Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.
Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.


Lethal aggression in mobile forager bands and implications for the origins of war.
It has been argued that warfare evolved as a component of early human behavior within foraging band societies. We investigated lethal aggression in a sample of 21 mobile forager band societies (MFBS) derived systematically from the standard cross-cultural sample. We hypothesized, on the basis of mobile forager ethnography, that most lethal events would stem from personal disputes rather than coalitionary aggression against other groups (war). More than half of the lethal aggression events were perpetrated by lone individuals, and almost two-thirds resulted from accidents, interfamilial disputes, within-group executions, or interpersonal motives such as competition over a particular woman. Overall, the findings suggest that most incidents of lethal aggression among MFBS may be classified as homicides, a few others as feuds, and a minority as war.


Pharmaceutical Company Targets and Strategies to Address Climate Change: Content Analysis of Public Reports from 20 Pharmaceutical Companies.
The pharmaceutical industry produces a large proportion of health system greenhouse gas (GHG) emissions, contributing to climate change. This urgently needs to be addressed. We aimed to examine pharmaceutical company climate change targets, GHG emissions, and strategies to reduce them. We performed content analysis of the 20 largest pharmaceutical companies' publicly available 2020/2021 reports, focusing on extracting information on their reported climate change targets, GHG emissions (and whether companies had demonstrated any reduction in emissions over their reporting period), and strategies being implemented to reduce company emissions and meet their targets. Nineteen companies have committed to reducing GHG emissions, ten to carbon neutrality and eight to net zero emissions between 2025 and 2050. Companies showed largely favorable reductions in scope 1 (in-house) and scope 2 (purchased energy), with variable results in scope 3 (supply chain) emissions. Strategies to reduce emissions included optimizing manufacturing and distribution, and responsible sourcing of energy, water, and raw materials. Pharmaceutical companies are setting climate change targets and reporting reduced emissions via a range of strategies. This varies, with scope to track actions and accountability to targets, improve consistency of reporting, especially of scope 3 emissions, and collaborate on novel solutions. There is need for further mixed methods research on progress with achieving reported climate change targets, as well as implementation of strategies to reduce emissions within the pharmaceutical industry.


Real-time FPGA data collection of pulsed-laser cavity ringdown signals.
This paper presents results from a pulsed-laser cavity ring-down spectrometer with novel field programable gate array real-time data collection. We show both theoretically and experimentally that the data extraction can be achieved from a single cavity ringdown event, and that the absorbance can be determined without the need to fit the ringdown time explicitly. This methodology could potentially provide data acquisition rate up to 1 MHz, with the accuracy and precision comparable to nonlinear least squares fitting algorithms.


Correlation between retinal morphological and functional findings and clinical severity in Parkinson's disease.
To measure the parapapillary retinal nerve fiber layer and macular thickness and macular volume in vivo and to evaluate whether retinal structural changes and visual cortical responses may be related to the clinical severity of the PD. We included 17 patients with Parkinson's disease and 11 healthy subjects of a similar age. Unified Parkinson's disease rating scale scores in Parkinson's disease and control subjects were assessed for clinical evaluation. The retinal nerve fiber layer thickness, macular thickness and volume were measured by commercially available optical coherence tomography Model 3000 unit. Peak latencies of P100 component were measured by pattern visual evoked potential examination. The mean retinal nerve fiber layer average thickness was significantly reduced in Parkinson's disease patients (98.76 +/- 10.90 microm) when compared with those of control subjects (114.54 +/- 5.72) (P < 0.05). The retinal thickness reduction was statistically significant in superior inner macula; temporal, nasal and inferior quadrants of outer macula (P < 0.05)(Table 2). The mean total macular volume of Parkinson's disease patients (6.82 +/- 0.32 mm(3)) was significantly reduced when compared with those of control subjects (7.09 +/- 0.23 mm(3)). Highly significant inverse correlation between foveal retinal thickness and total and motor subscores of Unified Parkinson's disease rating scale was observed in Parkinson's disease patients, respectively (r = -0.660; P = 0.004), (r = -0.625, P = 0.007). There was a moderate nearly significant inverse correlation between total macular volume and P100 latency in PD (r = -0.328; P = 0.058). In Parkinson's disease patients there is a reduction of retinal nerve fiber layer thickness, macular thickness and volume evaluated in vivo by optical coherence tomography. Reduced foveal thickness which is not found to be statistically different from normal is correlated to the severity of disease.


Direct measurement of critical nucleus size in confined volumes.
In crystallization, the critical nucleus size is of pivotal importance. Above this size, it is favorable for the new crystalline phase to form; below this size, the clusters will tend to dissolve rather than grow. To date, there has been no direct method for measuring the critical nucleus size. Instead, the size is typically calculated from the variation of crystallization rates with temperature. This involves using bulk values of the interfacial tension and enthalpy of fusion, which are inappropriate for small critical nucleus sizes. Here, we present a direct method for measuring the size of the critical nucleus, based on observing crystallization temperatures of materials within microemulsions. Using this approach, the number of molecules in the critical nucleus can be found simply by measuring the droplet size. Data on the freezing of water in water-in-oil microemulsions with and without the nucleating agent, heptacosanol, are presented to support our hypothesis. The results show that the critical nucleus contains 90-350 ice molecules for water pool radii of approximately 1.2-1.8 nm for the heptacosanol-doped microemulsions in which heterogeneous nucleation is initiated at the droplet interface. For the microemulsions without heptacosanol, the critical nucleus contains 70-210 ice molecules for water pool radii of approximately 1.2-1.8 nm. The smaller values arise because homogeneous nucleation occurs and therefore the crystallization temperatures are lower. We can also determine how bulk properties are perturbed at the nanoscale, and we find that the ratio of the ice-water interfacial tension to the enthalpy of fusion decreases significantly for water pool radii that are <2 nm.


ABM Clinical Protocol #25: Recommendations for preprocedural fasting for the breastfed infant: "NPO" Guidelines.
A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. These guidelines are not intended to be all-inclusive, but to provide a basic framework for physician education regarding breastfeeding.


On the particular importance of vibrational contributions to the static electrical properties of model linear molecules under spatial confinement.
The influence of the spatial confinement on the electronic and vibrational contributions to longitudinal electric-dipole properties of model linear molecules including HCN, HCCH and CO2 is discussed. The effect of confinement is represented by two-dimensional harmonic oscillator potential of cylindrical symmetry, which mimics the key features of various types of trapping environments like, for instance, nanotubes or quantum well wires. Our results indicate that in general both (electronic and vibrational) contributions to (hyper)polarizabilities diminish upon spatial confinement. However, since the electronic term is particularly affected, the relative importance of vibrational contributions is larger for confined species. This effect increases also with the degree of anharmonicity of vibrational motion.


Photothrombosis of corneal neovascularization by intravenous rose bengal and argon laser irradiation.
Management of corneal neovascularization by photocoagulation has been limited and rarely successful. We evaluated the efficacy and safety of the novel technique of photothrombosis to occlude corneal neovascularization. Sixteen rabbit corneas with previous ocular surface wounds that had healed with 360 degrees extensive neovascularization (persistent for 20 months) were used. After an intravenous injection of rose bengal solution (40 mg/kg of body weight [BW]), each vessel on the upper half of the cornea was occluded with a photochemically induced thrombus within ten shots of argon laser irradiation (514.5 nm, 130 mW, 63 microns, 0.2 s); those on the lower half were used as an internal control. Throughout the four-month study period, the treated vessels remained occluded, as evidenced by corneal fluorescein angiography. Corneal clarity was improved after treatment. A single injection of rose bengal at a dose of 8 mg/kg of BW or higher was sufficient for successful photothrombotic occlusion of corneal vessels within one hour of experimentation. Transient elevations of serum urea nitrogen, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels and decrease of serum phosphorus level were noted on the first day after injection with 40 mg/kg of BW of rose bengal solution.


Horizontal membrane-intrinsic α-helices in the stator a-subunit of an F-type ATP synthase.
ATP, the universal energy currency of cells, is produced by F-type ATP synthases, which are ancient, membrane-bound nanomachines. F-type ATP synthases use the energy of a transmembrane electrochemical gradient to generate ATP by rotary catalysis. Protons moving across the membrane drive a rotor ring composed of 8-15 c-subunits. A central stalk transmits the rotation of the c-ring to the catalytic F1 head, where a series of conformational changes results in ATP synthesis. A key unresolved question in this fundamental process is how protons pass through the membrane to drive ATP production. Mitochondrial ATP synthases form V-shaped homodimers in cristae membranes. Here we report the structure of a native and active mitochondrial ATP synthase dimer, determined by single-particle electron cryomicroscopy at 6.2 Å resolution. Our structure shows four long, horizontal membrane-intrinsic α-helices in the a-subunit, arranged in two hairpins at an angle of approximately 70° relative to the c-ring helices. It has been proposed that a strictly conserved membrane-embedded arginine in the a-subunit couples proton translocation to c-ring rotation. A fit of the conserved carboxy-terminal a-subunit sequence places the conserved arginine next to a proton-binding c-subunit glutamate. The map shows a slanting solvent-accessible channel that extends from the mitochondrial matrix to the conserved arginine. Another hydrophilic cavity on the lumenal membrane surface defines a direct route for the protons to an essential histidine-glutamate pair. Our results provide unique new insights into the structure and function of rotary ATP synthases and explain how ATP production is coupled to proton translocation.


The Advisory Committee on Immunization Practices' Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine - United States, December 2020.
On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the Pfizer-BioNTech COVID-19 (BNT162b2) vaccine (Pfizer, Inc; Philadelphia, Pennsylvania), a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine encoding the prefusion spike glycoprotein of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1). Vaccination with the Pfizer-BioNTech COVID-19 vaccine consists of 2 doses (30 μg, 0.3 mL each) administered intramuscularly, 3 weeks apart. On December 12, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation* for use of the Pfizer-BioNTech COVID-19 vaccine in persons aged ≥16 years for the prevention of COVID-19. To guide its deliberations regarding the vaccine, ACIP employed the Evidence to Recommendation (EtR) Framework,† using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.§ The recommendation for the Pfizer-BioNTech COVID-19 vaccine should be implemented in conjunction with ACIP's interim recommendation for allocating initial supplies of COVID-19 vaccines (2). The ACIP recommendation for the use of the Pfizer-BioNTech COVID-19 vaccine under EUA is interim and will be updated as additional information becomes available.


In-situ analysis of calcitonin and CGRP expression in medullary thyroid carcinoma.
A combination of immunocytochemistry (ICC) and in-situ hybridization (ISH) applied to formalin-fixed tissue sections was used to analyse the differential expression of calcitonin and CGRP genes, at both peptide and mRNA levels, in normal and neoplastic human thyroid C cells. Calcitonin peptide was readily detectable in normal C cells but its abundance in the neoplastic C cells of medullary thyroid carcinoma (MTC) was reduced in correlation with the degree of tumour differentiation. Conversely, the content of calcitonin mRNA was higher in MTC than in normal C cells and was not significantly related to tumour differentiation. Both the peptide and mRNA of CGRP were present at much lower levels than those of calcitonin in normal C cells but were increased in neoplastic C cells. We conclude that neoplasia of thyroid C cells is associated with (i) an increase in the content of CGRP mRNA and peptide relative to that of calcitonin, consistent with a defect in control of transcript processing, and (ii) a decrease in the ratio of calcitonin peptide to mRNA abundance relative to the normal, suggesting a defect in synthesis or storage of the peptide. ISH analysis of calcitonin mRNA may therefore be a very valuable addition to ICC analysis of the peptide as a diagnostic and prognostic marker for MTC.


Electron-Rich Metal Cations Enable Synthesis of High Molecular Weight, Linear Functional Polyethylenes.
Group 10 metal catalysts have shown much promise for the copolymerization of nonpolar with polar alkenes to directly generate functional materials, but access to high copolymer molecular weights nevertheless remains a key challenge toward practical applications in this field. In the context of identifying new strategies for molecular weight control, we report a series of highly polarized P(V)-P(III) chelating ligands that manifest unique space filling and electrostatic effects within the coordination sphere of single component Pd polymerization catalysts and exert important influences on (co)polymer molecular weights. Single component, cationic phosphonic diamide-phosphine (PDAP) Pd catalysts are competent to generate linear, functional polyethylenes with Mw up to ca. 2 × 105 g mol-1, significantly higher than prototypical catalysts in this field, and with polar content up to ca. 9 mol %. Functional groups are positioned by these catalysts almost exclusively along the main chain, not at chain ends or ends of branches, which mimics the microstructures of commercial linear low-density polyethylenes. Spectroscopic, X-ray crystallographic, and computational data indicate PDAP coordination to Pd manifests cationic yet electron-rich active species, which may correlate to their complementary catalytic properties versus privileged catalysts such as electrophilic α-diimine (Brookhart-type) or neutral phosphine-sulfonato (Drent-type) complexes. Though steric blocking within the catalyst coordination sphere has long been a reliable strategy for catalyst molecular weight control, data from this study suggest electronic control should be considered as a complementary concept less prone to suppression of comonomer enchainment that can occur with highly sterically congested catalysts.


Beyond Unconventional: What Do We Really Know about Group 2 Innate Lymphoid Cells?
Group 2 innate lymphoid cells (ILC2s) are a set of effectors that mediate the expulsion of helminthic parasites but also drive allergic lung inflammation. As innate agents, they do not recognize Ag, instead, they are sensitive to alarmin engagement, upon which they produce type 2 cytokines that amplify adaptive immunity. Their lymphoid identity appoints them as an intriguing group of unconventional cells; however, increasing evidence is unraveling a series of unprecedented functions that <5 years ago were unthinkable for ILC2s, such as acquiring a proinflammatory identity that enables them to support TH1 immune responses. Their plastic nature has allowed the characterization of ILC2s in more detail than ever; however, the novelty of ILC2 biology requires constant updates and recapitulations. This review provides an overview of ILC2s and describes memory ILC2, regulatory ILC2, inflammatory ILC2, and type 1 ILC2 subsets based on activation status, tissue environments, and function.


Triton X-114 phase separation in the isolation and purification of mouse liver microsomal membrane proteins.
Integral membrane proteins (IMPs) mediate several cellular functions including cell adhesion, ion and nutrient transport, and cell signalling. IMPs are typically hard to isolate and purify due to their hydrophobic nature and low cellular abundance, however, microsomes are small lipid vesicles rich in IMPs, which form spontaneously when cells are mechanically disrupted. In this study, we have employed mouse liver microsomes as a model for optimising a method for IMP isolation and characterisation. Microsomes were collected by differential centrifugation, purified with sodium carbonate, and subjected to GeLC-MS/MS analysis. A total of 1124 proteins were identified in the microsome fraction, with 47% (524/1124) predicted by TMHMM to contain at least one transmembrane domain (TMD). The ability of phase partitioning using the detergent Triton X-114 (TX-114) to further enrich for membrane proteins was evaluated. Microsomes were subjected to successive rounds of solubility-based phase separation, with proteins partitioning into the aqueous phase, detergent phase, or TX-114-insoluble pellet fraction. GeLC-MS/MS analysis of the three TX-114 fractions identified 1212 proteins, of which 146 were not detected in the un-fractionated microsome sample. Conspicuously, IMPs partitioned to the detergent phase, with 56% (435/770) of proteins identified in that fraction containing at least one TMD. GO Slim characterisation of the microsome proteome revealed enrichment of proteins from the endoplasmic reticulum, mitochondria, Golgi apparatus, endosome, and cytoplasm. Further, enzymes including monooxygenases were well represented with 35 cytochrome P450 identifications (CYPs 1A2, 2A5, 2A12, 2B10, 2C29, 2C37, 2C39, 2C44, 2C50, 2C54. 2C67, 2C68, 2C70, 2D10, 2D11, 2D22, 2D26, 2D9, 2E1, 2F2, 2J5, 2U1, 3A11, 3A13, 3A25, 4A10, 4A12A, 4A12B, 4F13, 4F14, 4F15, 4V3, 51,7B1, and 8B1). Evaluation of biological processes showed enrichment of proteins involved in fatty acid biosynthesis and elongation, as well as steroid synthesis. In addition, transport proteins including 24 members of the Rab family of GTPases were identified. Comparison of this dataset with the current mouse liver microsome proteome contributes an additional 648 protein identifications, of which 50% (326/648) contain at least one TMD.


Anti-neuronal antibodies in acute pandysautonomia.
We encountered two patients with acute pandysautonomia who subacutely exhibited extensive autonomic dysfunction after antecedent infections. Although these patients had been suffering from autonomic disturbance for several months, they both had a good clinical course after plasma exchange and intravenous immunoglobulin therapy. Thin-layer chromatography (TLC)-immunostaining did not demonstrate any antibodies against gangliosides, but immunoblot analysis showed antibodies against a neuroblastoma cell line, SH-SY5Y, in serum samples. Furthermore, ganglionic acetylcholine receptor autoantibodies were detected in one patient. These findings suggest that neuronal antibodies against the autonomic nervous system play an important role in the pathogenesis of acute pandysautonomia.


The genomes of four tapeworm species reveal adaptations to parasitism.
Tapeworms (Cestoda) cause neglected diseases that can be fatal and are difficult to treat, owing to inefficient drugs. Here we present an analysis of tapeworm genome sequences using the human-infective species Echinococcus multilocularis, E. granulosus, Taenia solium and the laboratory model Hymenolepis microstoma as examples. The 115- to 141-megabase genomes offer insights into the evolution of parasitism. Synteny is maintained with distantly related blood flukes but we find extreme losses of genes and pathways that are ubiquitous in other animals, including 34 homeobox families and several determinants of stem cell fate. Tapeworms have specialized detoxification pathways, metabolism that is finely tuned to rely on nutrients scavenged from their hosts, and species-specific expansions of non-canonical heat shock proteins and families of known antigens. We identify new potential drug targets, including some on which existing pharmaceuticals may act. The genomes provide a rich resource to underpin the development of urgently needed treatments and control.


Action representation of sound: audiomotor recognition network while listening to newly acquired actions.
The discovery of audiovisual mirror neurons in monkeys gave rise to the hypothesis that premotor areas are inherently involved not only when observing actions but also when listening to action-related sound. However, the whole-brain functional formation underlying such "action-listening" is not fully understood. In addition, previous studies in humans have focused mostly on relatively simple and overexperienced everyday actions, such as hand clapping or door knocking. Here we used functional magnetic resonance imaging to ask whether the human action-recognition system responds to sounds found in a more complex sequence of newly acquired actions. To address this, we chose a piece of music as a model set of acoustically presentable actions and trained non-musicians to play it by ear. We then monitored brain activity in subjects while they listened to the newly acquired piece. Although subjects listened to the music without performing any movements, activation was found bilaterally in the frontoparietal motor-related network (including Broca's area, the premotor region, the intraparietal sulcus, and the inferior parietal region), consistent with neural circuits that have been associated with action observations, and may constitute the human mirror neuron system. Presentation of the practiced notes in a different order activated the network to a much lesser degree, whereas listening to an equally familiar but motorically unknown music did not activate this network. These findings support the hypothesis of a "hearing-doing" system that is highly dependent on the individual's motor repertoire, gets established rapidly, and consists of Broca's area as its hub.


Circumstances of witnessed drug overdose in New York City: implications for intervention.
Drug users frequently witness the nonfatal and fatal drug overdoses of their peers, but often fail to intervene effectively to reduce morbidity and mortality. We assessed the circumstances of witnessed heroin-related overdoses in New York City (NYC) among a predominantly minority population of drug users. Among 1184 heroin, crack, and cocaine users interviewed between November 2001 and February 2004, 672 (56.8%) had witnessed at least one nonfatal or fatal heroin-related overdose. Of those, 444 (67.7%) reported that they or someone else present called for medical help for the overdose victim at the last witnessed overdose. In multivariable models, the respondent never having had an overdose her/himself and the witnessed overdose occurring in a public place were associated with the likelihood of calling for medical help. Fear of police response was the most commonly cited reason for not calling or delaying before calling for help (52.2%). Attempts to revive the overdose victim through physical stimulation (e.g., applying ice, causing pain) were reported by 59.7% of respondents, while first aid measures were attempted in only 11.9% of events. Efforts to equip drug users to manage overdoses effectively, including training in first aid and the provision of naloxone, and the reduction of police involvement at overdose events may have a substantial impact on overdose-related morbidity and mortality.


Role of H2O2 and cell wall monoamine oxidases in germination of Vigna radiata seeds.
Plant cell wall expresses monoamine oxidases (MAOs) that catalyze oxidation of secreted amines and produce H2O2 in the process. The H2O2, so produced is used by cell wall peroxidases for lignification of cell wall or for plant defense. The natural substrates for these MAOs are elusive, but polyamines and certain catecholamines have been proposed as candidates. Reactive oxygen species are also known to act as signaling molecules controlling plant metabolism. Mungbean (Vigna radiata) has long served as the plant model of choice while studying molecular programs followed during germination and seed development. In this study, we tested the effect of externally added MAO substrates epinephrine and H2O2 on storage protein mobilization in germinating seeds of Vigna radiata. The seeds were imbibed in the presence of 50 microM epinephrine and 10 microM H2O2. These low concentrations of the two compounds were used to exclude direct effects on proteolysis and were arrived at after testing a range of the two and choosing the most effective concentration. These seeds showed 11% and 7% decrease in fresh weight respectively, indicating greater storage mobilization and a corresponding 19% and 46% increase in axis length as compared to untreated seeds. Soluble protein in seeds treated with epinephrine and H2O2 decreased significantly by 34% and 33% as compared to untreated seeds. Electrophoretic analysis of seed proteins revealed a startling and selective depletion of storage proteins in treated seeds. The results indicated a clear involvement of H2O2 in storage protein mobilization in the cotyledons. We propose that H2O2 generated within cell walls of seeds serves as a signaling molecule guiding germination events, including protein reserve mobilization.


mu-Opioid receptor activation reduces multiple components of high-threshold calcium current in rat sensory neurons.
Whole-cell patch-clamp recordings were used to characterize calcium channel types that are modulated by mu-opioid receptor activation in rat dorsal root ganglion (DRG) neurons. Five distinct components of high-threshold calcium current were isolated on the basis of their sensitivity to the selective channel blockers omega-conotoxin GVIA, nifedipine, omega-conotoxin MVIIC, or omega-agatoxin IVA. The mu-opioid selective agonist Tyr-Pro-NMePhe-D-Pro-NH2 (PLO17) routinely suppressed high-threshold currents and this effect was always reduced by omega-conotoxin GVIA. A fraction of PLO17-sensitive current remained after omega-conotoxin GVIA that was eliminated by application of omega-agatoxin IVA alone or in combination with omega-conotoxin MVIIC. Nifedipine had no effect on mu-opioid responses nor did PLO17 affect the slow component of tail current induced by Bay K 8644. These data suggest that mu-opioid receptors are negatively coupled to three types of calcium channels in rat DRG neurons, including an omega-conotoxin GVIA-sensitive (N-type) channel, an omega-agatoxin IVA-sensitive (P-type) channel and an omega-conotoxin MVIIC-sensitive, nifedipine/GVIA/omega-Aga IVA-resistant (presumptive Q-type) channel.


Family-focused treatment for adolescents and young adults at high risk for psychosis: results of a randomized trial.
Longitudinal studies have begun to clarify the phenotypic characteristics of adolescents and young adults at clinical high risk for psychosis. This 8-site randomized trial examined whether a 6-month program of family psychoeducation was effective in reducing the severity of attenuated positive and negative psychotic symptoms and enhancing functioning among individuals at high risk. Adolescents and young adults (mean age 17.4 ± 4.1 years) with attenuated positive psychotic symptoms, brief and intermittent psychosis, or genetic risk with functional deterioration were randomly assigned to 18 sessions of family-focused therapy for individuals at clinical high risk (FFT-CHR) in 6 months or 3 sessions of family psychoeducation (enhanced care [EC]). FFT-CHR included psychoeducation about early signs of psychosis, stress management, communication training, and problem-solving skills training, whereas EC focused on symptom prevention. Independent evaluators assessed participants at baseline and 6 months on positive and negative symptoms and social-role functioning. Of 129 participants, 102 (79.1%) were followed up at 6 months. Participants in FFT-CHR showed greater improvements in attenuated positive symptoms over 6 months than participants in EC (F1,97 = 5.49, p = .02). Negative symptoms improved independently of psychosocial treatments. Changes in psychosocial functioning depended on age: participants more than 19 years of age showed more role improvement in FFT-CHR, whereas participants between 16 and 19 years of age showed more role improvement in EC. The results were independent of concurrent pharmacotherapy. Interventions that focus on improving family relationships may have prophylactic efficacy in individuals at high risk for psychosis. Future studies should examine the specificity of effects of family intervention compared to individual therapy of the same duration and frequency. Clinical trial registration information-Prevention Trial of Family Focused Treatment in Youth at Risk for Psychosis; http://clinicaltrials.gov/; NCT01907282.


Extracorporeal Membrane Oxygenation for Respiratory Failure.
This review focuses on the use of veno-venous extracorporeal membrane oxygenation for respiratory failure across all blood flow ranges. Starting with a short overview of historical development, aspects of the physiology of gas exchange (i.e., oxygenation and decarboxylation) during extracorporeal circulation are discussed. The mechanisms of phenomena such as recirculation and shunt playing an important role in daily clinical practice are explained.Treatment of refractory and symptomatic hypoxemic respiratory failure (e.g., acute respiratory distress syndrome [ARDS]) currently represents the main indication for high-flow veno-venous-extracorporeal membrane oxygenation. On the other hand, lower-flow extracorporeal carbon dioxide removal might potentially help to avoid or attenuate ventilator-induced lung injury by allowing reduction of the energy load (i.e., driving pressure, mechanical power) transmitted to the lungs during mechanical ventilation or spontaneous ventilation. In the latter context, extracorporeal carbon dioxide removal plays an emerging role in the treatment of chronic obstructive pulmonary disease patients during acute exacerbations. Both applications of extracorporeal lung support raise important ethical considerations, such as likelihood of ultimate futility and end-of-life decision-making. The review concludes with a brief overview of potential technical developments and persistent challenges.


Observation of Strong Reflection of Electron Waves Exiting a Ballistic Channel at Low Energy.
Wave scattering by a potential step is a ubiquitous concept. Thus, it is surprising that theoretical treatments of ballistic transport in nanoscale devices, from quantum point contacts to ballistic transistors, assume no reflection even when the potential step is encountered upon exiting the device. Experiments so far seem to support this even if it is not clear why. Here we report clear evidence of coherent reflection when electron wave exits the channel of a nanoscale transistor and when the electron energy is low. The observed behavior is well described by a simple rectangular potential barrier model which the Schrodinger's equation can be solved exactly. We can explain why reflection is not observed in most situations but cannot be ignored in some important situations. Our experiment also represents a direct measurement of electron injection velocity - a critical quantity in nanoscale transistors that is widely considered not measurable.


Genetic diversity of a dominant C4 grass is altered with increased precipitation variability.
Climate change has the potential to alter the genetic diversity of plant populations with consequences for community dynamics and ecosystem processes. Recent research focused on changes in climatic means has found evidence of decreased precipitation amounts reducing genetic diversity. However, increased variability in climatic regimes is also predicted with climate change, but the effects of this aspect of climate change on genetic diversity have yet to be investigated. After 10 years of experimentally increased intra-annual variability in growing season precipitation regimes, we report that the number of genotypes of the dominant C(4) grass, Andropogon gerardii Vitman, has been significantly reduced in native tallgrass prairie compared with unmanipulated prairie. However, individuals showed a different pattern of genomic similarity with increased precipitation variability resulting in greater genome dissimilarity among individuals when compared to unmanipulated prairie. Further, we found that genomic dissimilarity was positively correlated with aboveground productivity in this system. The increased genomic dissimilarity among individuals in the altered treatment alongside evidence for a positive correlation of genomic dissimilarity with phenotypic variation suggests ecological sorting of genotypes may be occurring via niche differentiation. Overall, we found effects of more variable precipitation regimes on population-level genetic diversity were complex, emphasizing the need to look beyond genotype numbers for understanding the impacts of climate change on genetic diversity. Recognition that future climate change may alter aspects of genetic diversity in different ways suggests possible mechanisms by which plant populations may be able to retain a diversity of traits in the face of declining biodiversity.


Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor.
Jasmonates are a family of plant hormones that regulate plant growth, development and responses to stress. The F-box protein CORONATINE INSENSITIVE 1 (COI1) mediates jasmonate signalling by promoting hormone-dependent ubiquitylation and degradation of transcriptional repressor JAZ proteins. Despite its importance, the mechanism of jasmonate perception remains unclear. Here we present structural and pharmacological data to show that the true Arabidopsis jasmonate receptor is a complex of both COI1 and JAZ. COI1 contains an open pocket that recognizes the bioactive hormone (3R,7S)-jasmonoyl-l-isoleucine (JA-Ile) with high specificity. High-affinity hormone binding requires a bipartite JAZ degron sequence consisting of a conserved α-helix for COI1 docking and a loop region to trap the hormone in its binding pocket. In addition, we identify a third critical component of the jasmonate co-receptor complex, inositol pentakisphosphate, which interacts with both COI1 and JAZ adjacent to the ligand. Our results unravel the mechanism of jasmonate perception and highlight the ability of F-box proteins to evolve as multi-component signalling hubs.


Short-Term Effects of Y-27632, a Rho-Associated Protein Kinase Inhibitor, on Chromatin Supraorganization and DNA Amount in Epithelial Cells of the Rat Cornea and Limbus.
To assess the short-term effects of instilling Y-27632, an inhibitor of Rho/Rho-associated protein kinases, on the chromatin supraorganization and DNA amount of corneal and limbal epithelial cells of healthy rats. Longitudinal sections (7 μm) of enucleated eyes of healthy rats that received, by instillation, balanced salt solution with or without 10 mM of Y-27632 daily for 7 or 15 days, were subjected to the Feulgen reaction. Feulgen-stained nuclei of corneal and limbal epithelial cells were studied by microscopy and video image analysis to establish the nuclear size (area and perimeter), supraorganization of chromatin (texture and degrees of condensation), and the Feulgen-DNA amount. Instillation of Y-27632 for up to 15 days did not change the size of the nucleus or the chromatin texture of corneal and limbal epithelial cells. Samples treated with Y-27632 for 7 days showed condensed chromatin and a high Feulgen-DNA amount. Both corneal and limbal epithelium showed the presence of near-tetraploid nuclei corresponding to cells in the S and G2 phases of the cell cycle. The degrees of condensation and Feulgen-DNA amount of the nuclei of epithelial cells of the cornea and limbus of eyes from rats receiving Y-27632 for 15 days did not differ from control (no drug). Changes in chromatin supraorganization and DNA amount, such as seen in this study, are indicative of cell proliferation and do not seem to be associated with disturbances in gene activity and transcription of DNA.


Spi-B is critical for plasmacytoid dendritic cell function and development.
Plasmacytoid dendritic cells (pDCs), originating from hematopoietic progenitor cells in the BM, are a unique dendritic cell subset that can produce large amounts of type I IFNs by signaling through the nucleic acid-sensing TLR7 and TLR9 (TLR7/9). The molecular mechanisms for pDC function and development remain largely unknown. In the present study, we focused on an Ets family transcription factor, Spi-B, that is highly expressed in pDCs. Spi-B could transactivate the type I IFN promoters in synergy with IFN regulatory factor 7 (IRF-7), which is an essential transcription factor for TLR7/9-induced type I IFN production in pDCs. Spi-B-deficient pDCs and mice showed defects in TLR7/9-induced type I IFN production. Furthermore, in Spi-B-deficient mice, BM pDCs were decreased and showed attenuated expression of a set of pDC-specific genes whereas peripheral pDCs were increased; this uneven distribution was likely because of defective retainment of mature nondividing pDCs in the BM. The expression pattern of cell-surface molecules in Spi-B-deficient mice indicated the involvement of Spi-B in pDC development. The developmental defects of pDCs in Spi-B-deficient mice were more prominent in the BM than in the peripheral lymphoid organs and were intrinsic to pDCs. We conclude that Spi-B plays critical roles in pDC function and development.


Ginsenoside Rg1 promotes endothelial progenitor cell migration and proliferation.
To investigate the effect of ginsenoside Rg1 on the migration, adhesion, proliferation, and VEGF expression of endothelial progenitor cells (EPCs). EPCs were isolated from human peripheral blood and incubated with different concentrations of ginsenoside Rg1 (0.1, 0.5, 1.0, and 5.0 micromol/L) and vehicle controls. EPC migration was detected with a modified Boyden chamber assay. EPC adhesion was determined by counting adherent cells on fibronectin-coated culture dishes. EPC proliferation was analyzed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In vitro vasculogenesis was assayed using an in vitro vasculogenesis detection kit. A VEGF-ELISA kit was used to measure the amount of VEGF protein in the cell culture medium. Ginsenoside Rg1 promoted EPC adhesion, proliferation, migration and in vitro vasculogenesis in a dose- and time-dependent manner. Cell cycle analysis showed that 5.0 micromol/L of ginsenoside Rg1 significantly increased the EPC proliferative phase (S phase) and decreased the resting phase (G(0)/G(1) phase). Ginsenoside Rg1 increased vascular endothelial growth factor production. The results indicate that ginsenoside Rg1 promotes proliferation, migration, adhesion and in vitro vasculogenesis.


How often is the office visit needed? Predicting total knee arthroplasty revision risk using pain/function scores.
Most patients have favorable outcomes after primary total knee arthroplasty (TKA). Well-validated methods to predict the risk of poor outcomes have not been developed or implemented. Several patients have annual clinic visits despite well-funcitoning TKA, as a routine practice, to detect early failure requiring revision surgery. It is not known whether assessment of pain and function can be used as a predictive tool for early failure and revision to guide practice. Our objective was to determine whether pain and function can predict revision after TKA. We retrospectively studied data from a large prospectively gathered TKA registry to examine changes in outcome scores for primary TKAs undergoing revision compared to those not requiring revision to determine the factors that are predictive for revision. Of the 1,012 patients, 721 had had a single-sided primary TKA and had American Knee Society (AKS) Scores for three or more visits. 46 patients underwent revision, 23 acutely (fracture, traumatic component failure or acute infection) and 23 for latent causes (late implant loosening, progressive osteolysis, or pain and indolent infection). Mean age was 70 years for the non-revision patients, and 64 years for those revised. Both AKS Clinical and AKS Function Scores for non-revised patients were higher than in revision patients, higher in acute revision compared to latent revision patients. Significant predictors of revision surgery were preoperative, 3- and 15-month postoperative AKS Clinical Scores and 3-month AKS Function Scores. At 15-month post-TKA, a patient with a low calculated probability of revision, 32 % or less, was unlikely to require revision surgery with a negative predictive value of 99 %. Time dependent interval evaluation post-TKA with the AKS outcome scores may provide the ability to assign risk of revision to patients at the 15-month follow-up visit. If these findings can be replicated using a patient-reported measure, a virtual follow-up with patient-reported outcomes and X-ray review may be an alternative to clinic visit for patients doing well.


Towards network-guided neuromodulation for epilepsy.
Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce seizures in adults with focal-onset epilepsy; and there is emerging evidence for their efficacy in children and generalized-onset seizure disorders. The convergence of these advancing fields is driving an era of 'network-guided neuromodulation' for epilepsy. In this review, we distil the current literature on network mechanisms underlying neurostimulation for epilepsy. We discuss the modulation of key 'propagation points' in the epileptogenic network, focusing primarily on thalamic nuclei targeted in current clinical practice. These include (i) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (ii) the centromedian nucleus of the thalamus, a target for both deep brain stimulation and responsive neurostimulation in generalized-onset epilepsies. We discuss briefly the networks associated with other emerging neuromodulation targets, such as the pulvinar of the thalamus, piriform cortex, septal area, subthalamic nucleus, cerebellum and others. We report synergistic findings garnered from multiple modalities of investigation that have revealed structural and functional networks associated with these propagation points - including scalp and invasive EEG, and diffusion and functional MRI. We also report on intracranial recordings from implanted devices which provide us data on the dynamic networks we are aiming to modulate. Finally, we review the continuing evolution of network-guided neuromodulation for epilepsy to accelerate progress towards two translational goals: (i) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (ii) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizure propagation through mapping and modulation of each patients' individual epileptogenic networks.


Expression, purification and crystallization of Aspergillus nidulans NmrA, a negative regulatory protein involved in nitrogen-metabolite repression.
The NmrA repressor protein of Aspergillus nidulans was overproduced in Escherichia coli and purified to homogeneity. Gel-exclusion chromatography showed that NmrA was monomeric in solution under the buffer conditions used. The protein was crystallized in three forms, belonging to trigonal, monoclinic and hexagonal space groups. Two of these crystal forms (A and B) diffract to high resolution and thus appear suitable for structure determination. Crystal form A belongs to space group P3((1))21, with unit-cell parameters a = b = 76.8, c = 104.9 A. Crystal form B belongs to space group C2, with unit-cell parameters a = 148.8, b = 64.3, c = 110.2 A, beta = 121.8 degrees.


An audit of trauma-related mortality in a provincial capital in South Africa.
It has been shown repeatedly that hospital-based mortality data do not capture the actual mortality rate in South Africa, as many corpses are taken directly to the state mortuary. A retrospective audit was conducted by reviewing all mortuary reports for the period 1 January 2010 - 31 December 2011. The data recorded included demographics, mechanism of trauma, and cause and site of death. A total of 1 105 trauma victims died. There were 930 males (84.2%) and 175 females (15.8%), of whom 615 were victims of blunt trauma (55.7%) and 490 victims of penetrating trauma (44.3%). The scenes of death were: on scene 584 (52.9%), Edendale Hospital 259 (23.4%), Grey's Hospital 144 (13.0%), Northdale Hospital 68 (6.2%), and 'other' 50 (4.5%). The 'other' group comprised nine deaths at primary healthcare clinics and 41 at private hospitals in Pietermaritzburg. Of deaths related to blunt trauma, 153 (24.9%) were secondary to assault and 462 (75.1%) to a road traffic collision. Of the victims of penetrating trauma, 81 (36.9%) had sustained gunshot wounds and 309 (63.1%) stab wounds. The three leading causes of trauma-related deaths were head injuries (32.6%), polytrauma (29.7%) and chest injuries (27.4%). Pietermaritzburg has both a high rate of trauma-related mortality and an immature trauma system, resulting in a significant number of preventable deaths.


Phylogeny and evolution of life-history strategies in the Sycophaginae non-pollinating fig wasps (Hymenoptera, Chalcidoidea).
Non-pollinating Sycophaginae (Hymenoptera, Chalcidoidea) form small communities within Urostigma and Sycomorus fig trees. The species show differences in galling habits and exhibit apterous, winged or dimorphic males. The large gall inducers oviposit early in syconium development and lay few eggs; the small gall inducers lay more eggs soon after pollination; the ostiolar gall-inducers enter the syconium to oviposit and the cleptoparasites oviposit in galls induced by other fig wasps. The systematics of the group remains unclear and only one phylogeny based on limited sampling has been published to date. Here we present an expanded phylogeny for sycophagine fig wasps including about 1.5 times the number of described species. We sequenced mitochondrial and nuclear markers (4.2 kb) on 73 species and 145 individuals and conducted maximum likelihood and Bayesian phylogenetic analyses. We then used this phylogeny to reconstruct the evolution of Sycophaginae life-history strategies and test if the presence of winged males and small brood size may be correlated. The resulting trees are well resolved and strongly supported. With the exception of Apocrytophagus, which is paraphyletic with respect to Sycophaga, all genera are monophyletic. The Sycophaginae are divided into three clades: (i) Eukoebelea; (ii) Pseudidarnes, Anidarnes and Conidarnes and (iii) Apocryptophagus, Sycophaga and Idarnes. The ancestral states for galling habits and male morphology remain ambiguous and our reconstructions show that the two traits are evolutionary labile. The three main clades could be considered as tribes and we list some morphological characters that define them. The same biologies re-evolved several times independently, which make Sycophaginae an interesting model to test predictions on what factors will canalize the evolution of a particular biology. The ostiolar gall-inducers are the only monophyletic group. In 15 Myr, they evolved several morphological adaptations to enter the syconia that make them strongly divergent from their sister taxa. Sycophaginae appears to be another example where sexual selection on male mating opportunities favored winged males in species with small broods and wingless males in species with large broods. However, some species are exceptional in that they lay few eggs but exhibit apterous males, which we hypothesize could be due to other selective pressures selecting against the re-appearance of winged morphs.


A molecular perspective on Tully models for nonadiabatic dynamics.
Over the past decades, an important number of methods have been developed to simulate the nonadiabatic dynamics of molecules, that is, the dynamics of molecules beyond the Born-Oppenheimer approximation. These nonadiabatic methods differ in the way they approximate the dynamics emanating from the time-dependent molecular Schrödinger equation. In 1990, Tully devised a series of three one-dimensional model systems to test the approximations of the method called trajectory surface hopping. The Tully models were designed to probe different scenarios of nonadiabatic processes, such as single and multiple nonadiabatic (re)crossings. These one-dimensional models rapidly became the testbed for any new nonadiabatic dynamics strategy. In this work, we present a molecular perspective to the Tully models by highlighting a correspondence between these simple one-dimensional models and processes happening during the excited-state dynamics of molecules. More importantly, each of these nonadiabatic processes can be connected to a given exemplary molecular system, and we propose here three molecules that could serve as molecular Tully models, reproducing some of the key features of the original models but this time in a high-dimensional space. We compare trajectory surface hopping with the ab initio multiple spawning for the three molecular Tully models and highlight particular features and differences between these methods resulting from their distinct approximations. We also provide all the necessary information - initial conditions and all required parameters for the dynamics as well as the electronic structure - employed in our simulations such that the molecular Tully models can become in the future a unified and standardized test for ab initio nonadiabatic molecular dynamics methods. The molecular Tully models also offer an exciting link between the world of low-dimensional model systems for nonadiabatic dynamics and the excited-state dynamics of molecular systems in their full dimensionality.


Upregulation of cytochrome c oxidase subunit 6b1 (Cox6b1) and formation of mitochondrial supercomplexes: implication of Cox6b1 in the effect of calorie restriction.
Calorie restriction (CR), a non-genetic intervention that promotes longevity in animals, may exert anti-aging effects by modulating mitochondrial function. Based on our prior mitochondrial proteome analysis, we focused on the potential roles of cytochrome c oxidase (Cox or Complex IV) subunit 6b1 on formation of mitochondrial supercomplexes comprised of Complex I, III, and IV. Blue native polyacrylamide gel electrophoresis followed by immunoblotting showed that the amount of Cox6b1 and the proportion of high molecular weight supercomplexes (SCs) comprised of Complexes I, III, and IV were increased in the liver of mice subjected to 30 % CR, compared with the liver of mice fed ad libitum. In in vitro experiments, in Cox6b1-overexpressing NIH3T3 (Cox6b1-3T3) cells, Cox6b1 was increased in the SC, III2IV1, and III2IV2 complexes and Cox was concomitantly recruited abundantly into the SC, compared with control (Con)-3T3 cells. The proportions of III2IV1, and III2IV2, relative to IV monomer were also increased in Cox6b1-3T3 cells. Cox6b1-3T3 cells showed increased oxygen consumption rates, Cox activity, and intracellular ATP concentrations, indicating enhanced mitochondrial respiration, compared with Con-3T3 cells. Despite the increased basal level of mitochondrial reactive oxygen species (ROS), cell viability after inducing oxidative stress was greater in Cox6b1-3T3 cells than in Con-3T3 cells, probably because of prompt activation of protective mechanisms, such as nuclear translocation of nuclear factor E2-related factor-2. These in vivo and in vitro studies show that Cox6b1 is involved in regulation of mitochondrial function by promoting the formation of SC, suggesting that Cox6b1 contributes to the anti-aging effects of CR.


Crack cocaine use and adherence to antiretroviral treatment among HIV-infected black women.
Since the appearance of crack cocaine in the 1980s, unprecedented numbers of women have become addicted. A disproportionate number of female crack users are Black and poor. We analyzed interview data of HIV-infected women > or = 18 years of age reported to 12 health departments between July 1997 and December 2000 to ascertain if Black women reported crack use more than other HIV-infected women and to examine the relationship between crack use and antiretroviral treatment (ART) adherence among Black women. Of 1655 HIV-infected women, 585 (35%) were nonusers of drugs, 694 (42%) were users of other drugs and 376 (23%) were crack users. Of the 1196 (72%) Black women, 306 (26%) were crack users. We used logistic regression to examine the effect of crack use on adherence to ART, controlling for age and education among Black women. In multivariate analysis, crack users and users of other drugs were less likely than non-users to take their ART medicines exactly as prescribed (odds ratio [OR] = 0.37; 95% confidence interval [CI] = 0.24-0.56), OR = 0.47; 95% CI = 0.36-0.68), respectively. HIV-infected Black women substance users, especially crack cocaine users, may require sustained treatment and counseling to help them reduce substance use and adhere to ART.


Tositumomab and (131)I therapy in non-Hodgkin's lymphoma.
Tositumomab and (131)I-tositumomab constitute a relatively new radioimmunotherapeutic regimen for patients with CD20+ follicular non-Hodgkin's lymphoma (NHL). Currently, it is approved for use in patients whose disease has relapsed after chemotherapy and is refactory to rituximab, including patients whose tumors have transformed to a higher histologic grade. This review outlines the current and evolving status of this therapeutic regimen at nonmyeloablative doses. Clinical data from multiple published studies and preliminary communications encompassing more than 1,000 patients were reviewed to describe the current status of tositumomab and (131)I-tositumomab therapy. The therapy is delivered in 2 parts, a dosimetric dose and a therapeutic dose. The therapeutic radioactivity millicurie dose is calculated on a patient-individualized ("tailored") basis. A series of 3 total-body gamma-camera scans are used to determine the patient-specific pharmacokinetics (total-body residence time) of the radiolabeled antibody conjugate required to deliver the desired total-body radiation dose, typically 75 cGy. In clinical trials, objective response rates in patients who had been extensively pretreated with chemotherapy ranged from 47% to 68%. Tositumomab and (131)I-tositumomab therapy also was effective in patients who had failed to respond to or who had relapsed after rituximab therapy, with a 68% overall response rate. Thirty percent of such patients achieved complete responses that were generally of several years duration. Single-center trials using tositumomab and (131)I-tositumomab therapy alone or after chemotherapy in previously untreated patients have shown response rates in excess of 90%, with most responses complete. Retreatment with tositumomab and (131)I-tositumomab and use of lower total-body radiation doses of tositumomab and (131)I-tositumomab to treat patients who have relapsed after stem cell transplantation have been shown feasible in limited clinical studies. Toxicity is predominately hematologic; however, human antimouse antibodies, hypothyroidism, and myelodysplastic syndrome have been reported in a small fraction of patients. Tositumomab and (131)I-tositumomab therapy at patient-specific, nonmyeloablative doses is safe and effective in treatment of relapsed and refractory follicular NHL. Toxicity is mainly hematologic and reversible. Tositumomab and (131)I-tositumomab therapy is assuming a growing role in this common malignancy.


Photodynamic therapy induces selective extravasation of macromolecules: Insights using intravital microscopy.
Photodynamic therapy (PDT) with Visudyne acts by direct cellular phototoxicity and/or by an indirect vascular-mediated effect. Here, we demonstrate that the vessel integrity interruption by PDT can promote the extravasation of a macromolecular agent in normal tissue. To obtain extravasation in normal tissue PDT conditions were one order of magnitude more intensive than the ones in tissue containing neovessels reported in the literature. Fluorescein isothiocyanate dextran (FITC-D, 2000 kDa), a macromolecular agent, was intravenously injected 10 min before (LK0 group, n=14) or 2h (LK2 group, n=16) after Visudyne-mediated PDT in nude mice bearing a dorsal skin fold chamber. Control animals had no PDT (CTRL group, n=8). The extravasation of FITC-D from blood vessels in striated muscle tissue was observed in both groups in real-time for up to 2500 s after injection. We also monitored PDT-induced leukocyte rolling in vivo and assessed, by histology, the corresponding inflammatory reaction score in the dorsal skin fold chambers. In all animals, at the applied PDT conditions, FITC-D extravasation was significantly enhanced in the PDT-treated areas as compared to the surrounding non-treated areas (p<0.0001). There was no FITC-D leakage in the control animals. Animals from the LK0 group had significantly less FITC-D extravasation than those from the LK2 group (p=0.0002). In the LK0 group FITC-D leakage correlated significantly with the inflammation (p<0.001). At the selected conditions, Visudyne-mediated PDT promotes vascular leakage and FITC-D extravasation into the interstitial space of normal tissue. The intensity of vascular leakage depends on the time interval between PDT and FITC-D injection. This concept could be used to locally modulate the delivery of macromolecules in vivo.


SU-E-T-306: An Optimized Dosimetry Study Comparing a Multichannel Cylinder versus Single Channel Cylinder in the Treatment of the Vaginal Cuff or Vagina with High Dose Rate Brachytherapy.
Elekta/Nucletron introduced a new CT/MRI multi-lumen brachytherapy applicator to optimize dosimetry and treatment of vaginal targets. The design includes several peripheral channels isotropically placed 5mm inside cylinder surface with a separate central channel allowing single lumen brachytherapy as an option. We compared optimized dosimetry plans between single channel versus multi-channel to determine potential dosimetric advantages in vaginal cancer treatment after hysterectomy. Patients were planned by CT simulation with each fraction of vaginal brachytherapy for postoperative endometrial cancer or vaginal cancer. Twenty CT cases representing five patients were compared. A single channel (standard) treatment approach was planned to the prescribed depth with the goal of providing maximal coverage to the tumor bed (the 5mm rind typically). Doses to the bladder and rectum were recorded by dose volume histogram. A second treatment plan was generated using a multichannel approach. The Oncentra brachytherapy planning system was used to generate both forward and IPSA inverse treatment plans. The target coverage percentage and doses to the bladder and rectum were optimized. The comparison demonstrates an improved V90, V95, V100 of the prescribed dose to the 5mm vaginal cuff rind was achieved in all cases. The average improvement in coverage was 9% (between 6-13%) for the cases evaluated. The multi-channel plan also reduced the maximal dose (hot spot) to the bladder and rectum within a range of 9-16% and 5-15% respectively. An increased non-critical vaginal mucosal dose of up to 75% was delivered as a result of the reduced bladder and rectal exposure via multichannel procedure. Optimization of vaginal cuff brachytherapy is possible by using a new multi-lumen vaginal cylinder. The new device can increase the therapeutic ratio by improving target coverage with a reduction in the potential toxicity of hot spots to the adjacent organs.


Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides.
We examined the dose-related effects of angiotensin-converting enzyme inhibitors on circulating and tissue levels of angiotensin and bradykinin peptides by administering perindopril or lisinopril to rats in drinking water for 7 days. A reduction in the ratio of plasma angiotensin II (Ang II) to Ang I was seen for 0.006 mg/kg per day perindopril, with an increase in plasma renin and Ang I at 0.017 mg/kg per day. Plasma Ang II levels did not decrease until 1.4 mg/kg per day perindopril, at which dose plasma Ang I levels reached a plateau of an approximate 25-fold increase. The effects of perindopril on Ang II and Ang I levels in heart, lung, aorta, and brown adipose tissue were parallel to those observed for plasma. By contrast, renal Ang I levels did not increase, and renal Ang II levels decreased by 40% at 0.017 mg/kg per day, the same threshold seen for the increase in plasma renin. Perindopril increased circulating bradykinin-(1-9) levels approximately eightfold, with a threshold dose of 0.052 mg/kg per day, and increased bradykinin-(1-9) levels in kidney, heart, and lung in parallel with the changes observed for plasma. By contrast, aortic and brown adipose tissue bradykinin-(1-9) and bradykinin-(1-7) levels increased severalfold for perindopril doses as low as 0.006 mg/kg per day. Lisinopril also increased aortic bradykinin-(1-9) and bradykinin-(1-7) levels at doses below the threshold for the decrease in the ratio of Ang II to Ang I. These data indicate that renal Ang II levels and vascular bradykinin-(1-9) levels respond to low doses of converting enzyme inhibitor and may be important mediators of the effects of these compounds. The parallel increases in bradykinin-(1-9) and bradykinin-(1-7) levels in aorta and brown adipose tissue, at inhibitor doses below the threshold for inhibition of Ang I conversion, may result from a mechanism different from inhibition of "classic" angiotensin-converting enzyme.


Exercise and working memory: an individual differences investigation.
In the current work we asked whether executive function, as measured by tests of working memory capacity, might benefit from an acute bout of exercise and, more specifically, whether individuals who are lower or higher in working memory to begin with would be more or less affected by an exercise manipulation. Healthy adults completed working memory measures in a nonexercise (baseline) session and immediately following a 30-min self-paced bout of exercise on a treadmill (exercise session). Sessions were conducted 1 week apart and session order was counterbalanced across participants. A significant Session x Working Memory interaction was obtained such that only those individuals lowest in working memory benefited from the exercise manipulation. This work suggests that acute bouts of exercise may be most beneficial for healthy adults whose cognitive performance is generally the lowest, and it demonstrates that the impact of exercise on cognition is not uniform across all individuals.


Multi-silicone bilateral soft physical twin as an alternative to traditional user interfaces for remote palpation: a comparative study.
Teleoperated medical technologies are a fundamental part of the healthcare system. From telemedicine to remote surgery, they allow remote diagnosis and treatment. However, the absence of any interface able to effectively reproduce the sense of touch and interaction with the patient prevents the implementation of teleoperated systems for primary care examinations, such as palpation. In this paper, we propose the first reported case of a soft robotic bilateral physical twin for remote palpation. By creating an entirely soft interface that can be used both to control the robot and receive feedback, the proposed device allows the user to achieve remote palpation by simply palpating the soft physical twin. This is achieved through a compact design showcasing 9 pneumatic chambers and exploiting multi-silicone casting to minimize cross-noise and allow teleoperation. A comparative study has been run against a traditional setup, and both the control and feedback of the physical twin are carefully analyzed. Despite distributed tactile feedback not achieving the same performance as the visual map, the soft control and visual feedback combination showcases a 5.1% higher accuracy. Moreover, the bilateral soft physical twin results always in a less invasive procedure, with 41% lower mechanical work exchanged with the remote phantom.


Wear debris inhibition of anti-osteoclastogenic signaling by interleukin-6 and interferon-gamma. Mechanistic insights and implications for periprosthetic osteolysis.
Wear debris challenge of macrophages provokes the generation of proinflammatory cytokines, which contribute to periprosthetic osteolysis. However, it is not known whether this effect is accompanied by reprogramming of other cytokines present within the periprosthetic tissue that may be involved in anti-osteoclastogenic activities. In the present study, we examined the ability of wear debris particles to inhibit the signaling of two such cytokines, interleukin-6 and interferon-gamma. Human osteoclast precursor cells were challenged with particles of titanium or polymethylmethacrylate bone cement prior to the addition of the cytokines interleukin-6 or interferon-gamma. Interleukin-6 signaling was determined by measuring the activation of STAT3 signal transduction with use of immunoblotting and electrophoretic mobility shift assays. Interferon-gamma signaling was determined by measuring the activation of STAT1 with use of immunoblotting and electrophoretic mobility shift assays and by measuring the expression of interferon-gamma-inducible genes with use of real-time reverse transcription-polymerase chain reaction assays. Involvement of mitogen-activated protein kinases in cytokine signaling was assessed by including mitogen-activated protein kinase inhibitors in these assays and also by means of immunoblot assessment of mitogen-activated protein kinase activation by wear debris particles. Wear debris modulation of expression of the cytokine suppressors SOCS1 and SOCS3 (as well as pro-inflammatory mediators) was assessed with use of real-time reverse transcription-polymerase chain reaction assays. Both titanium and polymethylmethacrylate particles potently inhibited interleukin-6-induced STAT3 activation in human osteoclast precursor cells. Inhibition of p38 mitogen-activated protein kinase, which is activated by titanium and polymethylmethacrylate, reversed the inhibitory effects of these particles on interleukin-6 signaling, whereas inhibition of ERK and JNK mitogen-activated protein kinases (which are also activated by both types of wear debris) had no effect. Titanium and polymethylmethacrylate also both induced expression of SOCS3, an inhibitor of interleukin-6 signaling. In addition to its effects on interleukin-6 signaling, titanium also profoundly inhibited the interferon-gamma-induced activation of STAT1 and the expression of interferon-gamma-inducible genes, whereas polymethylmethacrylate had no effect on interferon-gamma signaling. Titanium inhibits both interferon-gamma and interleukin-6 signaling in human osteoclast precursor cells, whereas polymethylmethacrylate bone cement inhibits only the latter. Wear particle inhibition of interleukin-6 specifically involves the activation of p38 mitogen-activated protein kinase and is accompanied by substantial induction of SOCS3, an inhibitor of interleukin-6 signaling. In contrast, titanium inhibition of interferon-gamma signaling is not dependent on mitogen-activated protein kinase activation and is accompanied by only modest induction of the interferon-gamma inhibitor SOCS1.


Case management by nurses in primary care: analysis of 73 'success stories'.
There is interest as to whether case management reduces unplanned patient admission to hospital. However, very little is known about how the intervention is delivered and what the most salient outcome measures are. Qualitative study embedded in a wider evaluation. Primary health care. Analysis of case manager case reports in a service innovation evaluation study. Case management provides home-based care to frail elderly patients using a process of assessment and medication review. This often leads to new diagnoses, to the co-ordination of further care and the tailoring of services to suit the needs of individuals. The benefits reported are complex and relate to improving a patient's quality of life more than the prevention or otherwise of admission to hospital. The type of attention provided by these roles seems to be absent from current NHS arrangements. The role enables time to be spent assessing the individual needs of patients who live at the margins of independent living. The case managers describe having the time and the skills to assess a mix of clinical and social problems, and then accessing the correct networks to help elderly people with multiple illnesses navigate a complex system of providers. More weight should be given to the ability of this intervention to result in improved quality of life for patients, and to the investigation of costs and benefits.


The Effect of a Charcoal-based Powder for Enamel Dental Bleaching.
Charcoal based-powders are not effective for dental bleaching. Charcoal-based dentifrices for dental whitening are a novelty in the market. Manufacturers claim that such charcoal-based products have whitening, remineralization, antimicrobial, and antifungal properties of charcoal in such products. However, there is no substantial scientific evidence for these claims. This laboratory randomized study was designed to evaluate the whitening properties of a charcoal-based toothpowder. A total of 45 bovine dental enamel discs were randomly distributed into three groups (n=15): group 1, mechanical brushing with a 1450-ppm F toothpaste (control group); group 2, mechanical brushing with an activated charcoal-based powder; group 3, bleaching per the standard protocol using 10% carbamide peroxide. The surface roughness and color of each specimen were analyzed at baseline and after 14 days of experiment. The surface of one randomly selected specimen from each group was examined using a scanning electron microscope (SEM). The Kruskal-Wallis test was used to compare groups at a significance level of 5%. Only group 3 promoted a statistically significant effect on ΔE compared with groups 1 and 2 (p<0.001 and p=0.003, respectively). No statistically significant difference was found between groups for surface roughness (p>0.05). SEM revealed a more irregular surface in group 1 specimens compared with group 2 and 3 specimens. The charcoal-based powder did not seem to have any bleaching effect.


[Protective effects and action mechanism of extract from Tibetan medicine Yajima(Chrysosplenium nudicaule) on mice with intrahepatic cholestasis induced by ANIT].
Chrysosplenium nudicaule,Tibetan name " Yajima",is recorded as an effective medicine for the treatment of liver and gallbladder diseases by Tibetan Pharmacopoeia published in the past dynasties,but its traditional efficacy has not yet been investigated by means of modern pharmacological research methods. In this paper,the protective effect of extract of C. nudicaule(ECN) on liver injury in mice was observed by using the mice model of intrahepatic cholestasis(IC) induced by α-naphthyl isothiocyanate(ANIT) and the possible mechanism by which ECN work as the therapeutic agent was discussed. The results showed that the serum levels of AST,ALT,ALP,DBIL,TBIL and TBA of the model mice were notably reduced in dose-dependent manner(P<0. 01,P<0. 05). The activity of SOD and GSH-Px in the liver homogenate of mice was increased,while the content of MDA was decreased(P<0. 01,P<0. 05).Pathological examination of liver in mice showed that ECN could improve the pathological changes of liver tissue in mice. The mRNA expression level of genes related to bile acid metabolism were detected by RT-PCR and the results suggested that ECN could significantly increase the expression of genes such as BSEP,FXR and MRP2(P<0. 01,P<0. 05),meanwhile significantly reduce the expression of CYP7 A1(P<0. 01,P<0. 05). These results confirmed the protective effect of ECN on intrahepatic cholestasis-induced liver injury in mice,and indicated that the mechanism may be related to activating FXR and its target genes,reducing bile acid synthesis and increasing bile acid excretion. This study provides a modern pharmacological basis for the clinical application of Yajima in Tibetan medicine.


A family intervention to delay nursing home placement of patients with Alzheimer disease. A randomized controlled trial.
To determine the long-term effectiveness of comprehensive support and counseling for spouse-caregivers and families in postponing or preventing nursing home placement of patients with Alzheimer disease (AD). Randomized controlled intervention study. Outpatient research clinic in the New York City metropolitan area. Referred, volunteer sample of 206 spouse-caregivers of AD patients who enrolled in the study during a 3 1/2-year period. All patients were living at home at baseline and had at least 1 relative living in the area. Caregivers in the treatment group were provided with 6 sessions of individual and family counseling within 4 months of enrollment in the study and were required to join support groups. In addition, counselors were available for further counseling at any time. Time from enrollment of caregivers in the study to placement of the AD patients in a nursing home. Using Kaplan-Meier survival analysis, we estimated that the median time (weighted average of estimates for male and female caregivers) from baseline to nursing home placement of AD patients was 329 days longer in the treatment group than in the control group (z=2.29; P=.02). The relative risk (RR) from a Cox proportional hazard model of nursing home placement (intent-to-treat estimate) after adjusting for caregiver sex, patient age, and patient income was 0.65 (95% confidence interval [CI], 0.45 to 0.94; P=.02), indicating that caregivers were approximately two thirds as likely to place their spouses in nursing homes at any point in time if they were in the treatment group than if they were in the control group. Treatment had the greatest effect on risk of placement for patients who were mildly demented (RR, 0.18; 95% CI, 0.04 to 0.77) or moderately demented (RR, 0.38; 95% CI, 0.17 to 0.82). A program of counseling and support can substantially increase the time spouse-caregivers are able to care for AD patients at home, particularly during the early to middle stages of dementia when nursing home placement is generally least appropriate.


Enablers and barriers of maternal and neonatal immunization programs in Latin America.
The Region of the Americas has a long history of implementing maternal and neonatal immunization (MNI) programs. Our study aimed to understand the state of MNI policies, strategies and implementation practices in Latin America (LA). Study conducted in 5 middle-income countries: Argentina, Brazil, Honduras, Mexico and Peru. The methods included a desk review, interviews with national stakeholders and health care providers, focus groups with pregnant women and observations in health facilities. Enablers and barriers were identified and categorized as individual, societal or related to the health system. All 5 participating countries had similar MNI policies and high access to antenatal care. Key enablers were the high acceptability of vaccination during pregnancy, high-level of political will and a national legal framework ensuring free access to vaccines. At the health system level, implementation was facilitated by the existence of immunization advisory committees, a pooled vaccine procurement mechanism, complementary vaccine delivery strategies, conditional cash transfer to users and performance incentives to health facilities. The main programmatic barriers were the lack of adequate MNI information; limited coordination between antenatal and immunization services; inadequate supply, resources and infrastructure; high staff turnover; insufficient training for health care providers; and weak monitoring and reporting systems. Middle-income countries in LA have successfully implemented MNI programs and several enablers were identified. To overcome remaining barriers, there is a need to focus on improving the "immunization journey" for pregnant women through providing more clear and timely information to users and providers; removing barriers to access; ensuring adequate supply, human resources and infrastructure; making the health service experience positive; and establishing integrated information systems that allow for monitoring the progress toward achieving MNI goals. Strengthening the MNI programs can also improve equitable access to health services and prepare for the introduction of future vaccines for pregnant women.


Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice.
Gastrointestinal functions decline with ageing leading to impaired quality of life, and increased morbidity and mortality. Neurodegeneration is believed to underlie ageing-associated dysmotilities but the mechanisms have not been fully elucidated. We used progeric mice deficient in the anti-ageing peptide Klotho to investigate the contribution of key cell types of the gastric musculature to ageing-associated changes in stomach function and the underlying mechanisms. Klotho expression, enteric neurons, interstitial cells of Cajal (ICC), smooth muscle cells and electrical activity were assessed by immunofluorescence, confocal microscopy, 3-dimensional reconstruction, flow cytometry, quantitative RT-PCR, Western immunoblotting and intracellular recordings. Gastric emptying of solids was analysed by the [13C]octanoic acid breath test. Circulating and tissue trophic factors were measured by enzyme immunoassays and quantitative RT-PCR. The role of oxidative stress was investigated in organotypic cultures. Klotho expression was detected in gastric glands, myenteric neurons and smooth muscle cells. Progeric Klotho-deficient mice had profound loss of ICC and ICC stem cells without a significant decrease in neuron counts, expression of neuronal nitric oxide synthase or smooth muscle myosin. Slow wave amplitude and nitrergic inhibitory junction potentials were reduced while solid emptying was unchanged. Klotho-deficient mice were marantic and had low insulin, insulin-like growth factor-I and membrane-bound stem cell factor. Klotho deficiency accentuated oxidative stress and ICC loss. We conclude that Klotho-deficient, progeric mice display a gastric phenotype resembling human ageing and involving profound ICC loss. Klotho protects ICC by preserving their precursors, limiting oxidative stress, and maintaining nutritional status and normal levels of trophic factors important for ICC differentiation.


The impact of ultrasonographic placental architecture on antenatal course, labor and delivery in a low-risk primigravid population.
To ascertain the impact of placental architecture on antenatal course and labor delivery in a low-risk primigravid population. This study involves prospective recruitment of 1011 low-risk primigravids with placental ultrasound at 22?24 weeks and 36 weeks. Detailed postnatal review of all mothers and infants was undertaken. Retrospective analysis of ultrasound and clinical outcome data was performed. Eight hundred ten women with complete outcome data were available. Anterior placentation was statistically associated with intrauterine growth restriction (IUGR) and preterm birth and fundal placentation was significantly associated with a higher incidence of pregnancy-induced hypertension and infants with a birthweight less than the 9th centile. Placental infarcts in the third trimester was significantly increased in cases complicated by pre-eclampsia (PET) and in cases with fetal acidosis. Placental calcification was associated a 40-fold increase in the incidence of IUGR. Placental lakes in the second trimester were more prevalent in patients with threatened miscarriage. Increased placental thickness was associated with a higher rate of fetal acidosis. The Grannum grade of the placenta was higher with threatened first or second trimester loss, PET and in infants born less than 9th centile for gestation. Placental site and architecture impact on the incidence of maternal and fetal disease.


Resident and Program Director Confidence in Resident Surgical Preparedness in Obstetrics and Gynecologic Training Programs.
To assess self-reported readiness of U.S. obstetrics and gynecology residents to perform surgical procedures compared with the perceptions of their program directors. The 2019 Council on Resident Education in Obstetrics and Gynecology Survey assessed resident self-confidence and perceived readiness to independently perform common surgical procedures. Concurrently, obstetrics and gynecology residency program directors were surveyed about the readiness of their graduating residents to independently perform the same procedures. The overall response rate was 99.3% for residents (5,473/5,514 examinees attempted to complete the survey) and 83% for program directors (241/292 returned surveys). There were no significant differences in graduating residents and program directors' assessments of graduating residents' surgical confidence in performing cesarean delivery (99.6% [95% CI 98.9-99.9] vs 100% [95% CI 98.2-100.0]), vacuum delivery (96.5% [95% CI 95.2-97.4] vs 98.6% [95% CI 95.9-99.7]), abdominal hysterectomy (95.1% [95% CI 93.6-96.2] vs 96.7% [95% CI 93.3-98.7]) or operative hysteroscopy (99.5% [95% CI 98.9-99.9] vs 100% [95% CI 98.2-100.0]). Ninety percent, 86%, and 69% of graduating residents felt that they could independently perform an abdominal hysterectomy, laparoscopic hysterectomy, and vaginal hysterectomy, respectively, in the event of an emergency. Ninety-seven percent (95% CI 93.3-98.7) of program directors reported their residents could perform a laparoscopic hysterectomy by graduation, as did 93% of graduating resident respondents (95% CI 90.8-94.0). Ninety percent (95% CI 85.3-93.8) of program directors felt their residents could perform vaginal hysterectomies by graduation, compared with 79% (95% CI 76.9-81.8) of fourth-year residents. Graduating obstetrics and gynecology residents and their program directors are confident in their abilities to perform the majority of core surgical procedures by graduation. By the second year, more than 90% of residents and their program directors were confident in their ability to perform cesarean deliveries and operative hysteroscopy. Sixty-nine percent and 86% of graduating residents felt comfortable performing vaginal and laparoscopic hysterectomies, respectively.


Practitioner consensus on the determinants of capacity building practice in high-income countries.
To assess and develop consensus among experienced public health nutrition practitioners from high-income countries regarding conceptualisation of capacity building in practice, and to test the content validity of a previously published conceptual framework for capacity building in public health nutrition practice. A Delphi study involving three iterations of email-delivered questionnaires testing a range of capacity determinants derived from the literature. Consensus was set at >50% of panellists ranking items as 'very important' on a five-point Likert scale across three survey rounds. Public health nutrition practice in Australia, the UK, Canada and the USA. Public health nutrition practitioners and academics. Result A total of thirty expert panellists (68% of an initial panel of forty-four participants) completed all three rounds of Delphi questionnaires. Consensus identified determinants of capacity building in practice including partnerships, resourcing, community development, leadership, workforce development, intelligence and quality of project management. The findings from the study suggest there is broad agreement among public health nutritionists from high-income countries about how they conceptualise capacity building in public health nutrition practice. This agreement suggests considerable content validity for a capacity building conceptual framework proposed by Baillie et al. (Public Health Nutr 12, 1031-1038). More research is needed to apply the conceptual framework to the implementation and evaluation of strategies that enhance the practice of capacity building approaches by public health nutrition professionals.


Comparison of haemodynamic responses to dobutamine and salbutamol in cardiogenic shock after acute myocardial infarction.
Nine patients with critically reduced cardiac output after acute myocardial infarction underwent a single cross-over comparison of dobutamine and salbutamol to compare the haemodynamic effects of these drugs, which have, respectively, predominantly beta 1-adrenergic and beta 2-adrenergic agonist activity. The responses were used to select the more appropriate treatment for individual patients. Only relatively small responses were obtained: those with poorest baseline measurements tended to show the least effect. When the results from the series were averaged, dobutamine (250-750 microgram/min) caused a small but progressive increase in cardiac index (1.8 to 2.2 1/min/m2) throughout the dose range. Systemic blood pressure was not increased, and calculated systemic vascular resistance fell from 25 to 19 units. Heart rate rose from 107 to 118 beats/min and stroke index from 17 to 19 ml/beat/m2. Pulmonary artery end-diastolic pressure fell from 18 to 15 mm Hg. Salbutamol (10-40 microgram/min) produced a similar progressive increase in cardiac index, from 1.6 to 2.21/min/m2. Systemic blood pressure was not altered, and systemic vascular resistance fell from 25 to 20 units. Heart rate rose from 105 to 119 beats/min and stroke index from 16 to 19 ml/beat/m2. Pulmonary artery end-diastolic pressure did not fall. Dobutamine and salbutamol have closely similar haemodynamic effects when used in cardiogenic shock after acute myocardial infarction. Both drugs increase cardiac index but heart rate also rises, and the increase in stroke index is relatively small. Mean arterial pressure is altered little by either agent, but dobutamine (in contrast with dopamine) tends to reduce pulmonary artery end-diastolic pressure, which may be beneficial.


A fast and accurate numerical tool to model the modal properties of photonic-bandgap fibers.
We describe a finite-difference numerical method that allows us to simulate the modes of air-core photonic-bandgap fibers (PBF) of any geometry in minutes on a standard PC. The modes' effective indices and fields are found by solving a vectorial transverse magnetic-field equation in a matrix form, which can be done quickly because this matrix is sparse and because we reduce its bandwidth by rearranging its elements. The Stanford Photonic-Bandgap Fiber code, which is based on this method, takes about 4 minutes to model 20 modes of a typical PBF on a PC. Other advantages include easy coding, faithful modeling of the abrupt discontinuities in the index profile, high accuracy, and applicability to waveguides of arbitrarily complex profile.


High-efficiency, multicrystal, single-pass, continuous-wave second harmonic generation.
We describe the critical design parameters and present detailed experimental and theoretical studies for efficient, continuous-wave (cw), single-pass second harmonic generation (SHG) based on novel cascaded multicrystal scheme, providing >55% conversion efficiency and multiwatt output powers at 532 nm for a wide range of input fundamental powers at 1064 nm. Systematic characterization of the technique in single-crystal, double-crystal and multicrystal schemes has been performed and the results are compared. Optimization of vital parameters including focusing and phase-matching temperature at the output of each stage is investigated and strategies to achieve optimum SHG efficiency and power are discussed. Relevant theoretical calculations to estimate the effect of dispersion between the fundamental and the SH beam in air are also presented. The contributions of thermal effects on SHG efficiency roll-off have been studied from quasi-cw measurements. Using this multicrystal scheme, stable SH power with a peak-to-peak fluctuation better than 6.5% over more than 2 hours is achieved in high spatial beam quality with M2<1.6.


Maternal and fetal nutrition in south India.
The relation between the nutrition of the mother and that of her baby was assessed in a south Indian community where malnutrition is common and women do not smoke. Unselected mothers and their infants of over 37 weeks' gestation were studied in two groups: those who paid for their care (150) and a poorer group who did not (172). There were significnat differences between the paying and non-paying groups in maternal triceps skinfold thickness, infant weight, and infant length. Overall there was a significant positive correlation between maternal triceps thickness and infant weight, length, and triceps and subscapular skinfold thickness. The correlation with the infant head circumference was less significant. These findings are further evidence that the nutrition of the mother has an important effect on the nutrition of her baby and that malnutrition is an important reason why Indian babies are lighter than European ones.


Maintenance haemodialysis: patients' experiences of their life situation.
The aim of this study was to examine how patients suffering from CKD on maintenance haemodialysis experience their life situation. The focus was on how treatment encroaches on time and space and how patients experience care. The rationale was that this knowledge is necessary to provide professional support that takes into consideration a person's whole life situation. The experiences of patients with chronic kidney disease (CKD) undergoing maintenance haemodialysis have been studied in many quantitative studies, which translate patients' subjective experiences into objectively quantifiable data. However, there are few qualitative studies examining the experiences of these patients' life situation and expressing their experiences within the context of a nursing and caregiver's perspective. Data were collected by interviews with 41 patients between the ages of 29 and 86 years who participated in the study. A content analysis was used to identify common themes that describe the patients' experiences of their life situation. Three main themes were identified: "not finding space for living", "feelings evoked in the care situation" and, "attempting to manage restricted life". The first theme "not finding space for living" consisted of two sub-themes: "struggling with time-consuming care" and "feeling that life is restricted". The second theme "feelings evoked in the care situation" consisted of two sub-themes: "sense of emotional distance" and "feeling vulnerable". The patients in this study indirectly expressed an existential struggle, indicating that encroachment of time and space were important existential dimensions of CKD. The findings indicated that caregivers were not always aware of this inducing a sense of emotional distance and a sense of vulnerability in the patients. Caregivers in dialysis units have to consider haemodialysis patients' experience of a sense of emotional distance in their relationship to caregivers. Nurses and doctors need to create routines within nursing practice to overcome this.


Arabidopsis GPAT9 contributes to synthesis of intracellular glycerolipids but not surface lipids.
GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE (GPAT) genes encode enzymes involved in glycerolipid biosynthesis in plants. Ten GPAT homologues have been identified in Arabidopsis. GPATs 4-8 have been shown to be involved in the production of extracellular lipid barrier polyesters. Recently, GPAT9 was reported to be essential for triacylglycerol (TAG) biosynthesis in developing Arabidopsis seeds. The enzymatic properties and possible functions of GPAT9 in surface lipid, polar lipid and TAG biosynthesis in non-seed organs, however, have not been investigated. Here we show that Arabidopsis GPAT9 exhibits sn-1 acyltransferase activity with high specificity for acyl-coenzyme A, thus providing further evidence that this GPAT is involved in storage lipid biosynthesis. We also confirm a role for GPAT9 in seed oil biosynthesis and further demonstrate that GPAT9 contributes to the biosynthesis of both polar lipids and TAG in developing leaves, as well as lipid droplet production in developing pollen grains. Conversely, alteration of constitutive GPAT9 expression had no obvious effects on surface lipid biosynthesis. Taken together, these studies expand our understanding of GPAT9 function to include modulation of several different intracellular glycerolipid pools in plant cells.