium of the pregnant uterus may be of importance for the myometrial activity during pregnancy and parturition.


Arterial gene transfer of the TGF-beta signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF.
Although transforming growth factor-beta (TGF-beta) is believed to stimulate intimal hyperplasia after arterial injury, its role in remodelling remains unclear. We investigate whether Smad3, a TGF-beta signalling protein, might facilitate its effect on remodelling. Using the rat carotid angioplasty model, we assess Smad3 expression following arterial injury. We then test the effect of arterial Smad3 overexpression on the response to injury, and use a conditioned media experimental design to confirm an Smad3-dependent soluble factor that mediates this response. We use small interfering RNA (siRNA) to identify this factor as connective tissue growth factor (CTGF). Finally, we attempt to replicate the effect of medial Smad3 overexpression through adventitial application of recombinant CTGF. Injury induced medial expression of Smad3; overexpression of Smad3 caused neointimal thickening and luminal expansion, suggesting adaptive remodelling. Smad3 overexpression, though exclusively medial, caused adventitial changes: myofibroblast transformation, proliferation, and collagen production, all of which are associated with adaptive remodelling. Supporting the hypothesis that Smad3 initiated remodelling and these adventitial changes via a secreted product of medial smooth muscle cells (SMCs), we found that media conditioned by Smad3-expressing recombinant adenoviral vector (AdSmad3)-infected SMCs stimulated adventitial fibroblast transformation, proliferation, and collagen production in vitro. This effect was attenuated by pre-treatment of SMCs with siRNA specific for CTGF, abundantly produced by AdSmad3-infected SMCs, and significantly up-regulated in Smad3-overexpressing arteries. Moreover, periadventitial administration of CTGF replicated the effect of medial Smad3 overexpression on adaptive remodelling and neointimal hyperplasia. Medial gene transfer of Smad3 promotes adaptive remodelling by indirectly influencing the behaviour of adventitial fibroblasts. This arterial cell-cell communication is likely to be mediated by Smad3-dependent production of CTGF.


Ductular reaction is helpful in defining early stromal invasion, small hepatocellular carcinomas, and dysplastic nodules.
Stromal invasion is 1 of the main features used to distinguish high-grade dysplastic nodules (DNs) from well-differentiated hepatocellular carcinomas (HCCs). The authors hypothesized that ductular reaction (DR) takes place around noninvasive hepatocellular nodules but not within the stroma contiguous to invasive HCC. DR/cytokeratin 7 (CK7)-positive patterns were evaluated in 105 resected small hepatic nodules according to the level of invasion. The nodules were classified histologically prior to immunostaining as noninvasive (large regenerative nodules, low-grade DNs, and high-grade DNs), minimally invasive (early HCCs with a vaguely nodular type), and overtly invasive (typical HCCs with a distinctly nodular type) in a review by expert pathologists, the current gold standard. Intranodular DR (inner DR) and DR around the nodule periphery (outer DR) were assessed separately on a semiquantitative scale from 0 to 4+. DR was 3 or 4+ in the majority of noninvasive nodules (inner DR, 81%; outer DR, 91%), whereas DR was 0 or 1+ in overtly invasive HCCs (inner DR, 96%; outer DR, 81%). Minimally invasive HCCs showed an intermediate DR pattern (2 or 3+ inner DR, 75%; 2+ outer DR, 67%). DR characteristically was absent at the stromal-invasive, leading edge of tumor cells in both minimally invasive HCCs (focal loss of DR/CK7) and overtly invasive HCCs (diffuse loss of DR/CK7). The DR patterns in 41 needle-biopsy samples were similar to the patterns observed in resected nodules. DR/CK7 immunostaining may help to identify small foci of invasion and to distinguish noninvasive, high-grade DNs from both minimally invasive and overtly invasive HCCs.


Fiber-coupled displacement interferometry without periodic nonlinearity.
Displacement interferometry is widely used for accurately characterizing nanometer and subnanometer displacements in many applications. In many modern systems, fiber delivery is desired to limit optical alignment and remove heat sources from the system, but fiber delivery can exacerbate common interferometric measurement problems, such as periodic nonlinearity, and account for fiber-induced drift. In this Letter, we describe a novel, general Joo-type interferometer that inherently has an optical reference after any fiber delivery that eliminates fiber-induced drift. This interferometer demonstrated no detectable periodic nonlinearity in both free-space and fiber-delivered variants.


Structural basis of selective ubiquitination of TRF1 by SCFFbx4.
TRF1 is a critical regulator of telomere length. As such, TRF1 levels are regulated by ubiquitin-dependent proteolysis via an SCF E3 ligase where Fbx4 contributes to substrate specification. Here, we report the crystal structure of the Fbx4-TRF1 complex at 2.4 A resolution. Fbx4 contains an unusual substrate-binding domain that adopts a small GTPase fold. Strikingly, this atypical GTPase domain of Fbx4 binds to a globular domain of TRF1 through an intermolecular beta sheet, instead of recognizing short peptides/degrons as often seen in other F-box protein-substrate complexes. Importantly, mutations in this interface abrogate Fbx4-dependent TRF1 binding and ubiquitination. Furthermore, the data demonstrate that recognition of TRF1 by SCF(Fbx4) is regulated by another telomere protein, TIN2. Our results reveal an atypical small GTPase domain within Fbx4 as a substrate-binding motif for SCF(Fbx4) and uncover a mechanism for selective ubiquitination and degradation of TRF1 in telomere homeostasis control.


Palliative care on the net: an online survey of health care professionals.
A survey was conducted to explore Internet use by palliative care health professionals (HCP). The survey was placed on the World Wide Web with an underlying database, and palliative care HCP were invited to participate via a palliative-care-related website, listserv, and newsletter. A total of 417 evaluable responses were received over a four-month period. Of these, 36% indicated they were from physicians and 30% from nurses, a third of respondents were practicing palliative care full time. Although 63% of respondents were from North America, regions from all over the world were represented. Eighty-eight percent of respondents were searching the Internet for clinical information, 80% were using email, 69% were accessing online medical journals, and 59% were subscribers to a palliative-care-related listserv or newsgroup. This survey illustrates the global outreach of the Internet and draws attention to the growing interest in the use of the Internet for education, research, and clinical use. Further development of online resources should address the needs of users. Evaluation of these resources is called for.


Cross-sectional versus prospective predictors of screening mammography.
Data from a population-based longitudinal study were used to compare cross-sectional versus prospective predictors of screening mammography. Although the results of the two analyses were not dramatically different, some important differences emerged. More attitudinal variables were related to future behavior compared with past behavior. Using purely cross-sectional data from this study to design an intervention would result in potentially important variables being deemphasized or omitted, which could have a significant impact on the strength of the intervention. Our findings strongly suggest that it may be unwise to generalize cross-sectionally obtained data to a longitudinal situation.


Seasonal variation in Escherichia coli bloodstream infection: a population-based study.
Seasonal variation in the rates of infection with certain Gram-negative organisms has been previously examined in tertiary-care centres. We performed a population-based investigation to evaluate the seasonal variation in Escherichia coli bloodstream infection (BSI). We identified 461 unique patients in Olmsted County, Minnesota, from 1 January 1998 to 31 December 2007, with E. coli BSI. Incidence rates (IR) and IR ratios were calculated using Rochester Epidemiology Project tools. Multivariable Poisson regression was used to examine the association between the IR of E. coli BSI and average temperature. The age- and gender-adjusted IR of E. coli BSI per 100 000 person-years was 50.2 (95% CI 42.9-57.5) during the warmest 4 months (June through September) compared with 37.1 (95% CI 32.7-41.5) during the remainder of the year, resulting in a 35% (95% CI 12-66%) increase in IR during the warmest 4 months. The average temperature was predictive of increasing IR of E. coli BSI (p 0.004); there was a 7% (95% CI 2-12%) increase in the IR for each 10-degree Fahrenheit (c. 5.5 degrees C) increase in average temperature. To our knowledge, this is the first study to demonstrate seasonal variation in E. coli BSI, with a higher IR during the warmest 4 months than during the remainder of the year.


Postsurgical changes in arterial compliance.
Mismatch in elasticity between artery and graft, a possible contributing factor to graft failure, has traditionally been believed to be caused by the graft. Compliance of the artery and/or graft may change after surgery, resulting in a different compliance mismatch. To study the arterial contribution to compliance mismatch, we measured compliance-pressure (CP) curves noninvasively in the femoral arteries of five dogs. One femoral artery was then simply exposed, and the incision was closed. Repeated CP curves were obtained after 24 hours, and after 1, 2, 3, and 4 weeks. Compliance remained normal after 24 hours, but by one week compliance of the dissected arteries had dropped significantly at all pressures between 70 and 120 mm Hg. Compliance reached a minimum after two weeks and remained low until after four weeks. Postsurgical arterial stiffening causes a significant decrease of arterial-graft compliance mismatch and may suggest an upper limit for synthetic graft compliance.


Adipose-tissue-derived therapeutic cells in their natural environment as an autologous cell therapy strategy: the microtissue-stromal vascular fraction.
The prerequisite for a successful clinical use of autologous adipose-tissue-derived cells is the highest possible regenerative potential of the applied cell population, the stromal vascular fraction (SVF). Current isolation methods depend on high enzyme concentration, lysis buffer, long incubation steps and mechanical stress, resulting in single cell dissociation. The aim of the study was to limit cell manipulation and obtain a derivative comprising therapeutic cells (microtissue-SVF) without dissociation from their natural extracellular matrix, by employing a gentle good manufacturing practice (GMP)-grade isolation. The microtissue-SVF yielded larger numbers of viable cells as compared to the improved standard-SVF, both with low enzyme concentration and minimal dead cell content. It comprised stromal tissue compounds (collagen, glycosaminoglycans, fibroblasts), capillaries and vessel structures (CD31+, smooth muscle actin+). A broad range of cell types was identified by surface-marker characterisation, including mesenchymal, haematopoietic, pericytic, blood and lymphatic vascular and epithelial cells. Subpopulations such as supra-adventitial adipose-derived stromal/stem cells and endothelial progenitor cells were significantly more abundant in the microtissue-SVF, corroborated by significantly higher potency for angiogenic tube-like structure formation in vitro. The microtissue-SVF showed the characteristic phenotype and tri-lineage mesenchymal differentiation potential in vitro and an immunomodulatory and pro-angiogenic secretome. In vivo implantation of the microtissue-SVF combined with fat demonstrated successful graft integration in nude mice. The present study demonstrated a fast and gentle isolation by minor manipulation of liposuction material, achieving a therapeutically relevant cell population with high vascularisation potential and immunomodulatory properties still embedded in a fraction of its original matrix.


Melatonin slowed the early biochemical progression of hormone-refractory prostate cancer in a patient whose prostate tumor tissue expressed MT1 receptor subtype.
Melatonin inhibited the proliferation of hormone-independent LNCaP prostate cancer cells partly via MT1 receptor activation both in vitro and in nude mice xenograft model. In this study, the melatonin receptor expression in the prostate cancer tissue of a patient with bone metastases and the effect of melatonin on the biochemical progression of hormone-refractory prostate tumor which later developed in the same patient were reported. Saturation and competition 2-[125I]iodomelatonin binding assays were conducted on prostate tumor tissue obtained by transurethral resection of the prostate from the index patient. The receptor subtype identity of melatonin receptor expressed in the cancer tissue was determined by comparison of the rank order of inhibition constants (Ki) of various melatonergic ligands and the affinity of 4-phenyl-2-propionamidotetraline relative to melatonin in inhibiting 2-[125I]iodomelatonin binding to the tumor sample and to human cell lines stably transfected with MT1 or MT2 melatonin receptor subtype. MT1 receptor expression in the cancer tissue was also examined by immunohistochemistry. The surgically castrated patient later developed biochemical relapse of his disease. His serum total prostate-specific antigen (PSA) level was monitored before and during treatment with 5 mg/day oral melatonin at 20:00 hr. High-affinity (Kd = 103.7 pm) MT1 melatonin receptor subtype was expressed by the patient's prostate cancer. As indicated by his PSA levels, melatonin induced stabilization of his hormone-refractory disease for 6 wk. This report validates melatonin's oncostatic action on prostate cancer and the potential involvement of MT1 receptor subtype in the attendant antiproliferative signal transduction as suggested by recent preclinical laboratory findings in a human.


Safety and efficacy of topical diclofenac sodium 1% gel in knee osteoarthritis: a randomized controlled trial.
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) may provide an alternative to oral NSAIDs to relieve pain from osteoarthritis (OA), reducing systemic exposure. This 12-week, randomized, double-blind, parallel-group, multicenter trial examined the efficacy and safety of topical diclofenac sodium 1% gel (DSG) for symptomatic knee OA. Eligible patients were aged >/= 35 years with symptomatic Kellgren-Lawrence grade (KLG) 1 to 3 OA in 1 or both knees for >/= 6 months. Patients meeting entry criteria applied DSG 4 g or vehicle 4 times daily to the symptomatic knee(s). Primary endpoints were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function subscales and global rating of benefit at week 12. Pain on movement at week 4 was an additional primary endpoint for European regulatory purposes. Secondary endpoints included primary outcomes at weeks 1, 4, and 8; WOMAC stiffness subscale; spontaneous pain; global rating of disease; and global evaluation of treatment. Subanalyses were performed according to KLG, the number of knees treated, and age. Four hundred twenty patients were randomly assigned to DSG (n = 208) or vehicle (n = 212). At week 12, DSG provided significantly greater reductions in WOMAC pain (52.6% vs 43.1%; P = 0.008) and physical function (49.7% vs 39.4%; P = 0.004) versus vehicle and provided significant improvements in most secondary endpoints. Treatment-related adverse events (AEs) were infrequent (DSG, 7.7%; vehicle, 4.2%), with application site dermatitis being the most common AE (DSG, 4.8%; vehicle, 0%). No treatment-related gastrointestinal or serious AEs occurred with DSG. Topical DSG treatment provided effective pain relief and functional improvement of OA in 1 or both knees and was well tolerated, irrespective of disease severity or patient age.


Effects of pentobarbital and isoflurane on conditioned learning after transient global cerebral ischemia in rabbits.
The acquisition of a conditioned eyeblink response has been used extensively to study the neurologic substrates of learning and memory. We examined the effects of the anesthetics isoflurane and pentobarbital, or hypothermia (30 degrees C), on the ability of rabbits to acquire an eyeblink conditioned response after 6.5 min of cerebral ischemia. New Zealand white rabbits (n = 48) were randomly assigned to sham, normothermic, hypothermic, isoflurane, or pentobarbital groups. In the normothermic, hypothermic, isoflurane, and pentobarbital groups, 6.5 min of global cerebral ischemia was produced. In animals randomized to the isoflurane and pentobarbital groups, a pattern of burst suppression was achieved on the electroencephalogram before the start of the ischemic episode. Animals in the hypothermia group were cooled to 30 degrees C before ischemia. Seven days after ischemia, eyeblink training was started using an audible tone presented for 100 ms as the conditioned stimulus. The unconditioned stimulus was an air puff directed at the cornea. The delay between the end of conditioned stimulus and the start of the unconditioned stimulus (the trace interval) was 300 ms in duration. A conditioned response was defined as an eyeblink that was initiated during the trace interval. Eighty trials per day and 15 days of training were delivered. Neurologic deficits were greatest in the normothermia group, and these animals also had fewer conditioned responses than those in the sham, hypothermia, or pentobarbital groups. Animals in the isoflurane group had an intermediate number of conditioned responses that was not significantly different from the normothermia group. This study demonstrates that a brief episode of cerebral ischemia results in the impairment of associative learning. Hypothermia and burst-suppressive doses of pentobarbital were able to improve neurobehavioral outcome as measured by ability to acquire a trace conditioned response.


English language proficiency and smoking prevalence among California's Asian Americans.
The authors documented California's tobacco control initiatives for Asian Americans and the current tobacco use status among Asian subgroups and provide a discussion of the challenges ahead. The California Tobacco Control Program has employed a comprehensive approach to decrease tobacco use in Asian Americans, including ethnic-specific media campaigns, culturally competent interventions, and technical assistance and training networks. Surveillance of tobacco use among Asian Americans and the interpretation of the results have always been a challenge. Data from the 2001 The California Health Interview Survey (CHIS) were analyzed to provide smoking prevalence estimates for all Asian Americans and Asian-American subgroups, including Korean, Filipino, Japanese, South Asian, Chinese, and Vietnamese. Current smoking prevalence was analyzed by gender and by English proficiency level. Cigarette smoking prevalence among Asian males in general was almost three times of that among Asian females. Korean and Vietnamese males had higher cigarette smoking prevalence rates than males in other subgroups. Although Asian females in general had low smoking prevalence rates, significant differences were found among Asian subgroups, from 1.1% (Vietnamese) to 12.7% (Japanese). Asian men who had high English proficiency were less likely to be smokers than men with lower English proficiency. Asian women with high English proficiency were more likely to be smokers than women with lower English proficiency. Smoking prevalence rates among Asian Americans in California differed significantly on the basis of ethnicity, gender, and English proficiency. English proficiency seemed to have the effect of reducing smoking prevalence rates among Asian males but had just the opposite effect among Asian females.


Human osteoclast formation from blood monocytes, peritoneal macrophages, and bone marrow cells.
Mononuclear precursors of the human osteoclast have been identified in both bone marrow and the circulation in man, but osteoclast membership of the mononuclear phagocyte system (MPS) and its precise cellular ontogeny remain controversial. We isolated human hematopoietic marrow cells, blood monocytes, and peritoneal macrophages and incubated each of these cell populations with UMR106 osteoblast-like cells on glass coverslips and dentine slices in both the presence and absence of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3), macrophage-colony stimulating factor (M-CSF), and dexamethasone. Cells isolated from peripheral blood and peritoneal dialysis fluid were positive only for monocyte/macrophage markers (CD11a, CD11b, CD14, and HLA-DR) and negative for osteoclast markers [tartrate-resistant acid phosphatase (TRAP), vitronectin reception (VNR), and calcitonin (CT) receptors and did not form resorption pits on dentine slices after 24 hours in culture. Similarly marrow cells did not form resorption pits on dentine slices after 24 hours in culture. However, after 14 days in co-culture with UMR106 cells, in the presence of 1,25(OH)2D3 and M-CSF, numerous TRAP, CT receptor, and VNR-positive multinucleated cells capable of extensive lacunar resorption were formed in co-cultures of all these preparations. The presence of 1,25 (OH)2D3, M-CSF, and UMR106 were absolute requirements for osteoclast differentiation. It is concluded that precursor cells capable of osteoclast differentiation are present in the marrow compartment, the monocyte fraction of peripheral blood, and in the macrophage compartment of extraskeletal tissues and that these cells are capable of differentiating into mature functional osteoclasts. These findings argue in favor of osteoclast membership of the human MPS.


Subjective satiety and other experiences of a Paleolithic diet compared to a diabetes diet in patients with type 2 diabetes.
We found marked improvement of glycemic control and several cardiovascular risk factors in patients with type 2 diabetes given advice to follow a Paleolithic diet, as compared to a diabetes diet. We now report findings on subjective ratings of satiety at meal times and participants' other experiences of the two diets from the same study. In a randomized cross-over study, 13 patients with type 2 diabetes (3 women and 10 men), were instructed to eat a Paleolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, and a diabetes diet designed in accordance with dietary guidelines, during two consecutive 3-month periods. In parallel with a four-day weighed food record, the participants recorded their subjective rating of satiety. Satiety quotients were calculated as the intra-meal quotient of change in satiety during a meal and consumed energy or weight of food and drink for that specific meal. All participants answered the same three open-ended questions in a survey following each diet: "What thoughts do you have about this diet?", "Describe your positive and negative experiences with this diet" and "How do you think this diet has affected your health?". The participants were equally satiated on both diets. The Paleolithic diet resulted in greater satiety quotients for energy per meal (p = 0.004), energy density per meal (p = 0.01) and glycemic load per meal (p = 0.02). The distribution of positive and negative comments from the survey did not differ between the two diets, and the comments were mostly positive. Among comments relating to recurring topics, there was no difference in distribution between the two diets for comments relating to tastelessness, but there was a trend towards more comments on the Paleolithic diet being satiating and improving blood sugar values, and significantly more comments on weight loss and difficulty adhering to the Paleolithic diet. A Paleolithic diet is more satiating per calorie than a diabetes diet in patients with type 2 diabetes. The Paleolithic diet was seen as instrumental in weight loss, albeit it was difficult to adhere to.


Second malignancy risk in patients with bronchopulmonary carcinoids: epidemiological results from Italian Network of Cancer Registries.
This epidemiological study aimed to determine the prevalence and characteristics of second tumors (STs) in patients with bronchopulmonary carcinoids (BCs). Data on neuroendocrine carcinomas (NECs) from the AIRTUM registry (1975-2011) were used for the analysis. Among 32,325 NECs, we focused our analysis on 3,205 patients (9.9%) affected by BCs. The overall ST number and incidence were calculated. The number of STs was compared with the expected cancer number in the healthy Italian population, and the standardized incidence ratio (SIR) and 95% confidence intervals were calculated. The male/female ratio was 1.5:1 and the mean age 61.7 years (range: 7-94). A total of 640 STs were observed (overall incidence: 20%): 198 tumors were metachronous, 23 synchronous, and 419 occurred before the diagnosis of BC. The most common STs were bladder tumors (12.2%) followed by breast tumors (11.1%). We observed a large number of thyroid tumors (SIR = 3.88), with a remarkably higher frequency of thyroid tumors being synchronously detected with BC in female patients (SIR = 61.39). In male patients there was an increased frequency of urinary system tumors, in particular metachronous tumors of the kidney and renal pelvis (SIR = 3.34) and synchronous tumors of the urinary bladder (SIR = 11.48). A high frequency of STs is predictable in patients with BCs, with synchronous thyroid tumors being observed in women and kidney and urinary bladder tumors in men. However, these data should be interpreted with caution, considering that the diagnosis of such tumors often occurs as an incidental finding during investigations for other malignancies.


Water fluoridation and osteoporotic fracture.
Osteoporotic fractures constitute a major public health problem. These fractures typically occur at the hip, spine and distal forearm. Their pathogenesis is heterogeneous, with contributions from both bone strength and trauma. Water fluoridation has been widely proposed for its dental health benefits, but concerns have been raised about the balance of skeletal risks and benefits of this measure. Fluoride has potent effects on bone cell function, bone structure and bone strength. These effects are mediated by the incorporation of fluoride ions in bone crystals to form fluoroapatite, and through an increase in osteoblast activity. It is believed that a minimum serum fluoride level of 100 ng/ml must be achieved before osteoblasts will be stimulated. Serum levels associated with drinking water fluoridated to 1 ppm are usually several times lower than this value, but may reach this threshold at concentrations of 4 ppm in the drinking water. Animal studies suggest no effect of low-level (0-3 ppm) fluoride intake on bone strength, but a possible decrease at higher levels. Sodium fluoride has been used to treat established osteoporosis for nearly 30 years. Recent trials of this agent, prescribed at high doses, have suggested that despite a marked increase in bone mineral density, there is no concomitant reduction in vertebral fracture incidence. Furthermore, the increase in bone density at the lumbar spine may be achieved at the expense of bone mineral in the peripheral cortical skeleton. As a consequence, high dose sodium fluoride (80 mg daily) is not currently used to treat osteoporosis. At lower doses, recent trials have suggested a beneficial effect on both bone density and fracture. The majority of epidemiological evidence regarding the effect of fluoridated drinking water on hip fracture incidence is based on ecological comparisons. Although one Finnish study suggested that hip fracture rates in a town with fluoridated water were lower than those in a matching town without fluoride, a later study failed to show differences. Ecological studies from the United States and Great Britain have, if anything, revealed a weak positive association between water fluoride concentration and hip fracture incidence. Two studies examining hip fracture rates before and after fluoridation yielded discordant results, and are complicated by underlying time trends in hip fracture incidence. Only two studies have attempted to examine the relation between water fluoride concentration and fracture risk at an individual level. In one of these, women in a high fluoride community had double the fracture risk of women in a low fluoride community. In the other, there was no relationship between years of fluoride exposure and incidence of spine or non-spine fractures. In conclusion, the epidemiological evidence relating water fluoridation to hip fracture is based upon ecological comparisons and is inconclusive. However, several studies suggest the possibility of a weak adverse effect, which warrants further exploration. Data on the relationship between fluoride intake and hip fracture risk at the individual level, and data relating fluoridation to bone mineral density are required. Until these become available, the burden of evidence suggesting that fluoridation might be a risk factor for hip fracture is weak and not sufficient to retard the progress of the water fluoridation programme.


The Effect of Two Speed Endurance Training Regimes on Performance of Soccer Players.
In order to better understand the specificity of training adaptations, we compared the effects of two different anaerobic training regimes on various types of soccer-related exercise performances. During the last 3 weeks of the competitive season, thirteen young male professional soccer players (age 18.5±1 yr, height 179.5±6.5 cm, body mass 74.3±6.5 kg) reduced the training volume by ~20% and replaced their habitual fitness conditioning work with either speed endurance production (SEP; n = 6) or speed endurance maintenance (SEM; n = 7) training, three times per wk. SEP training consisted of 6-8 reps of 20-s all-out running bouts followed by 2 min of passive recovery, whereas SEM training was characterized by 6-8 x 20-s all-out efforts interspersed with 40 s of passive recovery. SEP training reduced (p<0.01) the total time in a repeated sprint ability test (RSAt) by 2.5%. SEM training improved the 200-m sprint performance (from 26.59±0.70 to 26.02±0.62 s, p<0.01) and had a likely beneficial impact on the percentage decrement score of the RSA test (from 4.07±1.28 to 3.55±1.01%) but induced a very likely impairment in RSAt (from 83.81±2.37 to 84.65±2.27 s). The distance covered in the Yo-Yo Intermittent Recovery test level 2 was 10.1% (p<0.001) and 3.8% (p<0.05) higher after SEP and SEM training, respectively, with possibly greater improvements following SEP compared to SEM. No differences were observed in the 20- and 40-m sprint performances. In conclusion, these two training strategies target different determinants of soccer-related physical performance. SEP improved repeated sprint and high-intensity intermittent exercise performance, whereas SEM increased muscles' ability to maximize fatigue tolerance and maintain speed development during both repeated all-out and continuous short-duration maximal exercises. These results provide new insight into the precise nature of a stimulus necessary to improve specific types of athletic performance in trained young soccer players.


The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis.
The field of spondyloarthritis (SpA) has experienced major progress in the last decade, especially with regard to new treatments, earlier diagnosis, imaging technology and a better definition of outcome parameters for clinical trials. In the present work, the Assessment in SpondyloArthritis international Society (ASAS) provides a comprehensive handbook on the most relevant aspects for the assessments of spondyloarthritis, covering classification criteria, MRI and x rays for sacroiliac joints and the spine, a complete set of all measurements relevant for clinical trials and international recommendations for the management of SpA. The handbook focuses at this time on axial SpA, with ankylosing spondylitis (AS) being the prototype disease, for which recent progress has been faster than in peripheral SpA. The target audience includes rheumatologists, trial methodologists and any doctor and/or medical student interested in SpA. The focus of this handbook is on practicality, with many examples of MRI and x ray images, which will help to standardise not only patient care but also the design of clinical studies.


Antiretroviral drug susceptibility among drug-naive adults with recent HIV infection in Rakai, Uganda.
To analyze antiretroviral drug susceptibility in HIV from recently infected adults in Rakai, Uganda, prior to the availability of antiretroviral drug treatment. Samples obtained at the time of HIV seroconversion (1998-2003) were analyzed using the GeneSeq HIV and PhenoSense HIV assays (Monogram Biosciences, Inc., South San Francisco, California, USA). Test results were obtained for 104 samples (subtypes: 26A, 1C, 66D, 9A/D, 1C/D, 1 intersubtype recombinant). Mutations used for genotypic surveillance of transmitted antiretroviral drug resistance were identified in six samples: three had nucleoside reverse transcriptase inhibitor (NRTI) surveillance mutations (two had M41L, one had K219R), and three had protease inhibitor surveillance mutations (I47V, F53L, N88D); none had nonnucleoside reverse transcriptase inhibitor (NNRTI) surveillance mutations. Other resistance-associated mutations were identified in some samples. However, none of the samples had a sufficient number of mutations to predict reduced antiretroviral drug susceptibility. Ten (9.6%) of the samples had reduced phenotypic susceptibility to at least one drug (one had partial susceptibility to didanosine, one had nevirapine resistance, and eight had resistance or partial susceptibility to at least one protease inhibitor). Fifty-three (51%) of the samples had hypersusceptibility to at least one drug (seven had zidovudine hypersusceptibility, 28 had NNRTI hypersusceptibility, 34 had protease inhibitor hypersusceptibility). Delavirdine hypersusceptibility was more frequent in subtype A than D. In subtype D, efavirenz hypersusceptibility was associated with substitutions at codon 11 in HIV-reverse transcriptase. Phenotyping detected reduced antiretroviral drug susceptibility and hypersusceptibility in HIV from some antiretroviral-naive Ugandan adults that was not predicted by genotyping. Phenotyping may complement genotyping for analysis of antiretroviral drug susceptibility in populations with nonsubtype B HIV infection.


Design and Functionality of a Multilumen Thoracic Access Port for Pericardial Access Under Direct Visualization.
Small vasculature, venous obstruction, or congenital anomalies can preclude transvenous access to the heart, often resulting in open chest surgery to implant cardiac therapy leads for pacing, defibrillation, or cardiac resynchronization. A minimally invasive approach under direct visualization could reduce tissue damage, minimize pain, shorten recovery time, and obviate the need for fluoroscopy. Therefore, PeriPath was designed as a single-use, low-cost pericardial access tool based on clinical requirements. Its mechanical design aids in safe placement of conductive leads to the pericardium using a modified Seldinger technique. The crossed working channels provide an optimal view of the surgical field under direct visualization. Finite element analysis (FEA) confirms that the device is likely not to fail under clinical working conditions. Mechanical testing demonstrates that the tensile strength of its components is sufficient for use, with minimal risk of fracture. The PeriPath procedure is also compatible with common lead implantation tools and can be readily adopted by interventional cardiologists and electrophysiologists, allowing for widespread implementation. Prior animal work and a physician preliminary validation study suggest that PeriPath functions effectively for minimally invasive lead implantation procedures.


Trans-kingdom horizontal DNA transfer from bacteria to yeast is highly plastic due to natural polymorphisms in auxiliary nonessential recipient genes.
With the rapid accumulation of genomic information from various eukaryotes in the last decade, genes proposed to have been derived from recent horizontal gene transfer (HGT) events have been reported even in non-phagotrophic unicellular and multicellular organisms, but the molecular pathways underlying HGT remain to be explained. The development of in vitro HGT detection systems, which permit the molecular and genetic analyses of donor and recipient organisms and quantify HGT, are helpful in order to gain insight into mechanisms that may contribute to contemporary HGT events or may have contributed to past HGT events. We applied a horizontal DNA transfer system model based on conjugal gene transfer called trans-kingdom conjugation (TKC) from the prokaryote Escherichia coli to the eukaryote Saccharomyces cerevisiae, and assessed whether and to what extent genetic variations in the eukaryotic recipient affect its receptivity to TKC. Strains from a collection of 4,823 knock-out mutants of S. cerevisiae MAT-α haploids were tested for their individual TKC receptivity. Two types of mutants, an ssd1 mutant and respiratory mutants, which are also found in experimental strains and in nature widely, were identified as highly receptive mutants. The TKC efficiency for spontaneously accrued petite (rho (-/0)) mutants of the functional allele (SSD1-V) strain showed increased receptivity. The TKC efficiency of the ssd1Δ mutant was 36% for bacterial conjugation, while that of the petite/ssd1Δ double mutants was even higher (220% in average) compared to bacterial conjugation. This increased TKC receptivity was also observed when other conjugal transfer systems were applied and the donor bacterium was changed to Agrobacterium tumefaciens. These results support the idea that the genomes of certain eukaryotes have been exposed to exogenous DNA more frequently and continuously than previously thought.


Silicon-based metal-loaded plasmonic waveguides for low-loss nanofocusing.
We introduce plasmonic waveguides based on metal loading of silicon-on-insulator (SOI) substrates. Here slab waveguide modes hybridize with the plasmonic modes of either a metal nanowire or a slot in a metal film. By tapering a single dimension of either structure, the resulting hybrid mode can be converted from photon-like to plasmon-like, allowing up to millimeter-range transport and rapid nanoscale focusing down to mode areas ∼λ2/400. Metal loading is achievable with a single lithography step directly on SOI without the need for etching and, thus, opens practical possibilities for silicon nanoplasmonics.


Examining screening mammography participation among women aged 40 to 74.
To examine participation in screening mammography among women aged 40 to 74 and identify which factors are associated with those women who participate in screening. Secondary analysis of the cross-sectional 2012 Canadian Community Health Survey. Canada. A population-based national sample of 18 312 women aged 40 to 74. Women's participation in screening mammography in the 2 years preceding the 2012 Canadian Community Health Survey; women's preventive health activities (ie, having a regular doctor, a recent physical checkup, and a Papanicolaou test), which were adjusted for sociodemographic factors. Participation in recent screening mammography was highest among women aged 60 to 69 (70.3%), followed by those aged 50 to 59 (63.4%) and those aged 70 to 74 (58.4%). Almost one-third (31.4%) of women aged 40 to 49 had had a screening mammogram in the past 2 years. Having a regular doctor (odds ratio [OR] = 3.30, 95% CI 2.90 to 3.73), a physical checkup in the past year (OR = 3.06, 95% CI 2.30 to 4.08), or a Pap test in the past 3 years (OR = 3.47, 95% CI 3.18 to 3.79) more than tripled the odds that women had had a recent screening mammogram. Aside from age being a factor associated with women's participation in screening mammography, factors related to women's health care use (having a regular doctor, a recent physical checkup, and a recent Pap test) demonstrated a stronger association with women aged 40 to 74 having had recent mammograms. The association between women's participation in screening and their preventive health activities implies that the doctor's office is an appropriate venue for conversations regarding the potential benefits and harms of screening mammography.


Derivation and initial characterization of a mouse mammary tumor cell line carrying the polyomavirus middle T antigen: utility in the development of novel cancer therapeutics.
Here we describe the derivation of novel cell lines from spontaneous mammary tumors that arose in mouse mammary tumor virus-polyomavirus (MMTV-PyV) Middle T (MidT) transgenic mice. Clonal cell lines from four mixed cell populations were tested for adenovirus transducibility and sensitivity to p53 tumor suppressor gene therapy mediated by SCH58500, a replication-deficient adenovirus that expresses human p53. The MidT2-1 cell line was selected for further characterization in vitro and in vivo. This cell line carried the PyV MidT antigen, had wild-type p53 DNA, and was sensitive to suppression of proliferation by MMAC/PTEN tumor suppressor gene therapy. MidT2-1 cells gave rise to highly aggressive tumors in syngeneic FVB mice in both the mammary fat pad and the peritoneal cavity. The histopathology of MidT2-1 tumors closely resembled the histopathology of the primary transgenic tumors. Tumor growth in vivo was inhibited by p53 gene therapy or by MMAC gene therapy. In addition, combination therapy with a number of anticancer agents had synergistic or additive efficacy in vitro. In particular, MMAC gene therapy synergized with SCH58500 or paclitaxel. In the i.p. MidT2-1 tumor model p53 gene therapy enhanced the survival benefits of paclitaxel/cisplatin chemotherapy. Combination therapy has become a mainstay in cancer treatment. In this report, we use a novel transgenic mouse tumor cell line to suggest new combinations that might be explored in clinical cancer care. These include gene therapy using the tumor suppressors MMAC and p53, chemotherapy using farnesyl transferase inhibitors, the microtubule stabilizing taxanes, and the DNA synthesis disruptors gemcitabine and cisplatin. The precise biological mechanisms by which these therapies induce their antitumor effects are not fully elucidated. However, the work presented here suggests that many of these therapeutic approaches have synergistic antitumor activity when used in combination.


Do as eye say: gaze cueing and language in a real-world social interaction.
Gaze cues are important in communication. In social interactions gaze cues usually occur with spoken language, yet most previous research has used artificial paradigms without dialogue. The present study investigates the interaction between gaze and language using a real-world paradigm. Each participant followed instructions to build a series of abstract structures out of building blocks, while their eye movements were recorded. The instructor varied the specificity of the instructions (unambiguous or ambiguous) and the presence of gaze cues (present or absent) between participants. Fixations to the blocks were recorded and task performance was measured. The presence of gaze cues led to more accurate performance, more accurate visual selection of the target block and more fixations towards the instructor when ambiguous instructions were given, but not when unambiguous instructions were given. We conclude that people only utilize the gaze cues of others when the cues provide useful information.


Rationale and design of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) study.
Although its limitations for diagnosing critical coronary artery disease are well described, coronary angiography remains the predominant method for guiding decisions about stent implantation in patients with multivessel coronary artery disease. However, some have suggested that invasive physiologic guidance may improve decision making. The objective of this multicenter, randomized clinical trial is to compare the efficacy of 2 strategies, one based on angiographic guidance to one based on physiologic guidance with fractional flow reserve (FFR), for deciding which coronary lesions to stent in patients with multivessel coronary disease. Eligible patients must have coronary narrowings > 50% diameter stenosis in > or = 2 major epicardial vessels, > or = 2 of which the investigator feels require drug-eluting stent placement. Patients with previous coronary bypass surgery or left main coronary disease are excluded. Based on angiographic evaluation, the investigator notes the lesions that require stenting. The patient is then randomly assigned to either angiographic guidance or FFR guidance. Patients assigned to angiographic guidance undergo stenting as planned. Patients assigned to FFR guidance first have FFR measured in each diseased vessel and only undergo stenting if the FFR is < or = 0.80. The primary end point of the study is a composite of major adverse cardiac events, including death, myocardial infarction, and repeat coronary revascularization, at 1 year. Secondary end points will include the individual adverse events, cost-effectiveness, quality of life, and 30-day, 6-month, 2-year, and 5-year outcomes. The FAME study will examine for the first time in a large, multicenter, randomized fashion the role of measuring FFR in patients undergoing multivessel percutaneous coronary intervention.


Adipose tissue in obesity and obstructive sleep apnoea.
A European Respiratory Society research seminar on "Metabolic alterations in obstructive sleep apnoea (OSA)" was jointly organised in October 2009 together with two EU COST actions (Cardiovascular risk in the obstructive sleep apnoea syndrome, action B26, and Adipose tissue and the metabolic syndrome, action BM0602) in order to discuss the interactions between obesity and OSA. Such interactions can be particularly significant in the pathogenesis of metabolic abnormalities and in increased cardiovascular risk in OSA patients. However, studying the respective role of OSA and obesity is difficult in patients, making it necessary to refer to animal models or in vitro systems. Since most OSA patients are obese, their management requires a multidisciplinary approach. This review summarises some aspects of the pathophysiology and treatment of obesity, and the possible effects of sleep loss on metabolism. OSA-associated metabolic dysfunction (insulin resistance, liver dysfunction and atherogenic dyslipidaemia) is discussed from the perspective of both obesity and OSA in adults and children. Finally, the effects of treatment for obesity or OSA, or both, on cardio-metabolic variables are summarised. Further interdisciplinary research is needed in order to develop new comprehensive treatment approaches aimed at reducing sleep disordered breathing, obesity and cardiovascular risk.