NCCN Guidelines as a Model of Extended Criteria for Lung Cancer Screening.
Background: This review assessed the performance of patients in NCCN high-risk group 2 in a clinical CT lung screening (CTLS) program. Methods: We retrospectively reviewed screening results for all patients from our institution undergoing clinical CTLS from January 2012 through December 2016, with follow-up through June 2017. To qualify for screening, patients had to meet the NCCN Guidelines high-risk criteria for CTLS, have a physician order for screening, be asymptomatic, be lung cancer-free for 5 years, and have no known metastatic disease. We compared demographics and screening performance of NCCN high-risk groups 1 and 2 across >4 rounds of screening. Screening metrics assessed included rates of positive and suspicious examinations, significant incidental and infectious/inflammatory findings, false negatives, and cancer detection. We also compared cancer stage and histology detected in each NCCN high-risk group. Results: A total of 2,927 individuals underwent baseline screening, of which 698 (24%) were in NCCN group 2. On average, group 2 patients were younger (60.6 vs 63.1 years), smoked less (38.8 vs 50.8 pack-years), had quit longer (18.1 vs 6.3 years), and were more often former smokers (61.4% vs 44.2%). Positive and suspicious examination rates, false negatives, and rates of infectious/inflammatory findings were equivalent in groups 1 and 2 across all rounds of screening. An increased rate of cancer detection was observed in group 2 during the second annual (T2) screening round (2.7% vs 0.5%; P=.005), with no difference in the other screening rounds: baseline (T0; 2% vs 2.3%; P=.61), first annual (T1; 1.2% vs 1.7%; P=.41), and third annual and beyond (≥T3; 1.2% vs 1.1%; P=1.00). Conclusions: CTLS appears to be equally effective in both NCCN high-risk groups.


Patient-physician communication: why and how.
Patient-physician communication is an integral part of clinical practice. When done well, such communication produces a therapeutic effect for the patient, as has been validated in controlled studies. Formal training programs have been created to enhance and measure specific communication skills. Many of these efforts, however, focus on medical schools and early postgraduate years and, therefore, remain isolated in academic settings. Thus, the communication skills of the busy physician often remain poorly developed, and the need for established physicians to become better communicators continues. In this article, the authors briefly review the why and how of effective patient-physician communication. They begin by reviewing current data on the benefits of effective communication in the clinical context of physicians caring for patients. The authors then offer specific guidance on how to achieve effective communication in the patient-physician relationship.


Patterns of Recurrence After Postprostatectomy Fossa Radiation Therapy Identified by C-11 Choline Positron Emission Tomography/Computed Tomography.
To evaluate C-11 choline positron emission tomography/computed tomography (CholPET) in staging and determining patterns of recurrence in prostate cancer patients with rising prostate-specific antigen levels after prostatectomy radiation therapy (RT). The study includes patients with biochemical failure after postprostatectomy RT who underwent CholPET between 2008 and 2015. Patient and disease characteristics were examined in relation to sites of recurrence. All RT dosimetry records were reviewed, and recurrences were mapped on a representative computed tomography dataset with their relationship relative to the irradiated fossa field as out of field (OOF), edge of field (EOF; recurrence within <45-Gy isodose lines), or in field (IF; recurrence within ≥45-Gy isodose lines). Forty-one patients were identified with 121 sites of recurrence (median 2 sites; interquartile range [IQR], 1-4). The median prostate-specific antigen level at CholPET was 3.1 (IQR, 1.9-5.6) ng/mL. Median interval from RT to biochemical failure was 24 (IQR, 10-46) months, with recurrence identified on CholPET at a median of 15 (IQR, 7-28) months from biochemical failure. Histologic confirmation of recurrence was obtained in 20 patients (49%), with the remainder confirmed by treatment response. Five patients (12%) had IF recurrences, 10 patients (24%) had EOF recurrences (median dose 10 Gy; IQR, 5-30 Gy), and 36 patients (88%) had OOF recurrences. Ten patients had combination failures: 6 (15%) EOF/OOF and 4 (10%) IF/OOF. Fifty-seven recurrences (47%) were pelvic nodal sites inferior to the L5-S1 interspace, of which 52 (43%) were within a pelvic RT field. Eighty-one recurrences (67%) were nodal and inferior to the aortic bifurcation. Using CholPET, we found that the majority of patients evaluated for biochemical failure recurred outside of the postprostatectomy RT field. Furthermore, most recurrence sites were nodal and inferior to the aortic bifurcation. These results provide data that may be useful for examining strategies that include elective lymph node irradiation in postprostatectomy patients.


A coordinated temporal interplay of nucleosome reorganization factor, sister chromatin cohesion factor, and DNA polymerase alpha facilitates DNA replication.
DNA replication depends critically upon chromatin structure. Little is known about how the replication complex overcomes the nucleosome packages in chromatin during DNA replication. To address this question, we investigate factors that interact in vivo with the principal initiation DNA polymerase, DNA polymerase alpha (Polalpha). The catalytic subunit of budding yeast Polalpha (Pol1p) has been shown to associate in vitro with the Spt16p-Pob3p complex, a component of the nucleosome reorganization system required for both replication and transcription, and with a sister chromatid cohesion factor, Ctf4p. Here, we show that an N-terminal region of Polalpha (Pol1p) that is evolutionarily conserved among different species interacts with Spt16p-Pob3p and Ctf4p in vivo. A mutation in a glycine residue in this N-terminal region of POL1 compromises the ability of Pol1p to associate with Spt16p and alters the temporal ordered association of Ctf4p with Pol1p. The compromised association between the chromatin-reorganizing factor Spt16p and the initiating DNA polymerase Pol1p delays the Pol1p assembling onto and disassembling from the late-replicating origins and causes a slowdown of S-phase progression. Our results thus suggest that a coordinated temporal and spatial interplay between the conserved N-terminal region of the Polalpha protein and factors that are involved in reorganization of nucleosomes and promoting establishment of sister chromatin cohesion is required to facilitate S-phase progression.


Crossed flow microfluidics for high throughput screening of bioactive chemical-cell interactions.
This paper describes the use of crossed laminar flow microfluidics for the selective capture of multiple cell types on-chip aiming for high throughput screening of various cell treatment compounds. Parallel laminar streams containing different cell types were perfused and captured on a cell adhesion protein-functionalized reaction area. Thereafter, parallel streams containing cell treatment solutions were delivered orthogonally over the captured cells. Multiple cell types and a range of cell treatment conditions could therefore be assessed in a single experiment. We were also able to sort mixed cell populations via antibody array clusters, and to further deliver treatments to subpopulations of cells. Moreover, using solutions with different tonicities, we successfully demonstrated the incorporation of a live/dead cell viability assessment on-chip for a direct read out assay following the treatments. This crossed laminar flow microfluidics for generation of a cell-based assay could therefore offer an interesting platform for high throughput screening of potential drug candidates, nanoparticle toxicity testing, or other cellular and molecular interventions.


The optimal depot fat composition for hibernation by golden-mantled ground squirrels (Spermophilus lateralis).
Golden-mantled ground squirrels (Spermophilus lateralis) are herbivores that hibernate during winter. Although little is known about the nutritional/physiological constraints on hibernation, numerous studies have demonstrated that increasing the amount of linoleic acid (a polyunsaturated fatty acid) in the diet enhances hibernation. This is probably because high linoleic acid diets reduce the melting points of the depot fats produced for hibernation which makes them more metabolizable at low body temperatures. This suggests that a major limitation on hibernation may be obtaining enough linoleic acid in the diet for proper hibernation. In all previous studies, however, the amount of linoleic acid in the diets of free-ranging animals was either not considered, or the range of dietary linoleic acid contents in the experiments was less than that of natural diets. It is thus not known whether the amount of linoleic acid available to hibernators under natural conditions actually limits their torpor patterns. A series of laboratory feeding and hibernation experiments were conducted with S. lateralis and artificial diets with different linoleic acid contents that were either below or above the linoleic acid content of the natural diet. The results demonstrated that when dietary linoleic acid contents are either below or above natural levels, hibernation ability is greatly reduced. Hibernation ability was reduced when the squirrels were maintained on a high linoleic acid diet probably by the production of toxic lipid peroxides in brown adipose tissues. The results indicate that there is an optimal level of dietary linoleic acid for proper hibernation, and this is equal to that of the natural diet.(ABSTRACT TRUNCATED AT 250 WORDS)


Phthalocyanine-based coordination polymer nanoparticles for enhanced photodynamic therapy.
In the photodynamic therapy (PDT) of cancer, zinc phthalocyanine (ZnPc) as a photosensitizer possesses superior photosensitive properties. However, the therapeutic effect of ZnPc in PDT is limited due to its aggregation, low solubility and poor selectivity. In this study, charge-reversal phthalocyanine-based coordination polymer nanoparticles (PCPN) are developed for improving the curative effect of ZnPc. Tetra(4-carboxyphenoxy)-phthalocyaninatozinc(ii) (TPZnPc) is coordinated with the zinc ion to form the core of PCPN, which is coated with a lipid bilayer by self-assembly (PCPNs@Lip). TPZnPc molecules in the core of PCPN are in the monomeric state and can generate cytotoxic singlet oxygen (1O2) efficiently, which solves the solubility and aggregation problems of ZnPc. Meanwhile, 1,2-dicarboxylic-cyclohexane anhydride modified lysyl-cholesterol (DLC) is functionalized on the surface of PCPN (PCPNs@Lip/DLC), endowing PCPN with a charge-reversal ability which could be triggered by a mildly acidic tumor microenvironment. PCPNs@Lip/DLC is proved to enhance tumor cellular uptake and generate more intracellular 1O2 after irradiation. As confirmed by in vitro and in vivo studies, PCPNs@Lip/DLC remarkably increases the PDT effect. All these results demonstrate that PCPNs@Lip/DLC is a promising nanoplatform for the application of ZnPc in effective PDT.


Cancer survivors' experience of exercise-based cancer rehabilitation - a meta-synthesis of qualitative research.
Evidence for the safety and benefits of exercise training as a therapeutic and rehabilitative intervention for cancer survivors is accumulating. However, whereas the evidence for the efficacy of exercise training has been established in several meta-analyses, synthesis of qualitative research is lacking. In order to extend healthcare professionals' understanding of the meaningfulness of exercise in cancer survivorship care, this paper aims to identify, appraise and synthesize qualitative studies on cancer survivors' experience of participation in exercise-based rehabilitation. Five electronic databases (PubMed, PsychINFO, EMBASE, Cinahl and Scopus) were searched systematically for articles published up to May 2014 using keywords and MeSH terms. To be included, studies had to contain primary data pertaining to patient experiences from participation in supervised, structured moderate to vigorous-intensity exercise. In total 2447 abstracts were screened and 37 papers were read in full. Of these, 19 studies (n = 390) were selected for inclusion and critically appraised. Synthesis of data extracted from eight studies including in total 174 patients (77% women, age 28-76 years) exclusively reporting experiences of participation in structured, supervised exercise training resulted in nine themes condensed into three categories: 1) emergence of continuity; 2) preservation of health; and 3) reclaiming the body reflecting the benefits of exercise-based rehabilitation according to cancer survivors. Accordingly, the potential of rebuilding structure in everyday life, creating a normal context and enabling the individual to re-establish confidentiality and trust in their own body and physical potential constitute substantial qualities fundamental to the understanding of the meaningfulness of exercise-based rehabilitation from the perspective of patients. In addition to the accumulating evidence for the efficacy of exercise training in cancer rehabilitation, it is incumbent upon clinicians and policy-makers to acknowledge and promote the meaningfulness of exercise for the individual, and to use this knowledge to provide new solutions to current problems related to recruitment of underserved populations, long-term adherence and implementation.


In VITRO ASSEMBLY of the øX174 procapsid from external scaffolding protein oligomers and early pentameric assembly intermediates.
Bacteriophage øX174 morphogenesis requires two scaffolding proteins: an internal species, similar to those employed in other viral systems, and an external species, which is more typically associated with satellite viruses. The current model of øX174 assembly is based on structural and in vivo data. During morphogenesis, 240 copies of the external scaffolding protein mediate the association of 12 pentameric particles into procapsids. The hypothesized pentameric intermediate, the 12S⁎ particle, contains 16 proteins: 5 copies each of the coat, spike and internal scaffolding proteins and 1 copy of the DNA pilot protein. Assembly naïve 12S⁎ particles and external scaffolding oligomers, most likely tetramers, formed procapsid-like particles in vitro, suggesting that the 12S⁎ particle is a bona fide assembly intermediate and validating the current model of procapsid morphogenesis. The in vitro system required a crowding agent, was influenced by the ratio of the reactants and was most likely driven by hydrophobic forces. While the system reported here shared some characteristics with other in vitro internal scaffolding protein-mediated systems, it displayed unique features. These features most likely reflect external scaffolding protein-mediated morphogenesis and the øX174 procapsid structure, in which external scaffolding-scaffolding protein interactions, as opposed to coat-coat protein interactions between pentamers, constitute the primary lattice-forming contacts.


Pharmacological countermeasures for the acute radiation syndrome.
The acute radiation syndrome (ARS) is defined as the signs and symptoms that occur within several months after exposure to ionizing radiation (IR). This syndrome develops after total- or partial-body irradiation at a relatively high dose (above about 1 Gy in humans) and dose rate. Normal tissue injuries induced by IR differ depending on the target organ and cell type. Organs and cells with high sensitivity to radiation include the skin, the hematopoietic system, the gut, the spermatogenic cells and the vascular system. Exposure to IR causes damage to DNA, protein, and lipids in mammalian cells, as well as increased mitochondria-dependent generation of reactive oxygen species (ROS), with subsequent cell cycle checkpoint arrest, apoptosis, and stress-related responses. DNA double strand breaks (DSBs) are a primary lethal lesion induced by IR. The cellular response to damage is complex and relies on simultaneous activation of a number of signaling networks. Among these, the activation of DNA non-homologous end-joining (NHEJ) and homologous recombination (HR), and signaling pathways containing ataxia telangiectasia mutated (ATM), play important roles. The transcription factor NFkappaB has emerged as a pro-survival actor in response to IR in ATM and p53-induced protein with a death domain (PIDD) cascades. Although radiation-induced ARS has been well documented at the clinical level, and mechanistic information is accumulating, successful prophylaxis and treatment for ARS is problematic, even with the use of supportive care and growth factors. There is a pressing need to develop radiation countermeasures that can be used both in the clinic, for small-scale incidents, and outside the clinic, in mass casualty scenarios. In this review we summarize recent information on intracellular and extracellular signaling pathways relevant to radiation countermeasure research.


Comprehensive identification of single nucleotide polymorphisms associated with beta-lactam resistance within pneumococcal mosaic genes.
Traditional genetic association studies are very difficult in bacteria, as the generally limited recombination leads to large linked haplotype blocks, confounding the identification of causative variants. Beta-lactam antibiotic resistance in Streptococcus pneumoniae arises readily as the bacteria can quickly incorporate DNA fragments encompassing variants that make the transformed strains resistant. However, the causative mutations themselves are embedded within larger recombined blocks, and previous studies have only analysed a limited number of isolates, leading to the description of "mosaic genes" as being responsible for resistance. By comparing a large number of genomes of beta-lactam susceptible and non-susceptible strains, the high frequency of recombination should break up these haplotype blocks and allow the use of genetic association approaches to identify individual causative variants. Here, we performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) and indels that could confer beta-lactam non-susceptibility using 3,085 Thai and 616 USA pneumococcal isolates as independent datasets for the variant discovery. The large sample sizes allowed us to narrow the source of beta-lactam non-susceptibility from long recombinant fragments down to much smaller loci comprised of discrete or linked SNPs. While some loci appear to be universal resistance determinants, contributing equally to non-susceptibility for at least two classes of beta-lactam antibiotics, some play a larger role in resistance to particular antibiotics. All of the identified loci have a highly non-uniform distribution in the populations. They are enriched not only in vaccine-targeted, but also non-vaccine-targeted lineages, which may raise clinical concerns. Identification of single nucleotide polymorphisms underlying resistance will be essential for future use of genome sequencing to predict antibiotic sensitivity in clinical microbiology.


Quantitative three-dimensional confocal imaging of the cornea in situ and in vivo: system design and calibration.
A new depth encoding system (DES) is presented, which makes it possible to calculate, display, and record the z-axis position continuously during in vivo imaging using tandem scanning confocal microscopy (TSCM). In order to verify the accuracy of the DES for calculating the position of the focal plane in the cornea both in vitro and in vivo, we compared TSCM measurements of corneal thickness to measurements made using an ultrasonic pachymeter (UP, a standard clinical instrument) in both enucleated rabbit, cat, and human eyes (n = 15), and in both human patients (n = 7). Very close agreement was found between the UP and TSCM measurements in enucleated eyes; the mean percent difference was 0.50 +/- 2.58% (mean +/- SD, not significant). A significant correlation (R = 0.995, n = 15, p < 0.01) was found between UP and TSCM measurements. These results verify that the theoretical equation for calculating focal depth provided by the TSCM manufacturer is accurate for corneal imaging. Similarly, close agreement was found between the in vivo UP and TSCM measurements; the mean percent differences was 1.67 +/- 1.38% (not significant), confirming that z-axis drift can be minimized with proper applanation of the objective. These results confirm the accuracy of the DES for imaging of the cornea both ex vivo and in vivo. This system should be of great utility for applications where quantitation of the three-dimensional location of cellular structures is needed.


Genotypic diversity of an invasive plant species promotes litter decomposition and associated processes.
Following studies that showed negative effects of species loss on ecosystem functioning, newer studies have started to investigate if similar consequences could result from reductions of genetic diversity within species. We tested the influence of genotypic richness and dissimilarity (plots containing one, three, six or 12 genotypes) in stands of the invasive plant Solidago canadensis in China on the decomposition of its leaf litter and associated soil animals over five monthly time intervals. We found that the logarithm of genotypic richness was positively linearly related to mass loss of C, N and P from the litter and to richness and abundance of soil animals on the litter samples. The mixing proportion of litter from two sites, but not genotypic dissimilarity of mixtures, had additional effects on measured variables. The litter diversity effects on soil animals were particularly strong under the most stressful conditions of hot weather in July: at this time richness and abundance of soil animals were higher in 12-genotype litter mixtures than even in the highest corresponding one-genotype litter. The litter diversity effects on decomposition were in part mediated by soil animals: the abundance of Acarina, when used as covariate in the analysis, fully explained the litter diversity effects on mass loss of N and P. Overall, our study shows that high genotypic richness of S. canadensis leaf litter positively affects richness and abundance of soil animals, which in turn accelerate litter decomposition and P release from litter.


Primary surgical repair of acute Achilles tendon rupture: comparative results of three surgical techniques.
To determine which of the three surgical techniques for acute unilateral complete rupture of Achilles tendons in use at the University Clinical Centre Maribor gives the best short-term functional results. In the retrospective analysis of the results of 3 surgical techniques, 262 patients of which 244 (93.1%) were men (mean age 41.6 ± 10.0 years, range 21.5-83.0 years) operated on during the period from 2000 to 2008 were included. Group A (open technique with fascial augmentation) included 42 (16%) patients, group B (original modification of percutaneous suturing according to Čretnik and Kosanović) included 159 (60.7%) patients, and group C (original percutaneous fixation with two embracing and crossed loops according to Kruščić) included 61 (23.3%) patients. The rehabilitation protocol for group C included use of individually manufactured closed ankle functional orthosis, which replaced the plaster cast after 2 weeks of immobilization and permits early ankle range-of-motion exercising and full weight bearing. The functional outcome and incidence of postsurgical complications were analysed from medical records covering the period of 6 months. Patients from group C achieved the best functional results in the shortest time. The duration of immobilization (5.3 ± 0.1 weeks) and use of crutches (5.3 ± 0.5 weeks) were the shortest. The ability to rise up on toes on the affected leg, to walk on toes and heels, and duration of restriction of physical activities including sports were shorter than in the other two groups (p < 0.001 for all variables). Two reruptures were experienced in group B, one in group C, and none in group A. Good functional results and a relatively small number of postsurgical complications advocate the use of percutaneous suturing techniques. The best and fastest functional recovery was attained in the group treated with the original technique of percutaneous fixation with two embracing and crossed thread loops according to Kruščić.


Biofilms: survival mechanisms of clinically relevant microorganisms.
Though biofilms were first described by Antonie van Leeuwenhoek, the theory describing the biofilm process was not developed until 1978. We now understand that biofilms are universal, occurring in aquatic and industrial water systems as well as a large number of environments and medical devices relevant for public health. Using tools such as the scanning electron microscope and, more recently, the confocal laser scanning microscope, biofilm researchers now understand that biofilms are not unstructured, homogeneous deposits of cells and accumulated slime, but complex communities of surface-associated cells enclosed in a polymer matrix containing open water channels. Further studies have shown that the biofilm phenotype can be described in terms of the genes expressed by biofilm-associated cells. Microorganisms growing in a biofilm are highly resistant to antimicrobial agents by one or more mechanisms. Biofilm-associated microorganisms have been shown to be associated with several human diseases, such as native valve endocarditis and cystic fibrosis, and to colonize a wide variety of medical devices. Though epidemiologic evidence points to biofilms as a source of several infectious diseases, the exact mechanisms by which biofilm-associated microorganisms elicit disease are poorly understood. Detachment of cells or cell aggregates, production of endotoxin, increased resistance to the host immune system, and provision of a niche for the generation of resistant organisms are all biofilm processes which could initiate the disease process. Effective strategies to prevent or control biofilms on medical devices must take into consideration the unique and tenacious nature of biofilms. Current intervention strategies are designed to prevent initial device colonization, minimize microbial cell attachment to the device, penetrate the biofilm matrix and kill the associated cells, or remove the device from the patient. In the future, treatments may be based on inhibition of genes involved in cell attachment and biofilm formation.


Anti-neoplastic and immunomodulatory potency of co-treatment based on bovine lactoferrin and/or muramyl dipeptide in tumor-bearing mice.
The current study investigates anti-neoplastic and immunomodulatory activities of co-treatment based on bovine lactoferrin (bLF) and/or muramyl dipeptide (MDP) with or without cisplatin (Cis) in tumor-bearing mice. In the present study, bLF (100 mg/kg; orally) and MDP (0.5 mg/kg; subcutaneously) was administered alone or together. MDP or bLF was co-treated with Cis (1 mg/kg; intraperitoneally) in mice-bearing Ehrlich solid carcinoma. Tumor size, tumor mass proliferation, apoptosis using immunohistochemistry, the alteration in spleen cell proliferation, phenotype using flow cytometry and white blood cells total and differential counts were detected. Treatment with Cis or (bLF and MDP) significantly reduced tumor size, upregulated the pro-apoptotic p53 expression and downregulated the anti-apoptotic Bcl-2 and proliferative marker PCNA expression compared to non-treated tumor-bearing animals. Moreover, co-treatment of MDP and Cis significantly potentiated the reduction of the tumor size, downregulated the Bcl-2 and PCNA expression and upregulated the p53 expression compared to Cis-treated animals. While bLF and Cis co-treatment positively controlled PCNA and p53 expression compared to tumor-bearing animals, it significantly potentiated the reduction of the tumor size and downregulated the Bcl-2 expression compared to Cis-treated animals. Co-treatment of (bLF and MDP), (bLF and Cis) or (MDP and Cis) increased the spleen cell proliferation and altered the immunological profile of the CD3+CD4+, CD3+CD8+, CD3+CD4+CD69+, CD3+CD8+CD69+ and CD11b+Ly6G+ cells to achieve better immune response against tumor. In conclusion, co-treatments based on bLF and/or MDP are promising therapies against cancer, through their potency to control proliferation, enhance apoptosis and improve the immune status against tumor cells.


'Islands' and 'doctor's tool': the ethical significance of isolation and subordination in UK community pharmacy.
Empirical ethics research is increasingly valued in offering insights into how ethical problems and decision-making occur in healthcare. In this article, the findings of a qualitative study of the ethical problems and decision-making of UK community pharmacists are presented, and it is argued that the identified themes of pharmacists' relative isolation from others and their subordination to doctors are ethically significant. Semi-structured interviews were conducted with 23 community pharmacists in England, UK. Analysis of interviews revealed that isolation involved separation of pharmacists from their peers, other healthcare professionals, patients and customers. Such isolation is argued to be inimical to ethical practice - impeding ethical discourse as understood by Habermas, resulting in a form of anomie that inhibits the transmission of professional values, leading to a lack of proximity between pharmacist and patient or customer that may impede ethical relationships and resulting, psychologically, in less ethical concern for those who are less close. Pharmacists' subordination to doctors not only precipitated some ethical problems but also allowed some pharmacists to shift ethical responsibility to a prescribing doctor, as in the case of emergency hormonal contraception. The emergence of atrocity stories further supports a culture of subordination that may cause ethical problems. The study has implications for community pharmacy practice in terms of supervision issues, developments such as prescribing responsibilities and how ethical values can be taught and communicated. The potential for isolation and subordination in other healthcare professions, and resultant ethical problems, may also need to be addressed and researched.


Quality of life of patients with oesophageal cancer in Taiwan: validation and application of the Taiwan Chinese (Mandarin) version of the EORTC QLQ-OES18: a brief communication.
The aim of this study was to examine the reliability and validity, and the application of the Taiwan Chinese Version of the EORTC QLQ-OES18. The authors translated the questionnaire according to the guideline of the EORTC. Ninety-five patients with oesophageal cancer in National Taiwan University Hospital were interviewed using the questionnaire and the EORTC QLQ-C30 between October 2002 and September 2007. Answer distribution and psychometric properties of the EORTC QLQ-OES18 were examined. The mean age of the patients was 60 years (SD 12 years). Most of the patients were in advanced stages of disease, with two-thirds off-treatment. The Cronbach's alpha coefficients were satisfactory (0.77-0.82) or near-satisfactory (pain: 0.67). The item-to-own and item-to-other scale correlations showed satisfactory results. Patients who were on-treatment versus off-treatment had significantly poorer quality of life scores in dysphagia, dry mouth, and taste, and a borderline poorer score in cough. Opposite situations were seen in the scales of reflux and choking. The EORTC QLQ-OES18 is a valid instrument to assess quality of life issues in patients with oesophageal cancer in Taiwan.


Sharpening the focus on occupational safety and health in nanotechnology.
Increasing numbers of workers are involved with the production, use, distribution, and disposal of nanomaterials. At the same time, there is a growing number of reports of adverse biological effects of engineered nanoparticles in test systems. It is useful, at this juncture, to identify critical questions that will help address knowledge gaps concerning the potential occupational hazards of these materials. The questions address (i) hazard classification of engineered nanoparticles, (ii) exposure metrics, (iii) the actual exposures to the different engineered nanoparticles in the workplace, (iv) the limits of engineering controls and personal protective equipment with respect to engineered nanoparticles, (v) the kinds of surveillance programs that may be required at workplaces to protect potentially exposed workers, (vi) whether exposure registers should be established for workers potentially exposed to engineered nanoparticles, and, (vii) whether engineered nanoparticles should be treated as "new" substances and evaluated for safety and hazards?


Generation of a broadband continuum by a Ti:sapphire femtosecond oscillator with a 1-GHz repetition rate.
A five-element Ti:sapphire femtosecond ring oscillator emitting a broadband continuum that ranges from 560 to 1150 nm at -50 dB below the maximum with a repetition rate of 1 GHz is demonstrated. The key element is a slightly convex cavity mirror that increases the self-amplitude modulation of a short pulse inside the resonator. Flat negative intracavity group-delay dispersion is required only for the core spectral part of the pulse. We believe that the device presented will make optical frequency metrology and future optical atomic clocks simpler and more stable. Within the reported ultrabroad spectrum a distinct strong emission band near 655 nm occurs that can be extracted to a powerful femtosecond pulse source far out of the amplification of Ti:sapphire.


A movable unshielded magnetocardiography system.
Magnetocardiography (MCG), which uses high-sensitivity magnetometers to record magnetic field signals generated by electrical activity in the heart, is a noninvasive method for evaluating heart diseases such as arrhythmia and ischemia. The MCG measurements usually require the participant keeping still in a magnetically shielded room due to the immovable sensor and noisy external environments. These requirements limit MCG applications, such as exercise MCG tests and long-term MCG observations, which are useful for early detections of heart diseases. Here, we introduce a movable MCG system that can clearly record MCG signals of freely behaving participants in an unshielded environment. On the basis of optically pumped magnetometers with a sensitivity of 140 fT/Hz1/2, we successfully demonstrated the resting MCG and the exercise MCG tests. Our method is promising to realize a practical movable multichannel unshielded MCG system that nearly sets no limits to participants and brings another kind of insight into the medical diagnosis of heart disease.


Does a Patient-Directed Financial Incentive Affect Patient Choices About Controller Medicines for Asthma? A Discrete Choice Experiment and Financial Impact Analysis.
In Australia, many patients who are initiated on asthma controller inhalers receive combination inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) despite having asthma of sufficiently low severity that ICS-alone would be equally effective and less costly for the government. We conducted a discrete choice experiment (DCE) in a nationally representative sample of adults (n = 792) and parents of children (n = 609) with asthma. Mixed multinomial models were estimated and calibrated to reflect the estimated market shares of ICS-alone, ICS/LABA and no controller. We then simulated the impact of varying patient co-payment on demand and the financial impact on government pharmaceutical expenditure. Preference for inhaler decreased with increasing costs to the patient or government, increasing chance of a repeat visit to the doctor, and if fewer symptoms were present. Adults preferred high-strength controllers, but parents preferred low-strength inhalers for children (general beneficiaries only). The DCE predicted a higher proportion choosing controller treatment (89%) compared to current levels (57%) at the current co-payment level, with proportionately higher uptake of ICS-alone and a lower average cost per patient [32.73 Australian dollars (AU$) c.f. AU$38.54]. Reducing the co-payment on ICS-alone by 50% would increase its market share to 50%, whilst completely removing the co-payment would only have a small marginal impact on market share, but increased average cost of treatment to the government to AU$41.04 per person. Patient-directed financial incentives are unlikely to encourage much switching of medicines, and current levels of under-treatment are not explained by patient preferences. Interventions directed at prescribers are more likely to promote better use of asthma medicines.


GroEL1, a heat shock protein 60 of Chlamydia pneumoniae, impairs neovascularization by decreasing endothelial progenitor cell function.
The number and function of endothelial progenitor cells (EPCs) are sensitive to hyperglycemia, hypertension, and smoking in humans, which are also associated with the development of atherosclerosis. GroEL1 from Chlamydia pneumoniae has been found in atherosclerotic lesions and is related to atherosclerotic pathogenesis. However, the actual effects of GroEL1 on EPC function are unclear. In this study, we investigate the EPC function in GroEL1-administered hind limb-ischemic C57BL/B6 and C57BL/10ScNJ (a toll-like receptor 4 (TLR4) mutation) mice and human EPCs. In mice, laser Doppler imaging, flow cytometry, and immunohistochemistry were used to evaluate the degree of neo-vasculogenesis, circulating level of EPCs, and expression of CD34, vWF, and endothelial nitric oxide synthase (eNOS) in vessels. Blood flow in the ischemic limb was significantly impaired in C57BL/B6 but not C57BL/10ScNJ mice treated with GroEL1. Circulating EPCs were also decreased after GroEL1 administration in C57BL/B6 mice. Additionally, GroEL1 inhibited the expression of CD34 and eNOS in C57BL/B6 ischemic muscle. In vitro, GroEL1 impaired the capacity of differentiation, mobilization, tube formation, and migration of EPCs. GroEL1 increased senescence, which was mediated by caspases, p38 MAPK, and ERK1/2 signaling in EPCs. Furthermore, GroEL1 decreased integrin and E-selectin expression and induced inflammatory responses in EPCs. In conclusion, these findings suggest that TLR4 and impaired NO-related mechanisms could contribute to the reduced number and functional activity of EPCs in the presence of GroEL1 from C. pneumoniae.


Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes.
Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC.


Health-related quality of life and behavior of triplets at adolescent age.
To assess health-related quality of life (HRQoL) and behavior of triplets compared with matched singletons at adolescent age and to identify medical and sociodemographic predictors of outcome. Fifty-four triplets (19 sets, mean [SD] gestational age 32.0 [2.4] weeks, birth weight 1580 [450] g) and 51 gestational age-, birth weight-, and sex-matched singleton controls self-rated their HRQoL at age 14.5 (0.3) years. Proxy reports about HRQoL and behavior were obtained by parents and teachers. HRQoL was measured with the Kidscreen-52 questionnaire child and parent form, and behavior with the Achenbach Child Behavior Checklist. Self- and parent-reported HRQoL values was similar in both groups except for the dimensions "mood and emotions" and "autonomy," which were better (P = .001, P = .03) in triplets. Parents reported significantly less behavioral problems in triplets compared with controls. Compared with community norms, both HRQoL and behavior measures in triplets were in the normal range. Parent-reported HRQoL was predicted by dichorionicity. HRQoL and behavioral outcome in adolescent triplets was good in our study and was, in some aspects, better than in matched singleton controls. Dichorionicity is an important outcome determinant.


gdhB, a gene encoding a second quinoprotein glucose dehydrogenase in Pantoea citrea, is required for pink disease of pineapple.
The pink disease of pineapple, caused by the bacterium Pantoea citrea, is characterized by a dark coloration on fruit slices after canning. A glucose dehydrogenase (Gdh) encoded by the gdhA gene has been implicated in the colour formation activity of P. citrea. In this paper it has been shown that P. citrea contains a second, homologous gdh gene and its product, GdhB, represents the main source of Gdh activity in this organism. Unlike gdhA, gdhB is constitutively expressed during the exponential phase of growth and is induced in stationary phase. A previously isolated chemical mutant, CMC6, which is deficient in Gdh activity and pink disease formation, failed to express gdhB during the stationary phase of growth. The CMC6 mutant can be complemented by a 54 bp DNA fragment located upstream of gdhA. This fragment, which contains an operator-like 11 bp inverted repeat, strongly enhances the expression of gdhA, probably by titrating away a negative effector of its expression. These results illustrate the complex interplay operating between the two gdh genes and emphasize the role of glucose metabolism in the pathway leading to pink disease.


Unique modulation of cadherin expression pattern during posterior frontal cranial suture development and closure.
Cranial suture development involves coordinated expression of multiple genes and tissue contribution from neural crest cells and paraxial mesoderm for timely sutural morphogenesis. Transcription factors, growth factors, and neural crest determinant genes play critical roles in calvarial growth ensuring normal development of the underlying brain. In vitro studies have implicated cell-cell adhesion molecules as a driving force behind suture closure. We performed cDNA microarray to study differential expression of adhesion molecules during the timing of suture closure in a mouse model where only the posterior frontal (PF) suture closes. Our results indicate increased expression of E-cadherin during the period of PF suture closure. Quantitative RT-PCR analysis of E- and N-cadherin in PF closing suture revealed a biphasic expression of N-cadherin, the first phase coinciding with cellular condensation preceding chondrogenesis followed by a second phase coinciding with E-cadherin co-expression and suture closure. Furthermore, expression analysis of the N-cadherin and E-cadherin transcriptional repressors Wnt7a and Snail indicate a specific temporal regulation of these genes, suggesting their potential role as regulators of both E- and N-cadherin during the PF suture development and closure. Finally, given the in vitro evidence of fibroblast growth factor (FGF)-2 as a potential regulator of E- and N-cadherin we investigated the expression of E-cadherin during PF suture closure in Fgf-2 deficient mice. In contrast to in vitrodata previously reported, E-cadherin expression is normal in these animals, and PF suture closure occurs properly, probably due to potential redundancy of FGF ligands ensuring normal temporal expression of E-cadherin and PF suture closure.


Drosophila duplicate genes evolve new functions on the fly.
Gene duplication is thought to play a key role in phenotypic innovation. While several processes have been hypothesized to drive the retention and functional evolution of duplicate genes, their genomic contributions have never been determined. We recently developed the first genome-wide method to classify these processes by comparing distances between expression profiles of duplicate genes and their ancestral single-copy orthologs. Application of our approach to spatial gene expression profiles in two Drosophila species revealed that a majority of young duplicate genes possess new functions, and that new functions are acquired rapidly-often within a few million years. Surprisingly, new functions tend to arise in younger copies of duplicate gene pairs. Moreover, we found that young duplicates are often specifically expressed in testes, whereas old duplicates are broadly expressed across several tissues, providing strong support for the hypothetical "out-of-testes" origin of new genes. In this Extra View, I discuss our findings in the context of theoretical predictions about gene duplication, with a particular emphasis on the importance of natural selection in the evolution of novel phenotypes.


Low fertility awareness in United States reproductive-aged women and medical trainees: creation and validation of the Fertility & Infertility Treatment Knowledge Score (FIT-KS).
To create, validate, and use a fertility awareness survey based on current U.S. Cross-sectional study. Not applicable. Phase 1 included U.S. women ages 18-45; phase 2 included female medical students and obstetrics and gynecology trainees at two urban academic programs. Survey including demographics, the Fertility & Infertility Treatment Knowledge Score (FIT-KS) instrument, and General Nutrition Knowledge Questionnaire. Knowledge of natural fertility and infertility treatments. The FIT-KS was validated through detailed item and validity analyses. In phase 1, 127 women participated; their median age was 31 years, and 43.7% had children. Their mean FIT-KS score was 16.2 ± 3.5 (55.9% correct). In phase 2, 118 medical trainees participated; their median age was 25 years, and 12.4% had children. Their mean FIT-KS score was 18.8 ± 2.1 (64.9% correct), with year of training correlating to a higher score (r=0.40). Participant awareness regarding lifestyle factors varied, but it was particularly low regarding the effects of lubricants. The majority underestimated the spontaneous miscarriage rate and overestimated the fecundability of 40-year-old women. There was general overestimation of success rates for assisted reproductive technologies, particularly among medical trainees. The FIT-KS is validated to current U.S. data for use in both general and medical populations as a quick assessment of fertility knowledge. The knowledge gaps demonstrated in this study correlate with national trends in delayed childbearing and time to initiate treatment. For medical trainees, these results raise concerns about the quality of fertility counseling they may be able to offer patients. Greater educational outreach must be undertaken to enhance fertility awareness.


Tumor heterogeneity: does it matter?
Introduction: It has long been recognized that tumors are composed of a mosaic of cells and numerous methods have been developed to detect tumor heterogeneity, including in situ hybridization, multi-regional sampling, cytological assays, and whole genome and single cell sequencing. Using these methods, heterogeneity has been observed at the genetic, epigenetic, and phenotypic level in numerous cancers. With the advent of deep sequencing technology, we now appreciate a greater complexity of distinct genotypes and phenotypes that drive the biological behavior of cancer. Despite decades of progress in detecting tumor heterogeneity, the question remains: to what extent does it matter? Areas covered: This review explores the evidence for and against the importance of tumor heterogeneity in three main areas: prognostication, development of targeted therapeutics and tumor resistance; summarizing current understanding before evaluating ongoing experimental and clinical developments. Expert opinion: Theoretical understanding and in vitro detection of intratumour heterogeneity promises much but is yet to translate into meaningful clinical benefit. However, the recent emergence of a host of technological innovations and upcoming clinical trials may soon change the landscape of this field.


Activation of Manganese Oxidants with Bisulfite for Enhanced Oxidation of Organic Contaminants: The Involvement of Mn(III).
MnO4(-) was activated by HSO3(-), resulting in a process that oxidizes organic contaminants at extraordinarily high rates. The permanganate/bisulfite (PM/BS) process oxidized phenol, ciprofloxacin, and methyl blue at pHini 5.0 with rates (kobs ≈ 60-150 s(-1)) that were 5-6 orders of magnitude faster than those measured for permanganate alone, and ∼5 to 7 orders of magnitude faster than conventional advanced oxidation processes for water treatment. Oxidation of phenol was fastest at pH 4.0, but still effective at pH 7.0, and only slightly slower when performed in tap water. A smaller, but still considerable (∼3 orders of magnitude) increase in oxidation rates of methyl blue was observed with MnO2 activated by HSO3(-) (MO/BS). The above results, time-resolved spectroscopy of manganese species under various conditions, stoichiometric analysis of pH changes, and the effect of pyrophosphate on UV absorbance spectra suggest that the reactive intermediate(s) responsible for the extremely rapid oxidation of organic contaminants in the PM/BS process involve manganese(III) species with minimal stabilization by complexation. The PM/BS process may lead to a new category of advanced oxidation technologies based on contaminant oxidation by reactive manganese(III) species, rather than hydroxyl and sulfate radicals.


Mixing and capping techniques for activated carbon based sediment remediation - Efficiency and adverse effects for Lumbriculus variegatus.
Activated carbon (AC) has been proven to be highly effective for the in-situ remediation of sediments contaminated with a wide range of hydrophobic organic contaminants (HOCs). However, adverse biological effects, especially to benthic organisms, can accompany this promising remediation potential. In this study, we compare both the remediation potential and the biological effects of several AC materials for two application methods: mixing with sediment (MIX) at doses of 0.1 and 1.0% based on sediment dw and thin layer capping (TLC) with 0.6 and 1.2 kg AC/m2. Significant dose dependent reductions in PCB bioaccumulation in Lumbriculus variegatus of 35-93% in MIX treatments were observed. Contaminant uptake in TLC treatments was reduced by up to 78% and differences between the two applied doses were small. Correspondingly, significant adverse effects were observed for L. variegatus whenever AC was present in the sediment. The lowest application dose of 0.1% AC in the MIX system reduced L. variegatus growth, and 1.0% AC led to a net loss of organism biomass. All TLC treatments let to a loss of biomass in the test organism. Furthermore, mortality was observed with 1.2 kg AC/m2 doses of pure AC for the TLC treatment. The addition of clay (Kaolinite) to the TLC treatments prevented mortality, but did not decrease the loss in biomass. While TLC treatments pose a less laborious alternative for AC amendments in the field, the results of this study show that it has lower remediation potential and could be more harmful to the benthic fauna.


Uveal Metastasis: Clinical Features and Survival Outcome of 2214 Tumors in 1111 Patients Based on Primary Tumor Origin.
The purpose of this study is to evaluate patients with uveal metastasis based on primary tumor site. Retrospective analysis from Wills Eye Hospital, Philadelphia, PA, USA, for uveal metastasis clinical features and outcomes based on the primary tumor site. There were 2214 uveal metastases diagnosed in 1111 consecutive patients. The demographics included mean age of 60 years (median 61 years), Caucasian race (88%), and female gender (64%). The tumor was unilateral (82%) and primary site was established before uveal metastasis (67%). The primary tumor originated in the breast (37%), lung (26%), kidney (4%), gastrointestinal (GI) tract (4%), cutaneous melanoma (2%), lung carcinoid (2%), prostate (2%), thyroid (1%), pancreas (1%), other sites (3%), and unknown (16%). Comparative analysis of the 5 most common primary sites (breast, lung, kidney, GI tract, and cutaneous melanoma), revealed metastasis at mean age (57, 62, 66, 61, 59 years), as unilateral tumor (74%, 86%, 85%, 93%, 85%), with mean number of metastasis/eye (1.9, 1.7, 1.0, 1.1, 2.0), and in females (99%, 46%, 26%, 25%, 30%). Choroidal metastases measured mean base (9.3, 10.2, 9.1, 11.0, 7.3 mm), mean thickness (2.4, 3.6, 4.4, 4.0, 2.9 mm), and demonstrated predominant color yellow (94%, 91%, 56%, 97%, 36%). Of the 769 patients with documented follow-up, mean patient survival was poor (22.2, 11.5, 8.6, 12.4, 11.4 months) and Kaplan-Meier analysis revealed 3-year survival (33%, 19%, 0%, 14%, 21%) and 5-year survival (24%, 13%, 0%, 14%, 21%). The worst survival was found in patients with pancreatic metastasis (mean 4.2 months) and best survival with lung carcinoid (92% at 5 years). In a tertiary referral service, uveal metastasis originates from cancer in the breast, lung, kidney, GI tract, cutaneous melanoma, or others. Overall prognosis is poor with 5-year survival at 23% and worst survival with pancreatic metastasis whereas best survival with lung carcinoid metastasis.


People at Risk of Influenza Pandemics: The Evolution of Perception and Behavior.
Influenza pandemics can severely impact human health and society. Understanding public perception and behavior toward influenza pandemics is important for minimizing the effects of such events. Public perception and behavior are expected to change over the course of an influenza pandemic, but this idea has received little attention in previous studies. Our study aimed to understand the dynamics of public perception and behavior over the course of the 2009 H1N1 influenza pandemic. Three consecutive cross-sectional surveys were administered among Beijing residents with random-digit dialing techniques in March 2008 and August and November 2009. Effective samples of 507, 508 and 1006 respondents were interviewed in each of the three surveys, respectively. The mean scores of risk perception were low to moderate across the three surveys. The perceived risk of infection of self was significantly lower than that of the community, revealing an optimistic bias. Longitudinally, the perceived risk of contracting H1N1 increased, whereas the perceived risk of being unable to obtain medicine and medical care once influenza permeated the community first increased and then decreased. Responsive actions toward influenza varied. Most respondents took actions that required little extra effort, such as ventilating rooms; these actions did not change over time. Comparatively, a smaller number of respondents took actions for coping with influenza, such as vaccination; however, these actions were taken by an increasing number of respondents over time. The association between risk perception and behavior was unstable. Positive, insignificant, and negative associations were obtained in the three surveys. In conclusion, the evolving patterns of risk perception and responsive behavior over the course of an influenza pandemic are sensitive to how risk and behavior are defined and scoped.


Hypertension, nitric oxide, oxidants, and dietary plant polyphenols.
Fruits and vegetables are key foods whose high ingestion is associated with the improvement of numerous pathological conditions, including hypertension. Such health promoting actions have been increasingly ascribed to the antioxidant characteristics of different polyphenols in fruits and vegetables. Consequently, based on this assumption, many beverages and foods rich in polyphenols, grape, tea, cocoa, and soy products and many of their chemical constituents purified, are being studied both, as antioxidants and antihypertensive agents. This paper reviews the current evidence linking high polyphenol consumption with reductions in blood pressure. Basic chemical aspects of flavanols, flavonols, isoflavones and stilbenes, as possible responsible for the observed effects of those foods on blood pressure are included. Human interventions studies by using grapes and wine, cocoa and chocolate, black and green tea, soy products, and purified compounds ((+)-catequin, quercetin, (-)-epigallocatechin gallate) are summarized. The discussed hypothesis, strongly supported by experimental data in animals, is that by regulating nitric oxide bioavailability, polyphenols present in fruits and vegetables affect endothelial function and as a consequence, blood pressure. Even when data are not definitive and many questions remain open, the whole evidence is encouraging to start considering diets that can provide a benefit to hypertensive subjects, and those benefits will be more significant in people that do not have controlled his/her elevated blood pressure.


Pharmacological and molecular biological evidence for ETA endothelin receptor subtype mediating mechanical responses in the detrusor smooth muscle of the human urinary bladder.
The aim of this study was to characterize endothelin receptor subtypes of the detrusor muscle of the human urinary bladder. The receptor subtypes mediating endothelin (ET)-1-induced activity in the human detrusor smooth muscles have been characterized using isometric contraction and reverse transcription-polymerase chain reaction (RT-PCR). ET-1 (a non-selective ET receptor agonist; 10(-10) M to 10(-6) M) exhibited concentration-dependent contractions in human urinary bladder with a plateau at concentrations above 3x10(-7) M. Neither IRL1620 nor sarafotoxin S6c (both ETB-selective agonists; 10(-10) M to 10(-6) M) elicited contractile activity in the human urinary bladder detrusor smooth muscle. FR139317 (an ETA-selective antagonist; 10(-7) M to 10(-5) M) produced a marked shift to the right of the ET-1 concentration-response curve in human urinary bladder detrusor smooth muscle (from the Schild plot TpA2=7.96; slope=0.95). In contrast, RES701-1 (an ETB-selective antagonist; 10(-7) M to 10(-5) M) had no effect on the ET-1 concentration-response curve. RT-PCR revealed positive amplification of ETA receptor mRNA fragment, but not ETB. These results indicate that the ET-1-induced contractile effects of urinary bladder detrusor smooth muscle seem to be mediated mainly by the ETA receptor, not by the ETB receptor.


Upregulated expression of human neutrophil peptides 1, 2 and 3 (HNP 1-3) in colon cancer serum and tumours: a biomarker study.
Molecular markers for localized colon tumours and for prognosis following therapy are needed. Proteomics research is currently producing numerous biomarker studies with clinical potential. We investigate the protein composition of plasma and of tumour extracts with the aim of identifying biomarkers for colon cancer. By Surface Enhanced Laser Desorption/Ionisation--Time Of Flight/Mass spectrometry (SELDI-TOF/MS) we compare the protein profiles of colon cancer serum with serum from healthy individuals and the protein profiles of colon tumours with normal colon tissue. By size exclusion chromatography, we investigate the binding of HNP 1-3 to high mass plasma proteins. By microflow we investigate the effect of HNP 1-3 on mammalian cells. Human Neutrophil Peptides -1, -2 and -3 (HNP 1-3), also known as alfa-defensin-1, -2 and -3, are present in elevated concentrations in serum from colon cancer patients and in protein extracts from colon tumours. A fraction of HNP 1-3 in serum is bound to unidentified high mass plasma proteins. HNP 1-3 purified from colon tumours are lethal to mammalian cells. HNP 1-3 may serve as blood markers for colon cancer in combination with other diagnostic tools. We propose that HNP 1-3 are carried into the bloodstream by attaching to high mass plasma proteins in the tumour microenvironment. We discuss the effect of HNP 1-3 on tumour progression.


Ketamine-A Narrative Review of Its Uses in Medicine.
One of the most fascinating drugs in the anesthesiologist's armament is ketamine, an N-methyl-D-aspartate receptor antagonist with a myriad of uses. The drug is a dissociative anesthetic and has been used more often as an analgesic in numerous hospital units, outpatient pain clinics, and in the prehospital realm. It has been used to treat postoperative pain, chronic pain, complex regional pain syndrome, phantom limb pain, and other neuropathic conditions requiring analgesia. Research has also demonstrated its efficacy as an adjunct in psychotherapy, as a treatment for both depression and posttraumatic stress disorder, as a procedural sedative, and as a treatment for respiratory and neurologic conditions. Ketamine is not without its adverse effects, some of which can be mitigated with certain efforts. Such effects make it necessary for the clinician to use the drug only in situations where it will provide the greatest benefit with the fewest adverse effects. To the best of our knowledge, none of the reviews regarding ketamine have taken a comprehensive look at the drug's uses in all territories of medicine. This review will serve to touch on its chemical data, pharmacokinetics and pharmacodynamics, medical uses, and adverse effects while focusing specifically on the drugs usage in anesthesia and analgesia.


Association between multiple comorbidities and self-rated health status in middle-aged and elderly Chinese: the China Kadoorie Biobank study.
Understanding the correlates of self-rated health (SRH) can help public health professionals prioritize health-promotion and disease-prevention interventions. This study aimed to investigate the association between multiple comorbidities and global SRH and age-comparative SRH. A total of 512,891 participants aged 30-79 years old were recruited into the China Kadoorie Biobank study from ten regions between 2004 and 2008. Multivariate logistic regression models were used to estimate the odds ratios (ORs) for the associations between comorbidities (including diabetes, hypertension, coronary heart disease, rheumatic heart disease, stroke, tuberculosis, emphysema/bronchitis, asthma, cirrhosis/chronic hepatitis, peptic ulcer, gallbladder disease, kidney disease, fracture, rheumatic arthritis, psychiatric disorders, depressive symptoms, neurasthenia, head injury and cancer) and SRH. Population attributable risks (PARs) were used to estimate the contribution of multiple comorbidities to poor global SRH and worse age-comparative SRH. After adjusting for covariates, suffering from various diseases increased the chance of reporting a poor global SRH [OR (95% CI) ranged from 1.10 (1.07, 1.13) for fracture to 3.21 (2.68, 3.83) for rheumatic heart disease] and a worse age-comparative SRH [OR (95% CI) ranged from 1.18 (1.13, 1.23) for fracture to 7.56 (6.93, 8.25) for stroke]. From the population perspective, 20.23% of poor global SRH and 45.12% of worse age-comparative SRH could attributed to the cardiometabolic diseases, with hypertension (7.84% for poor global SRH and 13.79% for worse age-comparative SRH), diabetes (4.35% for poor global SRH and 10.71% for worse age-comparative SRH), coronary heart disease (4.44% for poor global SRH and 9.51% for worse age-comparative SRH) and stroke (3.20% for poor global SRH and 10.19% for worse age-comparative SRH) making the largest contribution. Various diseases were major determinants of global and age-comparative SRH, and cardiometabolic diseases had the strongest impact on both global SRH and age-comparative SRH at the population level. Prevention measures concentrated on these conditions would greatly reduce the total burden of poor SRH and its consequences such as poor quality of life and use of health care services.


Anti-fibrotic effects of phenolic compounds on pancreatic stellate cells.
Pancreatic fibrosis is a prominent histopathological characteristic of chronic pancreatitis and plausibly a dynamic process of transition to the development of pancreatic ductal adenocarcinoma. Conversely, the activation of pancreatic stellate cells (PSCs) has been recently suggested as the key initiating step in pancreatic fibrosis. As natural polyphenols had been largely applied in complementary therapies in the past decade, in this study, we aimed to investigate which groups of phenolic compounds exert promising inhibitory actions on fibrogenesis as there are few effective strategies for the treatment of pancreatic fibrosis to date. We examined the anti-fibrotic effects of a variety of herbal constituents using a cellular platform, the LTC-14 cells, which retained essential characteristics and morphologies of primary PSCs, by means of various biochemical assays including cell viability test, real-time polymerase chain reaction and Western blotting analysis. Among a number of commonly used herbal constituents, we found that the application of rhein, emodin, curcumin and resveratrol significantly suppressed the mRNA and protein levels of several fibrotic mediators namely alpha-smooth muscle actin, type I collagen and fibronectin in LTC-14 cells against transforming growth factor-beta stimulation. Though the values of cytotoxicity varied, the mechanism of the anti-fibrotic action of these four phenolic compounds was principally associated with a decrease in the activation of the nuclear factor-kappaB signaling pathway. Our findings suggest that the mentioned phenolic compounds may serve as anti-fibrotic agents in PSC-relating disorders and pathologies, particularly pancreatic fibrosis.


Enhanced renal prostaglandin production in the dog. I. Effects on renal function.
The changes in renal function produced by endogenous synthesis of prostaglandins by the kidney were evaluated by infusing sodium arachidonate, the prescursor of the prostaglandins, into one renal artery of the dog. These changes were compared with those produced by similar infusions on performed prostaglandin (PG) E2 and F2alpha.PGE2given at 0.01-0.3 mug/kg min--1 produced dose-related increases in urine flow, sodium and potassium excretion, free water clearance, and renal blood flow. The glomerular filtration rage increased only at the lowest dose and the calculated filtration fraction fell. Arachidonic acid at 1.0-30.0 mug/kg min--1 similarly produced dose-related increases in electrolyte excretion, but the increase in renal blood flow was much less than that produced by PGE2 and there were no changes in glomerular filtration rate, filtration fraction, or free water clearances. PGF2alpha had essentially no effects at infusion rates of 0.03-1.0 mug/kg min--1. All renal effects of arachidonic acid were inhibited by simultaneous infusions of an inhibitor of prostaglandin synthetase, 5, 8, 11,14-eicosatetraynoic acid (20:4). None of the effects produced by PGE2 were inhibited by 20:4. These results indicate that enhanced endogenous renal prostaglandin synthesis, which can be produced by arachidonate infusion, results in significant alterations of renal function. This finding strengthens the hypothesis that renal prostaglandins formed in vivo have physiological importance as regulators of renal function.


Thermithiobacillus plumbiphilus sp. nov., a sulfur-oxidizing bacterium isolated from lead sulfide.
A novel sulfur oxidizer, strain wk12T, was isolated from an industrially synthesized lead (II) sulfide. The G+C content of the genomic DNA was around 58.5 mol%. The major components in the cellular fatty acid profile were summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c), C16 : 0 and summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c). The strain oxidized lead sulfide, thiosulfate and tetrathionate as electron donors to support autotrophic growth. Cells of strain wk12T were motile, rod-shaped (0.5-1.0 × 0.7-2.2 μm), and Gram-stain-negative. For growth, the temperature range was 5-37 °C, and optimum growth was observed at 28-32 °C. The pH range for growth was 5.8-8.7, with optimum growth at pH 6.4-7.1. Optimum growth of the isolate was observed in medium without NaCl, and no growth was observed in the medium containing 0.5 M or more NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate belongs to the class Acidithiobacillia. The closest relative with a validly published name was Thermithiobacillus tepidarius DSM 3134T, with a 16S rRNA gene sequence similarity of 96 %. On the basis of phylogenetic and phenotypic properties, strain wk12T represents a novel species of the genus Thermithiobacillus, for which the name Thermithiobacillus plumbiphilus sp. nov. is proposed. The type strain is wk12T ( = NBRC 111508T = DSM 101799T).


Actinoplanes Swims into the Molecular Age.
The survival strategy of Actinoplanes is fascinating from an evolutionary perspective, combining a short motile phase in an otherwise nonmotile, filamentous life cycle and the somewhat paradoxical concept of spores-normally thought of as a resting stage-that swim. In the first paper to report a molecular genetic analysis of development in Actinoplanes, the authors identify a key regulator of the entry into development (Y. Mouri, K. Konishi, A. Fujita, T. Tezuka, Y. Ohnishi, J Bacteriol 199:e00840-16, 2017, https://doi.org/10.1128/JB.00840-16).


Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis.
Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7α,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2-/- mice and mice with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7α-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.


Evolutionary genetics of the capsular locus of serogroup 6 pneumococci.
The evolution of the capsular biosynthetic (cps) locus of serogroup 6 Streptococcus pneumoniae was investigated by analyzing sequence variation within three serotype-specific cps genes from 102 serotype 6A and 6B isolates. Sequence variation within these cps genes was related to the genetic relatedness of the isolates, determined by multilocus sequence typing, and to the inferred patterns of recent evolutionary descent, explored using the eBURST algorithm. The serotype-specific cps genes had a low percent G+C, and there was a low level of sequence diversity in this region among serotype 6A and 6B isolates. There was also little sequence divergence between these serotypes, suggesting a single introduction of an ancestral cps sequence, followed by slight divergence to create serotypes 6A and 6B. A minority of serotype 6B isolates had cps sequences (class 2 sequences) that were approximately 5% divergent from those of other serotype 6B isolates (class 1 sequences) and which may have arisen by a second, more recent introduction from a related but distinct source. Expression of a serotype 6A or 6B capsule correlated perfectly with a single nonsynonymous polymorphism within wciP, the rhamnosyl transferase gene. In addition to ample evidence of the horizontal transfer of the serotype 6A and 6B cps locus into unrelated lineages, there was evidence for relatively frequent changes from serotype 6A to 6B, and vice versa, among very closely related isolates and examples of recent recombinational events between class 1 and 2 cps serogroup 6 sequences.


Black Males, Trauma, and Mental Health Service Use: A Systematic Review.
To systematically review the evidence of and synthesize results from relevant studies that have examined barriers and facilitators to professional mental health service use for Black male trauma survivors ages 18 and older. A thorough search of selected databases that included EBSCO, ProQuest, and Web of Science Core Collection and careful consideration of inclusion and exclusion criteria yielded a final six studies for detailed review. Black male trauma survivors were significantly less likely to be utilizing mental health services than other sex-ethnic groups. High levels of daily crises, a lack of knowledge of steps to obtain services, and service eligibility issues were significant individual barriers to mental health service use for Black males, whereas social support, occupational disability, and PTSD symptoms severity were significant facilitators for mental health service use. Exposure to trauma, whether through witnessing or direct victimization, is often a daily reality for many Black males. Findings from this review suggest that 56-74% of Black males exposed to traumatic events may have an unmet need for mental health services. Future research examining the relationship between trauma and mental health service use for Black men and factors that moderate and/or mediate this relationship is warranted.


Viscum album-mediated COX-2 inhibition implicates destabilization of COX-2 mRNA.
Extensive use of Viscum album (VA) preparations in the complementary therapy of cancer and in several other human pathologies has led to an increasing number of cellular and molecular approaches to explore the mechanisms of action of VA. We have recently demonstrated that, VA preparations exert a potent anti-inflammatory effect by selectively down-regulating the COX-2-mediated cytokine-induced secretion of prostaglandin E2 (PGE2), one of the important molecular signatures of inflammatory reactions. In this study, we observed a significant down-regulation of COX-2 protein expression in VA-treated A549 cells however COX-2 mRNA levels were unaltered. Therefore, we hypothesized that VA induces destabilisation of COX-2 mRNA, thereby depleting the available functional COX-2 mRNA for the protein synthesis and for the subsequent secretion of PGE2. To address this question, we analyzed the molecular degradation of COX-2 protein and its corresponding mRNA in A549 cell line. Using cyclohexamide pulse chase experiment, we demonstrate that, COX-2 protein degradation is not affected by the treatment with VA whereas experiments on transcriptional blockade with actinomycin D, revealed a marked reduction in the half life of COX-2 mRNA due to its rapid degradation in the cells treated with VA compared to that in IL-1β-stimulated cells. These results thus demonstrate that VA-mediated inhibition of PGE2 implicates destabilization of COX-2 mRNA.


An improved technique for multiple organ harvesting.
A rapid technique for multiple organ harvesting is described which allows removal of all the major organs within 30 to 60 minutes after beginning the donor operation. No preliminary dissection of the liver or kidneys is required or necessary since these organs are cooled by infusion of cold solutions in situ and with subsequent rapid dissection in a bloodless field. The incidence of well functioning kidneys, livers and hearts has been better than with the previous methods. The acceptance of this procedure by other personnel has been almost universal.


Density- and trait-mediated effects of a parasite and a predator in a tri-trophic food web.
Despite growing interest in ecological consequences of parasitism in food webs, relatively little is known about effects of parasites on long-term population dynamics of non-host species or about whether such effects are density or trait mediated. We studied a tri-trophic food chain comprised of (i) a bacterial basal resource (Serratia fonticola), (ii) an intermediate consumer (Paramecium caudatum), (iii) a top predator (Didinium nasutum) and (iv) a parasite of the intermediate consumer (Holospora undulata). A fully factorial experimental manipulation of predator and parasite presence/absence was combined with analyses of population dynamics, modelling and analyses of host (Paramecium) morphology and behaviour. Predation and parasitism each reduced the abundance of the intermediate consumer (Paramecium), and parasitism indirectly reduced the abundance of the basal resource (Serratia). However, in combination, predation and parasitism had non-additive effects on the abundance of the intermediate consumer, as well as on that of the basal resource. In both cases, the negative effect of parasitism seemed to be effaced by predation. Infection of the intermediate consumer reduced predator abundance. Modelling and additional experimentation revealed that this was most likely due to parasite reduction of intermediate host abundance (a density-mediated effect), as opposed to changes in predator functional or numerical response. Parasitism altered morphological and behavioural traits, by reducing host cell length and increasing the swimming speed of cells with moderate parasite loads. Additional tests showed no significant difference in Didinium feeding rate on infected and uninfected hosts, suggesting that the combination of these modifications does not affect host vulnerability to predation. However, estimated rates of encounter with Serratia based on these modifications were higher for infected Paramecium than for uninfected Paramecium. A mixture of density-mediated and trait-mediated indirect effects of parasitism on non-host species creates rich and complex possibilities for effects of parasites in food webs that should be included in assessments of possible impacts of parasite eradication or introduction.


Structured illumination for the extension of imaging interferometric microscopy.
Structured illumination applied to imaging interferometric microscopy (IIM) allows extension of the resolution limit of low numerical aperture objective lenses to ultimate linear systems limits (<approximately lambda/4 in air) without requiring a reference beam around the objective lens. Instead, the reference beam is provided by an illumination beam just at the edge of the optical system numerical aperture resulting in a shift of the recorded spatial frequencies (equivalent to an intermediate frequency). The restoration procedure is discussed. This technique is adaptable readily to existing microscopes, since extensive access to the imaging system pupil plane is not required.


Cretan Mediterranean diet for prevention of coronary heart disease.
As a result of the Seven Countries Study, the Mediterranean diet has been popularized as a healthy diet. Nevertheless, it has not replaced the prudent diet commonly prescribed to coronary patients. Recently, we completed a secondary, randomized, prospective prevention trial in 605 patients recovering from myocardial infarction in which we compared an adaptation of the Cretan Mediterranean diet with the usual prescribed diet. After a mean follow-up period of 27 mo, recurrent myocardial infarction, all cardiovascular events, and cardiac and total death were significantly decreased by > 70% in the group consuming the Mediterranean diet. These protective effects were not related to serum concentrations of total, low-density-lipoprotein (LDL), or high-density-lipoprotein (HDL) cholesterol. In contrast, protective effects were related to changes observed in plasma fatty acids: an increase in n-3 fatty acids and oleic acid and a decrease in linoleic acid that resulted from higher intakes of linolenic and oleic acids, but lower intakes of saturated fatty acids and linoleic acid. In addition, higher plasma concentrations of antioxidant vitamins C and E were observed. We conclude that a Cretan Mediterranean diet adapted to a Western population protected against coronary heart disease much more efficiently than did the prudent diet. Thus, it appears that the favorable life expectancy of the Cretans could be largely due to their diet.


Italy's contribution to global health: the need for a paradigm shift.
This paper reviews Italian Development Assistance for Health and overall contribution to Global Health from 2001 to 2012. It analyses strategies and roles of central and decentralized authorities as well as those of private non-profit and corporate actors. The research illustrates a very low and unstable official contribution that lags far behind internationally agreed upon objectives, a highly fragmented institutional scenario, and controversial political choices favouring "vertical" global initiatives undermining national health systems, and in contrast with Italian deep-rooted principles, traditional approaches and official guidelines. Italy's contribution to global health goes beyond official development aid, however. The raising movement toward Universal Health Coverage may offer an extraordinary opportunity for a leading role to a country whose National Health System is founded on the principles of universal and equitable access to care. At the same time, the distinctive experience of Italian decentralized cooperation, with the involvement of a multiplicity actors in a coordinated effort for cooperation in health with homologous partners in developing countries, may offer--if adequately harnessed--new opportunities for an Italian "system" of development cooperation. Nevertheless, the indispensable prerequisite of a substantial increase in public funding is challenged by the current economic crisis and domestic political situation. For a renewed Italian role in development and global health, a paradigm shift is needed, requiring both conceptual revision and deep institutional and managerial reforms to ensure an appropriate strategic direction and an efficient and effective use of resources.


Emergence and serovar profiling of non-typhoidal Salmonellae (NTS) isolated from gastroenteritis cases-A study from South India.
Human infection with non-typhoidal Salmonella (NTS) serovars is often a neglected and undiagnosed infection in the developing world. Invasive NTS is now being established as having a new and emerging pathogenic role. There is not sufficient data on the prevalence of NTS serovars and their antibiotic susceptibility pattern from India. Faecal specimens collected from patients with acute gastroenteritis were processed to isolate Salmonella according to the standard protocol for a period from January 2011-December 2014. Salmonella isolates were serotyped and tested for antibiotic susceptibility. Of the total 320 (10.04%) bacterial enteric pathogens isolated, 64 (20%) were non-typhoidal Salmonella. Among the serogroup, O:4 (B) (n = 26; 40.6%) was found to be the commonest followed by O:7 (C1) (n = 11; 17.1%) and O:3,10 (E1) (n = 11; 17.1%). NTS infection in cancer patients could also be termed as nosocomial NTS diarrhoea due to primary community infection with prolonged incubation periods, consumption of contaminated food during hospital stay or Nosocomially acquired infection. Serovar Oslo has been predominant (9/17) in NTS isolates from cancer patients, whereas serovars Bovismorbificans, Wangata and Schleissheim have been reported for the first time in the country. The isolates were mostly susceptible to antibiotics except Salmonella ser Kentucky, which showed resistance to ciprofloxacin is reported for the first time in the country. Continuous surveillance is required to monitor resistance of NTS isolates.


Using self-determination theory to improve residency training: learning to make omelets without breaking eggs.
An inherent tension exists in clinical training between supervising learners to ensure quality and patient safety, and allowing learners to practice independently to gain experience. In this issue of Academic Medicine, Biondi and colleagues discuss this tension, highlighting the disconnect between faculty and resident perceptions of autonomous practice for housestaff. They report that each group perceives itself as more competent in its role than does the other group. Their work leads us to consider how medical educators might safely and effectively transform the learning process. Self-determination theory (SDT) holds that there is a human tendency to develop toward self-directed and autonomous regulation of behavior. This development of intrinsic motivation is governed by the complex relationships among autonomy, competence, and relatedness as well as educational content and the learning milieu. Applying an SDT framework to their findings, Biondi and colleagues report that faculty desire from residents the evidence of internal motivation and demonstration of competence and self-confidence that will allow faculty to entrust learners with autonomy. They conclude, however, that these are qualities that faculty find lacking in many residents. To optimize the balance between autonomy and supervision, this Commentary's author proposes the use of "scaffolding," a construct from developmental psychology. In the scaffolding model, the role of teachers is to support the learner's development and to provide support structures to help the learner get to the next stage of entrustment and competence. Achieving a balance is essential to providing the best patient care now and in the future.


Insights into fisheries management practices: using the theory of planned behavior to explain fish stocking among a sample of Swiss anglers.
Using inadequate management tools often threatens the natural environment. This study focuses on the example of Swiss recreational fishermen (hereafter called "anglers") as recreational fisheries management stakeholders. In recreational fisheries, fish stocking conducted by anglers has been identified as one important factor associated with declining fish catches. We therefore aimed to a) gain insights into why anglers want to maintain fish stocking and b) identify entry points for interventions to promote more pro-ecological management practices. Results (N = 349) showed that the majority of anglers think very uncritically about stocking and that they frequently engage in it. We conclude that outcome expectancies and beliefs about risks, in combination with a lack of stocking success controls are the main reasons that anglers retain stocking measures. We suggest that providing anglers with direct experience and feedback about stocking success is suitable to change their intentions regarding stocking and their actual stocking behavior, and thus, to promote more pro-ecological management methods. From a more general perspective, the results of this study are likely to help improve pro-ecological ecosystem management in other domains where problems similar to those in recreational fisheries management might exist.


High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia.
Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] < 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P =.0005), major molecular response (QPRC < 0.05%; P =.00001), and complete molecular response (undetectable BCR-ABL; P =.001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML.


Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF-alpha and correlates with the down-regulated expression of inducible nitric oxide synthase and other markers of macrophage activation.
C57BL/6 mice infected with the ME-49 strain of Toxoplasma gondii develop a progressive encephalitis culminating in 100% mortality between 12 and 15 wk after intraperitoneal inoculation of the parasite. Moreover, when injected at 4 wk after infection with anti-IFN-gamma mAb, progression of toxoplasmic encephalitis is markedly accelerated, resulting in death of the animals by 9 to 12 days posttreatment. In this study, we investigated the expression of mRNAs encoding cytokines as well as lymphocyte and macrophage markers during the development of toxoplasmic encephalitis. High levels of lymphocyte CD4 and CD8 surface Ag transcript were detected in the brains of mice throughout the infection. In addition from 2 to 4 wk we found elevations of Th1 (IFN-gamma and IL-2) but not of Th2 (IL-4 and IL-5) cytokine mRNAs. The elevation in Th1 cytokines was accompanied by increases in the expression of monokine (IL-1, IL-6, IL-10, granulocyte macrophage-colony stimulating factor [GM-CSF], and TNF-alpha) mRNAs, as well as markers expressed by activated macrophages (major histocompatibility class II [Ia], inducible nitric oxide synthase [iNOS] and macrophage activation gene 1 [Mag-1]). Interestingly, after 8 wk of infection with T. gondii we observed a dramatic decrease of Th1 cytokine and most monokine (IL-1, IL-6, GM-CSF, and TNF-alpha) as well as Mag-1 and iNOS mRNA levels. This down-regulation was associated with enhanced necrosis and neutrophilic infiltrates in the brain accompanied by increased expression of genes expressed specifically by the tachyzoite stage of T. gondii (T. gondii surface antigen 1 [SAG-1] and T. gondii surface antigen 2 [SAG-2]). Similarly, in mice chronically infected with T. gondii and treated with anti-IFN-gamma mAb the resulting pathology was associated with decreased expression of TNF-alpha and iNOS and increased expression of SAG-1 and SAG-2. Moreover, treatment with anti-TNF-alpha mAb also resulted in enhanced pathology, which correlated with low levels of iNOS mRNA and high levels of tachyzoite-specific mRNAs. Together these results suggest that reactivation of T. gondii results from a down-regulation of IFN-gamma and TNF-alpha expression leading to decreased macrophage or microglial cell activation, release of parasite growth, and subsequent tissue damage.


Site-specific drug delivery in the gastrointestinal tract.
In recent years there has been a significant increase in available strategies for site-specific delivery in the gastrointestinal tract both to maximize a therapeutic response and to reduce side effects. However, in only a few instances has there been close attention paid to how these products will perform in the heterogeneous environment of the human gut. Targeted oral delivery requires a multidisciplinary approach to research, involving contributions not only from polymer and pharmaceutical scientists but also from experts in gastroenterology and product evaluation. The objective of this article is, therefore, to examine our current understanding of human gastrointestinal physiology and to review the current "state of the art" of available targeting strategies. Emphasis will be placed on human data and, in particular, the interaction between the delivery system and the gastrointestinal tract, as assessed by product visualization studies.


Traumatic episodes experienced during the genocide period in Rwanda influence life circumstances in young men and women 17 years later.
During Rwanda's genocide period in 1994, about 800,000 people were killed. People were murdered, raped and seriously injured. This retrospective study investigated prevalence and frequency of traumatic episodes and associated psychosocial effects in young adults in Rwanda over the lifetime, during the genocide period and in the past three years. This is a cross-sectional population-based study conducted among men and women, aged 20 to 35 years, residing in the Southern province of Rwanda. The study population, randomly selected in a multi stage procedure, included 477 females and 440 males. Data collection was performed through individual interviewing with a structured questionnaire during the period December 2011- January 2012. The Harvard Trauma Questionnaire was used to assess traumatic episodes. All data was sex-disaggregated. Differences between groups were measured by chi square and Fischer's exact test. Associations with socio-demographic and psychosocial factors were estimated by use of odds ratios with 95% confidence intervals in bi- and multivariate analyses. The participants in this study were 3 to 18 years of age in 1994, the year of the genocide. Our sample size was 917 participants, 440 men and 477 women. Women were to a higher extent exposed to traumatic episodes than men during their lifetime, 83.6% (n = 399) and 73.4% (n = 323), respectively. During the genocide period, 37.5% of the men/boys and 35.4% of the women/girls reported such episodes while in the past three years (2009-2011) 25.0% of the men and 23.1% of the women did. Women were more exposed to episodes related to physical and sexual violence, while men were exposed to imprisonment, kidnapping and mass killings. Victims of such violence during the genocide period were 17 years later less educated although married (men OR 1.47; 0.98-2.19; women OR 1.54; 1.03-2.30), without children (men OR 1.59; 1.08-2.36; women OR 1.86; 1.11-3.08) and living under extremely poor circumstances. The participants in this population-based study witnessed or experienced serious traumatic episodes during the genocide, which influenced their life circumstances 17 years later. Such traumatic episodes are however still taking place. The reasons for this need further investigation.


Multi-domain semantic similarity in biomedical research.
Given the increasing amount of biomedical resources that are being annotated with concepts from more than one ontology and covering multiple domains of knowledge, it is important to devise mechanisms to compare these resources that take into account the various domains of annotation. For example, metabolic pathways are annotated with their enzymes and their metabolites, and thus similarity measures should compare them with respect to both of those domains simultaneously. In this paper, we propose two approaches to lift existing single-ontology semantic similarity measures into multi-domain measures. The aggregative approach compares domains independently and averages the various similarity values into a final score. The integrative approach integrates all the relevant ontologies into a single one, calculating similarity in the resulting multi-domain ontology using the single-ontology measure. We evaluated the two approaches in a multidisciplinary epidemiology dataset by evaluating the capacity of the similarity measures to predict new annotations based on the existing ones. The results show a promising increase in performance of the multi-domain measures over the single-ontology ones in the vast majority of the cases. These results show that multi-domain measures outperform single-domain ones, and should be considered by the community as a starting point to study more efficient multi-domain semantic similarity measures.


Compartment syndrome after intramedullary nailing of the tibia.
Three patients had compartment syndrome of the leg after tibial intramedullary nailing with reaming. They were all treated successfully with emergency fasciotomy. A prospective study was done of seven additional patients who had continual monitoring of the pressure in the deep posterior compartment during tibial intramedullary nailing with reaming. In five of them, the procedure was performed three weeks or less after injury and in the remaining two, the nailing was performed later for the treatment of non-union. Two pressure peaks in the deep posterior compartment were noted: one after strong longitudinal traction was applied and the fracture was reduced and the other during intramedullary reaming. Intraoperative pressure of thirty millimeters of mercury or more were recorded in three of the seven patients. In the treatment of tibial fractures, operative procedures that involve forceful traction for a long time may predispose the patient to compartment syndrome in the leg. Close clinical observation of such patients is needed. When there is a high risk of compartment syndrome, monitoring of the pressure in the compartment may be prudent.