Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.
The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.


Imaging Protocols in Clinical Studies in Advanced Age-Related Macular Degeneration: Recommendations from Classification of Atrophy Consensus Meetings.
To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. A panel of retina specialists. During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.


Two-wavelength, passive self-injection-controlled operation of diode-pumped cw Yb-doped crystal lasers.
We demonstrate and investigate a peculiar mode of cw Yb3+-doped crystal laser operation when two emissions, at two independently tunable wavelengths, are simultaneously produced. Both emissions are generated from a single pumped volume and take place in either a single beam or spatially separated beams. The laser employs original two-channel cavities that use a passive self-injection-locking (PSIL) control to reduce intracavity loss. The advantages of the application of the PSIL technique and some limitations are shown. The conditions for two-wavelength multimode operation of the cw quasi-three-level diode-pumped Yb3+ lasers and the peculiarity of such an operation are carried out both theoretically and experimentally. The results reported are based on the example of a Yb3+:GGG laser but similar results are also obtained with a Yb3+:YAG laser. The laser operates in the 1023-1033-nm (1030-1040-nm) range with a total output power of 0.4 W. A two-wavelength, single longitudinal mode generation is also obtained.


Lymphocyte dysfunction after DNA damage by toxic oxygen species. A model of immunodeficiency.
The metabolic causes for immune impairment in patients with severe chronic inflammatory diseases have not been clearly defined. Recently, the overproduction of poly(ADP-ribose) in resting lymphocytes with unrepaired DNA strand breaks has been suggested to contribute to immune dysfunction in adenosine deaminase-deficient patients. Our experiments have determined to what extent DNA damage and poly(ADP-ribose) synthesis might also explain the impaired mitogen responsiveness of PBL exposed to toxic oxygen species. Treatment of normal resting human lymphocytes with xanthine oxidase and hypoxanthine dose-dependently induced DNA strand breaks and triggered the rapid synthesis of poly(ADP-ribose). Subsequently, NAD+ and ATP pools decreased precipitously. Lymphocytes exposed previously to the enzymatic oxidizing system did not synthesize DNA after stimulation with PHA. However, if the medium was supplemented with 3-aminobenzamide or nicotinamide, two compounds that inhibit poly(ADP-ribose) formation, cellular NAD+ and ATP pools were preserved, and the lymphocytes responded vigorously to a mitogenic challenge. Excessive poly(ADP-ribose) synthesis, provoked by DNA strand breakage, may represent a common pathway that connects the immunodeficiency syndromes associated with (a) exposure of lymphocytes to toxic oxygen species during chronic inflammatory states, (b) adenosine deaminase deficiency, and (c) certain DNA repair disorders.


Improved single channel backpropagation for intra-channel fiber nonlinearity compensation in long-haul optical communication systems.
Backpropagation has been shown to be the most effective method for compensating intra-channel fiber nonlinearity in long-haul optical communications systems. However, effective compensation is computationally expensive, as it requires numerous steps and possibly increased sampling rates compared with the baud rate. This makes backpropagation difficult to implement in real-time. We propose: (i) low-pass filtering the compensation signal (the intensity waveform used to calculate the nonlinearity compensation) in each backpropagation step and (ii) optimizing the position of the nonlinear section in each step. With numerical simulations, we show that these modifications to backpropagation improve system performance, reducing the number of backpropagation steps and reducing the oversampling for a given system performance. Using our 'filtered backpropagation', with four backpropagation steps operating at the same sampling rate as that required for linear equalizers, the Q at the optimal launch power was improved by 2 dB and 1.6 dB for single wavelength CO-OFDM and CO-QPSK systems, respectively, in a 3200 km (40 x 80 km) single-mode fiber link, with no optical dispersion compensation. With previously proposed backpropagation methods, 40 steps were required to achieve an equivalent performance. A doubling in the sampling rate of the OFDM system was also required. We estimate this is a reduction in computational complexity by a factor of around ten.


Income inequality and child welfare interventions in England and Wales.
Previous research has identified a relationship between income inequality and child abuse and neglect in the USA. This association has received limited exploration outside the USA. Administrative data on child protection (CP) in 172 English and Welsh local authorities between 2013 and 2018 were combined with data on deprivation, ethnic density and education from publicly available data sources. Commercial income data were used for Gini coefficient estimation. We tested whether similar evidence for three key findings from a US study could be found in England and Wales. These included whether there was evidence of a relationship between income inequality and child maltreatment, whether this relationship was non-linear and whether this relationship varied dependent on the level of poverty. There was a significant non-linear relationship between income inequality and state care rates in England and Wales. Predicted state care rates were higher as income inequality increased, up until around average levels where the effect flattens. However, there was no significant relationship for models predicting CP plan/register rates. Income inequality, income deprivation, ethnic density and higher education were able to explain around 75% of the variance in English and Welsh state care rates. There is some evidence to support the claim of a relationship between income inequality and child maltreatment beyond the USA in England and Wales, and a case for further comparative research, but there are significant limitations in the comparability of data.


Chemically-modified graphenes for oxidation of DNA bases: analytical parameters.
We studied the electroanalytical performances of chemically-modified graphenes (CMGs) containing different defect densities and amounts of oxygen-containing groups, namely graphite oxide (GPO), graphene oxide (GO), thermally reduced graphene oxide (TR-GO) and electrochemically reduced graphene oxide (ER-GO) by comparing the sensitivity, selectivity, linearity and repeatability towards the oxidation of DNA bases. We have observed that for differential pulse voltammetric (DPV) detection of adenine and cytosine, all CMGs showed enhanced sensitivity to oxidation, while for guanine and thymine, ER-GO and TR-GO exhibited much improved sensitivity over bare glassy carbon (GC) as well as over GPO and GO. There is also significant selectivity enhancement when using GPO for adenine and TR-GO for thymine. Our results have uncovered that the differences in surface functionalities, structure and defects of various CMGs largely influence their electrochemical behaviour in detecting the oxidation of DNA bases. The findings in this report will provide a useful guide for the future development of label-free electrochemical devices for DNA analysis.


Generic HPLC platform for automated enzyme reaction monitoring: Advancing the assay toolbox for transaminases and other PLP-dependent enzymes.
Methods for rapid and direct quantification of enzyme kinetics independent of the substrate stand in high demand for both fundamental research and bioprocess development. This study addresses the need for a generic method by developing an automated, standardizable HPLC platform monitoring reaction progress in near real-time. The method was applied to amine transaminase (ATA) catalyzed reactions intensifying process development for chiral amine synthesis. Autosampler-assisted pipetting facilitates integrated mixing and sampling under controlled temperature. Crude enzyme formulations in high and low substrate concentrations can be employed. Sequential, small (1 µL) sample injections and immediate detection after separation permits fast reaction monitoring with excellent sensitivity, accuracy and reproducibility. Due to its modular design, different chromatographic techniques, e.g. reverse phase and size exclusion chromatography (SEC) can be employed. A novel assay for pyridoxal 5'-phosphate-dependent enzymes is presented using SEC for direct monitoring of enzyme-bound and free reaction intermediates. Time-resolved changes of the different cofactor states, e.g. pyridoxal 5'-phosphate, pyridoxamine 5'-phosphate and the internal aldimine were traced in both half reactions. The combination of the automated HPLC platform with SEC offers a method for substrate-independent screening, which renders a missing piece in the assay and screening toolbox for ATAs and other PLP-dependent enzymes.


Cranial nerve root entry zone primary cerebellopontine angle gliomas: a rare and poorly recognized subset of extraparenchymal tumors.
With the exception of patients with neurofibromatosis type II, pediatric extraparenchymal cerebellopontine angle (CPA) tumors of any sort are extremely rare. Most gliomas encountered in the CPA in either children or adults involve the CPA as exophytic extensions of primary brain stem and/or cerebellar tumors. We encountered an unusual case of a giant CPA pilocytic astrocytoma arising from the proximal trigeminal nerve, completely separate from the brain stem. A nine-year-old girl with no evidence for any neurocutaneous syndrome, presented with headaches, mild obstructive hydrocephalus, trigeminal hypesthesia and a subtle peripheral facial paresis. Pre-operative neuroimaging suggested a petroclival meningioma. The tumor was completely resected via a right pre-sigmoid, retro-labyrinthine, subtemporal, transtentorial ('petrosal') approach, using intraoperative neurophysiological monitoring, with minimal morbidity. This appears to be the first reported case of a pediatric primary CPA glioma and the seventh reported case of primary CPA glioma, overall. It represents the second reported case of a primary CPA pilocytic astrocytoma. Given the findings in this case and the six other cases of primary CPA gliomas reported in the literature, as well as the results of histological studies of normal cranial nerves, we hypothesize that the point of origin of these rare and unusual tumors is the root entry zone of the involved cranial nerves. The differential diagnosis of primary CPA tumors should be expanded to include cranial nerve root entry zone primary CPA gliomas.


Rapid detection of lactate dehydrogenase and genotyping of Plasmodium falciparum in saliva of children with acute uncomplicated malaria.
The diagnosis of malaria in biological fluids other than blood using non-invasive, rapid diagnostic techniques provides a valuable approach in case management and epidemiological studies of malaria. Rapid detection of Plasmodium falciparum lactate dehydrogenase (pLDH) in saliva samples from 130 of 144 children with microscopically confirmed P. falciparum infection was evaluated using Optimal-IT dipsticks. Genotyping of parasites was also performed in saliva and blood samples from a cohort of patients by polymerase chain reaction (PCR). The sensitivity of the dipstick in whole-blood, whole-saliva, or supernatant of spun saliva samples was 97.2%, 77.9%, and 48.4%, respectively. The sensitivity of the dipstick in whole-saliva samples was significantly higher than in supernatant of spun saliva samples (P < 0.0005). Mutant T76 allele was detectable in 60% and 57% of blood and saliva samples, respectively. This finding shows rapid detection of pLDH in patient saliva.


Neglecting the left side of a city square but not the left side of its clock: prevalence and characteristics of representational neglect.
Representational neglect, which is characterized by the failure to report left-sided details of a mental image from memory, can occur after a right hemisphere lesion. In this study, we set out to verify the hypothesis that two distinct forms of representational neglect exist, one involving object representation and the other environmental representation. As representational neglect is considered rare, we also evaluated the prevalence and frequency of its association with perceptual neglect. We submitted a group of 96 unselected, consecutive, chronic, right brain-damaged patients to an extensive neuropsychological evaluation that included two representational neglect tests: the Familiar Square Description Test and the O'Clock Test. Representational neglect, as well as perceptual neglect, was present in about one-third of the sample. Most patients neglected the left side of imagined familiar squares but not the left side of imagined clocks. The present data show that representational neglect is not a rare disorder and also support the hypothesis that two different types of mental representations (i.e. topological and non-topological images) may be selectively damaged in representational neglect.


Role of rainfall intensity and hydrology in nutrient transport via surface runoff.
Loss of soil nutrients in runoff accelerates eutrophication of surface waters. This study evaluated P and N in surface runoff in relation to rainfall intensity and hydrology for two soils along a single hillslope. Experiments were initiated on 1- by 2-m plots at foot-slope (6%) and mid-slope (30%) positions within an alfalfa (Medicago sativa L.)-orchardgrass (Dactylis glomerata L.) field. Rain simulations (2.9 and 7.0 cm h(-1)) were conducted under wet (spring) and dry (late-summer) conditions. Elevated, antecedent soil moisture at the foot-slope during the spring resulted in less rain required to generate runoff and greater runoff volumes, compared with runoff from the well-drained mid-slope in spring and at both landscape positions in late summer. Phosphorus in runoff was primarily in dissolved reactive form (DRP averaged 71% of total P), with DRP concentrations from the two soils corresponding with soil test P levels. Nitrogen in runoff was mainly nitrate (NO3-N averaged 77% of total N). Site hydrology, not chemistry, was primarily responsible for variations in mass N and P losses with landscape position. Larger runoff volumes from the foot-slope produced higher losses of total P (0.08 kg ha(-1)) and N (1.35 kg ha(-1)) than did runoff from the mid-slope (0.05 total P kg ha(-1); 0.48 kg N ha(-1)), particularly under wet, spring-time conditions. Nutrient losses were significantly greater under the high intensity rainfall due to larger runoff volumes. Results affirm the critical source area concept for both N and P: both nutrient availability and hydrology in combination control nutrient loss.


Conference scene: Latin American Pharmacogenomics and Personalized Medicine Conference.
There are nearly 600 million people living in 24 Latin American countries, speaking two major languages (Portuguese and Spanish) and sharing ancestral roots in America, Europe and Africa. Ethnic and cultural diversity, socioeconomical, scientific and technological disparities across Latin America must be taken into account in the design, interpretation and implications of pharmacogenomic studies in this region. The conference covered some of these aspects, but also took on a more global approach on the growing contribution of genomic information and biotechnological tools to the way medicines are developed, regulated and prescribed to patients. Translation of pharmacogenomics into clinical practice was the topic of a keynote lecture and two debate sessions. A preconference Introductory Course of Pharmacogenomics was offered.


Comparative analysis of environmental and clinical populations of Cryptococcus neoformans.
Cryptococcus neoformans is a major, global cause of meningoencephalitis in immunocompromised patients. Despite advances in the molecular epidemiology of C. neoformans, its population structure and mode of reproduction are not well understood. In the environment, it is associated with avian guano or vegetation. We collected nearly 800 environmental isolates from three locations in the United States (viz., North Carolina, California, and Texas) and compared them with one another and with clinical isolates from North Carolina. As expected, they consisted of the most prevalent serotypes, serotypes A and D, as well as serotype AD hybrids. The majority of environmental isolates were obtained from pigeon excreta. All environmental and clinical isolates of serotype A or D had the MATalpha mating-type allele. However, the AD hybrids included MATa alleles typical of serotypes A and D. Using an amplified fragment length polymorphism fingerprinting technique with two primer pairs, we identified 12 genotypes among the isolates of serotype A. Six of these genotypes were present in both the clinical and the environmental populations. However, one of the most prevalent environmental genotypes was absent from the clinical samples, and two other genotypes were isolated only from patients. The combined molecular data suggest that this environmental population of C. neoformans is predominantly clonal, although there was evidence for recent or past recombination.


Interactions of oxime reactivators with diethylphosphoryl adducts of human acetylcholinesterase and its mutant derivatives.
Diethylphosphoryl conjugates of human acetylcholinesterase (AChE) and selected mutants, carrying amino acid replacements at the active center and at the peripheral anionic site, were subjected to reactivation with the monopyridinium oxime 2-hydroxy-iminomethyl-1-methylpyridinium chloride and the bispyridinium oximes 1,3-bis(4'-hydroxyiminomethyl-1'-pyridinium),propane dibromide (TMB-4) and 1-(2'-hydroxyiminomethyl-1'-pyridinium)-3-(4"-carbamoyl-1"-pyridinium)-2 - oxapropane dichloride (HI-6). The kinetic profiles for all of the reactivation reactions indicate single populations of reactivatable species. Replacement of Trp86, the anionic subsite in the active center, lowered the affinity of the free enzyme toward all three reactivators, but in the corresponding diethylphosphoryl conjugate, only affinity toward TMB-4 was affected. Replacement of other constituents of the hydrophobic subsite (Tyr337, Phe338) had no major effect on either affinity to the free enzymes or rates of reactivation. Substitution of residues of the acyl pocket (Phe295, Phe297) lowered the affinities toward reactivators except for the 20-fold increase in affinity of F295A toward HI-6. Replacement of the acidic residues in the active center (Glu202, Glu450) affected mainly the rates of nucleophilic displacement of the phosphoryl moiety. The effect of substituting residues constituting the peripheral anionic site at the rim of the active site gorge (Tyr72, Asp74, Trp286) was particularly puzzling because for 2-hydroxy-iminomethyl-1-methylpyridinium chloride and HI-6, mainly the nucleophilic reaction rate constants were affected, whereas for TMB-4, the affinities of the phosphorylated enzymes were significantly reduced. The fact that perturbations of the functional architecture of HuAChE active center can account for only some of the observed effects on the reactivation rates suggests that the binding modes of oxime to the phosphorylated and nonphosphorylated enzymes are considerably different and/or that interactions of the reactivators with the phosphoryl moieties play a dominant role in the reactivation process.


Decreased Cry1Ac activation by midgut proteases associated with Cry1Ac resistance in Helicoverpa zea.
Field-evolved resistance of Helicoverpa zea to Bacillus thuringiensis (Bt) toxin Cry1Ac was first reported more than a decade ago, yet the underlying mechanisms remain elusive. Towards understanding the mechanisms of resistance to Cry1Ac, we analyzed a susceptible (LAB-S) and two resistant (GA and GA-R) strains of H. zea. The GA strain was derived from Georgia and exposed to Bt toxins only in the field. The GA-R strain was derived from the GA strain and selected for increased resistance to Cry1Ac in the laboratory. Resistance to MVPII, a liquid formulation containing a hybrid protoxin similar to Cry1Ac, was 110-fold for GA-R and 7.8-fold for GA relative to LAB-S. In midgut brush border membrane vesicles, activity of alkaline phosphatase and aminopeptidase N did not vary significantly among strains. The activity of total proteases, trypsin-like proteases and chymotrypsin-like proteases was significantly lower for GA-R and GA than LAB-S, but did not differ between GA-R and GA. When H. zea midgut cells were exposed to Cry1Ac protoxin that had been digested with midgut extracts, toxicity was significantly lower for extracts from GA-R and GA relative to extracts from LAB-S, but did not differ between GA-R and GA. Transcriptional analysis showed that none of the five protease genes examined was associated with the decline in Cry1Ac activation in GA-R and GA relative to LAB-S. The results suggest that decreased Cry1Ac activation is a contributing field-selected mechanism of resistance that helps explain the reduced susceptibility of the GA-R and GA strains. Relative to the LAB-S strain, the two Cry1Ac-resistant strains had lower total protease, trypsin and chymotrypsin activities, a lower Cry1Ac activation rate, and Cry1Ac protoxin incubated with their midgut extracts was less toxic to H. zea midgut cells. © 2018 Society of Chemical Industry.


Remodeling of DNA methylation and phenotypic and transcriptional changes in synthetic Arabidopsis allotetraploids.
The joining of different genomes in allotetraploids played a major role in plant evolution, but the molecular implications of this event are poorly understood. In synthetic allotetraploids of Arabidopsis and Cardaminopsis arenosa, we previously demonstrated the occurrence of frequent gene silencing. To explore the involvement of epigenetic phenomena, we investigated the occurrence and effects of DNA methylation changes. Changes in DNA methylation patterns were more frequent in synthetic allotetraploids than in the parents. Treatment with 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase, resulted in the development of altered morphologies in the synthetic allotetraploids, but not in the parents. We profiled mRNAs in control and 5-aza-2'-deoxycytidine-treated parents and allotetraploids by amplified fragment length polymorphism-cDNA. We show that DNA demethylation induced and repressed two different transcriptomes. Our results are consistent with the hypothesis that synthetic allotetraploids have compromised mechanisms of epigenetic gene regulation.


Microscopic measurement of photon echo formation in groups of individual excitonic transitions.
The third-order polarization emitted from groups of individual localized excitonic transitions after pulsed optical excitation is measured. We observe the evolution of the nonlinear response from the case of a free polarization decay for a single transition, to that of a photon echo for many transitions. The echo is shown to arise from the mutual rephasing of the emission from individual transitions.


The impact of amino acid side chain mutations in conformational design of peptides and proteins.
Local energetic effects of amino acid replacements are often considered to have only a moderate influence on the backbone conformation of proteins or peptides. As these effects are difficult to determine experimentally, no comparison has yet been performed. However, knowledge of the influence of side chain mutations is essential in protein homology modeling and in optimizing biologically active peptide ligands in medicinal chemistry. Furthermore, the tool of N-methylation of peptides is of increasing importance for the design of peptidic drugs to gain oral availability or receptor selectivity. However, N-methylation is often accompanied by considerable population of cis-peptide bond structures, resulting in completely different conformations compared with the parent peptide. To retain a favored structure, it might be important to understand the effect of different side chains on the backbone conformation and to enable the introduction of an N-methylation at the right position without disturbing a biologically active conformation. In order to detect even small energetic effects due to side chain mutations, we employed a trick to investigate the structural equilibrium of a selected cyclic pentapeptide in which two conformations are equally populated. Very small energetic differences between both conformations could easily be determined experimentally by identifying shifts in the population of both isomers.


After the Visit: An Overview of Government and Community Programs Supporting Children with Medical Complexity.
The optimal care of children with medical complexity (CMC) requires involvement from a network of professionals that includes physicians, nurses, ancillary service providers, and educators. Pediatric health care providers typically have early and frequent contact with the families of CMC. Therefore, they are in a unique position to connect families to developmental, educational, and psychosocial supports. This article reviews important government and community programs that support CMC living in the United States. It outlines the educational rights of children with disabilities and offers practical tips for collaborating with Early Intervention and the public school system. The article also provides an overview of financial assistance programs, respite care services, and support groups that are beneficial to CMC and their families.


Effect of electro-acupuncture on regulating the swallowing by activating the interneuron in ventrolateral medulla (VLM).
Ventrolateral medulla(VLM) was one of the essential part of central pattern generator(CPG) in swallowing and electro-acupuncture(EA) was an important intervention in swallowing disorder. But the effect and mechanism of EA at acupoints on swallowing were unknown. The present aim to detect the effect of EA at Lianquan (CV23) on swallowing and swallowing-related(SR) interneuron in VLM. Thirty-six Sprague-Dawley rats were operated and the swallowing reflex was induced through Double distilled water (DDW) infusion. Simultaneously, the numbers of swallowing were recorded. Then EA was given at Lianquan and Neiguan (PC6) and the neuron discharges in VLM were detected. A total of 72 neurons were recorded, 60 of which were correctly recorded after histology identification. Two types of SR neurons were found and the numbers of swallowing increased after EA at CV23 and PC6 compared with no EA group. The neuron response rates were 78.3% and 50% for EA at CV23 and PC6 respectively with significant difference (P < 0.05). Meanwhile, the neuron spike patterns were changed after EA at CV23 and PC6. In addition, twenty-four rats were used for immunofluorescence after EA at CV23 and PC6. The results showed that c-fos positive cells in CV23 group were 20.63±2.35, while PC6 group was 14.13±1.78 and 6.88±1.42 in control group. There were significant difference between them (P < 0.05). These results indicated that EA could regulate the swallowing function via activating the SR interneurons in VLM under the physiological condition.


Characterisation of the low affinity interaction between rat cell adhesion molecules CD2 and CD48 by analytical ultracentrifugation.
CD2 is a cell adhesion molecule found on the plasma membrane of T-lymphocytes. Its counter-receptor in rat is the structurally related CD48. This interaction is believed to contribute to the adhesion of T-cells to other cells such as cytotoxic targets and antigen presenting cells. Cell-cell adhesion involves the formation of multiple cell adhesion molecule complexes at the cell surface and if cell-cell de-adhesion is to occur, these complexes need to be disrupted. The affinities of cell adhesion molecule interactions are suggested to be relatively weak to allow this de-adhesion of cell-cell interactions. The CD2/CD48 interaction has been studied using recombinant extracellular proteins and the affinity of the interaction of soluble recombinant rat CD2-CD48 has been determined (at 37 degrees C) using surface plasmon resonance (and shown to be weak), with the dissociation constant Kd = 60-90 microM. The values determined by surface plasmon resonance results could be affected by the immobilisation of the ligand on the chip and any self-association on the chip. We used three different analytical ultracentrifuge procedures which each allowed the interaction to be studied in free solution without the need for an immobilisation medium. Both sedimentation equilibrium (using direct analysis of the concentration distribution and also modelling of molecular weight versus concentration data) and sedimentation velocity at 5 degrees C yielded dissociation constants in the range of 20-110 microM, supporting the surface plasmon resonance findings showing that binding between these cell adhesion molecules is relatively weak. These studies also ruled out the presence of any significant self-association of the reactants which could lead to systematic error in the surface plasmon resonance results.


miRNA-145 targets v-ets erythroblastosis virus E26 oncogene homolog 1 to suppress the invasion, metastasis, and angiogenesis of gastric cancer cells.
Recent evidence shows that v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1) is implicated in tumor development and progression. However, the clinical potentials and underlying mechanisms of Ets1 in gastric cancer progression and metastasis remain largely unknown. In this study, Ets1 immunostaining was identified in 56 of 84 (66.7%) gastric cancer tissues, which was correlated with tumor invasion and metastasis. In gastric cancer specimens and cell lines, miRNA-145 (miR-145) was downregulated and inversely correlated with Ets1 expression. Bioinformatics analysis and luciferase reporter assay revealed that miR-145 directly targeted the 3'-untranslated region (3'-UTR) of Ets1 mRNA. Overexpression or knockdown of miR-145 responsively altered both the mRNA and protein levels of Ets1 and its downstream genes, matrix metalloproteinase (MMP-1)-1 and -9, in gastric cancer cell lines SGC-7901 and MKN-45. Ectopic expression of miR-145 suppressed the invasion, metastasis, and angiogenesis of SGC-7901 and MKN-45 cells in vitro and in vivo. In addition, the effects of miR-145 on Ets1 expression, migration, invasion, and angiogenesis were rescued by restoration of Ets1 expression in these cells. Furthermore, anti-miR-145 inhibitor promoted the migration, invasion, and angiogenesis, whereas siRNA-mediated Ets1 knockdown phenocopied the effects of miR-145 overexpression in gastric cancer cells. These results show that miR-145 suppresses Ets1 expression via the binding site in the 3'-UTR, thus inhibiting the invasion, metastasis, and angiogenesis of gastric cancer cells.


"What is the FDA Going to Think?": Negotiating Values through Reflective and Strategic Category Work in Microbiome Science.
The US National Institute of Health's Human Microbiome Project aims to use genomic techniques to understand the microbial communities that live on the human body. The emergent field of microbiome science brought together diverse disciplinary perspectives and technologies, thus facilitating the negotiation of differing values. Here, we describe how values are conceptualized and negotiated within microbiome research. Analyzing discussions from a series of interdisciplinary workshops conducted with microbiome researchers, we argue that negotiations of epistemic, social, and institutional values were inextricable from the reflective and strategic category work (i.e., the work of anticipating and strategizing around divergent sets of institutional categories) that defined and organized the microbiome as an object of study and a potential future site of biomedical intervention. Negotiating the divergence or tension between emerging scientific and regulatory classifications also activated "values levers" and opened up reflective discussions of how classifications embody values and how these values might differ across domains. These data suggest that scholars at the intersections of science and technology studies, ethics, and policy could leverage such openings to identify and intervene in the ways that ethical/regulatory and scientific/technical practices are coproduced within unfolding research.


Divide and conquer: enriching environmental sequencing data.
In environmental sequencing projects, a mix of DNA from a whole microbial community is fragmented and sequenced, with one of the possible goals being to reconstruct partial or complete genomes of members of the community. In communities with high diversity of species, a significant proportion of the sequences do not overlap any other fragment in the sample. This problem will arise not only in situations with a relatively even distribution of many species, but also when the community in a particular environment is routinely dominated by the same few species. In the former case, no genomes may be assembled at all, while in the latter case a few dominant species in an environment will always be sequenced at high coverage to the detriment of coverage of the greater number of sparse species. Here we show that, with the same global sequencing effort, separating the species into two or more sub-communities prior to sequencing can yield a much higher proportion of sequences that can be assembled. We first use the Lander-Waterman model to show that, if the expected percentage of singleton sequences is higher than 25%, then, under the uniform distribution hypothesis, splitting the community is always a wise choice. We then construct simulated microbial communities to show that the results hold for highly non-uniform distributions. We also show that, for the distributions considered in the experiments, it is possible to estimate quite accurately the relative diversity of the two sub-communities. Given the fact that several methods exist to split microbial communities based on physical properties such as size, density, surface biochemistry, or optical properties, we strongly suggest that groups involved in environmental sequencing, and expecting high diversity, consider splitting their communities in order to maximize the information content of their sequencing effort.


The prevalence of Helicobacter pylori infection in patients undergoing upper gastrointestinal endoscopy in the Turks and Caicos Islands.
Helicobacter pylori infection remains a common problem and previous studies in the Caribbean revealed infection in over 50% of patients undergoing upper endoscopy. The present study determined the prevalence of H pylori infection in patients undergoing upper gastrointestinal endoscopy in the Turks and Caicos Islands over a two- year interval. All patients with upper gastrointestinal symptoms requiring endoscopy were evaluated clinically and H pylori testing performed histologically. There were 57 patients (21 males, 36 females) with a mean age of 43 years. Twenty-six patients presented with gastroesophageal reflux, 17 with upper abdominal pain, 10 with dyspepsia and 4 with upper gastrointestinal bleeding. H pylori infection was present in 24 patients (42%) and negative in 33 (58%). Upper gastrointestinal endoscopy was normal in 27 patients, 13 (54%) were H pylori positive and 14 (43%) negative. Antral gastritis was present in 13 patients, 7 (54%) were H pylori positive and 6 (46%) negative. Duodenal ulcer was present in 6 (33% H pylori positive) and gastric ulcer in 5 patients (40% H pylori positive). Distal oesophagitis was present in 5 patients (all negative for H pylori) and gastric carcinoma in 1 (H pylori positive). In patients with dyspepsia, 60% were positive for H pylori. H pylori infection was common in the patients in this study with gastrointestinal symptoms. However, the prevalence in endoscopic patients and peptic ulcer disease is lower than in other reports from the Caribbean.


Folate concentration dependent transport activity of the Multidrug Resistance Protein 1 (ABCC1).
The Multidrug Resistance Protein MRP1 (ABCC1) can confer resistance to a variety of therapeutic drugs. In addition, MRP1/ABCC1 mediates cellular export of natural folates, such as folic acid and l-leucovorin. In this study we determined whether cellular folate status affected the functional activity of MRP1/ABCC1 mediated efflux of an established substrate, the anthracycline daunorubicin (DNR). As a model system we used the human ovarian carcinoma cell line 2008wt, and its MRP1/ABCC1 transfected subline 2008/MRP1. Both types of these moderate- and high-MRP1/ABCC1 expressing cells displayed efflux of DNR when maintained in standard culture media (2.3microM folic acid). The initial total cellular DNR efflux rate in 2008/MRP1 cells was approximately 2-fold higher compared to 2008wt cells. This efflux consisted of MRP1/ABCC1 mediated transport, possibly non-MRP1 mediated transport, as well as passive diffusion. Benzbromarone, a specific MRP1 inhibitor, decreased the initial efflux rate in 2008/MRP1 cells (4-fold) and in 2008wt cells (2-fold). When 2008/MRP1 cells were challenged for 2 days in folate-free medium, total cellular DNR efflux was decreased to 43% of the initial efflux rate under folate-rich conditions. In 2008wt cells DNR efflux was decreased to 84% of the folate-rich conditions. Benzbromarone did not inhibit DNR efflux after the folate-free period in both cell lines. Repletion of folate by a 2-24hr exposure to 2.5microM l-leucovorin or folic acid resulted in a complete restoration of DNR efflux. In contrast, expression of MRP1/ABCC1 protein was not changed significantly during the folate-free period or the repletion-period, nor were cellular ATP or ADP pools. In conclusion, this study demonstrates that the cellular folate status can influence the transport activity of MRP1/ABCC1. These results have potentially important implications in the understanding of the (patho-)physiological roles of MRP1/ABCC1, and possibly other ABC transporter proteins in cellular folate homeostasis and drug resistance.


The nucleotide analog 2-aminopurine as a spectroscopic probe of nucleotide incorporation by the Klenow fragment of Escherichia coli polymerase I and bacteriophage T4 DNA polymerase.
The fluorescent properties and their sensitivity to the surrounding environment of the nucleotide analog 2-aminopurine (2-AP) have been well documented. In this paper we describe the use of 2-AP as a direct spectroscopic probe of the mechanism of nucleotide incorporation by Escherichia coli Pol I Klenow fragment (KF) and bacteriophage T4 DNA polymerase. The nucleotidyl transfer reaction may be monitored in real time by following the fluorescence of 2-AP, allowing the detection of transient intermediates along the reaction pathway that are inaccessible through traditional radioactive assays. Previous studies with Klenow fragment [Kuchta, R. D., Mizrahi, V., Benkovic, P. A., Johnson, K. A., & Benkovic, S. J. (1987) Biochemistry 26, 8410-8417] have revealed the presence of a nonchemical step prior to chemistry and have identified this conformational change as the rate-limiting step of correct nucleotide incorporation. During correct incorporation, phosphodiester bond formation occurs at a rate greater than the conformational change and has not been measured. However, during misinsertion, the rate of the chemical step becomes partially rate limiting and it becomes possible to detect both steps. We have successfully decoupled the chemical and conformational change steps for nucleotide insertion by KF using the misincorporation reaction, and we present direct spectroscopic evidence for an activated KF'-DNA-dNTP species following the conformational change step which features hydrogen bonding between the incoming and template bases. In addition, we have utilized these same experiments to demonstrate the existence of a similar nonchemical step in the mechanism of dNTP incorporation by bacteriophage T4 DNA polymerase.(ABSTRACT TRUNCATED AT 250 WORDS)


A novel role for catalase B in the maintenance of fungal cell-wall integrity during host invasion in the rice blast fungus Magnaporthe grisea.
Asexual spores of the rice blast fungus germinate to produce a specialized and melanized infection structure, the appressorium, which is pivotal to successful plant penetration. To investigate whether Magnaporthe grisea counteracts the toxic burst of H2O2 localized beneath the site of attempted invasion, we examined the temporal expression of five candidate antioxidant genes. Of these, the putatively secreted large subunit catalase CATB gene was 600-fold up-regulated in vivo, coincident with penetration, and moderately up-regulated in vitro, in response to exogenous H2O2. Targeted gene replacement of CATB led to compromised pathogen fitness; the catB mutant displayed paler pigmentation and accelerated hyphal growth but lower biomass, poorer sporulation, fragile conidia and appressoria, and impaired melanization. The catB mutant was severely less pathogenic than Guy 11 on barley and rice, and its infectivity was further reduced on exposure to H2O2. The wild-type phenotype was restored by the reintroduction of CATB into the catB mutant We found no evidence to support a role for CATB in detoxification of the host-derived H2O2 at the site of penetration. Instead, we demonstrated that CATB plays a part in strengthening the fungal wall, a role of particular importance during forceful entry into the host.


Passive sampling of DDT, DDE and DDD in sediments: accounting for degradation processes with reaction-diffusion modeling.
Passive sampling is becoming a widely used tool for assessing freely dissolved concentrations of hydrophobic organic contaminants in environmental media. For certain media and target analytes, the time to reach equilibrium exceeds the deployment time, and in such cases, the loss of performance reference compounds (PRCs), loaded in the sampler before deployment, is one of the common ways used to assess the fractional equilibration of target analytes. The key assumption behind the use of PRCs is that their release is solely diffusion driven. But in this work, we show that PRC transformations in the sediment can have a measurable impact on the PRC releases and even allow estimation of that compound's transformation rate in the environment of interest. We found that in both field and lab incubations, the loss of the 13C 2,4'-DDT PRC from a polyethylene (PE) passive sampler deployed at the sediment-water interface was accelerated compared to the loss of other PRCs (13C-labeled PCBs, 13C-labeled DDE and DDD). The DDT PRC loss was also accompanied by accumulation in the PE of its degradation product, 13C 2,4'-DDD. Using a 1D reaction-diffusion model, we deduced the in situ degradation rates of DDT from the measured PRC loss. The in situ degradation rates increased with depth into the sediment bed (0.14 d-1 at 0-10 cm and 1.4 d-1 at 30-40 cm) and although they could not be independently validated, these rates compared favorably with literature values. This work shows that passive sampling users should be cautious when choosing PRCs, as degradation processes can affect some PRC's releases from the passive sampler. More importantly, this work opens up the opportunity for novel applications of passive samplers, particularly with regard to investigating in situ degradation rates, pathways, and products for both legacy and emerging contaminants. However, further work is needed to confirm that the rates deduced from model fitting of PRC loss are a true reflection of DDT transformation rates in sediments.


An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults with ADHD.
To examine the efficacy and safety of atomoxetine combined with buspirone versus atomoxetine monotherapy and placebo in adult attention-deficit/hyperactivity disorder (ADHD). In this randomized, 8-week, 3-arm, double-blind, placebo-controlled trial conducted from November 2004 through December 2005, 241 adults with ADHD were randomly assigned in a 2:2:1 ratio to receive up to twice-daily atomoxetine and thrice-daily buspirone (n = 97), twice-daily atomoxetine (n = 97), or placebo (n = 47). Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD. The primary efficacy measure was the adult ADHD Investigator Symptom Rating Scale (AISRS). Decrease in the AISRS total score was significantly greater for atomoxetine-buspirone than placebo at all time points from weeks 1 to 7, with an estimated mean difference of -4.80 (P = .001). Reduction in the mean AISRS total score was numerically greater for atomoxetine-buspirone than for atomoxetine at all time points, but statistically significant at week 4 only (estimated difference = -2.04, P < .10). The effect size for atomoxetine plus buspirone was 0.51, and for atomoxetine alone, it was 0.40. Insomnia, nausea, dry mouth, headache, and asthenia were frequently reported adverse events for both active treatment groups, and dizziness was also frequently reported for the atomoxetine-buspirone group. Discontinuations due to treatment-related adverse effects were 15.5% for atomoxetine-buspirone, 11.3% for atomoxetine, and 14.9% for placebo. There was little indication of improvement for atomoxetine plus buspirone versus atomoxetine monotherapy, as most efficacy measures showed only slightly greater quantitative improvement for the combination, generally without statistical significance. It is of note, however, that the quantitative differences between these 2 groups were virtually all in the direction of greater efficacy for the atomoxetine plus buspirone group. clinicaltrials.gov Identifier: NCT00174226.


Restoration of cerebrovascular responsiveness to hyperventilation by the oxygen radical scavenger n-acetylcysteine following experimental traumatic brain injury.
Previous experiments have shown that, following experimental fluid-percussion brain injury, cyclo-oxygenase-dependent formation of oxygen radicals prevents arteriolar vasoconstriction in response to hyperventilation. The oxygen radical scavengers superoxide dismutase and catalase restore normal reactivity; however, they are not routinely available for clinical use. The present study tested whether n-acetylcysteine (Mucomyst), an agent currently available for acetaminophen toxicity, could be used as a radical scavenger to restore reactivity after brain injury. N-acetylcysteine (163 mg/kg) was given intraperitoneally prior to or 30 minutes after fluid-percussion brain injury (2.6 atm) in cats, and reactivity to hyperventilation was tested 1 hour after injury. The authors found either that pre- or postinjury administration led to normal reactivity. Additional experiments supported the hypothesis that n-acetylcysteine is an oxygen radical scavenger, since it reduced or prevented the free radical-dependent cerebral arteriolar dilation normally induced by the topical application of arachidonic acid or bradykinin. The mechanism by which n-acetylcysteine is effective in trauma may involve direct scavenging of radicals or stimulation of glutathione peroxidase activity. The results suggest that n-acetylcysteine may be useful for treatment of oxygen free radical-mediated brain injury.


Frontal lobe regulation of blood glucose levels: support for the limited capacity model in hostile violence-prone men.
Hostile men have reliably displayed an exaggerated sympathetic stress response across multiple experimental settings, with cardiovascular reactivity for blood pressure and heart rate concurrent with lateralized right frontal lobe stress (Trajanoski et al., in Diabetes Care 19(12):1412-1415, 1996; see Heilman et al., in J Neurol Neurosurg Psychiatry 38(1):69-72, 1975). The current experiment examined frontal lobe regulatory control of glucose in high and low hostile men with concurrent left frontal lobe (Control Oral Word Association Test [verbal]) or right frontal lobe (Ruff Figural Fluency Test [nonverbal]) stress. A significant interaction was found for Group × Condition, F (1,22) = 4.16, p ≤ .05 with glucose levels (mg/dl) of high hostile men significantly elevated as a function of the right frontal stressor (M = 101.37, SD = 13.75) when compared to the verbal stressor (M = 95.79, SD = 11.20). Glucose levels in the low hostile group remained stable for both types of stress. High hostile men made significantly more errors on the right frontal but not the left frontal stressor (M = 17.18, SD = 19.88) when compared to the low hostile men (M = 5.81, SD = 4.33). These findings support our existing frontal capacity model of hostility (Iribarren et al., in J Am Med Assoc 17(19):2546-2551, 2000; McCrimmon et al., in Physiol Behav 67(1):35-39, 1999; Brunner et al., in Diabetes Care 21(4):585-590, 1998), extending the role of the right frontal lobe to regulatory control over glucose mobilization.


Carbon Partitioning in Soybean Infected with Meloidogyne incognita and M. javanica.
Seven-day-old seedlings of two cultivars (Cristalina and UFV ITM1) of Glycine max were inoculated with 0, 3,000, 9,000, or 27,000 eggs of Meloidogyne incognita race 3 or M. javanica and maintained in a greenhouse. Thirty days later, plants were exposed to (1)CO for 4 hours. Twenty hours after (1)CO exposure, the root fresh weight, leaf dry weight, nematode eggs per gram of root, total and specific radioactivity of carbohydrates in roots, and root carbohydrate content were evaluated. Meloidogyne javanica produced more eggs than M. incognita on both varieties. A general increase in root weight and a decrease in leaf weight with increased inoculum levels were observed. Gall tissue appeared to account for most of the root mass increase in seedlings infected with M. javanica. For both nematodes there was an increase of total radioactivity in the root system with increased levels of nematodes, and this was positively related to the number of eggs per gram fresh weight and to the root fresh weight, but negatively related to leaf dry weight. In most cases, specific radioactivities of sucrose and reducing sugars were also increased with increased inoculum levels. Highest specific radioactivities were observed with reducing sugars. Although significant changes were not observed in endogenous levels of carbohydrates, sucrose content was higher than reducing sugars. The data show that nematodes are strong metabolic sinks and significantly change the carbon distribution pattern in infected soybean plants. Carbon partitioning in plants infected with nematodes may vary with the nematode genotype.


PGBD5 promotes site-specific oncogenic mutations in human tumors.
Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.


Occupational sensitization to lactase.
Occupational sensitization to lactase is reported in workers formulating and packaging this consumer product, which is used for the relief of gastrointestinal symptoms caused by intolerance to lactose. Allergic rhinitis, conjunctivitis, and some cases of asthma were noted. There was suggestive evidence that atopic individuals may be at greater risk of sensitization. Lactase should be added to the list of potential occupational respiratory sensitizers.


Chlorinated hydrocarbons and biomarkers of exposure in wading birds and fish of the lower Rio Grande Valley, Texas.
During 1997 we evaluated reproductive success in colonial water birds nesting in the Lower Rio Grande Valley (LRGV), Texas, and correlated success with concentrations of contaminants in eggs. We also measured steroid hormones and gonadosomatic index (GSI) as biomarkers of endocrine effects in common carp (Cyprinus carpio). Nest and fledging success of green herons (Butorides virescens) and great egrets (Ardea alba) were similar to those found in other parts of North America; however, nesting success of black-crowned night-herons (Nycticorax nycticorax) was lower, very likely due to flooding of the nesting area. Except for DDE and toxaphene, all chlorinated pesticides in bird eggs were low and not of concern for negative effects on any of the three species. DDE was highest in green heron eggs and seemed to increase along a geographic gradient from west to east, with eggs from Falcon Reservoir containing low concentrations, and those at Los Indios containing the highest concentrations (approx. 11,000 ng/g WW), near or above the threshold for reproductive impairment. DDE levels in great egrets and black-crowned night-herons were below those that are associated with reproductive impairment. Mean DDE levels in carp at the JAS Farms site were above the threshold level suggested for predator protection. Toxaphene was detected in about 20% of the samples with high levels observed in green heron eggs from Los Indios (mean = 4,402 ng/g WW). These are the highest toxaphene levels reported in bird eggs in the LRGV. Toxaphene levels in fish ranged between 90 and 312 ng/g WW. In general, PCBs in bird eggs and fish tissue were low and at levels not of concern for reproductive effects. The greatest concentrations of testosterone and 11-ketotestosterone were detected in fish from the JAS Farms site, which also had the greatest concentrations of DDE. Increased androgen production and gonad development in fish at this site, relative to Pharr, could be possibly associated with endocrine disrupting effects of p,p'-DDE. DDE, toxaphene, PCBs, and hormones were highest in birds and fish from the eastern edge of the study area.


Absolute and relative blindsight.
The concept of relative blindsight, referring to a difference in conscious awareness between conditions otherwise matched for performance, was introduced by Lau and Passingham (2006) as a way of identifying the neural correlates of consciousness (NCC) in fMRI experiments. By analogy, absolute blindsight refers to a difference between performance and awareness regardless of whether it is possible to match performance across conditions. Here, we address the question of whether relative and absolute blindsight in normal observers can be accounted for by response bias. In our replication of Lau and Passingham's experiment, the relative blindsight effect was abolished when performance was assessed by means of a bias-free 2AFC task or when the criterion for awareness was varied. Furthermore, there was no evidence of either relative or absolute blindsight when both performance and awareness were assessed with bias-free measures derived from confidence ratings using signal detection theory. This suggests that both relative and absolute blindsight in normal observers amount to no more than variations in response bias in the assessment of performance and awareness. Consideration of the properties of psychometric functions reveals a number of ways in which relative and absolute blindsight could arise trivially and elucidates a basis for the distinction between Type 1 and Type 2 blindsight.


Overview of guidelines on breast screening: Why recommendations differ and what to do about it.
Updated guidelines on breast cancer screening have been published by several major organisations over the past five years. Recommendations vary regarding both age range, screening interval, and even on whether breast screening should be offered at all. The variation between recommendations reflects substantial differences in estimates of the major benefit (breast cancer mortality reduction) and the major harm (overdiagnosis). Estimates vary considerably among randomised trials, as well as observational studies: from no benefit to large reductions, and from no overdiagnosis to substantial levels. The estimates vary according to the methodology of the randomised trials, and the design of the observational studies. Guideline recommendations reflect the choice of evidence informing them. While there are well-developed tools to deal with randomised trials in guideline work, these are not always used, or they may not be followed as recommended. Further, results of trials performed decades ago may no longer be applicable. For observational studies, the framework for inclusion in guidelines is not similarly well-developed and there are methodological concerns specific to screening interventions, such as small effects in absolute terms. There is a need for agreement on a hierarchy of observational study designs to quantify the major benefit and harm of cancer screening. This review provides a summary of recent guidelines on breast cancer screening and their major strengths and weaknesses, as well as a short overview of the major strengths and limitations of observational study designs. There is a need for agreement on a hierarchy of observational study designs in this field.


The effect of dobutamine and bolus crystalloid fluids on the cardiovascular function of isoflurane-anaesthetised horses.
Cardiac output does not always increase with dobutamine administration in anaesthetised horses and information on peripheral perfusion is lacking. To determine the effect of intravenous (i.v.) dobutamine infusion with and without a concurrent 20 mL/kg bodyweight (bwt) bolus of crystalloid fluids on the cardiovascular function of acepromazine premedicated, hypotensive, isoflurane-anaesthetised horses. Randomised, cross-over experiment. A total of 6 horses aged 5-13 years, weighing 464-578 kg were premedicated with acepromazine 0.02 mg/kg bwt and then sedated with xylazine 0.8 mg/kg bwt i.v. Anaesthesia was induced with ketamine 2.2 mg/kg bwt and diazepam 0.08 mg/kg bwt i.v. and maintained with isoflurane, adjusted to achieve a target mean arterial pressure (MAP) (60 mmHg ± 5%) 60 min post-induction of anaesthesia (T0). One of 2 treatments was then given. In treatment D, dobutamine was initially infused at 0.5 μg/kg bwt/min and adjusted to achieve a target MAP (80 mmHg ± 5%) within 30 min of infusion initiation. In treatment D+F dobutamine was administered as described for treatment D, with 20 mL/kg bwt Hartmann's solution infused i.v. over 20 min. Cardiac index (CI), haemoglobin concentration ([Hb]), arterial oxygen content (CaO2 ), oxygen delivery index (DO2 I) and bilateral femoral arterial blood flow (FBF) were recorded at T0, 30 min following dobutamine initiation (T1) and 15 min following dobutamine cessation (T2). Data were analysed using a mixed-effect linear model (P<0.05 considered significant). A significant increase in DO2 I (P = 0.008, T0/T1), CaO2 (P = 0.0002, T0/T1) and [Hb] (P<0.0001, T0/T1) and in CaO2 (P = 0.0005, T1/T2) and [Hb] (P = 0.002,T1/T2) occurred during treatment D. A significant increase in FBF (P = 0.005, upper limb; P = 0.042 lower limb, T0/T1) occurred during treatment D+F. Significant differences between treatments were recorded at T1 ([Hb] P = 0.0001, CaO2 P = 0.0003) and T2 ([Hb] P = 0.013). There was no change in CI during either treatment. The increase in FBF seen with co-administration of fluids and dobutamine may provide a beneficial effect on muscle compared with the use of dobutamine alone.


Protection of oral or intestinal candidiasis in mice by oral or intragastric administration of herbal food, clove (Syzygium aromaticum).
We examined the effect of a clove (Syzygium aromaticum) administered by two different routes on Candida albicans growth, using a murine oral candidiasis model. When the clove preparation was administered into the oral cavity of Candida-infected mice, their oral symptoms were improved and the number of viable Candida cells in the cavity was reduced. In contrast, when the clove preparation was administered intragastrically, oral symptoms were not improved, but viable cell numbers of Candida in the stomach and feces were decreased. These findings demonstrate that oral intake of an herbal food, clove, may suppress the overgrowth of C. albicans in the alimentary tract including the oral cavity.


Hospital cost control in Norway: a decade's experience with prospective payment.
Under Norway's prospective payment system, which was in existence from 1972 to 1980, hospital costs increased 15.8 percent annually, compared with 15.3 percent in the United States. In 1980 the Norwegian national government started paying for all institutional services according to a population-based, morbidity-adjusted formula. Norway's prospective payment system provides important insights into problems of controlling hospital costs despite significant differences, including ownership of medical facilities and payment and spending as a percent of GNP. Yet striking similarities exist. Annual real growth in health expenditures from 1972 to 1980 in Norway was 2.2 percent, compared with 2.4 percent in the United States. In both countries, public demands for cost control were accompanied by demands for more services. And problems of geographic dispersion of new technology and distribution of resources were similar. Norway's experience in the 1970s demonstrates that prospective payment is no panacea. The annual budget process created disincentives to hospitals to control costs. But Norway's changes in 1980 to a population-based methodology suggest a useful approach to achieve a more equitable distribution of resources. This method of payment provides incentives to control variations in both admissions and cost per case. In contrast, the Medicare approach based on Diagnostic Related Groups (DRGs) is limited, and it does not affect variations in admissions and capital costs. Population-based methodologies can be used in adjusting DRG rates to control both problems. In addition, the DRG system only applies to Medicare payments; the Norwegian experience demonstrates that this system may result in significant shifting of costs onto other payors.


Use of RAFT macro-surfmers for the synthesis of transparent aqueous colloids with tunable interactions.
We propose a new method to produce fluorinated nanoparticles (NPs) based on ab initio reversible addition-fragmentation chain transfer (RAFT) emulsion polymerization without the use of toxic surfactants. NP size, surface charge, and chemistry can be controlled via the adoption of different macromolecular transfer agents produced via RAFT polymerization of amphiphilic monomers. Thanks to this versatility, interparticle interactions can be easily tuned by changing solvent composition and temperature. In addition, the refractive index and density of the solvent can simultaneously match those of the NPs by adding sodium polytungstate, an organic salt widely used for density gradient centrifugation. These colloids may be used as model systems for the study of self-assembly and aggregation in aqueous media when optical methods are required.


Change-point analysis as a tool to detect abrupt climate variations.
Recently, there have been an increasing number of studies using change-point methods to detect artificial or natural discontinuities and regime shifts in climate. However, a major drawback with most of the currently used change-point methods is the lack of flexibility (able to detect one specific type of shift under the assumption that the residuals are independent). As temporal variations in climate are complex, it may be difficult to identify change points with very simple models. Moreover, climate time series are known to exhibit autocorrelation, which corresponds to a model misspecification if not taken into account and can lead to the detection of non-existent shifts. In this study, we extend a method known as the informational approach for change-point detection to take into account the presence of autocorrelation in the model. The usefulness and flexibility of this approach are demonstrated through applications. Furthermore, it is highly desirable to develop techniques that can detect shifts soon after they occur for climate monitoring. To address this, we also carried out a simulation study in order to investigate the number of years after which an abrupt shift is detectable. We use two decision rules in order to decide whether a shift is detected or not, which represents a trade-off between increasing our chances of detecting a shift and reducing the risk of detecting a shift while in reality there is none. We show that, as of now, we have good chances to detect an abrupt shift with a magnitude that is larger than that of the standard deviation in the series of observations. For shifts with a very large magnitude (three times the standard deviation), our simulation study shows that after only 4 years the probabilities of shift detection reach nearly 100 per cent. This reveals that the approach has potential for climate monitoring.


Urinary tract infection in very old women is associated with delirium.
The aim of the study was to investigate whether urinary tract infection (UTI) in a representative sample of 85-, 90- and ≥95-year-old women is associated with delirium. In 504 out of 643 women (78.4%) it was possible to evaluate UTI and delirium. Assessments such as the Organic Brain Syndrome (OBS) Scale, the Geriatric Depression Scale-15 (GDS-15) and the Mini-mental State Examination (MMSE) were performed during home visits. Delirium, dementia and depression were diagnosed according to the DSM-IV criteria. A diagnosed, symptomatic UTI with or without ongoing treatment, documented in medical records or detected in association with the assessments, was registered. Eighty-seven of 504 women (17.2%), were diagnosed as having a UTI with or without ongoing treatment when they were assessed, and almost half of them (44.8%) were diagnosed to be delirious or having had episodes of delirium during the past month. One hundred and thirty-seven of the 504 women (27.2%) were delirious or had had episodes of delirium during the past month and 39 (28.5%) of them were diagnosed to have a UTI. In a multivariate logistic regression model, delirium was significantly associated with Alzheimer's disease (OR = 5.8), multi-infarct dementia (OR = 5.4), depression (OR = 3.1), heart failure (OR = 2.3) and urinary tract infection (OR = 1.9). A large proportion of very old women with UTI suffered from delirium which might indicate that UTI is a common cause of delirium. There should be more focus on detecting, preventing and treating UTI to avoid unnecessary suffering among old women.


Projected costs of single-payer healthcare financing in the United States: A systematic review of economic analyses.
The United States is the only high-income nation without universal, government-funded or -mandated health insurance employing a unified payment system. The US multi-payer system leaves residents uninsured or underinsured, despite overall healthcare costs far above other nations. Single-payer (often referred to as Medicare for All), a proposed policy solution since 1990, is receiving renewed press attention and popular support. Our review seeks to assess the projected cost impact of a single-payer approach. We conducted our literature search between June 1 and December 31, 2018, without start date restriction for included studies. We surveyed an expert panel and searched PubMed, Google, Google Scholar, and preexisting lists for formal economic studies of the projected costs of single-payer plans for the US or for individual states. Reviewer pairs extracted data on methods and findings using a template. We quantified changes in total costs standardized to percentage of contemporaneous healthcare spending. Additionally, we quantified cost changes by subtype, such as costs due to increased healthcare utilization and savings due to simplified payment administration, lower drug costs, and other factors. We further examined how modeling assumptions affected results. Our search yielded economic analyses of the cost of 22 single-payer plans over the past 30 years. Exclusions were due to inadequate technical data or assuming a substantial ongoing role for private insurers. We found that 19 (86%) of the analyses predicted net savings (median net result was a savings of 3.46% of total costs) in the first year of program operation and 20 (91%) predicted savings over several years; anticipated growth rates would result in long-term net savings for all plans. The largest source of savings was simplified payment administration (median 8.8%), and the best predictors of net savings were the magnitude of utilization increase, and savings on administration and drug costs (R2 of 0.035, 0.43, and 0.62, respectively). Only drug cost savings remained significant in multivariate analysis. Included studies were heterogeneous in methods, which precluded us from conducting a formal meta-analysis. In this systematic review, we found a high degree of analytic consensus for the fiscal feasibility of a single-payer approach in the US. Actual costs will depend on plan features and implementation. Future research should refine estimates of the effects of coverage expansion on utilization, evaluate provider administrative costs in varied existing single-payer systems, analyze implementation options, and evaluate US-based single-payer programs, as available.


Functional characterization of a signal transducing motif present in the T cell antigen receptor zeta chain.
A conserved sequence motif has been identified in a number of signaling subunits associated with hematopoietic cell antigen receptors. Here, we characterize signaling by a 17 amino acid motif that is triplicated in the T cell antigen receptor zeta chain. Analysis of zeta truncations and constructs containing the isolated motif demonstrates that this motif is sufficient for the induction of both proximal and distal events associated with T cell activation. Stimulation of truncations that contain either one, two, or three copies of the motif results in induction of an identical pattern of tyrosine phosphoproteins. Moreover, triplication of the NH2-terminal zeta motif results in enhanced signaling, suggesting a redundant role in signal amplification for the three motifs in zeta. Finally, we demonstrate the association of a recently identified protein tyrosine kinase ZAP-70 with this motif, and provide evidence for its involvement in zeta function.


The use of propofol in a group of older patients undergoing oesophagoscopy.
Propofol (Diprivan; Stuart) a new, very short-acting intravenous anaesthetic agent, was tested in its aqueous emulsion formulation. Used as an induction and maintenance agent, its anaesthetic properties, dosage requirements and side-effects were compared with those of thiopentone in 40 American Society of Anesthesiologists class I and II patients scheduled for routine oesophagoscopy. Both heart rate and diastolic blood pressure were more stable in the propofol group, and recovery times were significantly shorter. Patients were remarkably clear-headed after propofol. When the quality of anaesthesia was independently assessed by an anaesthetist and a surgeon, propofol was rated good or satisfactory in all subjects, and thiopentone in 80%. Anaphylactoid reactions associated with the previous Cremophor EL formulation were not encountered, and pain on injection was experienced in 10% of propofol subjects as against 5% who received thiopentone. This new intravenous agent produces safe and predictable anaesthesia followed by rapid recovery, making it especially suitable for outpatient anaesthesia.


Suppression of the biological activity of neuroglioma cells by down-regulation of miR-1.
Neuroglioma is associated with high rates of malignancy, metastasis, and recurrence. Recently, research on the roles of microRNAs (miR) in cancer prognosis has formed an important area of research as differential expression of miRNAs has been observed in different cancers. However, the detailed mechanism by which miRNAs regulate glioma remains unknown. Thus, we investigated the effect of miR-1 on human glioma by inhibiting the expression of miR-1. Anti-miR-1, an anti-sense oligonucleotide against miR-1, significantly reduced the level of miR-1 in the human glioma cell line U87 (P < 0.05). Further, cell proliferation and colony formation assays were used to determine the effect of miR-1 on cell growth. The scratch assay and cell migration assay were performed to evaluate cell invasion. Our data demonstrated that the growth of glioma cells was impeded due to the decrease in miR-1 levels, compared to the untransfected control cells (P < 0.05). Interestingly, the invasion and mobility of the cells were also retarded after transfection with anti-miR-1 (P < 0.05). In conclusion, our results indicate that the down-regulation of miR-1 significantly inhibited cell proliferation and reduced cell motility, suggesting that anti-miR-1 could be used as a therapeutic intervention tool to counter the activity of neuroglioma cells.


Hemodynamic effects of isovolemic hemodilution during descending thoracic aortic cross clamping and lower torso reperfusion.
Isovolemic hemodilution has been suggested for blood conservation and to improve hemodynamic tolerance to abdominal aortic cross clamping. However, the hemodynamic effects of hemodilution during descending thoracic aortic cross clamping (DAC) have not been established. We evaluated them in anesthetized swine. Hemodilution (n = 7) was produced by the isovolemic exchange of blood for 6% hetastarch to a target hematocrit of 20%. Hematocrit in control pigs (n = 7) remained at 30%. DAC was performed at the T9 level for 45 minutes. During a 60-minute reperfusion period, control pigs were infused with lactated Ringer's solution; shed blood was returned to hemodilution pigs, followed by lactated Ringer's. If hypotension occurred despite left atrial pressure of 10 mm Hg or greater, boluses of phenylephrine were given to keep mean arterial pressure above 60 mm Hg. Hemodilution caused a marked reduction in hematocrit and in global oxygen delivery (DO2). DAC produced a significant increase in proximal arterial pressure, cardiac index, and DO2 and oxygen consumption (VO2) was markedly reduced in both groups. A significant increase in systemic vascular resistance during DAC occurred only in control pigs. After reperfusion, vascular resistance was significantly lower than baseline in hemodilution pigs, requiring a sixfold greater dose of phenylephrine to avoid hypotension. A lower global DO2 and supply-limited VO2 were also observed in hemodilution pigs. Isovolemic hemodilution maintains hemodynamic stability during DAC. During lower torso reperfusion, however, hemodilution caused hemodynamic instability, decreased global DO2, and limited VO2, which may offset its potential benefits.


Regulation of peroxisomal matrix protein import by ubiquitination.
Peroxisomes are organelles that play an important role in many cellular tasks. The functionality of peroxisomes depends on the proper import of their matrix proteins. Peroxisomal matrix proteins are imported posttranslationally in a folded, sometimes even oligomeric state. They harbor a peroxisomal targeting sequence (PTS), which is recognized by dynamic PTS-receptors in the cytosol. The PTS-receptors ferry the cargo to the peroxisomal membrane, where they become part of a transient import pore and then release the cargo into the peroxisomal lumen. Subsequentially, the PTS-receptors are ubiquitinated in order to mark them for the export-machinery, which releases them back to the cytosol. Upon deubiquitination, the PTS-receptors can facilitate further rounds of cargo import. Because the ubiquitination of the receptors is an essential step in the import cycle, it also represents a central regulatory element that governs peroxisomal dynamics. In this review we want to give an introduction to the functional role played by ubiquitination during peroxisomal protein import and highlight the mechanistic concepts that have emerged based on data derived from different species since the discovery of the first ubiquitinated peroxin 15years ago. Moreover, we discuss future tasks and the potential of using advanced technologies for investigating further details of peroxisomal protein transport.


Assessing adult mortality in HIV-1-afflicted Zimbabwe (1998 -2003).
To compare alternative methods to vital registration systems for estimating adult mortality, and describe patterns of mortality in Manicaland, Zimbabwe, which has been severely affected by HIV. We compared estimates of adult mortality from (1) a single question on household mortality, (2) repeated household censuses, and (3) an adult cohort study with linked HIV testing from Manicaland, with a mathematical model fitted to local age-specific HIV prevalence (1998 -2000). The crude death rate from the single question (29 per 1000 person-years) was roughly consistent with that from the mathematical model (22 -25 per 1000 person-years), but much higher than that from the household censuses (12 per 1000 person-years). Adult mortality in the household censuses (males 0.65; females 0.51) was lower than in the cohort study (males 0.77; females 0.57), while mathematical models gave a much higher estimate, especially for females (males 0.80 -0.83; females 0.75 -0.80). The population attributable fraction of adult deaths due to HIV was 0.61 for men and 0.70 for women, with life expectancy estimated to be 34.3 years for males and 38.2 years for females. Each method for estimating adult mortality had limitations in terms of loss to follow-up (cohort study), under-ascertainment (household censuses), transparency of underlying processes (single question), and sensitivity to parameterization (mathematical model). However, these analyses make clear the advantages of longitudinal cohort data, which provide more complete ascertainment than household censuses, highlight possible inaccuracies in model assumptions, and allow direct quantification of the impact of HIV.


Acceptability and Attitude towards a Mobile-Based Home Exercise Program among Stroke Survivors and Caregivers: A Cross-Sectional Study.
Stroke is a leading cause of disability and requires continued care after hospital discharge. Mobile-based interventions are suitable to reduce the cost of stroke rehabilitation and facilitate self-management among stroke survivors. However, before attempting to use mobile-based home exercise program, it is crucial to recognize the readiness of stroke survivors and their caregivers to opt for such interventions. To assess the acceptability and attitude towards a mobile-based home exercise program among stroke survivors and their primary caregivers. A cross-sectional study was conducted among 102 participants to understand their attitude and acceptability towards mobile-based home exercise program. A validated 10-item questionnaire was adapted for the study. The questions which assessed the attitude were rated on a three-point Likert scale, with three denoting agree and one denoting disagree. The acceptability was assessed by their willingness to opt for a mobile-based home program services. A Chi-square analysis and cross-tabulation were performed to test differences between caregivers and patients. A logistic regression was performed to determine the effects of age, gender, and mobile phone on acceptability. Ninety-two percent of caregivers and 90% of patients showed willingness to opt for mobile-based intervention. Majority of the participants showed a positive attitude towards this mode of treatment. There was no difference in the attitude noted among caregivers and patients (p>0.05) towards mobile-based intervention. The stroke survivors and caregivers welcomed the concept of mobile-based home exercise program even in a low-resource settings, but further studies to understand treatment and cost-effectiveness of this technology among the stroke survivors would lead to better implementation.


Femoral nerve block-sciatic nerve block vs. femoral nerve block-local infiltration analgesia for total knee arthroplasty: a randomized controlled trial.
The use of femoral nerve block (FNB) combined with sciatic nerve block (SNB) after total knee arthroplasty (TKA) has recently become controversial. Local infiltration analgesia (LIA) has been reported to be effective for postoperative TKA pain control. We aimed to assess whether LIA with continuous FNB is as effective as SNB combined with continuous FNB. This was a prospective, randomized, single-center, observer-blinded, parallel group comparison trial of 34 American Society of Anesthesiologists (ASA) physical status 1-3 patients who underwent TKA and fulfilled the inclusion and exclusion criteria. Patients were randomized into two groups: a periarticular LIA and FNB group (group L, n = 17), and an SNB and FNB group (group S, n = 17). In both groups, participants received FNB with 20 mL of 0.375% ropivacaine, and 5 mL h(-1) of 0.2% ropivacaine after surgery. In group L, participants received 100-ml injections of 0.2% ropivacaine and 0.5 mg epinephrine to the surgical region. In group S, participants received SNB with 20 ml of 0.375% ropivacaine. After TKA, Numeric Rating Scale (NRS) scores for the first 24 h post-operation were compared via repeated-measures analysis of variance (ANOVA) as the primary outcome. Other outcome measures included NRS score changes within groups, area under the curve for the NRS scores, total analgesic dose, change in knee flexion and extension, pain control satisfaction, nausea and vomiting, and hospital stay duration. NRS score changes were greater in group L than in group S (P < 0.01, ANOVA) and greater in group L than in group S at three postoperative time points: 3 h (P < 0.01), 6 h (P < 0.01), and 12 h (P = 0.013; Mann-Whitney U test). Changes in the mean NRS score were observed in each group (P < 0.01, Friedman test). No significant differences were detected in the other outcome measures (Mann-Whitney U, Wilcoxon signed-rank, and chi-squared tests). Sciatic nerve block with femoral nerve block is superior to local anesthetic infiltration with femoral nerve block for postoperative pain control within 3-12 h of total knee arthroplasty. UMIN-CTR ID: 000013364 R: 000015591.


Synthesis and characterization of some new 2(3H)-benzoxazolones with analgesic and antiinflammatory activities.
The synthesis, characterization and pharmacological activities of a new series of (6-difluorobenzoyl)-5-methyl-3-benzoylmethyl-2(3H)-benzoxazolone and 5-methyl-3-(2-hydroxyl-2-phenylethyl)-2(3H)-benzoxazolone are described. Antiinflammatory activity was investigated by the carrageenin-induced paw oedema test and analgesic activity by acetic acid writhing and hot plate tests in mice. Among the synthesized compounds, compound 3e 6-(2,5-difluorobenzoyl)-3-(4-bromobenzoylmethyl-2(3H)-benzoxazolone was found to be the most promising compound for analgesic activity. Reduced compounds (4a-4d) displayed considerable anti-inflammatory activity compared to the other derivatives.


Expression of the crucifer-infecting TMV-Cg movement protein in tobacco plants complements in trans a TMV-U1 trafficking-deficient mutant.
Tobamovirus movement proteins play a determinant role in the establishment of infections in plants, allowing the local movement of viral RNA genome through plasmodesmatas. We expressed the movement protein (MP) of the crucifer- and garlic-infecting Tobacco Mosaic Virus strain Cg (TMV-Cg) in both resistant Xanthi NN and sensitive Xanthi nn Nicotiana tabacum plants. MP-Cg function was assayed by inoculating transgenic plants with a trafficking-deficient mutant of TMV strain U1. Following infection, local necrotic lesions were developed in resistant transgenic plants, and a systemic infection was produced in sensitive tobaccos. Thus, movement function of the mutant virus was complemented in trans by MP-Cg expressed in transgenic plants, causing the same symptoms as wild-type strain. We demonstrated that the function of MP-U1 could be replaced efficiently by MP-Cg, even though these proteins share only 36% of identity. Similar hydrophobic patterns of MP-Cg and MP-U1 suggests structure and function conservations of both proteins. This work is an example of how two tobamoviruses differing in their host range help to understand viral movement mechanism during the infection.


Studies of the relationship between the catalytic activity and binding of non-substrate ligands by the glutathione S-transferases.
The dimeric enzyme glutathione S-transferase B is composed of two dissimilar subunits, referred to as Ya and Yc. Transferase B (YaYc) and two other transferases that are homodimers of the individual Ya and Yc subunits were purified from rat liver. Inhibition of these three enzymes by Indocyanine Green, biliverdin and several bile acids was investigated at different values of pH (range 6.0-8.0). Indocyanine Green, biliverdin and chenodeoxycholate were found to be effective inhibitors of transferases YaYc and YcYc at low (pH 6.0) but not high (pH 8.0) values of pH. Between these extremes of pH intermediate degrees of inhibition were observed. Cholate and taurochenodeoxycholate, however, were ineffective inhibitors of transferase YcYc at all values of pH. The observed differences in bile acids appeared to be due, in part, to differences in their state of ionization. In contrast with the above results, transferase YaYa was inhibited by at least 80% by the non-substrate ligands at all values of pH. These effects of pH on the three transferases could not be accounted for by pH-induced changes in the enzyme's affinity for the inhibitor. Thus those glutathione S-transferases that contain the Yc subunit are able to act simultaneously as both enzymes and binding proteins. In addition to enzyme structure, the state of ionization of the non-substrate ligands may also influence whether the transferases can perform both functions simultaneously.


M-wave modulation at relative levels of maximal voluntary contraction.
Frequency (mean and median power frequency, f and fm) and amplitude (average rectified and root mean square values, ARV and rms), parameters of the M-wave, and the dorsiflexor force parameters of the anterior tibial muscles were measured in seven healthy human subjects. Intermittent, voluntary contractions at relative intensities (40%, 60%, and 80%) of maximal voluntary contraction (MVC) were performed in conjunction with electrical stimulation. The M-wave parameter changes were measured over the course of the isometric contractions. At higher force levels, M-wave potentiation was observed as increases in both ARV and rms. The ARV augmentation attained levels as high as 206.1 (SD 7.4)% of resting values after both initial and final contractions of 80% MVC, reaching statistical significance (P < 0.01). The f and fm failed to show a significant difference at any level of contraction. It was surmised that potentiation of the M-wave was the result of an increased contribution of muscle fibre type IIb recruited during higher contraction levels, reflecting the change to larger, deeper innervating motoneurons as the intensity of contraction, as a percentage of MVC, rose. Recruitment of type IIb fibres, which have been reported to have a higher energy potential and frequency content, were thought to reflect changes in the local excitability threshold of some motor units as the force intensity increased during the intermittent voluntary contractions. It is suggested that the M-wave elicited after contractions has the potential to reflect, to some extent, motor unit recruitment changes resulting from the preceding contractions, and that through comparisons of M-wave amplitude parameters contributions of varying fibre types over the course of a contraction may be indicated.


Shape characterization of a large nonspherical particle by use of its Fraunhofer diffraction pattern.
We characterize the shape of a large nonspherical particle by means of the two-dimensional Fourier transformation of its diffraction pattern, called the S function. The main properties of S functions are considered. Some ways in which to retrieve the geometric parameters of a particle by use of its S function are discussed. In particular, the parameter of nonsphericity of a particle is defined by means of the S function.


Relationship between incoherent excitation energy migration processes and molecular structures in zinc(II) porphyrin dendrimers.
Multiporphyrin dendrimers are among the most promising architectures to mimic the oxygenic light-harvesting complex because of their structural similarities and synthetic convenience. The overall geometries of dendrimers are determined by the core structure, the type of dendron, and the number of generations of interior repeating units. The rigid core and bulky volume of exterior porphyrin units in multiporphyrin dendrimers give rise to well-ordered three-dimensional structures. As the number of generations of interior repeating units increases, however, the overall structures of dendrimers become disordered and randomized due to the flexibility of the repeating units. To reveal the relationship between molecular structure and processes of excitation-energy migration in multiporphyrin dendrimers, we calculated the molecular structure and measured the time-resolved transient absorption and fluorescence anisotropy decays for various hexaarylbenzene-anchored polyester zinc(II) porphyrin dendrimers along with three types of porphyrin dendrons as references. We found that the congested two-branched type dendrimers exhibit more efficient energy migration processes than one- or three-branched type dendrimers because of multiple energy migration pathways, and the three-dimensional packing efficiency of dendrimers strongly depends on the type of dendrons.


Locally adapted fish populations maintain small-scale genetic differentiation despite perturbation by a catastrophic flood event.
Local adaptation to divergent environmental conditions can promote population genetic differentiation even in the absence of geographic barriers and hence, lead to speciation. Perturbations by catastrophic events, however, can distort such parapatric ecological speciation processes. Here, we asked whether an exceptionally strong flood led to homogenization of gene pools among locally adapted populations of the Atlantic molly (Poecilia mexicana, Poeciliidae) in the Cueva del Azufre system in southern Mexico, where two strong environmental selection factors (darkness within caves and/or presence of toxic H2S in sulfidic springs) drive the diversification of P. mexicana. Nine nuclear microsatellites as well as heritable female life history traits (both as a proxy for quantitative genetics and for trait divergence) were used as markers to compare genetic differentiation, genetic diversity, and especially population mixing (immigration and emigration) before and after the flood. Habitat type (i.e., non-sulfidic surface, sulfidic surface, or sulfidic cave), but not geographic distance was the major predictor of genetic differentiation. Before and after the flood, each habitat type harbored a genetically distinct population. Only a weak signal of individual dislocation among ecologically divergent habitat types was uncovered (with the exception of slightly increased dislocation from the Cueva del Azufre into the sulfidic creek, El Azufre). By contrast, several lines of evidence are indicative of increased flood-induced dislocation within the same habitat type, e.g., between different cave chambers of the Cueva del Azufre. The virtual absence of individual dislocation among ecologically different habitat types indicates strong natural selection against migrants. Thus, our current study exemplifies that ecological speciation in this and other systems, in which extreme environmental factors drive speciation, may be little affected by temporary perturbations, as adaptations to physico-chemical stressors may directly affect the survival probability in divergent habitat types.


Ethics in the Pediatric Emergency Department: When Mistakes Happen: An Approach to the Process, Evaluation, and Response to Medical Errors.
The emergency department (ED) is an environment that is conducive to medical errors. The ED is a time-pressured environment where physicians aim to rapidly evaluate and treat patients. Quick thinking and problem-based solutions are often used to assist in evaluation and diagnosis. Error analysis leads to an understanding of the cause of a medical error and is important to prevent future errors. Research suggests mechanisms to prevent medical errors in the pediatric ED, but prevention is not always possible. Transparency about errors is necessary to assure a trusting doctor-patient relationship. Patients want to be informed about all errors, and apologies are hard. Apologizing for a significant medical error that may have caused a complication is even harder. Having a systematic way to go about apologizing makes the process easier, and helps assure that the right information is relayed to the patient and his or her family. This creates an environment of autonomy and shared decision making that is ultimately beneficial to all aspects of patient care.


Safety and efficacy of PNL vs RIRS in the management of stones located in horseshoe kidneys: A critical comparative evaluation.
To assess the efficacy and safety of two different techniques (Percutaneous nephrolithotomy (PNL) vs Retrograde intrarenal surgery (RIRS)) in the management of stones in patients with horseshoe kidneys (HSK). Departmental files of 88 cases with radiopaque kidney stones in horseshoe kidneys undergoing two different approaches (PNL vs RIRS) were evaluated with respect to the success and complication rates of in a retrospective manner. In addition to the factors related with the procedures (success and complication rates, additional procedures), patient and stone characteristics were all well evaluated. Findings obtained in both groups were evaluated in a comparative manner with respect to the statistical significance. Stone free rates were comparable in both groups after 1-week period (81.6% PNL vs 80% RIRS). As well as 3 months evaluation (84.2% PNL and 82.0% RIRS). The percentage of the cases with residual fragments (> 4 mm) were similar in both groups and while all PNL procedures were completed in one session, mean number of RIRS sessions was higher (1.22 ± 0.05). Mean duration of the procedure was slightly higher in RIRS group and based on Clavien scoring system, despite a higher risk of Hb drop noted in patients treated with PNL, all complication rates were found to be similar in both groups. Our results demonstrate that of the available minimally invasive treatment alternatives, both PNL and RIRS could be safe and effective alternatives for renal stone removal in patients with HSK.