Probability of infection with Trypanosoma cruzi of the vector Triatoma infestans fed on infected humans and dogs in northwest Argentina.
The probability that an uninfected Triatoma infestans would become infected with Trypanosoma cruzi after a single feed on people or dogs seropositive for T. cruzi was estimated in Amama, a rural village in northwest Argentina where transmission had resurged four years earlier. The prevalence of seropositivity for T. cruzi was 34.2% among 225 people tested, and 65.1% among 83 dogs tested. Parasitemia was detected by xenodiagnosis in 29.3% of 41 seropositive persons and in 85.3% of 34 seropositive dogs. Parasitemia decreased with age more sharply in seropositive people than in seropositive dogs. Seropositive humans infected 2.6% (95% confidence interval = 1.6%-3.6%) of 963 third or fourth instar nymphs fed once on them, whereas dogs infected 48.7% (44.7%-52.7%) of 610 nymphs. The probability of bug infection increased significantly with instar and was positively related to molting success. The infectivity to bugs of seropositive dogs was 12 times higher than that of seropositive children, and 100 times higher than that of seropositive adults. The weighted probability of infection of an uninfected bug fed randomly on any dog (0.3082) was about 50 times higher than that of bugs fed on any human (0.0062). Such differences in relative infectivity, combined with the relative host-feeding preference of domiciliary Triatoma infestans for dogs, reinforces the important role of domestic dogs as a risk factor for the domestic transmission of T. cruzi.


Selected reaction monitoring-mass spectrometric immunoassay responsive to parathyroid hormone and related variants.
Parathyroid hormone (PTH) assays able to distinguish between full-length PTH (PTH1-84) and N-terminally truncated PTH (PTH7-84) are of increasing significance in the accurate diagnosis of endocrine and osteological diseases. We describe the discovery of new N-terminal and C-terminal PTH variants and the development of selected reaction monitoring (SRM)-based immunoassays specifically designed for the detection of full-length PTH [amino acid (aa)1-84] and 2 N-terminal variants, aa7-84 and aa34-84. Preparation of mass spectrometric immunoassay pipettor tips and MALDI-TOF mass spectrometric analysis were carried out as previously described. We used novel software to develop SRM assays on a triple-quadrupole mass spectrometer. Heavy isotope-labeled versions of target peptides were used as internal standards. Top-down analysis of samples from healthy individuals and renal failure patients revealed numerous PTH variants, including previously unidentified aa28-84, aa48-84, aa34-77, aa37-77, and aa38-77. Quantitative SRM assays were developed for PTH1-84, PTH7-84, and variant aa34-84. Peptides exhibited linear responses (R(2) = 0.90-0.99) relative to recombinant human PTH concentration limits of detection for intact PTH of 8 ng/L and limits of quantification of 16-31 ng/L depending on the peptide. Standard error of analysis for all triplicate measurements was 3%-12% for all peptides, with <5% chromatographic drift between replicates. The CVs of integrated areas under the curve for 54 separate measurements of heavy peptides were 5%-9%. Mass spectrometric immunoassays identified new clinical variants of PTH and provided a quantitative assay for these and previously identified forms of PTH.


Influence of private practice setting and physician characteristics on the use of breast cancer adjuvant chemotherapy for elderly women.
Although >70% of younger women with nonmetastatic breast cancer (BC) received adjuvant chemotherapy, only approximately 15% to 20% of elderly women with BC received chemotherapy. The decision to treat may be associated with nonmedical factors, such as patient, physician, or practice characteristics. In the current study, the association between oncologist characteristics and the receipt of chemotherapy in elderly women with BC was evaluated. Women aged >65 years who were diagnosed with American Joint Committee on Cancer stages I to III BC between 1991 and 2002 were identified in the Surveillance, Epidemiology, and End Results-Medicare database. The Physician Unique Identification Number was linked to the American Medical Association Masterfile to obtain information on oncologists. Investigated was the association between demographic, tumor, and oncologist-related factors and the receipt of chemotherapy, using Generalized Estimating Equations to control for clustering. Patients were defined as low risk (estrogen/progesterone receptor positive, stage I/II disease) and high risk (estrogen/progesterone receptor-negative, stage II/III disease). Of 42,544 women identified, 8714 (20%) were treated with adjuvant chemotherapy. In a hierarchical analysis, women who underwent chemotherapy were more likely be treated by oncologists primarily employed in a private practice (odds ratio [OR], 1.40; 95% confidence interval [95% CI], 1.23-1.59) and who graduated after 1975 (OR, 1.12; 95% CI, 1.01-1.26) and were less likely to have an oncologist trained in the United States (OR, 0.83; 95% CI, 0.74-0.93). The association between a private practice setting and the receipt of chemotherapy was found to be similar for patients at high risk (OR, 1.55) and low risk (OR, 1.35) for cancer recurrence. Elderly women with BC treated by oncologists who were employed in a private practice were more likely to receive chemotherapy. Efforts to determine whether these associations reflected experience, practice setting, insurance type, or other economic incentives are warranted.


Bioabsorbable interbody spacers.
Bioabsorbable polymers have been used in surgery for more than four decades. With increased reliability and decreased incidence of complications, their application has become widespread. Although their role in spinal surgery continues to evolve, the theoretic biomechanical and biologic advantages over contemporary metallic and composite implant materials make bioabsorbable interbody spacers an attractive alternative. The lack of artifact on postoperative imaging studies and the ability to load share across fusion sites in a time-dependent manner can lead to more accurate fusion assessment and increased fusion rates. The preliminary data from small, short-term studies are promising. However, larger studies with long-term follow-up are lacking. The theoretic advantages of bioabsorbable materials must be tempered by the lack of long-term clinical evidence of their benefit. Until the results of more studies in human spinal applications become available, the precise indications for the use of bioabsorbable interbody spacers will continue to evolve.


Targeted deletion of the S-phase-specific Myc antagonist Mad3 sensitizes neuronal and lymphoid cells to radiation-induced apoptosis.
The Mad family comprises four basic-helix-loop-helix/leucine zipper proteins, Mad1, Mxi1, Mad3, and Mad4, which heterodimerize with Max and function as transcriptional repressors. The balance between Myc-Max and Mad-Max complexes has been postulated to influence cell proliferation and differentiation. The expression patterns of Mad family genes are complex, but in general, the induction of most family members is linked to cell cycle exit and differentiation. The expression pattern of mad3 is unusual in that mad3 mRNA and protein were found to be restricted to proliferating cells prior to differentiation. We show here that during murine development mad3 is specifically expressed in the S phase of the cell cycle in neuronal progenitor cells that are committed to differentiation. To investigate mad3 function, we disrupted the mad3 gene by homologous recombination in mice. No defect in cell cycle exit and differentiation could be detected in mad3 homozygous mutant mice. However, upon gamma irradiation, increased cell death of thymocytes and neural progenitor cells was observed, implicating mad3 in the regulation of the cellular response to DNA damage.


Sub-300-femtosecond operation from a MIXSEL.
Peak power scaling of semiconductor disk lasers is important for many applications, but their complex pulse formation mechanism requires a rigorous pulse characterization to confirm stable fundamental modelocking. Here we fully confirm sub-300-fs operation of Modelocked Integrated eXternal-cavity Surface Emitting Lasers (MIXSELs) with record high peak power at gigahertz pulse repetition rates. A strain-compensated InGaAs quantum well gain section enables an emission wavelength in the range of Yb-doped amplifiers at ≈1030 nm. We demonstrate the shortest pulses from a MIXSEL with a duration of 253 fs with 240 W of peak power, the highest peak power generated from any MIXSEL to date. This peak power performance is comparable to conventional SESAM-modelocked VECSELs for the first time. At a 10-GHz pulse repetition rate we still obtained 279-fs pulses with 310 mW of average output power, which is currently the highest output power of any femtosecond MIXSEL. Continuous tuning of the pulse repetition rate has been demonstrated with sub-400-fs pulse durations and >225 mW of average output power between 2.9 and 3.4 GHz. The strain-compensated MIXSEL chip allowed for more detailed parameter studies with regards to different heat sink temperatures, pump power, and epitaxial homogeneity of the MIXSEL chip for the first time. We discuss in detail, how the critical temperature balance between quantum well gain and quantum well absorber, the partially saturated absorber and a limited epitaxial growth quality influence the overall device efficiency.


A comparison of dexmedetomidine and midazolam for sedation in severe pediatric burn injury.
Dexmedetomidine (DEX) is an α-adrenergic agonist that has been used for sedation during invasive procedures and endotracheal intubation. In pediatric burn injury, DEX has been shown to be safe as a long-term sedative in the intensive care unit (ICU). However, comparison of DEX with traditional sedatives, such as midazolam, for sedation in pediatric burn injury has not been performed. The purpose of this study was to compare DEX with midazolam in terms of sedation, efficacy, and side effects in children with burn injury. A retrospective review of all children with a TBSA burn injury ≥20% admitted from December 2008 to September 2010 was performed. Children who received a continuous DEX infusion were compared with children receiving a continuous midazolam infusion. Data collected included: age, TBSA burn, ventilator days, ICU days, hypotensive episodes, bradycardic episodes, and Richmond Agitation Score (RAS). A total of 21 patients who received DEX infusions were compared with 21 age-matched and burn size-matched patients who received midazolam infusions. Of the 21 DEX patients, nine also received midazolam infusions, eight prior to DEX and one after. These patients did not receive DEX and midazolam simultaneously. There was no difference in age (6.9 vs 6.4 years), TBSA (45.5 vs 49.2%), ICU days (45.3 vs 55.4), and ventilator days (38.5 vs 45.5) between the DEX and midazolam patients, respectively. The mean duration of infusion was 22.5 ± 24.9 days for DEX and 20.1 ± 24.8 days for midazolam. DEX patients had a mean RAS of -0.91 ± 0.8. Midazolam patients were more sedated with a mean RAS of -1.33 ± 0.7. Only one episode of bradycardia was noted in the DEX group. The DEX group had fewer hypotensive episodes (mean arterial pressure <60 mm Hg) while on infusion compared with the midazolam group (15.8 vs 29.7 episodes). Thus, it can be surmised that DEX is a safe and effective sedative for pediatric burn patients. Compared to midazolam, DEX may provide more effective sedation and less sedation-related hypotension.


Preschoolers' understanding of others' desires: fulfilling mine enhances my understanding of yours.
We developed a gift-giving task requiring children to identify their mother's desire, when her desire differed from theirs. We found a developmental change: 3- and 4-year-olds performed more poorly than 5-year-olds (Experiment 1). A modified version of this task (Experiment 2) revealed that 3-, 4-, and 5-year-olds whose desires had been fulfilled chose an appropriate gift for their mothers significantly more often than children whose desires were unfulfilled. Children who merely anticipated desire fulfillment also outperformed children whose desires were unfulfilled. Analysis of children's verbal explanations provides converging evidence that desire fulfillment enhanced children's tendency to adopt the perspective of their mother and justify their choices by referencing her desires. Discussion focuses on why desire fulfillment enhances children's ability to consider the desires of others.


Selenomethionine induces p53 mediated cell cycle arrest and apoptosis in human colon cancer cells.
While there is an increasing interest in selenium chemoprevention against human colon polyp recurrence and other cancers, the mechanism(s) by which these agents inhibit carcinogenesis are uncertain. Some of the proposed mechanisms include the inhibition of cytosine methyltransferases, carcinogen bioactivation, and inhibition of cyclooxygenase (COX). More recently, it has been suggested that selenium may exert growth inhibitory effects by activating p53. However, the molecular mechanisms of action of selenomethionine, an organoselenium compound present in selenized yeast and currently being investigated in human clinical trials for colon polyp prevention, are unclear. In the present study we tested the hypothesis that selenomethionine might affect colon cancer cell growth by p53 mediated apoptosis and/or cell cycle regulation. Four human colon cancer cell lines including HCT116 and RKO (wild type p53), HCT116-p53KO (isogenic control of HCT116 cells with p53 knocked out) and Caco-2 (mutant p53) were treated with 0-100 microM of selenomethionine for 24, 48 and 72 h. Cell viability rates were determined by the MTT assay. Cell cycle analysis was performed by flow cytometry and apoptosis measured by Annexin V-Cy5 staining. Expression of p53 protein was determined by Western blotting and immunofluorescence assays. All cell lines showed concentration and time dependent growth inhibition with selenomethionine, although HCT116 and RKO cells were the most sensitive to such treatments. Interestingly, although HCT116 and HCT116-p53KO are isogenic cell lines, selenomethionine caused a G2/M cell cycle arrest in HCT116 and RKO cells, but not in HCT116-p53KO cells. Similarly, both HCT116 and RKO demonstrated a significant increase in apoptosis (100-170%; p < 0.01) with 50-100 microM selenomethionine. Cell cycle arrest and apoptosis observed in HCT116 and RKO cell lines were accompanied by a marked increase in p53 protein expression following selenium treatment. These results clearly suggest that selenomethionine exerts p53 dependent growth inhibitory effects in colon cancer cells by inducing G2/M cell cycle arrest as well as apoptosis.


Advance care planning dispositions: the relationship between knowledge and perception.
Legal dispositions for advance care planning (ACP) are available but used by a minority of older adults in Switzerland. Some studies found that knowledge of and perception of those dispositions are positively associated with their higher usage. The objective of the present study is to test the hypothesis of an association between increased knowledge of ACP dispositions and a more positive perception of them. Data collected in 2014 among 2125 Swiss community-dwellers aged 71 to 80 of the Lausanne cohort 65+ (Lc65+), a population-based longitudinal study on aging and frailty. Data collection was conducted through a questionnaire on knowledge, use and perception of lasting power of attorney, advance directives and designation of a health care proxy. Covariables were extracted from the Lc65+ database. Bivariable and multivariable regression analyses assessed the association between level of knowledge and perception. Half the participants did not know about legal dispositions for ACP; filing rates were 14% for advance directives, 11% for health care proxy and 6% for lasting power of attorney. Level of knowledge about the dispositions was associated with a more positive perception of them, even when adjusting for confounding factors. Although the direction of the association's causality needs more investigation, results indicate that better knowledge on ACP dispositions could improve the perception older people have of them. Communication on dispositions should take into account individual knowledge levels and address commonly enunciated barriers that seem to diminish with increased knowledge.


Evidence-based practice: what are dietitians' perceptions, attitudes, and knowledge?
The objective of this study was to measure dietitians' perceptions, attitudes, and knowledge of evidence-based practice (PAK score), and to determine whether antecedent factors (eg, sociodemographic characteristics, education and training, professional experiences, and employment setting) predicted PAK score. This cross-sectional, descriptive study used the Dietitian Research Involvement Survey following the Tailored Design Method. This study surveyed 500 randomly selected registered dietitians from seven dietetic practice groups of the American Dietetic Association. Bivariate relationships were examined between antecedent factors and PAK score. Multiple linear regression analyses were conducted to test whether these factors predicted PAK score. Higher PAK scores were associated with registered dietitians who completed more years of education (r=0.28, P<.0005), had taken a research course (r=0.28, P<.0005), frequently read research articles (r=0.41, P<.0005), earned an advanced-level board certification (r=0.18, P=.004), worked full-time (r=0.26, P<.0005), or belonged to professional organizations (r=0.18, P=.003). The strongest predictors for PAK score were "last time read research" (beta=.33, P<.0005), work status (beta=.20, P<.0005), level of education (beta=.19, P=.001), and association memberships (beta=.14, P=.01). Results indicated that dietitians' ability to incorporate an evidence-based approach is largely determined by their education and training, work experience, and professional association involvement. This study identified a need to integrate concepts and principles of evidence-based practice into dietetics curriculums so that practitioners are able to routinely apply research findings to clinical practice.


Attending to the parts of a single object: part-based selection limitations.
Studies of object-based attention have demonstrated poorer performance in dividing attention between two objects in a scene than in focusing attention on a single object. However, objects often are composed of several parts, and parts are central to theories of object recognition. Are parts also important for visual attention? That is, can attention be limited in the number of parts processed simultaneously? We addressed this question in four experiments. In Experiments 1 and 2, participants reported two attributes that appeared on the same part or on different parts of a single multipart object. Participants were more accurate in reporting the attributes on the same part than attributes on different parts. This part-based effect was not influenced by the spatial distance between the parts, ruling out a simple spatial attention interpretation of our results. A control study demonstrated that our spatial manipulation was sufficient to observe shifts of spatial attention. This study revealed an effect of spatial distance, indicating that our spatial manipulation was adequate for observing spatial attention. The absence of a distance effect in Experiments 1 and 2 suggests that part-based attention may not rely entirely on simple shifts of spatial attention. Finally, in Experiment 4 we found evidence for part-based attention, using stimuli controlled for the distance between the parts of an object. The results of these experiments indicate that visual attention can selectively process the parts of an object. We discuss the relationship between parts and objects and the locus of part-based attentional selection.


Amyloid deposition in transplanted human pancreatic islets: a conceivable cause of their long-term failure.
Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.


Differential DNA methylation in discrete developmental stages of the parasitic nematode Trichinella spiralis.
DNA methylation plays an essential role in regulating gene expression under a variety of conditions and it has therefore been hypothesized to underlie the transitions between life cycle stages in parasitic nematodes. So far, however, 5'-cytosine methylation has not been detected during any developmental stage of the nematode Caenorhabditis elegans. Given the new availability of high-resolution methylation detection methods, an investigation of life cycle methylation in a parasitic nematode can now be carried out. Here, using MethylC-seq, we present the first study to confirm the existence of DNA methylation in the parasitic nematode Trichinella spiralis, and we characterize the methylomes of the three life-cycle stages of this food-borne infectious human pathogen. We observe a drastic increase in DNA methylation during the transition from the new born to mature stage, and we further identify parasitism-related genes that show changes in DNA methylation status between life cycle stages. Our data contribute to the understanding of the developmental changes that occur in an important human parasite, and raises the possibility that targeting DNA methylation processes may be a useful strategy in developing therapeutics to impede infection. In addition, our conclusion that DNA methylation is a mechanism for life cycle transition in T. spiralis prompts the question of whether this may also be the case in any other metazoans. Finally, our work constitutes the first report, to our knowledge, of DNA methylation in a nematode, prompting a re-evaluation of phyla in which this epigenetic mark was thought to be absent.


Positive impact of hepatitis C virus (HCV) treatment on antiretroviral treatment adherence in human immunodeficiency virus-HCV coinfected patients: one more argument for expanded access to HCV treatment for injecting drug users.
Treatment for the hepatitis C virus (HCV) may be delayed significantly in human immunodeficiency virus (HIV)/HCV coinfected patients on antiretroviral treatment (ART) for fear that its burden could compromise ART adherence. However, the effect such treatment has on ART adherence in observational settings remains largely unknown. Longitudinal data were used to investigate the relationship between initiating HCV treatment and adherence to ART in HIV/HCV coinfected patients. The French national prospective cohort of patients coinfected with HIV and HCV (ANRS-CO-13-HEPAVIH) is a multi-centre cohort. Seventeen out-patient hospital services delivering HIV and HCV care in France. HIV/HCV coinfected patients on ART (n = 593 patients, 976 visits). Self-administered questionnaires and medical records. A mixed logistic regression model based on generalized estimates equations (GEE) to identify factors associated with non-adherence to ART. Among the 593 patients, 36% were classified as non-adherent to ART at the enrolment visit and 12% started HCV treatment during follow-up. ART adherence was not associated statistically with HCV treatment initiation. The proportion of patients maintaining adherence or becoming adherent to ART for those starting HCV treatment was higher than in the rest of the sample (P = 0.07). After multiple adjustment for known correlates, such as poor housing conditions, binge drinking, recent drug use and depressive symptoms, patients who initiated HCV treatment were less likely to be non-adherent to ART [odds ratio (95% confidence interval) = 0.41 (0.24-0.71)]. Engaging human immunodeficiency virus/hepatitis C virus coinfected individuals in hepatitis C virus treatment is associated with high adherence to antiretroviral treatment. Physicians should prioritize hepatitis C virus treatment as part of a multi-disciplinary approach.


Tuning a bacterial chemoreceptor with protein-membrane interactions.
Chemoreceptors in Escherichia coli are homodimeric transmembrane proteins that convert environmental stimuli into intracellular signals controlling flagellar motion. Chemoeffectors bind to the extracellular (periplasmic) domain of the receptors, whereas their cytoplasmic domain mediates signaling and adaptation. The second transmembrane helix (TM2) connects these two domains. TM2 contains an aliphatic core flanked by amphipathic aromatic residues that have specific affinity for polar-hydrophobic membrane interfaces. We previously showed that Trp-209, near the cytoplasmic end of TM2, helps maintain the normal baseline-signaling state of the aspartate chemoreceptor (Tar) and that Tyr-210 plays an auxiliary role in this control. We have now repositioned the Trp-209/Tyr-210 pair in single-residue increments about the cytoplasmic polar-hydrophobic interface. Changes from WY-2 to WY+1 modulate the baseline-signaling state of the receptor in predictable and incremental steps that can be compensated by adaptive methylation/demethylation. Greater displacements, as in WY-3, WY+2, and WY+3, bias the receptor to the off kinase-inhibiting state or the on kinase-stimulating state, respectively, to a degree that cannot be fully compensated by the adaptation system. Aromatic residues analogous to Trp-209/Tyr-210 are present in other chemoreceptors and many transmembrane sensor kinases, where they may serve a similar function.


A method for patterned in situ biofunctionalization in injection-molded microfluidic devices.
We developed a method to modify the surface in injection molded polymer microdevices prior to bonding and to pattern biomolecules in the completed microsystem in situ by a sequence of simple perfusion steps directly before utilization of the device. This method is compatible with production technology such as injection molding and bonding processes currently employed in the fabrication of polymer microsystems. It solves the problem of the inherent incompatibility of biomolecules with microfabrication technology as it allows for the biofunctionalization step to be performed after completion of the microsystem. Injection molded cyclic olefin copolymer (COC) microfluidic chips were modified by irradiating the surface with UV-light at lambda = 185 nm. This results in the formation of stable acidic groups which were further modified by binding of the extracellular matrix protein collagen type I. Non-irradiated surfaces were modified by binding of Pluronic® F-127 to become non-adhesive. Density of acid groups decreases to 50% within 45 days and to 25% within 19 weeks after irradiation. However, even then the remaining density of functional groups was shown to be sufficient to bind proteins and promote cell adhesion. Selective adhesion of primary hepatocytes on surfaces patterned by UV-irradiation and a biofunctional coating with collagen type I were demonstrated in injection molded microsystems.


Pure Psychiatric Injury Pursuant to the Civil Liability Legislation: An(other) Economic Perspective.
Despite the enactment of civil liability legislation affecting claims for pure mental harm in many jurisdictions in Australia, the High Court decision in Wicks v State Rail Authority (NSW) (2010) 241 CLR 60; [2010] HCA 22 has caused some concern that the economic goals underpinning the civil liability legislation will be threatened. In this article, the economic sustainability of the law of negligence with respect to pure mental harm is considered in light of three particular issues. The first is the High Court's 2015 decision in King v Philcox (2015) 255 CLR 304; [2015] HCA 19 in which the South Australian civil liability legislation was considered. The second is the threat to healthy insurance markets posed by the civil liability legislation itself as a result of inconsistencies between jurisdictions. The third relates to the threat posed by the civil liability legislation to the ability of the law of negligence to achieve economically efficient levels of accident and accident-prevention costs. It is argued that the civil liability legislation is not only not well-suited to achieve its primary goal of reducing the social costs of accidents, but may well be a greater threat to that goal than the common law.


The use of healing touch in integrative oncology.
The use of complementary therapies by patients with cancer has become increasingly prevalent; as a result, oncology nurses find themselves needing to understand those therapies and the evidence-based support for their use. This article describes the integrative use of the biofield therapy healing touch in conjunction with the chemoradiation received by patients with cervical cancer (stages IB1 to IVA) as reported in a 2010 research study. Findings indicated effects on the immune response and depression in healing touch recipients compared to patients receiving relaxation or standard care. Specifically, healing touch recipients demonstrated a minimal decrease in natural killer cell cytotoxicity over the course of treatment, whereas the cytotoxicity of patients receiving relaxation therapy and standard care declined sharply during radiation. Healing touch recipients also showed decreases in depressed mood compared to relaxation therapy and standard care recipients. The findings suggest that appropriate integration of complementary modalities into oncology care can enhance the impact of conventional care by putting patients in the best condition to use their innate healing resources.


Mitochondria, Temperature, and the Pace of Life.
Life history strategies, physiological traits, and behavior are thought to covary along a "pace of life" axis, with organisms at the fast end of this continuum having higher fecundity, shorter lifespan, and more rapid development, growth, and metabolic rates. Countergradient variation represents a special case of pace of life variation, in which high-latitude organisms occupy the fast end of the continuum relative to low-latitude conspecifics when compared at a common temperature. Here, we use Atlantic killifish (Fundulus heteroclitus) to explore the role of mitochondrial properties as a mechanism underlying countergradient variation, and thus variation in the pace of life. This species is found along the Atlantic coast of North America, through a steep latitudinal thermal gradient. The northern subspecies has faster development, more rapid growth, higher routine metabolic rate, and higher activity than the southern subspecies when compared at a common temperature. The northern subspecies also has greater mitochondrial respiratory capacity in the liver, although these differences are not evident in other tissues. The increased respiratory capacity of liver mitochondria in northern fish is associated with increases in the activity of multiple electron transport complexes, which largely reflects an increase in the amount of inner mitochondrial membrane per mitochondrion in the northern fish. There are also differences in the lipid composition of liver mitochondrial membranes, including differences in cardiolipin species, which could also influence respiratory capacity. These data suggest that variation in mitochondrial properties could, at least in part, underlie variation in the pace of life in Atlantic killifish.


Vascular remodeling in autogenous arterio-venous fistulas by MRI and CFD.
Hemodynamic parameters play an important role in regulating vascular remodeling in arterio-venous fistula (AVF) maturation. Investigating the changes in hemodynamic parameters during AVF maturation is expected to improve our understanding of fistula failure, but very little data on actual temporal changes in human AVFs is available. The present study aimed to assess the feasibility of using a noncontrast-enhanced MRI protocol combined with CFD modeling to relate hemodynamic changes to vascular remodeling following native AVF placement. MR angiography (MRA) and MR velocimetry (MRV) data was acquired peri-operatively, 1 month, and 3 months later in three patients. Vascular geometries were obtained by segmentation of the MRA images. Pulsatile flow simulations were performed in the patient specific vascular geometries with time-dependent boundary conditions prescribed from MRV measurements. A principal result of the study is the description of WSS changes over time in the same patients. The disturbed flow observed in the venous segments resulted in a variability of the WSS distribution and could be responsible for the non-uniform remodeling of the vessel. The artery did not show regions of disturbed flow upstream from the anastomosis, which would be consistent with the uniform remodeling. MRI use demonstrated the ability to provide a comprehensive evaluation of clinically relevant information for the investigation of upper extremity AVFs. 3D geometry from MRA in combination with MRV provides the opportunity to perform detailed CFD analysis of local hemodynamics in order to determine flow descriptors affecting fistula maturation.


Cardiac surgery for inmates in the Texas Department of Corrections.
All Texas prison inmates requiring hospitalization since 1983 have been transferred to a separate prison hospital adjacent to a tertiary care university hospital. We reviewed and analyzed the data regarding one major tertiary care service, namely cardiac surgery, to describe the rate of utilization of this service and its results. From January 1, 1984, to June 30, 1988, 73 inmates underwent 74 cardiac operations, 50 of which were coronary revascularizations. The age-adjusted rates of utilization for coronary artery bypass grafting were substantially higher for inmates over age 45 than for that described for the general population, whereas the utilization rates for valve surgery were comparable. There were no perioperative or late deaths, and 86% of the inmate patients are currently employed within the Texas Department of Corrections system or were employed at the time of their release. The utilization rates and the results of this representative tertiary medical care service for the state's prison population are comparable to those achieved in the private sector, and may have a substantial beneficial effect on inmate rehabilitation.


Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer.
Angioinvasion is critical for metastasis with urokinase-type plasminogen activator receptor (uPAR) and tumor hypoxia-activated hypoxia-inducible factor 1 (HIF-1) as key players. Transcriptional control of uPAR expression by HIF has never been reported. The aim of the present study, therefore, was to test whether tumor hypoxia-induced HIF expression may be linked to transcriptional activation of uPAR and dependent angioinvasion. We used human pancreatic cancer cells and a model of parental and derived HIF-1beta-deficient mouse liver cancer cell lines and performed Northern blot analysis, nuclear runoff assays, electrophoretic mobility shift assay, polymerase chain reaction-generated deletion mutants, luciferase assays, Matrigel invasion assays, and in vivo angioinvasion assays in the chorioallantoic membrane of fertilized chicken eggs. Urokinase-type plasminogen activator receptor promoter analysis resulted in four putative HIF binding sites. Hypoxia strongly induced de novo transcription of uPAR mRNA. With sequential deletion mutants of the uPAR promoter, it was possible to identify one HIF binding site causing a nearly 200-fold increase in luciferase activity. Hypoxia enhanced the number of invading tumor cells in vitro and in vivo. In contrast, HIF-1beta-deficient cells failed to upregulate uPAR expression, to activate luciferase activity, and to invade on hypoxia. Taken together, we show for the first time that uPAR is under transcriptional control of HIF and that this is important for hypoxia-induced metastasis.


A new carnivorous dinosaur from the Late Jurassic Solnhofen archipelago.
Small Late Jurassic theropod dinosaurs are rare worldwide. In Europe these carnivorous dinosaurs are represented primarily by only two skeletons of Compsognathus, neither of which is well preserved. Here we describe a small new theropod dinosaur from the Late Jurassic period of Schamhaupten in southern Germany. Being exquisitely preserved and complete from the snout to the distal third of the tail, the new fossil is the best-preserved predatory, non-avian dinosaur in Europe. It possesses a suite of characters that support its identification as a basal coelurosaur. A cladistic analysis indicates that the new taxon is closer to maniraptorans than to tyrannosauroids, grouping it with taxa often considered to be compsognathids. Large portions of integument are preserved along its tail. The absence of feathers or feather-like structures in a fossil phylogenetically nested within feathered theropods indicates that the evolution of these integumentary structures might be more complex than previously thought.


Variables affecting outcome in blunt chest trauma: flail chest vs. pulmonary contusion.
We reviewed 144 consecutive patients with flail chest and/or pulmonary contusion between 1979 and 1984. The purpose was to analyze the factors adversely affecting morbidity and mortality. There were 97 males and 47 females, with an average age of 40 years +/- 18 S.D. (range, 2-83). Seventy-five per cent of the injuries were caused by motor vehicle accidents, with the remainder due to falls (17%), cardiopulmonary resuscitation (4%), altercations (2%), or falling objects (2%). The Injury Severity Score (ISS) averaged 32 +/- 14 S.D. in all survivors versus 60 +/- 14 S.D. in those who died. Eighty-three patients (58%) required mechanical ventilation. Thirty-six patients died (25%). Isolated pulmonary contusion or flail chest had a mortality of 16% each. However, the mortality more than doubled when there was a combined pulmonary contusion and flail chest (42%). More than half of all deaths were directly attributed to central nervous system injuries with another third due to massive hemorrhage. Factors that were associated with a higher morbidity and mortality included severe associated thoracic injuries, a high ISS, the presence of shock, falls from heights, and the combination of pulmonary contusion and flail chest.


An adenovirus-derived protein: A novel candidate for anti-diabetic drug development.
Exposure to human adenovirus Ad36 is causatively and correlatively linked with better glycemic control in animals and humans, respectively. Although the anti-hyperglycemic property of Ad36 may offer some therapeutic potential, it is impractical to use an infectious agent for therapeutic benefit. Cell-based studies identified that Ad36 enhances cellular glucose disposal via its E4orf1 protein. Ability to improve glycemic control in vivo is a critical prerequisite for further investigating the therapeutic potential of E4orf1. Therefore, the aim of this study was to determine the ability of E4orf1 to improve glycemic control independent of insulin despite high fat diet. 8-9wk old male C57BL/6J mice fed a high-fat diet (60% kcal) were injected with a retrovirus plasmid expressing E4orf1, or a null vector (Control). Glycemic control was determined by glucose and insulin tolerance test. Islet cell size, amount of insulin and glucagon were determined in formalin-fixed pancreas. Rat insulinoma cell line (832/13) was infected with E4orf1 or control to determine changes in glucose stimulated insulin secretion. Protein from flash frozen adipose tissue depots, liver and muscle was used to determine molecular signaling by western blotting. In multiple experiments, retrovirus-mediated E4orf1 expression in C57BL/6J mice significantly and reproducibly improved glucose excursion following a glucose load despite a high fat diet (60% energy). Importantly, E4orf1 improved glucose clearance without increasing insulin sensitivity, production or secretion, underscoring its insulin-independent effect. E4orf1 modulated molecular signaling in mice tissue, which included greater protein abundance of adiponectin, p-AKT and Glucose transporter Glu4. This study provides the proof of concept for translational development of E4orf1 as a potential anti-diabetic agent. High fat intake and impaired insulin signaling are often associated with obesity, diabetes and insulin resistance. Hence, the ability of E4orf1 to improve glycemic control despite high fat diet and independent of insulin, is particularly attractive.


Enterococcal biofilm formation and virulence in an optimized murine model of foreign body-associated urinary tract infections.
Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial UTIs and pose significant clinical challenges. Enterococcal species are among the predominant causative agents of CAUTIs. However, very little is known about the pathophysiology of Enterococcus-mediated UTIs. We optimized a murine model of foreign body-associated UTI in order to mimic conditions of indwelling catheters in patients. In this model, the presence of a foreign body elicits major histological changes and induces the expression of several proinflammatory cytokines in the bladder. In addition, in contrast to naïve mice, infection of catheter-implanted mice with Enterococcus faecalis induced the specific expression of interleukin 1β (IL-1β) and macrophage inflammatory protein 1α (MIP-1α) in the bladder. These responses resulted in a favorable niche for the development of persistent E. faecalis infections in the murine bladders and kidneys. Furthermore, biofilm formation on the catheter implant in vivo correlated with persistent infections. However, the enterococcal autolytic factors GelE and Atn (also known as AtlA), which are important in biofilm formation in vitro, are dispensable in vivo. In contrast, the housekeeping sortase A (SrtA) is critical for biofilm formation and virulence in CAUTIs. Overall, this murine model represents a significant advance in the understanding of CAUTIs and underscores the importance of urinary catheterization during E. faecalis uropathogenesis. This model is also a valuable tool for the identification of virulence determinants that can serve as potential antimicrobial targets for the treatment of enterococcal infections.


One-unit versus two-unit cord-blood transplantation for hematologic cancers.
Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation. Between December 1, 2006, and February 24, 2012, a total of 224 patients 1 to 21 years of age with hematologic cancer were randomly assigned to undergo double-unit (111 patients) or single-unit (113 patients) cord-blood transplantation after a uniform myeloablative conditioning regimen and immunoprophylaxis for graft-versus-host disease (GVHD). The primary end point was 1-year overall survival. Treatment groups were matched for age, sex, self-reported race (white vs. nonwhite), performance status, degree of donor-recipient HLA matching, and disease type and status at transplantation. The 1-year overall survival rate was 65% (95% confidence interval [CI], 56 to 74) and 73% (95% CI, 63 to 80) among recipients of double and single cord-blood units, respectively (P=0.17). Similar outcomes in the two groups were also observed with respect to the rates of disease-free survival, neutrophil recovery, transplantation-related death, relapse, infections, immunologic reconstitution, and grade II-IV acute GVHD. However, improved platelet recovery and lower incidences of grade III and IV acute and extensive chronic GVHD were observed among recipients of a single cord-blood unit. We found that among children and adolescents with hematologic cancer, survival rates were similar after single-unit and double-unit cord-blood transplantation; however, a single-unit cord-blood transplant was associated with better platelet recovery and a lower risk of GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00412360.).


Observations on animal and human health during the outbreak of Mycobacterium bovis in game farm wapiti in Alberta.
This report describes and discusses the history, clinical, pathologic, epidemiologic, and human health aspects of an outbreak of Mycobacterium bovis infection in domestic wapiti in Alberta between 1990 and 1993, shortly after legislative changes allowing game farming. The extent and seriousness of the outbreak of M. bovis in wapiti in Alberta was not fully known at its onset. The clinical findings in the first recognized infected wapiti are presented and the postmortem records for the herd in which the animal resided are summarized. Epidemiologic findings from the subsequent field investigation are reviewed, the results of recognition and investigation of human exposure are updated, and recommendations for reduction of human exposure are presented.


Compounds isolated from Eriobotrya deflexa leaves protect against ultraviolet radiation B-induced photoaging in human fibroblasts.
Ultraviolet (UV) irradiation leads to skin photoaging because of the upregulation of matrix metalloproteinase (MMP)-1 and downregulation of type I collagen and tissue inhibitor of metalloproteinase (TIMP)-1. Eriobotrya deflexa (Hemsl.) Nakai (Rosaceae) is a flowering plant endemic to Taiwan, and its leaves have been used as an expectorant and in antitussive folk remedy. Our previous studies have demonstrated that an E. deflexa leaf extract functions as a free radical scavenger. The current evaluated the antiphotoaging effect of partitioned fractions and specific compounds from the leaves of E. deflexa by using bioguided isolation, compound identification, and biological activity testing with UVB-irradiated human fibroblasts (WS-1 cells). E. deflexa leaves were extracted with 95% ethanol and then partitioned using a sequential treatment of n-hexane, ethyl acetate, and n-butanol (n-BuOH). The bioactive n-BuOH fraction was used for isolation and purification through chromatography. The compounds were identified by analyzing their physical and spectroscopic properties. We identified eight compounds from this fraction; of these compounds, 3-O-α-l-rhamnopyranosyl-(1‴→6″)-β-d-galactopyranoside (1), hyperin (2), afzelin (5), and cryptochlorogenic acid methyl ester (7) were isolated from E. deflexa for the first time, and they exhibited MMP-1 inhibition activity. The IC50 values were 96.5, 89.5, 93.4, and 92.8μM for 1, 2, 5, and 7, respectively. These compounds also enhanced the expression of procollagen type I, and TIMP-1 and hyperin (2) were found to be most effective with IC50 values of 56.7 and 70.3μM, respectively. Hyperin (2) could reduce intracellular reactive oxygen species production in UVB-irradiated WS-1 cells, with the corresponding IC50 value being 80.7μM. Liquid chromatography triple-quadrupole mass spectrometry was used for the quantitative and chemical fingerprint analysis of active compounds. Quercetin 3-O-α-l-rhamnopyranosyl-(1‴→6″)-β-d-galactopyranoside (1), hyperin (2), afzelin (5), and cryptochlorogenic acid methyl ester (7) constituted 24.2±3.9, 5.5±1.0, 3.4±0.3, and 67.1±8.1mg/g of dry weight in the active n-BuOH fraction, respectively. Our results demonstrate that the extract and the isolated active compounds from E. deflexa leaves possess the potential for protection against skin photoaging.


D2R striatopallidal neurons inhibit both locomotor and drug reward processes.
The specific functions of dopamine D(2) receptor-positive (D(2)R) striatopallidal neurons remain poorly understood. Using a genetic mouse model, we found that ablation of D(2)R neurons in the entire striatum induced hyperlocomotion, whereas ablation in the ventral striatum increased amphetamine conditioned place preference. Thus D(2)R striatopallidal neurons limit both locomotion and, unexpectedly, drug reinforcement.


Do you see what I'm singing? Visuospatial movement biases pitch perception.
The nature of the connection between musical and spatial processing is controversial. While pitch may be described in spatial terms such as "high" or "low", it is unclear whether pitch and space are associated but separate dimensions or whether they share representational and processing resources. In the present study, we asked participants to judge whether a target vocal note was the same as (or different from) a preceding cue note. Importantly, target trials were presented as video clips where a singer sometimes gestured upward or downward while singing that target note, thus providing an alternative, concurrent source of spatial information. Our results show that pitch discrimination was significantly biased by the spatial movement in gesture, such that downward gestures made notes seem lower in pitch than they really were, and upward gestures made notes seem higher in pitch. These effects were eliminated by spatial memory load but preserved under verbal memory load conditions. Together, our findings suggest that pitch and space have a shared representation such that the mental representation of pitch is audiospatial in nature.


Effectiveness of a computer-based educational program on nurses' knowledge, attitude, and skill level related to evidence-based practice.
To conduct a baseline assessment of nurses' perceptions of knowledge, attitude, and skill level related to evidence-based practice (EBP) and research utilisation; determine the level of organisational readiness for implementing EBP and research; and examine the effectiveness of a computer-based educational program on nurses' perceptions of knowledge, attitude, and skill level related to EBP and research utilisation. A descriptive, quasi-experimental design with a one-group, pre-intervention survey, intervention, and post-intervention survey method was used. A convenience sample of 744 nurses working in an integrated health care system was recruited. The study was conducted from May 2006 through November 2006. Data collection instruments were a demographic data questionnaire and the Evidence-Based Nursing Questionnaire. An education intervention on principles of EBP and research utilisation was conducted via three computer-based learning modules. Statistically significant differences in perceptions of knowledge, attitude, and skill level, as well as beliefs about organisational readiness were found after nurses participated in the computer-based education intervention. Although nurses indicated having positive attitudes about using research to support best nursing practice, gaps in knowledge and skills in retrieving research publications, evaluating the evidence, and incorporating the evidence into practice remain. Nurses rated their managers, senior nursing administrators, and staff nurses on their unit higher than hospital managers in supporting changes to practice based on research. Nurses in clinical settings need to be able to use research findings and incorporate EBP into their nursing practice to promote positive patient outcomes. Appropriate organisational infrastructures are essential for promoting EBP and research utilisation in clinical settings. Diverse and effective methods are essential in educating and engaging nurses in EBP and research utilisation. Computer-based education is an effective approach that can be used by nursing leaders in health care organisations to educate and engage nurses in EBP initiatives and research utilisation.


Model-based dynamic off-resonance correction for improved accelerated fMRI in awake behaving nonhuman primates.
To estimate dynamic off-resonance due to vigorous body motion in accelerated fMRI of awake behaving nonhuman primates (NHPs) using the echo-planar imaging reference navigator, in order to attenuate the effects of time-varying off-resonance on the reconstruction. In NHP fMRI, the animal's head is usually head-posted, and the dynamic off-resonance is mainly caused by motion in body parts that are distant from the brain and have low spatial frequency. Hence, off-resonance at each frame can be approximated as a spatially linear perturbation of the off-resonance at a reference frame, and is manifested as a relative linear shift in k-space. Using GRAPPA operators, we estimated these shifts by comparing the navigator at each time frame with that at the reference frame. Estimated shifts were then used to correct the data at each frame. The proposed method was evaluated in phantom scans, simulations, and in vivo data. The proposed method is shown to successfully estimate spatially low-order dynamic off-resonance perturbations, including induced linear off-resonance perturbations in phantoms, and is able to correct retrospectively corrupted data in simulations. Finally, it is shown to reduce ghosting artifacts and geometric distortions by up to 20% in simultaneous multislice in vivo acquisitions in awake-behaving NHPs. A method is proposed that does not need sequence modification or extra acquisitions and makes accelerated awake behaving NHP imaging more robust and reliable, reducing the gap between what is possible with NHP protocols and state-of-the-art human imaging.


Seasonal trends in whale shark Rhincodon typus sightings in an established tourism site in the Gulf of California, Mexico.
The number of individual whale shark Rhincodon typus sightings registered October 2015-March 2018 in Bahia de La Paz, Mexico, ranged from 73 to 129 animals per season (total 1662), with the majority of them identified as males. Density plot maps showed high correlations in sightings between sample seasons and revealed potential hotspot areas. Our study provides an essential baseline of information for the management of whale shark conservation and the associated touristic activities in the region.


Plant integrity: an important factor in plant-pathogen interactions.
The effect of plant integrity and of aboveground-belowground defense signaling on plant resistance against pathogens and herbivores is emerging as a subject of scientific research. There is increasing evidence that plant defense responses to pathogen infection differ between whole intact plants and detached leaves. Studies have revealed the importance of aboveground-belowground defense signaling for plant defenses against herbivores, while our studies have uncovered that the roots as well as the plant integrity are important for the resistance of the potato cultivar Sarpo Mira against the hemibiotrophic oomycete pathogen Phytophthora infestans. Furthermore, in the Sarpo Mira-P. infestans interactions, the plant's meristems, the stalks or both, seem to be associated with the development of the hypersensitive response and both the plant's roots and shoots contain antimicrobial compounds when the aerial parts of the plants are infected. Here, we present a short overview of the evidence indicating the importance of plant integrity on plant defense responses.


The effect of an oral care protocol and honey mouthwash on mucositis in acute myeloid leukemia patients undergoing chemotherapy: a single-blind clinical trial.
The purpose of the study is to evaluate and compare the effectiveness of honey mouthwash and an oral care protocol on mucositis and weight loss in patients with acute myeloid leukemia receiving chemotherapy. In this single-blind clinical trial, 53 acute myeloid leukemia (AML) patients receiving chemotherapy were randomly assigned into three groups: honey mouthwash (n = 17), oral care (n = 17), and control (n = 19). The severity of mucositis and weights was examined blindly at the baseline and 4-week follow-up. The prevalence of grades of mucositis in the study groups was significant at the end of the third (p = 0.002) and fourth (p < 0.001) weeks. The mucositis severity decreased at the end of the third and fourth weeks in the honey mouthwash group (p < 0.05), whereas it increased in the control group (p < 0.001). The difference in the weight was significant between the honey mouthwash and the control groups (p < 0.05, MD = 1.95) at the end of the third week, and between the honey mouthwash group with the control (p < 0.01, MD = 2.92) and oral care groups (p < 0.05, MD = 1.95) at the end of the fourth week. Honey mouthwash is effective in preventing and reducing the severity of mucositis, and weight loss and can be recommended for patients undergoing chemotherapy. The results of this study suggest that honey mouthwash can reduce the incidence and severity of mucositis in patients, reduce or eliminate the possibility of weight loss in them, as well as encourage some weight gain. Compared to routine oral care, honey mouthwash is also easier to use and handle. IRCT2015121419919N7.


Mortality risk prediction in COPD by a prognostic biomarker panel.
Chronic obstructive pulmonary disease (COPD) is a complex disease with various phenotypes. The simultaneous determination of multiple biomarkers reflecting different pathobiological pathways could be useful in identifying individuals with an increased risk of death. We derived and validated a combination of three biomarkers (adrenomedullin, arginine vasopressin and atrial natriuretic peptide), assessed in plasma samples of 385 patients, to estimate mortality risk in stable COPD. Biomarkers were analysed in combination and defined as high or low. In the derivation cohort (n = 142), there were 73 deaths during the 5-year follow-up. Crude hazard ratios for mortality were 3.0 (95% CI 1.8-5.1) for one high biomarker, 4.8 (95% CI 2.4-9.5) for two biomarkers and 9.6 (95% CI 3.3-28.3) for three high biomarkers compared with no elevated biomarkers. In the validation cohort (n = 243), 87 individuals died. Corresponding hazard ratios were 1.9 (95% CI 1.1-3.3), 3.1 (95% CI 1.8-5.4) and 5.4 (95% CI 2.5-11.4). Multivariable adjustment for clinical variables as well as the BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index and stratification by the Global Initiative for Chronic Obstructive Lung Disease stages provided consistent results. The addition of the panel of three biomarkers to the BODE index generated a net reclassification improvement of 57.9% (95% CI 21.7-92.4%) and 45.9% (95% CI 13.9-75.7%) at 3 and 5 years, respectively. Simultaneously elevated levels of adrenomedullin, arginine vasopressin and atrial natriuretic peptide are associated with increased risk of death in patients with stable COPD.


Development and removal ability of non-toxigenic Aspergillus section Flavi in presence of atrazine, chlorpyrifos and endosulfan.
This study evaluated the in vitro effect of three concentrations of atrazine, chlorpyrifos and endosulfan on the growth parameters of four non-toxigenic Aspergillus section Flavi strains. The ability of the strains to remove these pesticides in a synthetic medium was also determined. Growth parameters were measured on soil extract solid medium supplied with 5, 10 and 20mg/l of each pesticide, and conditioned to -0.70, -2.78, -7.06 and -10.0 water potential (MPa). Removal assays were performed in Czapek Doc medium (CZD) supplied with 20mg/l of each pesticide under optimal environmental conditions (-2.78 of MPa and 25°C). The residual levels of each pesticide were detected by the reversed-phase HPLC/fluorescence detection system. The lag phases of the strains significantly decreased in the presence of the pesticides with respect to the control media. This result indicates a fast adaptation to the conditions assayed. Similarly, the mycelial growth rates in the different treatments increased depending on pesticide concentrations. Aspergillus oryzae AM 1 and AM 2 strains showed high percentages of atrazine degradation (above 90%), followed by endosulfan (56 and 76%) and chlorpyrifos (50 and 73%) after 30 days of incubation. A significant (p<0.001) correlation (r=0.974) between removal percentages and growth rate was found. This study shows that non-toxigenic Aspergillus section Flavi strains from agricultural soils are able to effectively grow in the presence of high concentrations of atrazine, chlorpyrifos and endosulfan under a wide range of MPa conditions. Moreover, these strains have the ability to remove high levels of these pesticides in vitro in a short time.


Fine Mapping and Identification of BMI Loci in African Americans.
Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.


Reliability of leg muscle electromyography in vertical jumping.
In this study we aimed to determine the reliability of the surface electromyography (EMG) of leg muscles during vertical jumping between two test sessions, held 2 weeks apart. Fifteen females performed three maximal vertical jumps with countermovement. The displacement of the body centre of mass (BCM), duration of propulsion phase (time), range of motion (ROM) and angular velocity of the knee and surface EMG of four leg muscles (rectus femoris, vastus medialis. biceps femoris and gastrocnemius) were recorded during the jumps. All variables were analysed throughout the propulsion and mid-propulsion phases. Intraclass correlation coefficients (ICC) for the rectus femoris, vastus medialis, biceps femoris and gastrocnemius were calculated to be 0.88, 0.70, 0.24 and 0.01, respectively. BCM, ROM and time values all indicated ICC values greater than 0.90, and the mean knee angular velocity was slightly lower, at 0.75. ICCs between displacement of the BCM and integrated EMG (IEMG) of the muscles studied were less than 0.50. The angular velocity of the knee did not correlate well with muscle activity. Factors that may have affected reliability were variations in the position of electrode replacement, skin resistance, cross-talk between muscles and jump mechanics. The results of this study suggest that while kinematic variables are reproducible over successive vertical jumps, the degree of repeatability of an IEMG signal is dependent upon the muscle studied.


A randomized phase 2 study of erlotinib alone and in combination with bortezomib in previously treated advanced non-small cell lung cancer.
This phase 2 study was conducted to determine the efficacy and safety of erlotinib alone and with bortezomib in patients with non-small cell lung cancer (NSCLC). Patients with histologically or cytologically confirmed relapsed or refractory stage IIIb/IV NSCLC were randomized (1:1; stratified by baseline histology, smoking history, sex) to receive erlotinib 150 mg/d alone (arm A; n = 25) or in combination with bortezomib 1.6 mg/m2, days 1 and 8 (arm B; n = 25) in 21-day cycles. Responses were assessed using Response Evaluation Criteria in Solid Tumors. Tumor samples were evaluated for mutations predicting response. Six additional patients received the combination in a prior dose deescalation stage and were included in safety analyses. Response rates were 16% in arm A and 9% in arm B; disease control rates were 52 and 45%, respectively. The study was halted at the planned interim analysis due to insufficient clinical activity in arm B. Median progression-free survival and overall survival were 2.7 and 7.3 months in arm A, and 1.3 and 8.5 months in arm B. Six-month survival rates were 56.0% in both arms; 12-month rates were 40 and 30% in arms A and B, respectively. Response rate to erlotinib+/-bortezomib was significantly higher in patients with epidermal growth factor receptor mutations (50 versus 9% for wild type). The most common treatment-related grade > or =3 adverse event was skin rash (three patients in each treatment group). Insufficient activity was seen with erlotinib plus bortezomib in patients with relapsed/refractory advanced NSCLC to warrant a phase 3 study of the combination.


A mathematical model for analysis of the cell cycle in cell lines derived from human tumors.
The growth of human cancers is characterised by long and variable cell cycle times that are controlled by stochastic events prior to DNA replication and cell division. Treatment with radiotherapy or chemotherapy induces a complex chain of events involving reversible cell cycle arrest and cell death. In this paper we have developed a mathematical model that has the potential to describe the growth of human tumour cells and their responses to therapy. We have used the model to predict the response of cells to mitotic arrest, and have compared the results to experimental data using a human melanoma cell line exposed to the anticancer drug paclitaxel. Cells were analysed for DNA content at multiple time points by flow cytometry. An excellent correspondence was obtained between predicted and experimental data. We discuss possible extensions to the model to describe the behaviour of cell populations in vivo.


Differences in fatigue severity in a sample of adult cancer patients.
To describe differences in fatigue severity in a sample of adult Puerto Rican patients during and postcancer treatments. Hispanics, including Puerto Ricans, are an understudied population who are under-represented in clinical trials, especially in symptom research. Although symptom management is a clinical priority in oncology care, treatment-related differences in Puerto Rican cancer patients' report of fatigue severity have not been well described. A cross-sectional survey was conducted from data of self-report of 138 Puerto Rican patients during and postcancer treatments at two ambulatory facilities located in San Juan, Puerto Rico. Fatigue severity was assessed using the Fatigue subscale from the Functional Assessment of Cancer Therapy-Fatigue quality of life questionnaire Spanish version. Differences in fatigue severity across type of treatment (radiation therapy, chemotherapy, combined radiation chemotherapy and post-treatment) were evaluated using nonparametric (Kruskal-Wallis and Mann-Whitney test) statistical tests. The majority of the participants had prostate (33%) and breast (32%) cancers and were receiving radiation therapy (43%) or chemotherapy (28%). The Kruskal-Wallis test showed that there was a statistically significant difference in fatigue scores between the different four treatment conditions, χ2 (3) = 39.1, p = .001 with patients on combined radiation chemotherapy or chemotherapy alone experiencing more severe fatigue. Findings from the current study suggest that type of treatment is a key component of the symptom burden of fatigue among the Puerto Rican oncology population. Specially, patients receiving combined therapy or chemotherapy alone were at increased risk for experiencing severe fatigue, compared to radiation therapy and post-treatment patients. With the worldwide increase in migration of Puerto Rican families, nurses need to recognise that type of treatment is a key component of the symptom burden of fatigue among the Puerto Rican population. The results of this study will improve understanding of treatment-related fatigue to identify therapeutic targets and improve quality of life of patients.


Status of respiratory care profession in Saudi Arabia: A national survey.
Respiratory care (RC) is an allied health profession that involves assessing and treating patients who have pulmonary diseases. Research indicates that respiratory therapists' (RT's) involvement in caring for patients with respiratory disorders improves important outcome measures. In Kingdome of Saudi Arabia (KSA), RC has been practiced by RTs for more than 30 years. We sought to investigate the status of the RC workforce in Saudi Arabia in terms of demographic distribution, number, education, and RC service coverage. We used a specially designed survey to collect data. A list of 411 working hospitals in KSA was obtained. All hospitals were contacted to inquire if RC is practiced by RTs. Data were collected from hospitals that employ RTs. Only 88 hospitals, 21.4% of total hospitals in the country, have RTs. Out of the 244 Ministry of Health (MOH) hospitals, only 31 hospitals (12.7%) employ RTs. There are 1,477 active RTs in KSA. Twenty-five percent of them, or 371, are Saudis. The majority of the RT workforce (60%) work for non-MOH government hospitals, and almost half the total RTs work in Riyadh province. About 60% of RTs work in critical care settings. RC coverage of critical care was 44.5% of ideal. The overall RT-to-ICU bed ratio was 1:11. The ratio was 1:9 for non-MOH government hospitals, and 1:20 for MOH hospitals. We report the first insightful data on RC workforce in KSA. These data should be used by educational institutions and health policy makers to plan better RC coverage in the country.


HCV-infected cells and differentiation increase monocyte immunoregulatory galectin-9 production.
The lectin galectin-9 may help establish and maintain chronic hepatitis C virus infection. Galectin-9 is elevated in the liver and sera of hepatitis C virus patients, induces apoptosis of hepatitis C virus-specific T cells, and increases inhibitory regulatory T cells. Kupffer cells stain strongly for galectin-9 protein in hepatitis C virus patients. In the current study, we determined stimuli that induce galectin-9 production by monocytes and macrophages in hepatitis C virus infection. With the use of real-time PCR and flow cytometry, we analyzed galectin-9 mRNA and protein from human monocytes cocultured with hepatitis C virus-infected cells or noninfectious hepatitis C virus subgenomic replicon cells. We focused on finding the stimuli for galectin-9 production. Additionally, we measured galectin-9 during monocyte-to-macrophage maturation. Finally, we examined galectin-9 in peripheral monocytes from hepatitis C virus patients using flow cytometry. Galectin-9 mRNA increased 8-fold when primary monocytes were exposed to hepatitis C virus--infected cells. Maximum induction required proximity or contact and did not require IFN-γ or hepatitis C virus virions. Coculture of monocytes with subgenomic replicon cells increased galectin-9 5-fold, and purified exosomes from infected cells stimulated galectin-9 production. Stimulation of monocyte TLR3, -7, and -8 increased galectin-9 production. Differentiation of monocytes to macrophages increased galectin-9, and nonclassic monocytes from hepatitis C virus patients had the highest levels of galectin-9. Hepatitis C virus-infected cells stimulated monocytes to produce galectin-9 in close proximity, possibly, in part, as a result of exosomes and endosomal TLRs. Differentiation of monocytes to macrophages increased galectin-9. Nonclassic monocytes from hepatitis C virus patients express the highest galectin-9 levels, suggesting they may contribute to elevated galectin-9 and adaptive immune inhibition in hepatitis C virus infection.


MTH1 and RGT1 demonstrate combined haploinsufficiency in regulation of the hexose transporter genes in Saccharomyces cerevisiae.
The SNF3 gene in the yeast Saccharomyces cerevisiae encodes a low glucose sensor that regulates expression of an important subset of the hexose transporter (HXT) superfamily. Null mutations of snf3 result in a defect in growth on low glucose concentrations due to the inability to relieve repression of a subset of the HXT genes. The snf3 null mutation phenotype is suppressed by the loss of either one of the downstream co-repressor proteins Rgt1p or Mth1p. The relief of repression allows expression of HXT transporter proteins, the resumption of glucose uptake and therefore of growth in the absence of a functional Snf3 sensor. Strains heterozygous for both the RGT1 and MTH1 genes (RGT1/rgt1Δ MTH1/mth1Δ snf3Δ/snf3Δ) but homozygous for the snf3∆ were found to grow on low glucose. Since null alleles in the heterozygous state lead to suppression, MTH1 and RGT1 display the phenomenon of combined haploinsufficiency. This observed haploinsufficiency is consistent with the finding of repressor titration as a mechanism of suppression of snf3. Mutants of the STD1 homolog of MTH1 did not display haploinsufficiency singly or in combination with mutations in RGT1. HXT gene reporter fusion assays indicated that the presence of heterozygosity at the MTH1 and RGT1 alleles leads to increased expression of the HXT2 gene. Deletion of the HXT2 gene in a heterozygous diploid, RGT1/rgt1Δ MTH1/mth1Δ snf3Δ/snf3Δ hxt2Δ/hxt2Δ, prevented the suppression of snf3Δ. These findings support the model of relief of repression as the mechanism of restoration of growth on low glucose concentrations in the absence of functional Snf3p. Further, the observation that HXT2 is the gene responsible for restoration of growth under these conditions suggests that the numbers of repressor binding domains found in the regulatory regions of members of the HXT family may have biological relevance and enable differential regulation.


Medical and psychosocial services in drug abuse treatment: do stronger linkages promote client utilization?
To examine the extent to which linkage mechanisms (on-site delivery, external arrangements, case management, and transportation assistance) are associated with increased utilization of medical and psychosocial services in outpatient drug abuse treatment units. Survey of administrative directors and clinical supervisors from a nationally representative sample of 597 outpatient drug abuse treatment units in 1995. We generated separate two-stage multivariate generalized linear models to evaluate the correlation of on-site service delivery, formal external arrangements (joint program/venture or contract), referral agreements, case management, and transportation with the percentage of clients reported to have utilized eight services: physical examinations, routine medical care, tuberculosis screening, HIV treatment, mental health care, employment counseling, housing assistance, and financial counseling services. On-site service delivery and transportation assistance were significantly associated with higher levels of client utilization of ancillary services. Referral agreements and formal external arrangements had no detectable relationship to most service utilization. On-site case management was related to increased clients' use of routine medical care, financial counseling, and housing assistance, but off-site case management was not correlated with utilization of most services. On-site service delivery appears to be the most reliable mechanism to link drug abuse treatment clients to ancillary services, while referral agreements and formal external mechanisms offer little detectable advantage over ad hoc referral. On-site case management might facilitate utilization of some services, but transportation seems a more important linkage mechanism overall. These findings imply that initiatives and policies to promote linkage of such clients to medical and psychosocial services should emphasize on-site service delivery, transportation and, for some services, on-site case management.


C²Maps: a network pharmacology database with comprehensive disease-gene-drug connectivity relationships.
Network pharmacology has emerged as a new topic of study in recent years. It aims to study the myriad relationships among proteins, drugs, and disease phenotypes. The concept of molecular connectivity maps has been proposed to establish comprehensive knowledge links between molecules of interest in a given biological context. Molecular connectivity maps between drugs and genes/proteins in specific disease contexts can be particularly valuable, since the functional approach with these maps helps researchers gain global perspectives on both the therapeutic profiles and toxicological profiles of candidate drugs. To assess drug pharmacological effect, we assume that "ideal" drugs for a patient can treat or prevent the disease by modulating gene expression profiles of this patient to the similar level with those in healthy people. Starting from this hypothesis, we build comprehensive disease-gene-drug connectivity relationships with drug-protein directionality (inhibit/activate) information based on a computational connectivity maps (C²Maps) platform. An interactive interface for directionality annotation of drug-protein pairs with literature evidences from PubMed has been added to the new version of C²Maps. We also upload the curated directionality information of drug-protein pairs specific for three complex diseases - breast cancer, colorectal cancer and Alzheimer disease. For relevant drug-protein pairs with directionality information, we use breast cancer as a case study to demonstrate the functionality of disease-specific searching. Based on the results obtained from searching, we perform pharmacological effect evaluation for two important breast cancer drugs on treating patients diagnosed with different breast cancer subtypes. The evaluation is performed on a well-studied breast cancer gene expression microarray dataset to portray how useful the updated C²Maps is in assessing drug efficacy and toxicity information. The C²Maps platform is an online bioinformatics resource that provides biologists with directional relationships between drugs and genes/proteins in specific disease contexts based on network mining, literature mining, and drug effect annotating. A new insight to assess overall drug efficacy and toxicity can be provided by using the C²Maps platform to identify disease relevant proteins and drugs. The case study on breast cancer correlates very well with the existing pharmacology of the two breast cancer drugs and highlights the significance of C²Maps database.


Limited Coping Skills, Young Age, and High BMI Are Risk Factors for Injuries in Contemporary Dance: A 1-Year Prospective Study.
This study investigated potential risk factors (coping, perfectionism, and self-regulation) for substantial injuries in contemporary dance students using a prospective cohort design, as high-quality studies focusing on mental risk factors for dance injuries are lacking. Student characteristics (age, sex, BMI, educational program, and history of injury) and psychological constructs (coping, perfectionism, and self-regulation) were assessed using the Performing artist and Athlete Health Monitor (PAHM), a web-based system. Substantial injuries were measured with the Oslo Sports Trauma Research Center (OSTRC) Questionnaire on Health Problems and recorded on a monthly basis as part of the PAHM system. Univariate and multivariate logistic regression analyses were conducted to test the associations between potential risk factors (i.e., student characteristics and psychological constructs) and substantial injuries. Ninety-nine students were included in the analyses. During the academic year 2016/2017, 48 students (48.5%) reported at least one substantial injury. Of all factors included, coping skills (OR: 0.91; 95% CI: 0.84-0.98), age (OR: 0.67; 95% CI: 0.46-0.98), and BMI (OR: 1.38; 95% CI: 1.05-1.80) were identified as significant risk factors in the multivariate analysis. The model explained 24% of the variance in the substantial injury group. Further prospective research into mental risk factors for dance injuries with larger sample sizes is needed to develop preventive strategies. Yet, dance schools could consider including coping skills training as part of injury prevention programs and, perhaps, providing special attention to younger dancers and those with a higher BMI through transitional programs to assist them in managing the stress they experience throughout their (academic) career.


The relationship between literacy and health.
In non-industrialized countries, populations with the lowest literacy rates have the poorest health status. In the United States, however, there is no published research on whether illiteracy, independently of other sociodemographic factors, is related to health status. There are numerous plausible mechanisms by which such a relationship could occur. For example, published reports indicate that most information handouts, consent forms, and other materials for patients are written at reading levels too difficult for most American adults. These and other findings may have important implications in the health care of underserved populations. Research is needed to determine the health effects of impaired literacy skills among Americans, and to develop non-literacy-dependent methods for providing patient education, obtaining informed consent, and administering diagnostic tests.


Rare Earth elements in returned lunar samples.
A linear correlation between concentrations of Sm and ratios of Sm to Eu for nine lunar samples suggests that those samples could correspond to liquids from equilibrium partial melting of a common source. On the basis of partition coefficients in terrestrial systems, the fraction of melting would not have exceeded about 15 percent and the immediate source could have been composed of olivine, orthopyroxene, and opaque minerals plus at least 25 percent feldspar, with at most a few percent calcic clinopyroxene and less than 1 percent apatite. The large Eu depletions could also have been produced by fractional crystallization if the ratio of Eu(2+) to Eu(3+) in lunar magmas significantly exceeds the values for terrestrial magmas.


Generation and analysis of infectious virus-like particles of uukuniemi virus (bunyaviridae): a useful system for studying bunyaviral packaging and budding.
In the present report we describe an infectious virus-like particle (VLP) system for the Uukuniemi (UUK) virus, a member of the Bunyaviridae family. It utilizes our recently developed reverse genetic system based on the RNA polymerase I minigenome system for UUK virus used to study replication, encapsidation, and transcription by monitoring reporter gene expression. Here, we have added the glycoprotein precursor expression plasmid together with the minigenome, nucleoprotein, and polymerase to generate VLPs, which incorporate the minigenome and are released into the supernatant. The particles are able to infect new cells, and reporter gene expression can be monitored if the trans-acting viral proteins (RNA polymerase and nucleoprotein) are also expressed in these cells. No minigenome transfer occurred in the absence of glycoproteins, demonstrating that the glycoproteins are absolutely required for the generation of infectious particles. Moreover, expression of glycoproteins alone was sufficient to produce and release VLPs. We show that the ribonucleoproteins (RNPs) are incorporated into VLPs but are not required for the generation of particles. Morphological analysis of the particles by electron microscopy revealed that VLPs, either with or without minigenomes, display a surface morphology indistinguishable from that of the authentic UUK virus and that they bud into Golgi vesicles in the same way as UUK virus does. This infectious VLP system will be very useful for studying the bunyaviral structural components required for budding and packaging of RNPs and receptor binding and may also be useful for the development of new vaccines for the human pathogens from this family.


Patterns of Substance Use During Early Pregnancy and Associations With Behavioral Health Characteristics.
The aims of the study are to identify patterns of early pregnancy substance use and to examine how these patterns relate to behavioral health conditions measured in early pregnancy. We conducted a retrospective observational study (N= 265,274 pregnancies) screened for alcohol, cannabis, nicotine, pharmaceutical opioids, and stimulants during the first trimester via self-report and urine toxicology tests in Kaiser Permanente Northern California from January 1, 2012, to December 31, 2019. To identify patterns of prenatal substance use, we conducted latent class analysis. We then calculated the prevalence of depression, anxiety, intimate partner violence, and family drug use history for each prenatal substance use group and compared the prevalences by estimating prevalence ratios using modified Poisson regression, adjusting for sociodemographic characteristics. We identified the following 4 latent groups with different patterns of substance use: ( a ) predominantly alcohol and no other substances (9.30%), ( b ) predominantly cannabis and no other substances (4.88%), ( c ) predominantly nicotine and some pharmaceutical opioids (1.09%), and ( d ) high-polysubstance (alcohol, cannabis, nicotine, and stimulants; 0.36%); these pregnancies were compared with ( e ) no prenatal substance use (84.37%). The prevalence of all behavioral health conditions was elevated in all prenatal substance use groups compared with the no substance use group. Furthermore, the prevalence of depressive and anxiety disorders, intimate partner violence and family drug use history were greater in the high-polysubstance cluster than the alcohol and cannabis clusters. Results highlight the importance of screening and interventions for all types of substance use during early pregnancy and suggest a particularly high need to prioritize targeting early interventions to pregnant and reproductive age individuals with polysubstance use.


Prevalence of Arrhythmias in Dogs Examined between 2008 and 2014.
The prevalence of arrhythmias in dogs and the influence of sex, breed, age, and body weight were analysed over a seven-year span. In total, 1189 referrals for cardiological examination by electrocardiography were received at one academic centre in Poland between 2008 and 2014. The largest proportion of the examined dogs were cross-breeds with body weight below 25 kg (n = 153, 12.87%), followed by German Shepherds (n = 122, 10.26%), Labrador Retrievers (n = 68, 5.72%), Yorkshire Terriers (n = 63, 5.3%), and Boxers (n = 60, 5.05%). Retrospective analysis was made of 1201 standing or right recumbent electrocardiograms without pharmacological sedation. The prevalence of arrhythmias was examined in terms of sex, age, body weight, and breed of the dogs. A total of 630 (52.46%) electrocardiograms showed no signs of arrhythmia, but 96 (7.99%) and 475 (39.55%) pointed to physiological and pathological arrhythmias respectively. The most commonly diagnosed type was atrial fibrillation with 33.68% incidence, followed by ventricular arrhythmias (28%), sinus pauses (27.58%), supraventricular arrhythmias (24%), and atrioventricular blocks (22.95%). Pathological arrhythmias were most commonly found in male dogs and in German Shepherds. Atrial fibrillation predominated, followed by premature ventricular complexes. Male dogs were generally more prone to heart rhythm disturbances.


AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia.
Resistance to or intolerance of imatinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC50 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.


Diagnosing multiple parasitic infections: trypanosomiasis, loiasis and schistosomiasis in a single case.
A case is reported of a 32-year-old traveller with loiasis, schistosomiasis and African trypanosomiasis. The patient had been working in oil exploration in Nigeria and Gabon and presented with Calabar swellings and carpal tunnel syndrome. Serology for all 3 diseases was positive but microfilariae of Loa loa and ova of schistosomiasis were not found. Treatment with diethylcarbamazine and praziquantel was given for loiasis and schistosomiasis respectively. Trypanosomes were isolated from a lymph node aspirate only after repetition of the procedure 2 months later and the patient was treated with suramin. He developed a drug induced nephritis and was then treated successfully with alpha-difluoromethylornithine. There is a discussion of the difficulties encountered making these diagnoses in Europeans particularly where there are atypical clinical features. The risks of rural work in West Africa are noted and the importance of considering all parasitic diseases relevant to the travel/occupational history is emphasised.


Mass spectrometric characterization of limited proteolysis activity in human plasma samples under mild acidic conditions.
We developed a limited proteolysis assay for estimating dynamics in plasma-borne protease activities using MALDI ToF MS analysis as readout. A highly specific limited proteolysis activity was elicited in human plasma by shifting the pH to 6. Mass spectrometry showed that two singly charged ion signals at m/z 2753.44 and m/z 2937.56 significantly increased in abundance under mild acidic conditions as a function of incubation time. For proving that a provoked proteolytic activity in mild acidic solution caused the appearance of the observed peptides, control measurements were performed (i) with pepstatin as protease inhibitor, (ii) with heat-denatured samples, (iii) at pH 1.7, and (iv) at pH 7.5. Mass spectrometric fragmentation analysis showed that the observed peptides encompass the amino acid sequences 1-24 and 1-26 from the N-terminus of human serum albumin. Investigations on peptidase specificities suggest that the two best candidates for the observed serum albumin cleavages are cathepsin D and E. Reproducibility, robustness, and sensitivity prove the potential of the developed limited proteolysis assay to become of clinical importance for estimating dynamics of plasma-borne proteases with respect to associated pathophysiological tissue conditions.


Clinical geneticists' views of VACTERL/VATER association.
VACTERL association (sometimes termed "VATER association" depending on which component features are included) is typically defined by the presence of at least three of the following congenital malformations, which tend to statistically co-occur in affected individuals: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. Although the clinical criteria for VACTERL association may appear to be straightforward, there is wide variability in the way clinical geneticists define the disorder and the genetic testing strategy they use when confronted with an affected patient. In order to describe this variability and determine the most commonly used definitions and testing modalities, we present the results of survey responses by 121 clinical geneticists. We discuss the results of the survey responses, provide a literature review and commentary from a group of physicians who are currently involved in clinical and laboratory-based research on VACTERL association, and offer an algorithm for genetic testing in patients with this association.


The tube versus trabeculectomy study: design and baseline characteristics of study patients.
The Tube Versus Trabeculectomy (TVT) Study will compare the safety and efficacy of nonvalved tube shunt surgery to trabeculectomy with mitomycin C in patients with previous intraocular surgery. Multicenter randomized clinical trial. 17 Clinical Centers. Patients 18 to 85 years of age who have undergone previous trabeculectomy, cataract extraction with intraocular lens implantation, or both and have inadequately controlled glaucoma with intraocular pressure (IOP) >or=18 mm Hg and <or=40 mm Hg on tolerated medical therapy. Study patients were randomized to undergo placement of a 350-mm(2) Baerveldt glaucoma implant or trabeculectomy with mitomycin C (0.4 mg/ml for 4 minutes). IOP, complication rates, visual acuity, visual field, quality of life, reoperations for glaucoma, and need for supplemental medical therapy. A total of 212 patients were enrolled between October 1999 and April 2004. The age of the study population was 71.0 +/- 10.4 years (mean +/- SD), and 53% were women. The baseline IOP was 25.3 +/- 5.3 mm Hg (mean +/- SD). There were no significant differences in the demographic and ocular characteristics between the 2 treatment groups. Practice patterns vary in the surgical management of glaucoma, and there are differing opinions among glaucoma surgeons regarding the preferred surgical approach in patients who have undergone previous cataract extraction and/or failed filtering surgery. Forthcoming data from the TVT Study should provide valuable information comparing two surgical procedures commonly used in this patient population.


Coagulant plus ballast technique provides a rapid mitigation of cyanobacterial nuisance.
Cyanobacteria blooms are a risk to environmental health and public safety due to the potent toxins certain cyanobacteria can produce. These nuisance organisms can be removed from water bodies by biomass flocculation and sedimentation. Here, we studied the efficacy of combinations of a low dose coagulant (poly-aluminium chloride-PAC-or chitosan) with different ballast compounds (red soil, bauxite, gravel, aluminium modified zeolite and lanthanum modified bentonite) to remove cyanobacterial biomass from water collected in Funil Reservoir (Brazil). We tested the effect of different cyanobacterial biomass concentrations on removal efficiency. We also examined if zeta potential was altered by treatments. Addition of low doses of PAC and chitosan (1-8 mg Al L-1) to the cyanobacterial suspensions caused flock formation, but did not settle the cyanobacteria. When those low dose coagulants were combined with ballast, effective settling in a dose-dependent way up to 99.7% removal of the flocks could be achieved without any effect on the zeta potential and thus without potential membrane damage. Removal efficacy was influenced by the cyanobacterial biomass and at higher biomass more ballast was needed to achieve good removal. The combined coagulant-ballast technique provides a promising alternative to algaecides in lakes, ponds and reservoirs.