Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma: Asian versus non-Asian subgroup analysis of the COMPARZ trial.
The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%). A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations. ClinicalTrials.gov, NCT00720941 , Registered July 22, 2008 ClinicalTrials.gov, NCT01147822 , Registered June 22, 2010.


A chemiluminescence array sensor based on graphene-magnetite-molecularly imprinted polymers for determination of benzenediol isomers.
A chemiluminescence (CL) array sensor for determination of benzenediol isomers simultaneously using the system of luminol-NaOH-H(2)O(2) based on a graphene-magnetite-molecularly imprinted polymer (GM-MIP) is described. Use of graphene in the GM-MIP thus prepared is helpful to improve the adsorption capacity, while use of magnetite nanoparticles can facilitate the isolation of GM-MIP at end of their synthesis, and rendering easier the use of the polymers in the array sensor. The adsorption performance and properties were characterized. The GM-MIP was used to increase the selectivity in CL analysis. In addition, the sensor was reusable and of good selectivity and adsorption capacity. The array sensor was finally used for the determination of hydroquinone, resorcinol and catechol in waste water samples simultaneously.


The effects of biocides (antiseptics and disinfectants) on the endospores of Rhinosporidium seeberi.
No data exists on the activity of biocides (antiseptics and disinfectants) on Rhinosporidium seeberi that causes rhinosporidiosis in humans and animals. On account of the inability to culture R. seeberi, in vitro, dyes were used to assess the morphological integrity and viability of biocide-treated endospores that are considered to be the infective stage of this pathogen. Evan's Blue (EvB) identifies the morphological integrity of the endospores while MTT (3-[4, 5-dimethylthiazol-2yl]-2, 5-diphenyl tetrazolium bromide) identifies metabolic activity through its reduction by cellular dehydrogenases to microscopically visible deposits of insoluble formazan. MTT-negativity has earlier been shown to correlate with absence of growth of yeast and mycelial fungi in culture and could thus indicate the loss of viability of MTT-negative rhinosporidial endospores. Hydrogen peroxide, glutaraldehyde, chloroxylenol, chlorhexidine, cetrimide, thimerosal, 70% ethanol, iodine in 70% ethanol, 10% formalin, povidone-iodine, sodium azide and silver nitrate were tested on freshly-harvested endospores and all biocides caused metabolic inactivation with or without altered structural integrity as shown by absence of MTT-staining after 3, 24 or 36 hour after exposure, while EvB stained only the endospores treated with sodium azide, ethanol, thimerosal, chloroxylenol, glutaraldehyde and hydrogen peroxide. With clinically useful biocides - chlorhexidine, cetrimide-chlorhexidine, 70% ethanol, povidone-iodine and silver nitrate, a total period of exposure of endospores to the biocide, for seven minutes, produced metabolic inactivation of the endospores. Anti-rhinosporidial antiseptics that could be used in surgery on rhinosporidial patients include povidone-iodine in nasal packs for nasal and naso-pharyngeal surgery, chlorhexidine and cetrimide-chlorhexidine on the skin, while povidone-iodine and silver nitrate could have application in ocular rhinosporidiosis.


Unmet needs in the pharmacological management of depression.
Newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), selective noradrenaline reuptake inhibitors (NRIs) and drugs acting on both serotonin and noradrenaline, represent a clinically significant advance over the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors. Nevertheless, all current pharmacological treatments for depression fall somewhat short of the 'ideal', and unmet needs remain in the pharmacological management of depression. In general, current antidepressants differ little in terms of efficacy. However, in terms of tolerability, SSRIs appear to offer clear advantages over older therapies. For example, the proportion of patients who discontinue treatment because of adverse events and the risk of fatal toxicity both appear to be lower with SSRIs, compared with TCAs. Some adverse events, however, such as sexual dysfunction and nausea (typical serotonergic side effects), tend to be more frequent with SSRIs. Also, individual SSRIs appear to differ in the likelihood that they will be associated with these side effects. However, no clear advantage emerges for any one SSRI over another, and the current recommendation is that the anticipated side-effect profile should be tailored to the patient. Current pharmacoeconomic data do not appear to favour any antidepressant over another, with no cost benefits associated with prescribing TCAs instead of SSRIs.The refinement of current drugs arising from the introduction of their active enantiomers may translate into clinical benefit, bringing closer the 'ideal' antidepressant. Potential benefits of a single enantiomer versus the racemate in the management of depression include: a reduction in the total dose, while maintaining desired outcomes, as well as a possible greater efficacy, dose for dose,simpler assessment of dose-response relationships,a reduction in pharmacokinetic and pharmacodynamic variability between patients, anda reduction in any toxicity arising from the inactive stereoisomer. However, these benefits remain to be proved in clinical trials and naturalistic studies. Further refinement of the benefit:risk ratio of current 'gold standard' drugs may go some way to addressing the shortfalls in existing antidepressant therapy. Copyright 2001 John Wiley & Sons, Ltd.


Human leukocyte antigen (HLA)-E and HLA-F expression in gastric cancer.
Human leukocyte antigen (HLA)-E and HLA-F are classified as non-classical HLA class Ib antigens. Ectopic HLA-E and HLA-F expression was recently detected in cancer cells; however, the clinical implication of their expression remains unknown. A total of 209 patients with gastric cancer were enrolled in this study. Immunohistochemistry was used to evaluate the expression of HLA-E and HLA-F in gastric cancer specimens. HLA-E and HLA-F expression were seen in the cell membrane. HLA-E and HLA-F expression significantly correlated with depth of invasion, nodal involvement, lymphatic invasion, and venous invasion. No significant correlation between HLA-E and HLA-F expression was found (p<0.05, r=0.24). The five-year survival rate of the HLA-E-positive group and HLA-F-positive group were significantly poorer than that of their respective negative groups. Combination of HLA-E and HLA-F made the p-value smaller than single analysis (p<0.009). This is the first report detailing a clinical implication of HLA-E and HLA-F expression simultaneously in gastric cancer. We identified that the HLA-E and HLA-F in gastric cancer independently affected clinical factors, including postoperative outcome. For HLA-E- or HLA-F-positive gastric cancer, we should settle on a treatment strategy that reinforces the host immune response.


Quadrature phase-shift error analysis using a homodyne laser interferometer.
The influence of quadrature phase shift on the measured displacement error was experimentally investigated using a two-detector polarizing homodyne laser interferometer with a quadrature detection system. Common nonlinearities, including the phase-shift error, were determined and effectively corrected by a robust data-processing algorithm. The measured phase-shift error perfectly agrees with the theoretically determined phase-shift error region. This error is systematic, periodic and severely asymmetrical around the nominal displacement value. The main results presented in this paper can also be used to assess and correct the detector errors of other interferometric and non-interferometric displacement-measuring devices based on phase-quadrature detection.


Pharmacokinetics and PK-PD modelling of danofloxacin in camel serum and tissue cage fluids.
The pharmacokinetics and pharmacodynamics of danofloxacin were studied in the camel in a two period cross-over study. After intravenous (i.v.) administration at a dose rate of 1.25 mg/kg, the pharmacokinetics of danofloxacin indicated a high volume of distribution (V(d(area))=3.43 L/kg), relatively rapid clearance (0.44 L/kg/h) and half-life of 5.37 h. After intramuscular (i.m.) dosing absorption was complete (F=114.5) and rapid (T((1/2)abs)=0.12 h) and terminal half-life was 5.71 h. Danofloxacin penetrated fairly slowly into both inflamed (exudate) and non-inflamed (transudate) tissue cage fluids and was cleared slowly from these fluids, elimination half-life being at least twice that for serum for both exudate and transudate after both i.v. and i.m. dosing. The antibacterial actions of danofloxacin against the camel pathogen Escherichia coli 0157-H7 were determined by measurement of minimum inhibitory concentration (MIC) in vitro (single measurement) and ex vivo measurements of bacterial count at nine times between one and 48 h after i.m. dosing in each of the fluids, serum, exudate, and transudate. Using in vitro MIC data and in vivo pharmacokinetic parameters, the surrogate markers of antimicrobial activity, C(max)/MIC, AUC/MIC and T>MIC, were determined for all three fluids. The ex vivo serum AUC(24 h)/MIC data were integrated with reduction in bacterial count to provide values producing a bacteriostatic action (no change in bacterial count), inhibition of bacterial count by 50%, reduction in bacterial count by 99.9% (bactericidal action) and elimination of bacteria. Mean AUC(24h)/MIC values were 17.20, 20.07, 21.24, and 68.37 h, respectively. To describe the latter, the introduction of a new term to supplement MIC and minimum bactericidal concentration (MBC) is proposed, namely minimum elimination concentration (MEC). A novel means of designing antimicrobial drug dosage schedules for evaluation in clinical trials is proposed, using ex vivo AUC(24h)/MIC values for bactericidal activity and elimination of bacteria together with MIC(90) data for camel pathogens.


Ensuring that education, certification, and practice are evidence based.
The occupational therapy profession has put forth a vision for evidence-based practice. Although many practitioners express a commitment to the provision of services informed by evidence, the reality that tradition still determines much of our education, certification, and practice cannot be ignored. In this article, we highlight the disconnect between the profession's aspirations and actual practices using neurophysiological models as an example. We describe actions to actualize the shift from traditional interventions to evidence-based approaches. We challenge readers to become agents of change and facilitate a culture shift to a profession informed by evidence. It is our hope that this article will provoke critical discourse among educators, practitioners, authors, and editors about why a reluctance to let go of unsubstantiated traditions and a hesitancy to embrace scientific evidence exist. A shift to providing evidence-based occupational therapy will enable us to meet the objectives of the Centennial Vision.


KH domain: one motif, two folds.
The K homology (KH) module is a widespread RNA-binding motif that has been detected by sequence similarity searches in such proteins as heterogeneous nuclear ribonucleoprotein K (hnRNP K) and ribosomal protein S3. Analysis of spatial structures of KH domains in hnRNP K and S3 reveals that they are topologically dissimilar and thus belong to different protein folds. Thus KH motif proteins provide a rare example of protein domains that share significant sequence similarity in the motif regions but possess globally distinct structures. The two distinct topologies might have arisen from an ancestral KH motif protein by N- and C-terminal extensions, or one of the existing topologies may have evolved from the other by extension, displacement and deletion. C-terminal extension (deletion) requires ss-sheet rearrangement through the insertion (removal) of a ss-strand in a manner similar to that observed in serine protease inhibitors serpins. Current analysis offers a new look on how proteins can change fold in the course of evolution.


Determination of permethrin resistance allele frequency of human head louse populations by quantitative sequencing.
A quantitative sequencing (QS) protocol that detects the frequencies of sodium channel mutations (M815I, T917I, and L920F) responsible for knockdown resistance in permethrin-resistant head lice (Pediculus humanus capitis De Geer) was tested as a population genotyping method for use as a preliminary resistance monitoring tool. Genomic DNA fragments of the sodium channel a-subunit gene that encompass the three mutation sites were polymerase chain reaction (PCR)-1 amplified from individual head lice with either resistant or susceptible genotypes, and combined in various ratios to generate standard DNA template mixtures for QS. After sequencing, the signal ratios between resistant and susceptible nucleotides were calculated and plotted against the corresponding resistance allele frequencies. Quadratic regression coefficients of the plots were close to 1, demonstrating that the signal ratios are highly correlated with the resistance allele frequencies. Resistance allele frequencies predicted by QS, using either "pooled DNA" (DNA extracted from individual louse specimens and pooled) or "pooled specimen DNA" (DNA simultaneously extracted from multiple louse specimens), agreed well with those determined by individual sequencing, confirming the reliability and accuracy of QS as a population genotyping method and validating our approach of using the pooled specimen DNA as the DNA template for QS. Our protocol for QS was determined to be highly reliable for the prediction of resistance allele frequencies higher than approximately 7.4% at the 95% confidence level. According to the resistance allele frequencies determined by QS, pyrethroid resistance varies substantially among different geographical regions, emphasizing the importance of early resistance detection and proper management strategies.


Mutations in two independent pathways are sufficient to create hermaphroditic nematodes.
Although the nematode Caenorhabditis elegans produces self-fertile hermaphrodites, it descended from a male/female species, so hermaphroditism provides a model for the origin of novel traits. In the related species C. remanei, which has only male and female sexes, lowering the activity of tra-2 by RNA interference created XX animals that made spermatids as well as oocytes, but their spermatids could not activate without the addition of male seminal fluid. However, by lowering the expression of both tra-2 and swm-1, a gene that regulates sperm activation in C. elegans, we produced XX animals with active sperm that were self-fertile. Thus, the evolution of hermaphroditism in Caenorhabditis probably required two steps: a mutation in the sex-determination pathway that caused XX spermatogenesis and a mutation that allowed these spermatids to self-activate.


Cloning and sequence of the crp gene of Escherichia coli K 12.
We have determined the nucleotide sequence of the crp gene of Escherichia coli K 12. From a lambda transducing phage, the crp region was subcloned into pBR322. The gene was localized on the cloned fragment by determining the length of deletions which affect its expression. Its nucleotide sequence was established by using the technique of Maxam and Gilbert. The deduced amino-acid sequence is in agreement with the previously published amino acid composition of the protein (1, 2). Analysis of the sequence confirms that the DNA binding domain is located in the C-terminal portion of the protein.


Acanthosis nigricans predicts the clustering of metabolic syndrome components in Hispanic elementary school-aged children.
Acanthosis nigricans (AN) is a dermatologic condition associated with hyperinsulinemia, a marker of insulin resistance that is the principal abnormality in metabolic syndrome (MetS). We examined the association of AN with the clustering of MetS components. A cross-sectional study was conducted in an urban school-based health center in New Mexico. Students without diabetes were evaluated for AN, a family history of type 2 diabetes, body mass index (BMI), and MetS components. The clustering of MetS components by BMI category and AN status was assessed by comparing the group means of summed average z-scores of fasting insulin, triglycerides, high-density lipoprotein-cholesterol, and systolic blood pressure among the students. A multivariate model with BMI category and AN status controlling for Tanner stage was performed to identify the variables associated with the clustering of MetS components. Complete data were available for 90 children (age, 9.7±1.4 years; 94% Hispanic; 60% female). In multivariate modeling of MetS cluster z-score, significant differences were found between the students with BMI <85th percentile [-0.27; 95% confidence interval (95% CI)=-0.42 to -0.11] and (a) the students with BMI 85th-94.9th percentile with AN (0.74; 95% CI=0.17-1.31) and (b) the students with BMI ≥95th percentile with AN (0.86; 95% CI=0.54-1.18). No significant differences in the MetS cluster z-score were seen between the students with BMI <85th percentile and those with BMI 85th-94.9th percentile without AN (0.24; 95% CI=-0.33 to 0.81) or those with BMI ≥95th percentile without AN (0.31; 95% CI=-0.13 to 0.75). Overweight/obese Hispanic elementary school-aged children with AN exhibit clustering of MetS components and could benefit from early intervention.


Case mix adjustment in hospital cost analysis: information theory revisited.
Acute care hospitals have long been viewed as multi-product 'firms', a characteristic which has necessitated special adjustments for cost analyses of this sector. Output mix adjustment has generally had an ad hoc flavour, with service/facility proxies and patient mix variables often being used interchangeably. Where specific patient mix adjustment has been applied, methodologies have varied widely. In this paper a framework for viewing output standardization in cost analyses is offered. It is suggested that adjustment is necessary in two dimensions--activity mix and, within patient care activities, patient mix. Patient mix standardization may be accomplished through left-side (dependent variable) or right-side (independent variables) adjustment, and right-side efforts may, in turn, be classified according to diagnostic grouping/weighing combinations. A number of right-side patient mix standardization methods are reviewed briefly and one--using information theory to compute diagnostic complexities--is tested in a time series/cross section analysis of 87 British Columbia acute care hospitals over an eight-year period. Case mix complexity is found to vary within individual hospitals over time, and is confirmed as an important determinant of unit cost variation. The information theory approach is shown to generate intertemporally stable case complexity measures. Teaching activities are found to exert a strong indirect influence on inpatient unit costs.


Sensitization to cockroach allergen: immune regulation and genetic determinants.
Asthma is a major public health concern. Cockroach allergen exposure and cockroach allergic sensitization could contribute to the higher prevalence of asthma. However, the underlying immune mechanism and the genetic etiology remain unclear. Recent advances have demonstrated that several receptors (PAR-2, TLRs, CLRs) and their pathways mediate antigen uptake from the environment and induce allergies by signaling T cells to activate an inappropriate immune response. Cockroach-derived protease can disturb airway epithelial integrity via PAR-2 and leads to an increased penetration of cockroach allergen, resulting in activation of innate immune cells (e.g., DCs) via binding to either TLRs or CLRs. The activated DCs can direct cells of the adaptive immune system to facilitate promotion of Th2 cell response and subsequently increase risk of sensitization. Mannose receptor (MR), as a CLR, has been shown to mediate Bla g2 (purified cockroach allergen) uptake by DCs and to determine allergen-induced T cell polarization. Additionally, genetic factors may play an important role in conferring the susceptibility to cockroach sensitization. Several genes have been associated with cockroach sensitization and related phenotypes (HLA-D, TSLP, IL-12A, MBL2). In this review, we have focused on studies on the cockroach allergen induced immunologic responses and genetic basis for cockroach sensitization.


Membrane Anchoring and Ion-Entry Dynamics in P-type ATPase Copper Transport.
Cu+-specific P-type ATPase membrane protein transporters regulate cellular copper levels. The lack of crystal structures in Cu+-binding states has limited our understanding of how ion entry and binding are achieved. Here, we characterize the molecular basis of Cu+ entry using molecular-dynamics simulations, structural modeling, and in vitro and in vivo functional assays. Protein structural rearrangements resulting in the exposure of positive charges to bulk solvent rather than to lipid phosphates indicate a direct molecular role of the putative docking platform in Cu+ delivery. Mutational analyses and simulations in the presence and absence of Cu+ predict that the ion-entry path involves two ion-binding sites: one transient Met148-Cys382 site and one intramembranous site formed by trigonal coordination to Cys384, Asn689, and Met717. The results reconcile earlier biochemical and x-ray absorption data and provide a molecular understanding of ion entry in Cu+-transporting P-type ATPases.


Processing conflicting information: facilitation, interference, and functional connectivity.
When a conflict task involves congruent, neutral, and incongruent conditions, it is possible to examine facilitation (neutral vs. congruent) and interference (incongruent vs. neutral) components. Very few studies investigated the brain areas that are specifically involved in facilitation or interference. We used functional magnetic resonance imaging while participants performed a magnitude conflict task (the size congruity paradigm). We observed four findings: (1) while most of the brain areas that were activated by conflict tasks showed interference effects, the intraparietal sulcus was the only region activated for both interference and facilitation components. (2) Two groups of participants could be distinguished based on the pattern of anterior cingulate cortex (ACC) activity, one with classical facilitation (congruent<neutral), one with reverse facilitation. (3) Functional connectivity analysis of the areas that were modulated by the conflict task revealed an anterior cingulate - lateral prefrontal cortex network and a dorsal parietal - premotor cortex network. We suggest that the former plays a role in cognitive control and conflict detection, whereas the latter participates in top-down selection of task-relevant stimuli and response mapping. (4) These networks were modulated by the two groups that we distinguished based on the ACC activation.


Residual vein thrombosis and D-dimer for optimizing duration of anticoagulation in idiopathic deep vein thrombosis.
Long-term anticoagulant treatment is highly effective in preventing recurrent Venous Thrombo-Embolism (VTE) in patients with idiopathic Deep Vein Thrombosis (DVT) of the lower limbs, though associated with an increased risk for major bleeding that may offset the benefits of anticoagulation. Accordingly to recent guidelines, patients with idiopathic DVT should be treated for at least 3 months and then should be evaluated for the risk-benefit ratio of long-term therapy. However, such 'time for decision' is often unclear and the optimal duration of VKA remains debatable. In recent studies, markers for the assessment of the individual risk for recurrent thrombosis have been proposed, which can be of help to establish the optimal duration of VKA treatment; among them, the D-dimer (D-d) assay and the Residual Vein Thrombosis (RVT) assessment by Compression Ultra-Sonography (CUS) were shown to be the most suitable. Studies' results showed that negative results of these parameters after 3 to 6 months of therapy, identify a group of patients at low-risk for recurrent thrombosis in whom VKA treatment can be withheld. In the present review we will discuss advantages and potential limits of using these individual markers for the management of patients with a first episode of DVT of the lower limbs.


Genetic analysis of tolerance to boron toxicity in the legume Medicago truncatula.
Medicago truncatula Gaertn. (barrel medic) is cultivated as a pasture legume for its high protein content and ability to improve soils through nitrogen fixation. Toxic concentrations of the micronutrient Boron (B) in agricultural soils hamper the production of cereal and leguminous crops. In cereals, the genetic analysis of B tolerance has led to the development of molecular selection tools to introgress and maintain the B tolerance trait in breeding lines. There is a comparable need for selection tools in legumes that grow on these toxic soils, often in rotation with cereals. Genetic variation for B tolerance in Medicago truncatula was utilised to generate two F2 populations from crosses between tolerant and intolerant parents. Phenotyping under B stress revealed a close correlation between B tolerance and biomass production and a segregation ratio explained by a single dominant locus. M. truncatula homologues of the Arabidopsis major intrinsic protein (MIP) gene AtNIP5;1 and the efflux-type transporter gene AtBOR1, both known for B transport, were identified and nearby molecular markers screened across F2 lines to verify linkage with the B-tolerant phenotype. Most (95%) of the phenotypic variation could be explained by the SSR markers h2_6e22a and h2_21b19a, which flank a cluster of five predicted MIP genes on chromosome 4. Three CAPS markers (MtBtol-1,-2,-3) were developed to dissect the region further. Expression analysis of the five predicted MIPs indicated that only MtNIP3 was expressed when leaf tissue and roots were assessed. MtNIP3 showed low and equal expression in the roots of tolerant and intolerant lines but a 4-fold higher expression level in the leaves of B-tolerant cultivars. The expression profile correlates closely with the B concentration measured in the leaves and roots of tolerant and intolerant plants. Whereas no significant difference in B concentration exists between roots of tolerant and intolerant plants, the B concentration in the leaves of tolerant plants is less than half that of intolerant plants, which further supports MtNIP3 as the best candidate for the tolerance trait-defining gene in Medicago truncatula. The close linkage of the MtNIP3 locus to B toxicity tolerance provides a source of molecular selection tools to pasture breeding programs. The economical importance of the locus warrants further investigation of the individual members of the MIP gene cluster in other pasture and in grain legumes.


When in Rome ... Learn why the Romans do what they do: how multicultural learning experiences facilitate creativity.
Research suggests that living in and adapting to foreign cultures facilitates creativity. The current research investigated whether one aspect of the adaptation process-multicultural learning-is a critical component of increased creativity. Experiments 1-3 found that recalling a multicultural learning experience: (a) facilitates idea flexibility (e.g., the ability to solve problems in multiple ways), (b) increases awareness of underlying connections and associations, and (c) helps overcome functional fixedness. Importantly, Experiments 2 and 3 specifically demonstrated that functional learning in a multicultural context (i.e., learning about the underlying meaning or function of behaviors in that context) is particularly important for facilitating creativity. Results showed that creativity was enhanced only when participants recalled a functional multicultural learning experience and only when participants had previously lived abroad. Overall, multicultural learning appears to be an important mechanism by which foreign living experiences lead to creative enhancement.


Occlusal Outcome Of Non-Extraction And All First Premolars Extraction Treatment In Patients With Class-I Malocclusion.
Class-1 malocclusion commonly presents with crowding and poses an aesthetic concern to patients. An orthodontist may encounter a variety of dental problems and must handle them strategically to establish adequate occlusal relationships. Hence, this study was conducted to evaluate the occlusal characteristics of patients who have undergone non-extraction or all first premolars extraction treatment for class I malocclusion using the peer assessment rating (PAR) index. The pre-treatment and post treatment dental casts of 94 subjects with class-I malocclusion were retrospectively screened. The sample was distributed into two groups, i.e., nonextraction and all first premolars extraction groups. The Mann Whitney-U test was used to compare the mean percentage improvement in the PAR scores between the two groups. A p-value of ≤0.05 was considered statistically significant. The mean percentage improvement in the non-extraction group was 74.28% in the non-extraction group and 74.5% in the all first premolars extraction group. A significant difference (p=0.04) was found between the pretreatment PAR scores for the two treatment modalities. There was no significant difference between the post treatment PAR scores (p=0.45) and the mean percentage improvement in PAR scores (p=0.41) between the treatment groups. The improvement in occlusal characteristics in patients who underwent non-extraction treatment and all first premolar extraction treatment was comparable as assessed through mean percentage improvement in PAR scores.


Efficient Neural Codes That Minimize Lp Reconstruction Error.
The efficient coding hypothesis assumes that biological sensory systems use neural codes that are optimized to best possibly represent the stimuli that occur in their environment. Most common models use information-theoretic measures, whereas alternative formulations propose incorporating downstream decoding performance. Here we provide a systematic evaluation of different optimality criteria using a parametric formulation of the efficient coding problem based on the [Formula: see text] reconstruction error of the maximum likelihood decoder. This parametric family includes both the information maximization criterion and squared decoding error as special cases. We analytically derived the optimal tuning curve of a single neuron encoding a one-dimensional stimulus with an arbitrary input distribution. We show how the result can be generalized to a class of neural populations by introducing the concept of a meta-tuning curve. The predictions of our framework are tested against previously measured characteristics of some early visual systems found in biology. We find solutions that correspond to low values of [Formula: see text], suggesting that across different animal models, neural representations in the early visual pathways optimize similar criteria about natural stimuli that are relatively close to the information maximization criterion.


Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers.
There is limited pharmacokinetic data available for the combination artesunate + amodiaquine, which is used widely to treat uncomplicated malaria. This study examines the bioavailability and tolerability of a fixed (200 mg artesunate + 540 mg amodiaquine) and loose (200 mg + 612 mg) combination with a 2x2 cross-over design in 24 healthy volunteers. Parent compounds and metabolites [dihydroartemisinin (DHA) and desethylamodiaquine (DEAQ)] were measured by high-performance liquid chromatography-electrochemical detection, and the area under the curve (AUC)(0-t) and C(max) were compared by an analysis of variance (ANOVA) based on geometric least square means using the Schuirmann two one-sided test. The AUC(0-t) for total DHA and DEAQ were 1522 +/- 633 and 30021 +/- 14211 ng h/ml for the fixed products and 1688 +/- 767 and 40261 +/- 19824 ng h/ml (mean +/- standard deviation) for the loose products. The ANOVA showed no statistical differences except for sequence effect for DHA. The values obtained with the fixed product were within the 125% bioequivalent limits but extend below the 80% bioequivalence limits. Both combinations were well tolerated and had comparable pharmacokinetic profiles; differences are unlikely to be clinically relevant.


A meta-analysis of randomized controlled trials on mid-term angiographic outcomes for radial artery versus saphenous vein in coronary artery bypass graft surgery.
Currently, saphenous vein (SV) and radial artery (RA) are the most commonly used conduits in combination with the left internal mammary artery for conventional coronary artery bypass graft surgery (CABG). The present meta-analysis aimed to assess the existing evidence from randomized controlled trials (RCTs) to compare the angiographic outcomes of these two conduits at mid-term follow-up. Four relevant and updated RCTs with follow-up beyond 3 years were identified using five electronic databases. Angiographic endpoints included complete occlusion, 'string sign', graft failure and complete patency. The incidence of complete occlusion was significantly lower after using RA compared to SV [6.7% vs. 17.2%; odd ratio (OR), 0.36; 95% confidence interval (CI), 0.23-0.58; P<0.0001]. The angiographic 'string sign' was significantly more likely to be identified after using RA compared to SV (3.1% vs. 0%; OR, 5.65; 95% CI, 1.21-26.39; P=0.03). Graft failure was significantly lower after RA compared to SV (9.6% vs. 18.8%; OR, 0.47; 95% CI, 0.30-0.72; P=0.0005). Complete graft patency was found to be significantly higher after RA compared to SV (88.6% vs. 75.8%; OR, 3.19; 95% CI, 1.42-7.16; P=0.005). Results of the present meta-analysis suggest that selected patients with severe, proximal stenosis may have superior angiographic outcomes at mid-term follow-up after using RA compared to SV for CABG. However, RA is associated with a significantly higher incidence of the 'string sign'. Future studies should aim to collect additional data on symptomatic outcomes.


The preference for sugar over sweetener depends on a gut sensor cell.
Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.


Vps51p mediates the association of the GARP (Vps52/53/54) complex with the late Golgi t-SNARE Tlg1p.
Multisubunit tethering complexes may contribute to the specificity of membrane fusion events by linking transport vesicles to their target membrane in an initial recognition event that promotes SNARE assembly. However, the interactions that link tethering factors to the other components of the vesicle fusion machinery are still largely unknown. We have previously identified three subunits of a Golgi-localized complex (the Vps52/53/54 complex) that is required for retrograde transport to the late Golgi. This complex interacts with a Rab and a SNARE protein found at the late Golgi and is related to two other multisubunit tethering complexes: the COG complex and the exocyst. Here we show that the Vps52/53/54 complex has an additional subunit, Vps51p. All four members of this tetrameric GARP (Golgi-associated retrograde protein) complex are required for two distinct retrograde transport pathways, from both early and late endosomes, back to the TGN. vps51 mutants exhibit a distinct phenotype suggestive of a regulatory role. Indeed, we find that Vps51p mediates the interaction between Vps52/53/54 and the t-SNARE Tlg1p. The binding of this small, coiled-coil protein to the conserved N-terminal domain of the t-SNARE therefore provides a crucial link between components of the tethering and the fusion machinery.


Physical victimization of rural methamphetamine and cocaine users.
Substance use and physical violence often coincide, but little has been published on the correlates associated with receipt of partner versus nonpartner physical violence for rural users of methamphetamine and/or cocaine. In this study, participants' substance use, depression and past-year physical victimization were assessed. In separate logistic regression models, received partner violence in females was associated with age; alcohol, cocaine, and methamphetamine abuse/dependence; and number of drugs used in the past 6 months. In males, received nonpartner violence was associated with age, cocaine abuse/dependence, and being Caucasian. Findings suggest a relationship between stimulant use and received violence among rural substance users and a need for victimization screenings in settings where such individuals seek health care.


Brassinosteroids regulate root meristem development by mediating BIN2-UPB1 module in Arabidopsis.
Plant steroid hormones brassinosteroids (BRs) regulate plant growth and development at many levels. While negative regulatory factors that inhibit development and are counteracted by BRs exist in the root meristem, these factors have not been characterized. The functions of UPB1 transcription factor in BR-regulated root growth have not been established, although its role in regulating root are well documented. Here, we found that BIN2 interacts with and phosphorylates the UPB1 transcription factor consequently promoting UPB1 stability and transcriptional activity. Genetic analysis revealed that UPB1 deficiency could partially recover the short-root phenotype of BR-deficient mutants. Expression of a mutated UPB1S37AS41A protein lacking a conserved BIN2 phosphorylation sites can rescue shorter root phenotype of bin2-1 mutant. In addition, UPB1 was repressed by BES1 at the transcriptional level. The paclobutrazol-resistant protein family (PRE2/3) interacts with UPB1 and inhibits its transcriptional activity to promote root meristem development, and BIN2-mediated phosphorylation of UPB1 suppresses its interaction with PRE2/3, and subsequently impairing root meristem development. Taken together, our data elucidate a molecular mechanism by which BR promotes root growth via inhibiting BIN2-UPB1 module.


Future imaging of atherosclerosis: molecular imaging of coronary atherosclerosis with (18)F positron emission tomography.
Atherosclerosis is characterized by the formation of complex atheroma lesions (plaques) in arteries that pose risk by their flow-limiting nature and propensity for rupture and thrombotic occlusion. It develops in the context of disturbances to lipid metabolism and immune response, with inflammation underpinning all stages of plaque formation, progression and rupture. As the primary disease process responsible for myocardial infarction, stroke and peripheral vascular disease, atherosclerosis is a leading cause of morbidity and mortality on a global scale. A precise understanding of its pathogenic mechanisms is therefore critically important. Integral to this is the role of vascular wall imaging. Over recent years, the rapidly evolving field of molecular imaging has begun to revolutionize our ability to image beyond just the anatomical substrate of vascular disease, and more dynamically assess its pathobiology. Nuclear imaging by positron emission tomography (PET) can target specific molecular and biological pathways involved in atherosclerosis, with the application of (18)Fluoride PET imaging being widely studied for its potential to identify plaques that are vulnerable or high risk. In this review, we discuss the emergence of (18)Fluoride PET as a promising modality for the assessment of coronary atherosclerosis, focusing on the strengths and limitations of the two main radionuclide tracers that have been investigated to date: 2-deoxy-2-((18)F)fluoro-D-glucose ((18)F-FDG) and sodium (18)F-fluoride ((18)F-NaF).


Contribution of lianas to plant area index and canopy structure in a Panamanian forest.
Lianas are an important component of tropical forests, where they reduce tree growth, fecundity, and survival. Competition for light from lianas may be intense; however, the amount of light that lianas intercept is poorly understood. We used a large-scale liana-removal experiment to quantify light interception by lianas in a Panamanian secondary forest. We measured the change in plant area index (PAI) and forest structure before and after cutting lianas (for 4 yr) in eight 80 m × 80 m plots and eight control plots (16 plots total). We used ground-based LiDAR to measure the 3-dimensional canopy structure before cutting lianas, and then annually for 2 yr afterwards. Six weeks after cutting lianas, mean plot PAI was 20% higher in control vs. liana removal plots. One yr after cutting lianas, mean plot PAI was ~17% higher in control plots. The differences between treatments diminished significantly 2 yr after liana cutting and, after 4 yr, trees had fully compensated for liana removal. Ground-based LiDAR revealed that lianas attenuated light in the upper- and middle-forest canopy layers, and not only in the upper canopy as was previously suspected. Thus, lianas compete with trees by intercepting light in the upper- and mid-canopy of this forest.


Midterm Results of Porous Tantalum Femoral Cones in Revision Total Knee Arthroplasty.
Severe bone loss during a revision total knee arthroplasty (TKA) remains a challenging problem. The purpose of this study was to determine the midterm clinical outcomes, fixation as evaluated radiographically, and survivorship of tantalum femoral cones used during revision TKAs in patients with severe femoral bone loss. From 2003 to 2011, 159 tantalum metaphyseal femoral cones were implanted in 157 patients at a single institution. Knee Society scores, radiographic results, and implant survivorship were analyzed. Two patients were lost to follow-up. Nineteen died of causes unrelated to the surgery but had been followed for >2 years and thus were included in the study. The mean age at the time of the index surgery was 64 years, and 82 patients were male. The mean duration of follow-up was 5 years (range, 2 to 10 years). The mean Knee Society score increased from 47 preoperatively to 65 at the most recent follow-up evaluation (p = 0.1). Radiographically, all 134 unrevised femoral cones were seen to be well fixed without any evidence of loosening. At 5 years, 23 cones had been revised: 14 because of infection, 6 because of aseptic loosening of the cone (all in hinged TKAs in patients with a Type-3 defect), and 3 because of ligamentous instability. The 5-year survivorship was 96% when the end point was revision of the cone due to aseptic loosening, 84% when it was revision of the cone for any reason, and 70% when it was any reoperation. In what we believe to be the largest series of such implants, femoral cones provided a durable and reliable option for metaphyseal fixation during revision TKA with severe femoral bone loss. Aseptic failure of the femoral cone was associated with use of a hinged TKA in a patient with a Type-3 bone defect. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Evolution of columns, modules, and domains in the neocortex of primates.
The specialized regions of neocortex of mammals, called areas, have been divided into smaller functional units called minicolumns, columns, modules, and domains. Here we describe some of these functional subdivisions of areas in primates and suggest when they emerged in mammalian evolution. We distinguish several types of these smaller subdivisions. Minicolumns, vertical arrays of neurons that are more densely interconnected with each other than with laterally neighboring neurons, are present in all cortical areas. Classic columns are defined by a repeating pattern of two or more types of cortex distinguished by having different inputs and neurons with different response properties. Sensory stimuli that continuously vary along a stimulus dimension may activate groups of neurons that vary continuously in location, producing "columns" without specific boundaries. Other groups or columns of cortical neurons are separated by narrow septa of fibers that reflect discontinuities in the receptor sheet. Larger regions of posterior parietal cortex and frontal motor cortex are parts of networks devoted to producing different sequences of movements. We distinguish these larger functionally distinct regions as domains. Columns of several types have evolved independently a number of times. Some of the columns found in primates likely emerged with the first primates, whereas others likely were present in earlier ancestors. The sizes and shapes of columns seem to depend on the balance of neuron activation patterns and molecular signals during development.


Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression.
Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20 mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100 mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2'-deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS-induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action.


MUC7 polymorphisms are associated with a decreased risk of a diagnosis of asthma in an African American population.
Mucin glycoproteins contribute to lung pathophysiology in asthma. The protein backbone of mucin glycoproteins is encoded by specific MUC genes, which exhibit a high degree of polymorphisms that generate a variable number of tandem repeat (VNTR) domains. MUC7 typically encodes for 6 VNTRs, each with 23 amino acids. In a northern European cohort, a polymorphism encoding MUC7*5 (5-VNTR) is in 100% linkage disequilibrium with the single nucleotide polymorphism rs9982010 and associated with a decreased risk of being asthmatic and having better lung function. African Americans have a 5- to 10-fold increase in incidence of asthma relative to whites, who are believed to be partially associated with higher genetic susceptibility. Occurrence of the rs9982010 and MUC7 allelic frequencies was evaluated in inner-city African Americans to test their association with a diagnosis of asthma. Genomic DNA, collected from a cohort of African American asthmatic subjects, was used to detect the MUC7 VNTR polymorphisms and to analyze the rs9982010 single nucleotide polymorphism. A logistic regression analysis showed that the MUC7*5-VNTR allele decreased the likelihood of a diagnosis of asthma (odds ratio, 0.173 [95% confidence interval, 0.041-0.737]; P < 0.018) and is not in a strong linkage disequilibrium with the rs9982010 (r = 0.03; odds ratio, 66; confidence interval, 5.913-736.72). A novel MUC7*4-VNTR polymorphism, identified in an African American nonasthmatic individual, was linked to a structural rearrangement of the VNTR domain. These data extend the association of MUC7*5 allelic polymorphisms and asthma to inner-city African Americans.


Mixed modeling for irregularly sampled and correlated functional data: Speech science applications.
The speech sciences often employ complex experimental designs requiring models with multiple covariates and crossed random effects. For curve-like data such as time-varying signals, single-time-point feature extraction is commonly used as data reduction technique to make the data amenable to statistical hypothesis testing, thereby discarding a wealth of information. The present paper discusses the application of functional linear mixed models, a functional analogue to linear mixed models. This type of model allows for the holistic evaluation of curve dynamics for data with complex correlation structures due to repeated measures on subjects and stimulus items. The nonparametric, spline-based estimation technique allows for correlated functional data to be observed irregularly, or even sparsely. This means that information on variation in the temporal domain is preserved. Functional principal component analysis is used for parsimonious data representation and variance decomposition. The basic functionality and usage of the model is illustrated based on several case studies with different data types and experimental designs. The statistical method is broadly applicable to any types of data that consist of groups of curves, whether they are articulatory or acoustic time series data, or generally any types of data suitably modeled based on penalized splines.


Ultrasound and Doppler micro-imaging in a model of rheumatoid arthritis in mice.
The evaluation of joints in arthritis using conventional ultrasonography is not really feasible in mice because of the small size of the animal. However, compared with classical analysis (clinical and histological examination) it is a non-invasive method that allows follow-up of the same animal throughout the whole experiment. Moreover, power Doppler allows the study of blood flow that reflects inflammatory activity within the synovium of arthritic joints. Our aim was to determine whether ultrasonography analysis could accurately detect arthritis lesions in a mouse model of rheumatoid arthritis, namely collagen-induced arthritis. Collagen-induced arthritis was induced in 28 mice by immunising with collagen type II. Every week for 8 weeks, ultrasonography and Doppler analysis were performed on knees and ankles of all mice using the ultrasound biomicroscope (UBM), which is particularly dedicated to studying the mouse. Clinical and histological evaluations were performed as usual. We established a semiquantitative analysis by setting an UBM scoring. UBM grades were correlated to clinical and histological scores of arthritis. Vascularisation within the synovium could be estimated by power Doppler analysis and a semiquantitative vascularisation scale was established, which allowed us to show a good correlation between vascularisation scores and histological or clinical scores of arthritis. This is one of the first studies that shows it is possible to visualise a selected set of joints in a small animal using UBM analysis. It provides new perspectives in evaluating experimental models of rheumatoid arthritis and other joint diseases.


Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation.
Germline mutations in LKB1 (also known as STK11) are associated with Peutz-Jeghers syndrome (PJS), a disorder with predisposition to gastrointestinal polyposis and cancer. PJS polyps are unusual neoplasms characterized by marked epithelial and stromal overgrowth but have limited malignant potential. Here we show that Lkb1(+/-) mice develop intestinal polyps identical to those seen in individuals affected with PJS. Consistent with this in vivo tumour suppressor function, Lkb1 deficiency prevents culture-induced senescence without loss of Ink4a/Arf or p53. Despite compromised mortality, Lkb1(-/-) mouse embryonic fibroblasts show resistance to transformation by activated Ha-Ras either alone or with immortalizing oncogenes. This phenotype is in agreement with the paucity of mutations in Ras seen in PJS polyps and suggests that loss of Lkb1 function as an early neoplastic event renders cells resistant to subsequent oncogene-induced transformation. In addition, the Lkb1 transcriptome shows modulation of factors linked to angiogenesis, extracellular matrix remodelling, cell adhesion and inhibition of Ras transformation. Together, our data rationalize several features of PJS polyposis--notably its peculiar histopathological presentation and limited malignant potential--and place Lkb1 in a distinct class of tumour suppressors.


Immunisation coverage of adults: a vaccination counselling campaign in the pharmacies in Switzerland.
To assess vaccination coverage for adults living in Switzerland. Through a media campaign, the general population was invited during 1 month to bring their vaccination certificates to the pharmacies to have their immunisation status evaluated with the software viavac©, and to complete a questionnaire. A total of 496 pharmacies in Switzerland participated in the campaign, of which 284 (57%) submitted valid vaccination information. From a total of 3,634 participants in the campaign, there were 3,291 valid cases (participants born ≤ 1992) and 1,011 questionnaires completed. Vaccination coverage for the participants was 45.9% and 34.6% for five and six doses of diphtheria, 56.4% and 44.0% for tetanus and 66.3% and 48.0% for polio, respectively. Coverage estimates for one and two doses of measles vaccine were 76.5% and 49.4%, respectively, for the birth cohort 1967-1992 and 4.0% and 0.8%, respectively, for the cohort ≤ 1966. There was a significant difference in coverage for most vaccinations between the two aforementioned birth cohorts. A plot of the measles vaccine coverage over time shows that the increase in coverage correlated with policy changes in the Swiss Immunisation Schedule. Despite selection bias and low participation, this study indicates that vaccination coverage for the basic recommended immunisations in the adult population in Switzerland is suboptimal. More efforts using various means and methods are needed to increase immunisation coverage in adolescents before they leave school. An established method to determine vaccination coverage for the general population could provide invaluable insights into the effects of changes in vaccination policies and disease outbreaks.


Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study.
Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2-amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non-small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.


Development of an assistive motorized hip orthosis: kinematics analysis and mechanical design.
With the increase of life expectancy, a higher number of elderly need assistance to maintain their mobility and their independance. The hip joint is crucial for walking and is problematic for a large number of aged people. In this paper we present a novel design of a motorized hip orthosis to assist elderly people while walking, stair climbing and during the sit-to-stand transistions. The kinematics was developed based on biomechanics considerations. To be able to achieve a large assistance rate, velocity and torques of the hip joint were studied from the literature. In order to fit with these requirements, an amplification mechanism inspired by excavators was developed and implemented. Comfort considerations were also taken into account and a custom interface was designed with the collaboration of a professional orthopaedic technician. First tests with the prototype showed that the workspace is sufficient for walking, for stair climbing as well as for sit-to-stand transitions. The assistance rate can go up to 30% for a 70 kg subject during walking at a cadence of 100 steps/min. The comfort is guaranteed despite the important weight (4.3 kg) of this first prototype.


Improved partition equilibrium model for predicting analyte response in electrospray ionization mass spectrometry.
A previously proposed partition equilibrium model for quantitative prediction of analyte response in electrospray ionization mass spectrometry is modified to yield an improved linear relationship. Analyte mass spectrometer response is modeled by a competition mechanism between analyte and background electrolytes that is based on partition equilibrium considerations. The correlation between analyte response and solution composition is described by the linear model over a wide concentration range and the improved model is shown to be valid for a wide range of experimental conditions. The behavior of an analyte in a salt solution, which could not be explained by the original model, is correctly predicted. The ion suppression effects of 16:0 lysophosphatidylcholine (LPC) on analyte signals are attributed to a combination of competition for excess charge and reduction of total charge due to surface tension effects. In contrast to the complicated mathematical forms that comprise the original model, the simplified model described here can more easily be employed to predict analyte mass spectrometer responses for solutions containing multiple components.


Depression of endothelium-dependent relaxation in aorta from rats with Brugia pahangi lymphatic filariasis.
A role for altered endothelial cell function is emerging in the pathogenesis of disease. We have previously demonstrated that Dirofilaria immitis, the canine heartworm, depresses endothelium-dependent responses and alters the mechanism of relaxation in the in vivo femoral artery of infected dogs. Exposure of rat aorta to the parasite or parasite-conditioned medium selectively depresses endothelium-dependent relaxation. D. immitis is closely related to the major human filarial pathogens. This study was designed to examine the effect of chronic infection with the filarial nematode Brugia pahangi on endothelium-mediated responses of the rat aorta in vitro. We tested the hypothesis that endothelium-dependent responses are depressed in the aorta from rats infected with B. pahangi. Rings of thoracic and abdominal aorta were suspended in muscle baths for measurement of isometric tension. Dose-response relations to norepinephrine, endothelium-dependent dilators (acetylcholine, histamine, and A23187), and nitroglycerin were done. In some experiments, inhibitors of cyclooxygenase (indomethacin and aspirin), guanylate cyclase (methylene blue), and nitric oxide formation (N-nitro-L-arginine methyl ester; L-NOARG) were used. No differences in vascular reactivity were detected in the thoracic aorta. In contrast, endothelium-dependent responses in abdominal aorta of Brugia-infected rats were significantly depressed when compared with control aorta from noninfected rats. Acetylcholine relaxation was further depressed by indomethacin and aspirin. After L-NOARG, acetylcholine relaxation in control abdominal aorta was completely abolished; however, in abdominal aorta of Brugia-infected rats, acetylcholine still caused relaxation. Methylene blue inhibited acetylcholine relaxation in both control and Brugia-infected abdominal aorta; however, relaxation in Brugia-infected aorta was significantly greater than control. This study demonstrates that endothelium-dependent relaxation can be altered by chronic experimental filarial infection in the absence of direct contact between the blood vessel and the parasite. The mechanism of relaxation in the Brugia-infected abdominal aorta appears to be altered when compared with control, suggesting that parasites are capable of modulating vascular reactivity by inducing changes in endothelial cell behavior. The mechanism may involve parasite-induced local inflammation or alterations in endothelial cell metabolism. Understanding how chronic experimental filarial infection alters vascular reactivity may enhance our understanding of the pathogenesis of human filariasis.


Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy.
In response to stress, the heart undergoes extensive cardiac remodeling that results in cardiac fibrosis and pathological growth of cardiomyocytes (hypertrophy), which contribute to heart failure. Alterations in microRNA (miRNA) levels are associated with dysfunctional gene expression profiles associated with many cardiovascular disease conditions; however, miRNAs have emerged recently as paracrine signaling mediators. Thus, we investigated a potential paracrine miRNA crosstalk between cardiac fibroblasts and cardiomyocytes and found that cardiac fibroblasts secrete miRNA-enriched exosomes. Surprisingly, evaluation of the miRNA content of cardiac fibroblast-derived exosomes revealed a relatively high abundance of many miRNA passenger strands ("star" miRNAs), which normally undergo intracellular degradation. Using confocal imaging and coculture assays, we identified fibroblast exosomal-derived miR-21_3p (miR-21*) as a potent paracrine-acting RNA molecule that induces cardiomyocyte hypertrophy. Proteome profiling identified sorbin and SH3 domain-containing protein 2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) as miR-21* targets, and silencing SORBS2 or PDLIM5 in cardiomyocytes induced hypertrophy. Pharmacological inhibition of miR-21* in a mouse model of Ang II-induced cardiac hypertrophy attenuated pathology. These findings demonstrate that cardiac fibroblasts secrete star miRNA-enriched exosomes and identify fibroblast-derived miR-21* as a paracrine signaling mediator of cardiomyocyte hypertrophy that has potential as a therapeutic target.


Hormone-regulated expansins: expression, localization, and cell wall biomechanics in Arabidopsis root growth.
Expansins facilitate cell expansion by mediating pH-dependent cell wall (CW) loosening. However, the role of expansins in controlling CW biomechanical properties in specific tissues and organs remains elusive. We monitored hormonal responsiveness and spatial specificity of expression and localization of expansins predicted to be the direct targets of cytokinin signaling in Arabidopsis (Arabidopsis thaliana). We found EXPANSIN1 (EXPA1) homogenously distributed throughout the CW of columella/lateral root cap, while EXPA10 and EXPA14 localized predominantly at three-cell boundaries in the epidermis/cortex in various root zones. EXPA15 revealed cell type-specific combination of homogenous vs. three-cell boundaries localization. By comparing Brillouin frequency shift and AFM-measured Young's modulus, we demonstrated Brillouin light scattering (BLS) as a tool suitable for non-invasive in vivo quantitative assessment of CW viscoelasticity. Using both BLS and AFM, we showed that EXPA1 overexpression upregulated CW stiffness in the root transition zone. The dexamethasone-controlled EXPA1 overexpression induced fast changes in the transcription of numerous CW-associated genes, including several EXPAs and XYLOGLUCAN:XYLOGLUCOSYL TRANSFERASEs (XTHs), and associated with rapid pectin methylesterification determined by in situ Fourier transform infrared spectroscopy in the root transition zone. The EXPA1-induced CW remodeling associated with shortening of the root apical meristem, leading to root growth arrest. Based on our results, we propose that expansins control root growth by a delicate orchestration of CW biomechanical properties, possibly regulating both CW loosening and CW remodeling.


Specialty differences in primary care physician reports of papanicolaou test screening practices: a national survey, 2006 to 2007.
Cervical cancer screening guidelines were substantially revised in 2002 and 2003. Little information is available about primary care physicians' current Papanicolaou (Pap) test screening practices, including initiation, frequency, and stopping. To assess current Pap test screening practices in the United States. Cross-sectional survey. Nationally representative sample of physicians during 2006 to 2007. 1212 primary care physicians. The survey included questions about physician and practice characteristics and recommendations for Pap screening presented as clinical vignettes describing women by age and by sexual and screening histories. A composite measure-guideline-consistent recommendations-was created by using responses to vignettes in which major guidelines were uniform. Most physicians reported providing Pap tests to their eligible patients (91.0% [95% CI, 89.0% to 92.6%]). Among Pap test providers (n = 1114), screening practices, including number of tests ordered or performed, use of patient reminder systems, and cytology method used, varied by physician specialty (P < 0.001). Although most Pap test providers reported that screening guidelines were very influential in their clinical practice, few had guideline-consistent recommendations for starting and stopping Pap screening across multiple vignettes (22.3% [CI, 19.9% to 25.0%]). Guideline-consistent recommendations varied by specialty (obstetrics/gynecology, 16.4%; internal medicine, 27.5%; and family or general practice, 21.1%). Compared with obstetricians/gynecologists, internal medicine specialists and family or general practice specialists were more likely to have guideline-consistent screening recommendations (odds ratio, 1.98 [CI, 1.22 to 3.23] and 1.45 [CI, 0.99 to 2.13], respectively) in multivariate analysis. Physician self-report may reflect idealized rather than actual practice. Primary care physicians' recommendations for Pap test screening are not consistent with screening guidelines, reflecting overuse of screening. Implementation of effective interventions that focus on potentially modifiable physician and practice factors is needed to improve screening practice. National Cancer Institute, Centers for Disease Control and Prevention, and Agency for Healthcare Research and Quality.


Nuclear factor I X deficiency causes brain malformation and severe skeletal defects.
The transcription factor family of nuclear factor I (NFI) proteins is encoded by four closely related genes: Nfia, Nfib, Nfic, and Nfix. A potential role for NFI proteins in regulating developmental processes has been implicated by their specific expression pattern during embryonic development and by analysis of NFI-deficient mice. It was shown that loss of NFIA results in hydrocephalus and agenesis of the corpus callosum and that NFIB deficiency leads to neurological defects and to severe lung hypoplasia, whereas Nfic knockout mice exhibit specific tooth defects. Here we report the knockout analysis of the fourth and last member of this gene family, Nfix. Loss of NFIX is postnatally lethal and leads to hydrocephalus and to a partial agenesis of the corpus callosum. Furthermore, NFIX-deficient mice develop a deformation of the spine, which is due to a delay in ossification of vertebral bodies and a progressive degeneration of intervertebral disks. Impaired endochondral ossification and decreased mineralization were also observed in femoral sections of Nfix-/- mice. Consistent with the defects in bone ossification we could show that the expression level of tetranectin, a plasminogen-binding protein involved in mineralization, is specifically downregulated in bones of NFIX-deficient mice.


Rational design of potent antagonists to the human growth hormone receptor.
A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially--a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.


Precautionary labelling of foods for allergen content: are we ready for a global framework?
Food allergy appears to be on the rise with the current mainstay of treatment centred on allergen avoidance. Mandatory allergen labelling has improved the safety of food for allergic consumers. However an additional form of voluntary labelling (termed precautionary allergen labelling) has evolved on a wide range of packaged goods, in a bid by manufacturers to minimise risk to customers, and the negative impact on business that might result from exposure to trace amounts of food allergen present during cross-contamination during production. This has resulted in near ubiquitous utilisation of a multitude of different precautionary allergen labels with subsequent confusion amongst many consumers as to their significance. The global nature of food production and manufacturing makes harmonisation of allergen labelling regulations across the world a matter of increasing importance. Addressing inconsistencies across countries with regards to labelling legislation, as well as improvement or even banning of precautionary allergy labelling are both likely to be significant steps forward in improved food safety for allergic families. This article outlines the current status of allergen labelling legislation around the world and reviews the value of current existing precautionary allergen labelling for the allergic consumer. We strongly urge for an international framework to be considered to help roadmap a solution to the weaknesses of the current systems, and discuss the role of legislation in facilitating this.


[Complications and costs associated with chickenpox in immunocompetent children].
Chickenpox is a common infection of childhood in countries that have not included the corresponding vaccination in their immunization schedules. Chickenpox is usually benign in immunocompetent children, and treatment is not needed. The objectives of this study were to investigate the frequency and characteristics of chickenpox complications that require hospital treatment in immunocompetent children and the clinical progression in children of mothers with perinatal chickenpox. In addition, the hospital costs associated with chickenpox in the studied children were calculated. This was a retrospective study using the clinical records of children with chickenpox hospitalized at the Children's Hospital of Panama, from January 1991 through December 2000. We analyzed the types of complications, the clinical progression, and the hospital costs of the chickenpox patients. Of 5 203 children seen in outpatient consultations, 568 of them (11%) were hospitalized. We included 513 children in our study: 381 (74%) with chickenpox acquired in the community, 92 (18%) the children of mothers with chickenpox, and 40 (8%) with nosocomial chickenpox. The most frequent complications were cutaneous and subcutaneous infections (45%), respiratory infections (25%), and neurological changes (7%). The respiratory and cutaneous complications occurred sooner and among younger patients than did the neurological changes. Overall, 13 of the children (2.5%) died. The case fatality rate was 8% for chickenpox with respiratory and neurological complications and 0% for chickenpox with cutaneous complications. Of the 92 children with a mother with chickenpox, 60 of them (65%) did not develop the disease, and none of the 92 died. In contrast, 2 of the 32 neonates (6%) with perinatal chickenpox died. The mean length of hospitalization was 8.9 days (standard deviation, +/- 17.4 days). Parenteral pharmacotherapy was used with the great majority of the children, particularly antibiotics (54%), acyclovir (17%), and intravenous immunoglobulin (14%). The mean per-patient cost of hospitalization was US$ 1 209. Our results show that chickenpox is associated with a sizable number of expensive complications and a not-insignificant case fatality rate in immunocompetent children. Routine vaccination against chickenpox could reduce the impact of this disease on the health of children in Panama


Small intestinal perforation due to a huge gastrointestinal stromal tumor in a kidney transplant recipient: a case report and literature review.
Gastrointestinal stromal tumors (GISTs) in transplant recipients are very rare and only a handful of cases have been reported to date. Here we present the first known case of a huge GIST in a kidney transplant recipient with perforation of small intestine. A 64-year-old male presented at our hospital with right colic pain; he had received an ABO incompatible kidney transplant 6 years earlier and was treated with cyclosporine, mycophenolate mofetil, and methylprednisolone. Radiological evaluation revealed a huge (11 cm in diameter) solitary tumor at the small intestine without distant metastasis. The small intestinal wall at the tumor location was perforated one week after diagnosis and the patient underwent emergency surgery. The pathological findings were compatible with GIST and the tumor consisted of spindle cells with positive staining for KIT, CD34, and DOG1 and negative or weak staining for desmin and S-100 protein. A mutation in exon 11 of the c-kit gene was also detected. Cyclosporine was withdrawn and imatinib mesylate (400 mg daily) was introduced. However, thereafter, we needed to decrease the dose at 300 mg daily due to severe hyponatremia. Reduced imatinib treatment was well tolerated and recurrence was not observed for 18 months after surgery. The occurrence of GISTs in transplant patients is rare, and huge GISTs should be resected immediately after diagnosis because gastrointestinal tract at the tumor site could be perforated. Imatinib treatment is feasible in transplant recipients under immunosuppression, although immunosuppressive drugs metabolized by CYP3A4 should be used at a reduced dosage or withdrawn.


Detecting hospital-acquired infections: A document classification approach using support vector machines and gradient tree boosting.
Hospital-acquired infections pose a significant risk to patient health, while their surveillance is an additional workload for hospital staff. Our overall aim is to build a surveillance system that reliably detects all patient records that potentially include hospital-acquired infections. This is to reduce the burden of having the hospital staff manually check patient records. This study focuses on the application of text classification using support vector machines and gradient tree boosting to the problem. Support vector machines and gradient tree boosting have never been applied to the problem of detecting hospital-acquired infections in Swedish patient records, and according to our experiments, they lead to encouraging results. The best result is yielded by gradient tree boosting, at 93.7 percent recall, 79.7 percent precision and 85.7 percent F1 score when using stemming. We can show that simple preprocessing techniques and parameter tuning can lead to high recall (which we aim for in screening patient records) with appropriate precision for this task.


The efficacy of a paste containing Myrtus communis (Myrtle) in the management of recurrent aphthous stomatitis: a randomized controlled trial.
Recurrent aphthous stomatitis (RAS) is a common, painful, and ulcerative disorder of the oral cavity with unknown etiology. Treatment is a highly controversial topic. The aim of this study was to evaluate the clinical efficacy of a novel paste containing Myrtus communis (Myrtle) in the treatment of recurrent aphthous stomatitis. Myrtle is a particular herb used in some cultures as treatment for mouth ulcers. The study was a randomized, double-blind, controlled before-after clinical trial. Forty-five patients with RAS randomly participated in this study. The subjects were treated with placebo paste and myrtle oral paste in two consecutive episodes. The paste was applied by subjects themselves four times a day for 6 days. Five parameters (size change, pain scale, erythema and exudation level, oral health impact profile, and patient overall assessment of their treatment) were recorded both before (baseline) and during each episodes of treatment (on the morning of days 2, 4, and 6). There were no statistically significant differences between baseline parameters (p > 0.05). The data indicated a statistically significant reduction of ulcer size (p < 0.001), pain severity (p < 0.05), and erythema and exudation level (p < 0.001). Oral Health Impact Profile improved significantly in the treatment group (p < 0.001). Patient overall assessment of their treatment improved after applying paste containing myrtle (p < 0.05). No side effects were reported. This study has shown myrtle to be effective in decreasing the size of ulcers, pain severity and the level of erythema and exudation, and improving the quality of life in patients who suffer from RAS.


Management of primary malignant germ cell tumor of the mediastinum.
Primary mediastinal malignant germ cell tumors (GCTs) are rare and have a worse prognosis than their gonadal counterparts. Although multimodality treatment is a standard therapeutic strategy in mediastinal GCTs, the clinical implications of surgical intervention remain unclear. Forty-eight patients with primary mediastinal malignant GCT who were treated at the National Cancer Center Hospital, Tokyo, from 1962 to 2002 were studied retrospectively with regard to their histology and clinical profile. Mediastinal GCT occurred predominantly in young males, with a mean age of 28.8 years at the time of diagnosis. There were 46 males (96%) and two females (4%). Histologically, seven patients (15%) were diagnosed as having pure seminoma and 41 (85%) had non-seminomatous GCT. Treatment consisted of surgery alone in nine patients, surgery followed by chemotherapy in two, and chemotherapy followed by surgery in 20. The other 17 patients received chemotherapy and/or radiotherapy without surgery. Of these latter 17 patients, 14 developed progressive disease and three were followed up with a sustained partial response. Among the 31 patients who underwent surgery, complete resection was performed in 27 (87%) and incomplete resection was performed in four (13%). Twelve (41%) patients had elevated serum tumor marker levels preoperatively. Among the 20 patients who received preoperative chemotherapy, viable cells were found in the resected specimen in six (30%). With regard to tumor recurrence in patients with surgical intervention, the preoperative serum tumor marker levels and the presence of viable cells in the resected specimen were significantly associated with recurrence. There was no significant association between surgical curability and recurrence. The 5-year overall survival rate in all 48 patients was 45.5%. Surgical intervention for mediastinal GCT may be needed to remove a chemotherapy-refractory tumor or to assess the pathological response to chemotherapy to determine the indications for further chemotherapy.


Green tea: a promising natural product in oral health.
Green tea is a leading beverage in the Far East for thousands of years; it is regarded for a long time as a health product. Green tea is important source of polyphenol antioxidants. Polyphenols including epigallocatechin 3 gallate (EGCG) constitute the most interesting components in green tea leaves. Green tea has the potential to protect against various malignant, cardiovascular and metabolic diseases. There is a growing body of evidence pointing a beneficial role of green tea and its polyphenols in oral health. Green tea protects against bacterial induced dental caries. Tea polyphenols possess antiviral properties, believed to help in protection from influenza virus. Additionally, green tea polyphenols can abolish halitosis through modification of odorant sulphur components. Oral cavity oxidative stress and inflammation, consequent to cigarette smoking and cigarettes' deleterious compounds nicotine and acrolein, may be reduced in the presence of green tea polyphenols. Generally, green tea defends healthy cells from malignant transformation and locally has the ability to induce apoptosis in oral cancer cells. All together, there is an increasing interest in the health benefits of green tea in the field of oral health. Nonetheless, there is still a need for more clinical and biological studies to support guidelines for green tea intake as part of prevention and treatment of specific oral pathologies.


Phosphorylase a activity as an indicator of neutrophil activation by chemotactic peptide.
The activity of glycogen phosphorylase, an enzyme that is activated by both cAMP and calcium, was used as an indicator of the state of the cytoplasm after chemotactic stimulation of polymorphonuclear leukocytes (neutrophils). The activity of the enzyme showed a clear dependence on cytoplasmic calcium. Addition of the calcium ionophore A23187 caused a 4-5-fold increase in activity of phosphorylase a. In the absence of external Ca2+, A23187 caused only brief transient activation of phosphorylase; probably reflecting release of sequestered intracellular Ca2+. Addition of the chemotactic peptide N-formylnorleucylleucylphenylalanine (FNLLP) caused a transient 2-3-fold activation of the enzyme. The dose-dependence of activation by FNLLP showed a peak at 10(-8) M, near the Kd of the receptor for FNLLP. The phosphorylase activity peaks by 90 s and then declines, returning to basal levels by 20 min after stimulation with 10(-8) M peptide and by 60 min with 10(-7) M peptide. This finding suggests that the cells do not need to maintain elevated cytoplasmic calcium levels to exhibit stimulated locomotion. Thus, if calcium continues to modulate the motility, there either must be highly localized changes that are not detected in measures of the total cytoplasm, or the sensitivity to calcium must be variable such that basal levels are sufficient to maintain locomotion. Cells loaded with the fluorescence calcium probe quin2 (0.6 mM) in the presence or absence of external Ca2+ had elevated phosphorylase levels before addition of FNLLP. Thus, the presence of quin2 may alter the cytoplasmic Ca2+ level, and it clearly alters some aspects of the neutrophil physiology. Phosphorylase a appears to be a sensitive, nonperturbing indicator of the cytoplasmic calcium levels.


Community engagement: A central feature of NOSM's socially accountable distributed medical education.
Northern Ontario School of Medicine (NOSM) serves as the Faculty of Medicine of Lakehead and Laurentian Universities, and views the entire geography of Northern Ontario as its campus. This paper explores how community engagement contributes to achieving social accountability in over 90 sites through NOSM's distinctive model, Distributed Community Engaged Learning (DCEL). Studies involving qualitative and quantitative methods contribute to this paper, which draws on administrative data from NOSM and external sources, as well as surveys and interviews of students, graduates and other informants including the joint NOSM-CRaNHR (Centre for Rural and Northern Health Research) tracking and impact studies. Community engagement contributes throughout the lifecycle stages of preadmission, admission, and undergraduate medical education. High school students from 70 Northern Ontario communities participate in NOSM's week-long Health Sciences Summer Camps. The MD admissions process involves approximately 128 volunteers assessing written applications and over 100 volunteer interviewers. Thirty-six Indigenous communities host first year students and third-year students learn their core clinical medicine in 15 communities, throughout Northern Ontario. In general, learners and communities report net benefits from participation in NOSM programs. Community engagement makes a key contribution to the success of NOSM's socially accountable distributed medical education.


Tight glycemic control may favor fibrinolysis in patients with sepsis.
To investigate whether tight glycemic control, in patients with sepsis, may restore a normal fibrinolysis by lowering plasminogen activator inhibitor (PAI)-1 levels. Prospective randomized clinical trial. Three Italian university hospital intensive care units. Ninety patients with severe sepsis/septic shock. Patients were randomized to receive either tight glycemic control (treatment group, target glycemia, 80-110 mg/dL) or conventional glycemic control (control group, target glycemia, 180-200 mg/dL). Inflammation, coagulation, and fibrinolysis markers were assessed, along with Sepsis-related Organ Failure Assessment scores, >28 days. In the whole population, at enrolment, inflammation and coagulation were activated in >80 of 90 patients, whereas fibrinolysis, as assessed by PAI-1 activity and concentration, was impaired in only 34 patients. The extent of the inflammatory reaction or of the coagulation activation was unrelated to outcome. In contrast, 90-day mortality rate of the 34 patients in whom fibrinolysis was definitely inhibited at study entry was twice that of the 56 patients in whom fibrinolysis was intact (44% vs. 21%, p = 0.02). After randomization, during the study, daily glycemia averaged 112 +/- 23 mg/dL in the treatment group and 159 +/- 31 mg/dL in controls (p < 0.001), with total daily administered insulin 57 +/- 59 IU and 36 +/- 44 IU, respectively (p < 0.001). A small, but significant, enhancement of fibrinolysis could be observed in the treatment group, as indicated by the time course of PAI-1 activity (p < 0.001), PAI-1 concentration (p = 0.004), and plasmin-antiplasmin complexes (p < 0.001). Morbidity, rated with the Sepsis-related Organ Failure Assessment score, became significantly lower (p = 0.03) in the treatment group. Fibrinolysis inhibition, in severe sepsis/septic shock, seems to have a relevant pathogenetic role. In this context, tight glycemic control seems to reduce, with time, the fibrinolytic impairment and morbidity.


Molecular and genomic data identify the closest living relative of primates.
A full understanding of primate morphological and genomic evolution requires the identification of their closest living relative. In order to resolve the ancestral relationships among primates and their closest relatives, we searched multispecies genome alignments for phylogenetically informative rare genomic changes within the superordinal group Euarchonta, which includes the orders Primates, Dermoptera (colugos), and Scandentia (treeshrews). We also constructed phylogenetic trees from 14 kilobases of nuclear genes for representatives from most major primate lineages, both extant colugos, and multiple treeshrews, including the pentail treeshrew, Ptilocercus lowii, the only living member of the family Ptilocercidae. A relaxed molecular clock analysis including Ptilocercus suggests that treeshrews arose approximately 63 million years ago. Our data show that colugos are the closest living relatives of primates and indicate that their divergence occurred in the Cretaceous.


Angiostrongylus vasorum in Great Britain: a nationwide postal questionnaire survey of veterinary practices.
The lungworm, Angiostrongylus vasorum, was first reported in indigenous dogs in southwestern England in 1980 and has since been recorded in Wales, southeastern England and, more recently, in the West Midlands, northern England and Scotland. The nationwide distribution of the parasite was evaluated using a postal questionnaire sent to 3950 small animal practices during 2009. Information was sought on the location of each practice, awareness of the parasite locally, number of cases diagnosed over the past year and whether diagnosis was based on clinical signs alone or supported by additional tests. 1419 practices returned a usable response, the majority being located in a city/town. Nearly one-third of responding practices were aware of the parasite locally, 20.7 per cent had seen at least one confirmed case and 0.3 per cent >20 confirmed cases over the past year. The most widely used tests were faecal examination and any type of imaging. Existing clusters of infection were detected in southeastern England and south Wales; infection was also found to be widespread in central England, though patchy in northern England and Scotland. Using distribution of clinical cases as an indicator of parasite distribution, this study confirmed that A. vasorum has spread beyond traditional UK endemic foci.


Interleukin (IL)-1 alpha- and -1 beta-, IL-6-, and tumor necrosis factor-alpha-like immunoreactivities in human common and dysplastic nevocellular nevi and malignant melanoma.
Interleukin-1 alpha and -1 beta, interleukin-6, and tumor necrosis factor-alpha may have a protective effect against malignant transformation of melanocytes. By using monoclonal and polyclonal antisera we investigated, in paraformaldehyde-fixed tissue, the cellular distribution of these cytokines in human common and dysplastic nevocellular nevi and in malignant melanoma. Generally, the immunolabeling for all of these cytokines was both cytoplasmic and perinuclear as well as present in the basement membrane, which surrounds the individual cells or cellular nests of some of the nevi. In compound and intradermal nevi the immunolabeling was abundant, although there was a variation in the staining intensity between individual cells and even inside a single nevus cell, ranging from weak to strong. There was a strong labeling of the basement membrane around the cellular nests and around individual cells inside or outside the nests in the papillary and reticular dermis. With regard to the common junctional and dysplastic nevi and malignant melanoma, occasional immunolabeling could be seen in some cells within the cellular nests in the junctional area or papillary dermis, ranging from faint to moderate in intensity, but in this case the basement membrane around individual cells or cellular nests was not stained. The staining of nevocellular nevi and malignant melanoma indicates the possibility of these cytokines being synthesized by the nevi and melanoma cells. The labeling of the basement membrane in compound and intradermal nevi suggests that cytokines produced by nevocellular cells may be stored in the basement membrane, from which they could be released upon environmental or mechanical challenge. This distribution pattern would support the hypothesis that these cytokines may protect the common nevi from malignant transformation.


Breast cancer screening among older racial/ethnic minorities and whites: barriers to early detection.
Screening mammography for early detection of breast cancer has been shown to be an effective method for reducing mortality in older women. Based on the results from the 1987-88 National Health Interview Survey, older minority women have low prevalence rates of screening mammography. Among women aged 75 and older, 83.5% of Black women, 93.2% of Hispanic women, and 75.0% of White women have never had a mammogram. On the average, about 12% of minority women over the age of 65 have had a screening mammogram within the preceding year, compared with about 15% of White women. Among women 75 + years of age, Black and Hispanic women had markedly lower rates of clinical breast examination in the last year (23.4% and 20.5% respectively) as compared to White women (35.2%). The most common reason for not having a mammogram among Black women 65 years of age and older was that the doctor did not recommend a mammogram. For Hispanic and White women in this age group, the most common reason was that a mammogram was not needed or not necessary. Aggressive and creative breast cancer screening activities for minority aged 65 and older are clearly indicated.


What makes a pediatric or young adult patient an appropriate transplant candidate?
A 3-year-old child with chronic granulomatous disease was brought to the transplant clinic by his parents. The patient has a history of Aspergillus fumigatus pneumonia, which required mechanical ventilation, and sepsis, resulting in several intensive care stays. He has failure to thrive and developmental delay. His parents are seeking guidance whether allogeneic hematopoietic cell transplantation (HCT) is a reasonable treatment option given concerns about his upfront major health limitations. Based on the original HCT-Comorbidity Index (CI), this child's risk for nonrelapse mortality (NRM) would be negligible with a score of 0. With use of the validated youth-nonmalignant HCT-CI, the score increases to 5, due to prior mechanical ventilation (+3), history of fungal infection (+1), and being underweight (+1), with at least 2-fold increase in risk of NRM. The role of developmental delay is unclear and not currently validated to prognosticate survival. While HCT was ultimately recommended in this case, the family was counseled to have a more realistic sense of NRM risk.