Mitochondria-targeted apoptosis in human cytomegalovirus-infected cells.
Mitochondria often play central roles in apoptotic pathways, and disruption of the mitochondrial transmembrane potential (ΔΨm) has been observed in various cells undergoing apoptosis. Human cytomegalovirus (HCMV) infection induces apoptosis in permissive cells; however, investigations of mitochondria-targeted apoptosis in HCMV-infected human foreskin fibroblast (HFF) cells have been limited. Here, we investigated the mitochondrial apoptosis pathway in HCMV-infected HFF cells. Flow cytometry analysis using JC-1 revealed that HCMV infection induces disruption of ΔΨm in HFF cells when administered 24 h postinfection (hpi), and this disruption was maximized at 48 hpi. Moreover, cytochrome c, normally a mitochondrial inner membrane protein, was detected in cytoplasmic extracts of HCMV-infected cells, but not mock-infected cells, by western blot analysis at 24 hpi. A caspase activity assay based on fluorescence spectrophotometry using a fluorogenic substrate revealed an increase in caspase-3 activity at 48 hpi in HCMV-infected cells. Caspase-8 activity was increased at 72 hpi in HCMV-infected cells. These results imply that HCMV infection induces mitochondria-mediated apoptosis in HFF cells.


The road to a greener hospital.
The healthcare industry has as its major objective, the improvement of the health of the population. With this in mind it is a complete contradiction for hospitals to pollute the environment or unnecessarily consume resources. As part of the implementation of an environmental management system, we analysed the different environmental impacts the National Maternity Hospital has on the environment. In particular, we quantified the consumption of energy, water and wastes produced. Reduction of negative environmental impacts and cost savings can easily be achieved. Energy consumption can decrease by 20%, water consumption by 15%. Proper waste segregation requires continuous staff training and can result in reductions of up to 40% of healthcare risk waste. common sense, policies and procedures applied result in reductions of environmental impacts. Environmental management systems do not manage themselves and require dedicated staff to be successful. Hospital are obliged morally and legislatively to minimise environmental impacts by ensuring efficient use of resources.


Sequential adjuvant therapy: the Memorial Sloan-Kettering Cancer Center experience.
Adjuvant chemotherapy has a real but modest impact on the disease-free and overall survival of patients with breast cancer. Recent attempts to improve its effectiveness have focused on dose intensity and new agents. Sequential therapy maximized dose intensity while limiting overlapping toxicity. Sequential therapy using doxorubicin followed by cyclophosphamide/methotrexate/5-fluorouracil (CMF) has been found superior in patients with high-risk resectable breast cancer. The novel chemotherapy agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is now known to be highly active in advanced breast cancer and appears to be clinically non-cross-resistant with doxorubicin. Therefore, this drug is being studied as a component of the next generation of adjuvant chemotherapy regimens. The most appropriate way to incorporate paclitaxel has not yet been defined, but its concurrent administration with other agents has, in some cases, been troublesome. Based on the demonstrated advantage of the sequential plan for doxorubicin and CMF, we conducted a series of pilot trials testing sequential high-dose therapy. Initially, we studied multiple cycles of doxorubicin followed by cyclophosphamide; we later added paclitaxel to this regimen. These phase II studies demonstrate the feasibility of sequential therapy with doxorubicin, paclitaxel, and cyclophosphamide, and early disease-free survival results are promising. Cooperative group projects are under way or planned to further define the activity of these regimens.


An equine model of chronic atrial fibrillation: methodology.
We describe the development and the different features of an experimental model of chronic atrial fibrillation (AF) in equines. In four healthy ponies a dual-chamber pacemaker, with an adapted pacemaker program, was implanted transvenously in the standing animal. This adapted pacemaker induced episodes of AF by delivering a 2s burst of electrical stimuli (42 Hz) as soon as sinus rhythm was detected. Simultaneous with a surface electrocardiogram, the intra-atrial electrogram could be recorded to determine the atrial electrogram morphology. Programmed electrical stimulation (PES) was used to determine the atrial effective refractory period (AERP) and the rate adaptation of the AERP, the sinus node recovery time (SNRT) and the corrected SNRT, AF vulnerability, AF cycle length and AF duration. This experimental AF model can be used to study the pathophysiology of chronic AF in equines.


Effects of interleukin 5-induced pulmonary eosinophilia on airway reactivity in the guinea pig.
Administration of interleukin 5 (IL-5) to guinea pigs by tracheal injection was associated with increased recovery of eosinophils and neutrophils from bronchoalveolar lavage (BAL) fluid. The number of eosinophils recovered from BAL fluid increased in a dose-dependent manner from 9 +/- 2 X 10(3)/ml to a plateau of 143 +/- 29 X 10(3)/ml after the administration of recombinant human IL-5 (rhIL-5). Tracheal administration of recombinant guinea pig IL-5 (gpIL-5) also increased eosinophil recovery but was less potent than rhIL-5. Histological analysis confirmed the presence of inflammatory cells in the lung; there were higher grades of inflammation in airway than in parenchymal tissue after gpIL-5 administration. In addition, the histological grade of airway inflammation was greater 24 and 72 h after gpIL-5 administration than it was 6 days after administration. Airway hyperresponsiveness is reported to occur in guinea pigs exposed to rhIL-5 by intraperitoneal cellular production. It is surprising that airway infiltration with eosinophils induced by the topical application of IL-5 was not associated with hyperresponsiveness to substance P, histamine, or platelet-activating factor in intact animals or to methacholine in tracheally perfused lungs. Furthermore, the microvascular leakage induced by substance P was not altered by rhIL-5 administration. These findings indicate that the presence of eosinophils alone is not sufficient for the expression of airway hyperresponsiveness. Our ability to separate eosinophil recruitment and retention in the tissues from airway hyperresponsiveness indicates that these two processes are distinct and that the presence of eosinophils in lung tissue, by itself, is not sufficient to alter airway contractile responses.


Genome Organizations and Functional Analyses of a Novel Gammapartitivirus from Rhizoctonia solani AG-1 IA Strain D122.
Here, we describe a novel double-stranded (ds) RNA mycovirus designated Rhizoctonia solani dsRNA virus 5 (RsRV5) from strain D122 of Rhizoctonia solani AG-1 IA, the causal agent of rice sheath blight. The RsRV5 genome consists of two segments of dsRNA (dsRNA-1, 1894 bp and dsRNA-2, 1755 bp), each possessing a single open reading frame (ORF). Sequence alignments and phylogenetic analyses showed that RsRV5 is a new member of the genus Gammapartitivirus in the family Partitiviridae. Transmission electron microscope (TEM) images revealed that RsRV5 has isometric viral particles with a diameter of approximately 20 nm. The mycovirus RsRV5 was successfully removed from strain D122 by using the protoplast regeneration technique, thus resulting in derivative isogenic RsRV5-cured strain D122-P being obtained. RsRV5-cured strain D122-P possessed the traits of accelerated mycelial growth rate, increased sclerotia production and enhanced pathogenicity to rice leaves compared with wild type RsRV5-infection strain D122. Transcriptome analysis showed that three genes were differentially expressed between two isogenic strains, D122 and D122-P. These findings provided new insights into the molecular mechanism of the interaction between RsRV5 and its host, D122 of R. solani AG-1 IA.


[Treatment results in children with the standard risk acute lymphoblastic leukemia treated with high dose of methotrexate (5.0 g/m2). 11 years of the Polish Pediatric Leukemia/Lymphoma Study Group experience].
Since 01.07.1993 to 30.09.2004, 675 children with ALL-SR were diagnosed and treated according to the modified ALL-BFM 90 protocol. Subject to statistical analysis (Kaplan-Meier method) were thus 197 children with ALL-SR treated with HD-MTX in a dose 5.0g/ m2. Among them, 21 patients failed to respond to therapy: 2 (1.0%) early deaths, 2 (1.0%) deaths during I complete remission, 16 (8.2%) relapses, 1 (0.5%) second neoplasm. Relapses occured: 12 (6.2%) in bone marrow, 2 (1.0%) in central nervous system, 1 (0.5%) in testicle and in 1 (0.5%) child combined relapse was observed. Probability rates for 11-year event free survival (EFS) was 0.80 (0.03). Application of high dose of methotrexate is safety and effective in prevention of relapses, especially meningeal and testicular involvement.


Clinical and genetic heterogeneity of primary ciliopathies (Review).
Ciliopathies comprise a group of complex disorders, with involvement of the majority of organs and systems. In total, >180 causal genes have been identified and, in addition to Mendelian inheritance, oligogenicity, genetic modifications, epistatic interactions and retrotransposon insertions have all been described when defining the ciliopathic phenotype. It is remarkable how the structural and functional impairment of a single, minuscule organelle may lead to the pathogenesis of highly pleiotropic diseases. Thus, combined efforts have been made to identify the genetic substratum and to determine the pathophysiological mechanism underlying the clinical presentation, in order to diagnose and classify ciliopathies. Yet, predicting the phenotype, given the intricacy of the genetic cause and overlapping clinical characteristics, represents a major challenge. In the future, advances in proteomics, cell biology and model organisms may provide new insights that could remodel the field of ciliopathies.


Early Blood Biomarkers to Improve Sepsis/Bacteremia Diagnostics in Pediatric Emergency Settings.
Background: Sepsis is the leading cause of death in children worldwide. Early recognition and treatment are essential for preventing progression to lethal outcomes. CRP and Complete Blood Count (CBC) are the initial preferred tests to distinguish between bacterial and viral infections. Specific early diagnostic markers are still missing. Aim: To investigate diagnostic value of Neutrophil-Lymphocyte Ratio (NLR), Mean Platelet Volume (MPV) and Platelet-MPV ratio (PLT/MPV) to distinguish sepsis/bacteremia and viral infection. Methods: We conducted a retrospective data analysis of case records of 115 children from 1 month to 5 years of age. All cases were divided into two groups-sepsis/bacteremia (n = 68) and viral (n = 47) patients, and further subdivided according to the time of arrival into early or late (≤12 or 12-48 h post the onset of fever, respectively). Analysis of CBC and CRP results was performed. NLR and PLT/MPV were calculated. Results: Sepsis/bacteremia group demonstrated higher absolute platelets count (370.15 ± 134.65 × 10⁸/L versus 288.91 ± 107.14 × 10⁸/L; p = 0.001), NLR (2.69 ± 2.03 versus 1.83 ± 1.70; p = 0.006), and PLT/MPV (41.42 ± 15.86 versus 33.45 ± 17.97; p = 0.001). PLT/MPV was increased in early arrival sepsis/bacteremia infants (42.70 ± 8.57 versus 31.01 ± 8.21; p = 0.008). NLR and MPV were significantly lower in infants (≤12 months) with viral infection on late arrival (1.16 ± 1.06 versus 1.90 ± 1.25, p = 0.025 for NLR and 8.94 ± 0.95fl versus 9.44 ± 0.85fl, p = 0.046 for MPV). Conclusion: Together with standard blood biomarkers, such as CRP, neutrophils, or platelets count, PLT/MPV is a promising biomarker for clinical practice to help discriminate between viral disease or sepsis/bacteremia in all children, especially in early onset of symptoms. NLR and MPV could support exclusion of sepsis/bacteremia in late arrival cases.


Nonlinear Dynamic Response Analysis of a Three-Stage Gear Train Based on Lightweight Calculation for Edge Equipment.
Bevel gears are widely used in aerospace transmission systems as well as modern mechanical equipment. In order to meet the needs and development of aerospace, high-speed dynamic vehicles, and various defense special equipment, higher and higher requirements are made for the high precision and stability of gear transmission systems, as well as the prediction and control of noise and vibration. Considering the nonlinear factors such as comprehensive gear error and tooth side clearance, a dynamic model of the three-stage gear transmission system is established. The relevant physical parameters, geometric parameters, and load parameters in the gear system are considered random variables to obtain the stochastic vibration model. When the random part of the random parameters is much smaller than the deterministic part, the vibration differential equation is expanded into a first-order term at the mean of the random parameter vector according to the Taylor series expansion theorem, and the ordering equation is solved numerically. Based on the improved stochastic regression method, the nonlinear dynamic response analysis of the three-stage gear train is carried out. This results in a relatively stable system when the dimensionless excitation frequency is in the range of 0.716 to 0.86 and the magnitude of the dimensionless integral meshing error is < 1.089.


Dual targets for mouse mast cell protease-4 in mediating tissue damage in experimental bullous pemphigoid.
Mouse mast cell protease-4 (mMCP-4) has been linked to autoimmune and inflammatory diseases, although the exact mechanisms underlying its role in these pathological conditions remain unclear. Here, we have found that mMCP-4 is critical in a mouse model of the autoimmune skin blistering disease bullous pemphigoid (BP). Mice lacking mMCP-4 were resistant to experimental BP. Complement activation, mast cell (MC) degranulation, and the early phase of neutrophil (PMN) recruitment occurred comparably in mMCP-4(-/-) and WT mice. However, without mMCP-4, activation of matrix metalloproteinase (MMP)-9 was impaired in cultured mMCP-4(-/-) MCs and in the skin of pathogenic IgG-injected mMCP-4(-/-) mice. MMP-9 activation was not fully restored by local reconstitution with WT or mMCP-4(-/-) PMNs. Local reconstitution with mMCP-4(+/+) MCs, but not with mMCP-4(-/-) MCs, restored blistering, MMP-9 activation, and PMN recruitment in mMCP-4(-/-) mice. mMCP-4 also degraded the hemidesmosomal transmembrane protein BP180 both in the skin and in vitro. These results demonstrate that mMCP-4 plays two different roles in the pathogenesis of experimental BP, by both activating MMP-9 and by cleaving BP180, leading to injury of the hemidesmosomes and extracellular matrix of the basement membrane zone.


EMG-Free Monitorization of the Acoustic Startle Reflex with a Mobile Phone: Implications of Sound Parameters with Posture Related Responses.
(1) Background: Acute acoustic (sound) stimulus prompts a state of defensive motivation in which unconscious muscle responses are markedly enhanced in humans. The orbicularis oculi (OO) of the eye is an easily accessed muscle common for acoustic startle reaction/response/reflex (ASR) investigations and is the muscle of interest in this study. Although the ASR can provide insights about numerous clinical conditions, existing methodologies (Electromyogram, EMG) limit the usability of the method in real clinical conditions. (2) Objective: With EMG-free muscle recording in mind, our primary aim was to identify and investigate potential correlations in the responses of individual and cooperative OO muscles to various acoustic stimuli using a mobile and wire-free system. Our secondary aim was to investigate potential altered responses to high and also relatively low intensity acoustics at different frequencies in both sitting and standing positions through the use of biaural sound induction and video diagnostic techniques and software. (3) Methods: This study used a mobile-phone acoustic startle response monitoring system application to collect blink amplitude and velocity data on healthy males, aged 18-28 community cohorts during (n = 30) in both sitting and standing postures. The iPhone X application delivers specific sound parameters and detects blinking responses to acoustic stimulus (in millisecond resolution) to study the responses of the blinking reflex to acoustic sounds in standing and sitting positions by using multiple acoustic test sets of different frequencies and amplitudes introduced as acute sound stimuli (<0.5 s). The single acoustic battery of 15 pure-square wave sounds consisted of frequencies and amplitudes between 500, 1000, 2000, 3000, and 4000 Hz scales using 65, 90, and 105 dB (e.g., 3000 Hz_90 dB). (4) Results: Results show that there was a synchronization of amplitude and velocity between both eyes to all acoustic startles. Significant differences (p = 0.01) in blinking reaction time between sitting vs. standing at the high intensity (105 dB) 500 Hz acoustic test set was discovered. Interestingly, a highly significant difference (p < 0.001) in response times between test sets 500 Hz_105 dB and 4000 Hz_105 dB was identified. (5) Conclusions: To our knowledge, this is the first mobile phone-based acoustic battery used to detect and report significant ASR responses to specific frequencies and amplitudes of sound stimulus with corresponding sitting and standing conditions. The results from this experiment indicate the potential significance of using the specific frequency, amplitude, and postural conditions (as never before identified) which can open new horizons for ASR to be used for diagnosis and monitoring in numerous clinical and remote or isolated conditions.


Interfacing the Ab initio multiple spawning method with electronic structure methods in GAMESS: Photodecay of trans-azomethane.
This work presents a nonadiabatic molecular dynamics study of the nonradiative decay of photoexcited trans-azomethane, using the ab initio multiple spawning (AIMS) program that has been interfaced with the General Atomic and Molecular Electronic Structure System (GAMESS) quantum chemistry package for on-the-fly electronic structure evaluation. The interface strategy is discussed, and the capabilities of the combined programs are demonstrated with a nonadiabatic molecular dynamics study of the nonradiative decay of photoexcited trans-azomethane. Energies, gradients, and nonadiabatic coupling matrix elements were obtained with the state-averaged complete active space self-consistent field method, as implemented in GAMESS. The influence of initial vibrational excitation on the outcome of the photoinduced isomerization is explored. Increased vibrational excitation in the CNNC torsional mode shortens the excited state lifetime. Depending on the degree of vibrational excitation, the excited state lifetime varies from ∼60-200 fs. These short lifetimes are in agreement with time-resolved photoionization mass spectroscopy experiments.


Increased plasma malondialdehyde associated with cerebellar structural defects.
Malondialdehyde (MDA) in plasma is regarded as an indicator for increased lipid peroxidation. Measurements of MDA concentrations in plasma were compared among healthy children (n = 31), patients with neurological disorders or epileptic syndromes (n = 15), and children with pontocerebellar structural defects (n = 31), where the cause or genetic defect remained unknown. In healthy children the median MDA value was 5.86 nmol/ml (mean (SD) value: 6.25 (1.97), range: 3.76-11.19). For the group with various neurological disorders or epilepsy, the values were similar with the median value at 5.66 nmol/ml (range 0.22-10.86). Compared with healthy controls and the neurological/ epileptic group, the 31 children with pontocerebellar structural defects had significantly increased MDA values with a median value at 11.29 nmol/ml (mean (SD) value: 11.62 (3.27), range 3.65-19.22). These findings of increased plasma MDA in the majority of children with pontocerebellar structural defects of unknown origin raised the question whether increased lipid peroxidation leads to prenatal and postnatal pontocerebellar maldevelopment or degeneration.


Drug effects: a search for outcomes.
In order to best understand the developmental and behavioral effects of prenatal cocaine exposure, two important activities must occur. The first is the continuing development and refinement of research methodologies. Information-sharing activities such as conferences support this goal. Second, agencies such as NIDA need to support longitudinal followup of prenatally drug-exposed child cohorts and controls to identify outcomes beyond infancy and toddler years. Without support for information exchange and longitudinal followup, researchers will still be in the dark regarding the effects of prenatal drug exposure on school functioning when the next drug epidemic occurs. This message was not heeded in the 1970s and early 1980s, leaving researchers in the 1990s in the uncomfortable position of saying they do not know the longer term effects of prenatal drug exposure.


The two major glucokinase isoforms show conserved functionality in β-cells despite different subcellular distribution.
Glucokinase (GCK) is crucial to regulating glucose metabolism in the liver and in pancreatic β-cells. There are two major GCK isoforms, hepatic and pancreatic GCKs, which differ only in exon 1. However, the functional differences between the two GCK isoforms remain poorly understood. Here, we used a β-cell-targeted gene transfer vector to determine the impact of isoform-specific GCK overexpression on β-cells in vitro and in vivo. We showed that pancreatic GCK had a nuclear localization signal unique to the pancreatic isoform, facilitating its nuclear distribution in β-cells. Despite the difference in subcellular distribution, overexpression of GCK isoforms similarly enhanced glucose uptake and β-cell proliferation in vitro. Overexpression of hepatic or pancreatic GCK also similarly enhanced β-cell proliferation in normal diet mice without affecting fasting glucose and intraperitoneal glucose tolerance tests (IPGTT). Our further study on human GCK sequences identified disproportional GCK amino acid variants in exon 1, while mutations linked to maturity onset diabetes of the young type 2 (MODY2) were disproportionally found in exons 2 through 10. Our results therefore indicate functional conservation between the two major GCK isoforms despite their distinct subcellular distribution.


Are trade-offs in plant resprouting manifested in community seed banks?
Trade-offs in allocation to resprouting vs. seedling regeneration in plants are predicted to occur along fire disturbance gradients. Increased resprouting ability should be generally favored in plant communities with a high probability of crown fire return. Hence, communities dominated by resprouters are predicted to have smaller seed banks than those dominated by species killed by fire. We tested whether there were trait shifts in resprouting ability among growth forms (short-lived herbaceous vs. ground-dwelling perennials vs. shrubs) and among communities (rocky outcrop vs. sclerophyll forest) with contrasting probabilities of crown fire return. Resprouting was more common in ground-dwelling perennials and in the sclerophyll forest community with a high probability of crown fire. Soil seed banks were sampled in rocky outcrop and sclerophyll forest communities in recently burned (18 months) and long-since-burned (12 years) locations at interspersed replicated sites. Collected seed banks were treated with orthogonal treatments of fire stimuli or no stimuli, and seedling emergence was measured in controlled conditions. Seed bank composition reflected the pattern of extant vegetation, with resprouting species being more common in the community with a higher probability of crown fire. Overall, however, resprouting species were poorly represented in the seed bank compared to those species killed by fire. Predicted shifts in allocation to seed production were strongly manifested in community seed banks across the disturbance gradient. Fewer species, seedlings, and seedlings per adult emerged from seed banks in the sclerophyll forest. This suggests that the dominance of resprouting species influences recruitment at the community scale. Community patterns in the seed bank also reflected predicted trade-offs with plant size and growth rate. Short-lived species that are killed by fire dominated the seed bank on rocky outcrops, while longer-lived resprouting species were found in low abundance. Life history trade-offs in persistence and regeneration strongly contribute to coexistence patterns between and within communities with contrasting probabilities of fire return.


Nitrendipine does not impair long-term glucose control in hypertensive noninsulin-dependent diabetic patients.
The subjects, 15 noninsulin-dependent diabetic hypertensive patients (mean age, 61 years) and 15 nondiabetic hypertensive patients (mean age, 60 years), received placebo for four weeks and then 20 to 40 mg of nitrendipine once daily for 24 weeks. At the end of the placebo period their blood pressures were greater than or equal to 160 mmHg systolic or greater than or equal to 95 mmHg diastolic. Blood pressures declined significantly during treatment in both patient groups; after 24 weeks, 13 of 15 diabetic patients and 12 of 15 nondiabetic patients were normotensive (diastolic blood pressure less than 90 mmHg). Meanwhile, heart rate, indices of glycemic control (serum glucose, hemoglobin A1c, fructosamine, and C-peptide levels), and serum lipids (cholesterol, high-density cholesterol, triglycerides, apolipoprotein A1 and B levels) did not change. It is concluded that nitrendipine does not impair glucose or lipid metabolism in diabetic hypertensive patients.


Teenage use of portable listening devices: a hazard to hearing?
Recently, a number of popular media articles have raised some concern that portable listening devices (PLDs) may be increasing the risk for music-induced hearing loss (MIHL). However, literature regarding adolescents' listening behavior and how their attitudes and beliefs relate to behavior is currently limited. The purposes of this study were (1) to investigate the relationship between volume control settings and output levels of PLDs, (2) to examine how adolescents' listening behavior changes as a function of background noise and noise isolation, (3) to investigate the relationship between self-reported listening levels and laboratory-measured listening levels, and (4) to evaluate the validity of the Listening Habits Questionnaire as a research tool for evaluating how attitudes and beliefs relate to PLD use behavior. A descriptive study. Experiment 1 evaluated the output levels of a set of PLDs, and Experiment 2 characterized the listening behavior and attitudes toward PLD use of a group of adolescents. Twenty-nine adolescents aged 13-17 yr, with normal hearing, participated in Experiment 2. Experiment 1 evaluated the output levels of a set of PLDs with stock and accessory earphones using an acoustic manikin. Experiment 2 included survey measures of listening behavior and attitudes as well as output levels measured using a probe microphone. The output levels of PLDs are capable of reaching levels that could increase the risk for MIHL, and 14% of teenagers in this study reported behavior that puts them at increased risk for hearing loss. However, measured listening levels in the laboratory settings did not correlate well with self-reported typical listening levels. Further, the Listening Habits Questionnaire described in this study may provide a useful research tool for examining the relationship between attitudes and beliefs and listening behavior.


Rapid growth responses of Avena coleoptile segments to lanthanum and other cations.
The rapid growth responses of oat (var. Victory) coleoptile segments treated with millimolar concentrations of the chlorides of La(3+), Ca(2+), K(+), and NH(4) (+), respectively, have been measured. La(3+) and Ca(2+) initially depressed the endogenous elongation rate. In the case of La(3+) a prolonged stimulatory effect on the rate of elongation was produced by concentrations of 50 millimolar down to 20 micromolar after an initial depression of elongation rate. The effect of K(+) was slightly stimulatory and showed a synergistic effect in combination with La(3+). NH(4) (+) produced an immediate rapid increase in elongation rate. La(3+) did not behave as a "super calcium" in its action upon the spontaneous growth response. The prolonged elongation of the La(3+)-treated segments exhibiting the spontaneous growth response is apparently a newly observed effect. These rapid growth responses are interpreted as an interaction between anionic lipid-protein complexes in the plasmalemma and the respective ions.


Identification of pharmacogenetic variants from large scale next generation sequencing data in the Saudi population.
It is well documented that drug responses are related to Absorption, Distribution, Metabolism, and Excretion (ADME) characteristics of individual patients. Several studies have identified genetic variability in pharmacogenes, that are either directly responsible for or are associated with ADME, giving rise to individualized treatments. Our objective was to provide a comprehensive overview of pharmacogenetic variation in the Saudi population. We mined next generation sequencing (NGS) data from 11,889 unrelated Saudi nationals, to determine the presence and frequencies of known functional SNP variants in 8 clinically relevant pharmacogenes (CYP2C9, CYP2C19, CYP3A5, CYP4F2, VKORC1, DPYD, TPMT and NUDT15), recommended by the Clinical Pharmacogenetics Implementation Consortium (CPIC), and collectively identified 82 such star alleles. Functionally significant pharmacogenetic variants were prevalent especially in CYP genes (excluding CYP3A5), with 10-44.4% of variants predicted to be inactive or to have decreased activity. In CYP3A5, inactive alleles (87.5%) were the most common. Only 1.8%, 0.7% and 0.7% of NUDT15, TPMT and DPYD variants respectively, were predicted to affect gene activity. In contrast, VKORC1 was found functionally, to be highly polymorphic with 53.7% of Saudi individuals harboring variants predicted to result in decreased activity and 31.3% having variants leading to increased metabolic activity. Furthermore, among the 8 pharmacogenes studied, we detected six rare variants with an aggregated frequency of 1.1%, that among several other ethnicities, were uniquely found in Saudi population. Similarly, within our cohort, the 8 pharmacogenes yielded forty-six novel variants predicted to be deleterious. Based upon our findings, 99.2% of individuals from the Saudi population carry at least one actionable pharmacogenetic variant.


Bone Regeneration Using MMP-Cleavable Peptides-Based Hydrogels.
Accumulating evidence has suggested the significant potential of chemically modified hydrogels in bone regeneration. Despite the progress of bioactive hydrogels with different materials, structures and loading cargoes, the desires from clinical applications have not been fully validated. Multiple biological behaviors are orchestrated precisely during the bone regeneration process, including bone marrow mesenchymal stem cells (BMSCs) recruitment, osteogenic differentiation, matrix calcification and well-organized remodeling. Since matrix metalloproteinases play critical roles in such bone metabolism processes as BMSC commitment, osteoblast survival, osteoclast activation matrix calcification and microstructure remodeling, matrix metalloproteinase (MMP) cleavable peptides-based hydrogels could respond to various MMP levels and, thus, accelerate bone regeneration. In this review, we focused on the MMP-cleavable peptides, polymers, functional modification and crosslinked reactions. Applications, perspectives and limitations of MMP-cleavable peptides-based hydrogels for bone regeneration were then discussed.


[The establishment of B(a)P and TPA transformed cell line and its biological characteristics].
To transform HPV E6/E7 immortalized human oral epithelial cell line HIOEC cells by benzo(a)pyrene B(a)P and tetradecanoyl phorbol acetate (TPA) in vitro, and establish a carcinogenesis model of oral squamous cell carcinoma. HIOEC cells were treated with 0.1 microg/ml -1.2 microg/ml B(a)P for 6 months. Some of these cells were treated with 0.1 microg/ml TPA 24 hours at 4th passage and 10th passage, respectively. The cells were cloned at 18th passage, and then were cultured with DMEM medium contain 10% FBS at 21st passage. The cells were cultured in vitro for 1 year and developed into a malignant cell line HIOEC-B(a)P-TPA. The morphological changes of the cells were observed with differential interference contrast microscope and HE staining. The expression of cytokeratin and vimentin was identified with immunohistochemical staining. The soft agar colonies forming ability and tumorigenesity of the cells were identified to confirm the malignant characteristics of HIOEC-B(a)P-TPA cells. (1) After HIOEC cells were treated with B(a)P plus TPA for 6 months, HIOEC-B(a)P-TPA cells grew well in DMEM medium containing with physical concentration of calcium and 10% FBS. (2) During HIOEC cells were treated with chemical carcinogens, the morphology of the cells was changed. HIOEC-B(a)P-TPA cells showed as fibroblast-like cells with many atypical mitosis. (3) The expression of cytokeratin decreased in the cells while that of vimentin increased in the cells. (4) HIOEC-B(a)P-TPA cells had strong soft agar colony formation ability and the colony formation ratio was 24.5%. (5) HIOEC-B(a)P-TPA cells have no tumorigenisity till now. We established a biological factors and chemical carcinogens induced malignant cell line-HIOEC-B(a)P-TPA after a long period. It will provide a good multiple factors, multistage carcinogenesis model of OSCC for further research.


Nidovirus infections: experimental model systems of human neurologic diseases.
The presence of terminally differentiated slow- and non-dividing cells in the central nervous system (CNS) provides a safe harbor for viral persistence and latency and constitutes a unique immunologic environment for viral infections. Studies of experimental model systems of viral infections of the CNS provide insight into mechanisms of viral persistence and immune-mediated pathology. Nidoviruses are comprised of 2 families of viruses, coronaviruses and arteriviruses, and are common pathogens of humans and a variety of animal species. Both families of viruses contain neurotropic strains that produce experimental neurologic diseases in rodents. These include acute meningitis and encephalitis; acute poliomyelitis; and chronic inflammatory, immune-mediated, demyelination. Coronavirus-induced demyelinating disease mimics many of the pathologic features of Multiple Sclerosis (MS).


Extracellular human immunodeficiency virus type-1 Tat protein activates phosphatidylinositol 3-kinase in PC12 neuronal cells.
We have here investigated the effect of the regulatory Tat protein of the human immunodeficiency virus type 1 (HIV-1) on the PI 3-kinase catalytic activity in PC12 rat pheochromocytoma cells. After as early as 1 min from the beginning of the treatment with recombinant HIV-1 Tat protein, a significant increase in the tyrosine phosphorylation levels of the p85 regulatory subunit of PI 3-kinase was noticed in 48 h serum-starved PC12 cells. Moreover, the addition of Tat to PC12 cells induced a great increase in PI 3-kinase immunoprecipitated with an anti-phosphotyrosine antibody with a peak of activity (19-fold increase with respect to the basal levels) after a 15-min treatment. This increase in PI 3-kinase activity was significantly higher in PC12 cell cultures supplemented with Tat protein than in cultures stimulated by 100 ng/ml nerve growth factor (NGF; 8-fold increase with respect to the basal levels). Further experiments showed that Tat protein was able to specifically activate PI 3-kinase at picomolar concentrations. In fact: (i) maximal activation of PI 3-kinase was observed at concentrations as low as 1 ng/ml and was specifically blocked by anti-Tat neutralizing antibody; (ii) a Tat-dependent activation was also observed in experiments in which PI 3-kinase activity was evaluated in either anti-Tyr(P) or anti-p85 immunoprecipitates; (iii) 100 nM wortmannin completely blocked the Tat-mediated increase in PI 3-kinase activity both in vitro and in vivo. Our data strongly support the concept that extracellular Tat acts as a cell stimulator, inducing intracellular signal transduction in uninfected cells.


Prospective post-traumatic stress disorder symptom trajectories in active duty and separated military personnel.
Post-traumatic stress disorder (PTSD) is a serious mental illness that affects current and former military service members at a disproportionately higher rate than the civilian population. Prior studies have shown that PTSD symptoms follow multiple trajectories in civilians and military personnel. The current study examines whether the trajectories of PTSD symptoms of veterans separated from the military are similar to continuously serving military personnel. The Millennium Cohort Study is a population-based study of military service members that commenced in 2001 with follow-up assessments occurring approximately every 3 years thereafter. PTSD symptoms were assessed at each time point using the PTSD Checklist. Latent growth mixture modeling was used to compare PTSD symptom trajectories between personnel who separated (veterans; n = 5292) and personnel who remained in military service (active duty; n = 16,788). Four distinct classes (resilient, delayed-onset, improving, and elevated-recovering) described PTSD symptoms trajectories in both veterans and active duty personnel. Trajectory shapes were qualitatively similar between active duty and veterans. However, within the resilient, improving, and elevated recovering classes, the shapes were statistically different. Although the low-symptom class was the most common in both groups (veterans: 82%; active duty: 87%), veterans were more likely to be classified in the other three classes (in all cases, p < 0.01). The shape of each trajectory was highly similar between the two groups despite differences in military and civilian life.


Transcriptome analysis reveals molecular mechanisms responsive to acute cold stress in the tropical stenothermal fish tiger barb (Puntius tetrazona).
Tropical stenothermal fish exhibit special tolerance and response to cold stress. However current knowledge of the molecular mechanisms response to cold stress in aquatic ectotherms is largely drawn from eurythermal or extreme stenothermal species. The tiger barb Puntius tetrazona is a tropical stenothermal fish, with great popularity in aquarium trade and research. To investigate the response mechanism of P. tetrazona to low temperature, fish were exposed to increasing levels of acute cold stress. Histopathological analysis showed that the brain, gill, liver and muscle tissues appeared serious damage after cold stress (13 °C). Brain, gill, liver and muscle tissues from control (CTRL) groups (27 °C) and COLD stress groups (13 °C) of eight-month fish (gender-neutral) were sampled and assessed for transcriptomic profiling by high-throughput sequencing. 83.0 Gb of raw data were generated, filtered and assembled for de novo transcriptome assembly. According to the transcriptome reference, we obtained 392,878 transcripts and 238,878 unigenes, of which 89.29% of the latter were annotated. There were 23,743 differently expressed genes (DEGs) been filtered from four pairs of tissues (brain, gill, liver and muscle) between these cold stress and control groups. These DEGs were mainly involved in circadian entrainment, circadian rhythm, biosynthesis of steroid and fatty acid. There were 64 shared DEGs between the four pairs of groups, and five were related to ubiquitylation/deubiquitylation. Our results suggested that ubiquitin-mediated protein degradation might be necessary for tropical stenothermal fish coping with acute cold stress. Also, the significant cold-induced expression of heat shock 70 kDa protein (HSP70) and cold-induced RNA-binding protein (CIRBP) was verified. These results suggested that the expression of the molecular chaperones HSP70 and CIRBP in P. tetrazona might play a critical role in coping with acute cold stress. This is the first transcriptome analysis of P. tetrazona using RNA-Seq technology. Novel findings about tropical stenothermal fish under cold stress (such as HSP70 and CIRBP genes) are presented here. This study contributes new insights into the molecular mechanisms of tropical stenothermal species response to acute cold stress.


Short communication: the use of sodium ironedetate (Sytron) as an MRI rectal contrast agent.
The use of bowel contrast medium in abdominal and pelvic MRI examinations is increasingly being recognized as a useful adjunct. A contrast agent which produces a negative contrast effect with T2 weighted (T2W) sequences might help distinguish bowel pathology, which has increased signal intensity, from bowel content. A solution of 7.6 mg ml-1 of sodium ironedetate (Sytron, Link Pharmaceuticals) produces positive contrast on the first (proton density) echo and negative contrast (signal void) on the second (T2W) echo of a dual echo sequence at 0.5 T. When administered rectally it provides a negative contrast bowel marker for pelvic examinations.


[Quality control of the self-measurement of blood sugar in unselected type I diabetics. The importance of patient training].
Unselected type I diabetics were hospitalized for group training and treatment programme during which blood-sugar was self-monitored with the Haemo-Glukotest 20-800; quality of self-monitoring improved appropriately. The patients had taken part in either the standard training programme (67 patients) or in the "intensive" training programme (101 patients). At the beginning of the training week, after the first theoretical and practical instructions, the quality of blood-sugar self-monitoring was equally poor among patients of both programmes. At the end of the "standard" training week, self-monitoring results were still unsatisfactory, though slightly better than at the onset. Because of these poor results, the training programme was intensified. Optimal quality of self-monitoring was then achieved at the end of the training period. In 69 others, also unselected, type I diabetics the quality of self-monitoring was determined 14 months after their participation in the training programme. Using the Haemo-Glukotest 20-800 (57 patients), self-monitoring gave excellent results; using a blood-glucose measuring instrument (12 patients) it was slightly worse. Assuming intensive training, even unselected type I diabetics can obtain accurate blood-sugar measurements using test-strips.


Additively Manufactured Flexible Electronics with Ultrabroad Range and High Sensitivity for Multiple Physiological Signals' Detection.
Flexible electronics can be seamlessly attached to human skin and used for various purposes, such as pulse monitoring, pressure measurement, tensile sensing, and motion detection. Despite their broad applications, most flexible electronics do not possess both high sensitivity and wide detection range simultaneously; their sensitivity drops rapidly when they are subjected to even just medium pressure. In this study, ultrabroad-range, high-sensitivity flexible electronics are fabricated through additive manufacturing to address this issue. The key to possess high sensitivity and a wide detection range simultaneously is to fabricate flexible electronics with large depth-width ratio circuit channels using the additive manufacturing inner-rinsing template method. These electronics exhibit an unprecedented high sensitivity of 320 kPa-1 over the whole detection range, which ranges from 0.3 to 30,000 Pa (five orders of magnitude). Their minimum detectable weight is 0.02 g (the weight of a fly), which is comparable with human skin. They can stretch to over 500% strain without breaking and show no tensile fatigue after 1000 repetitions of stretching to 100% strain. A highly sensitive and flexible electronic epidermal pulse monitor is fabricated to detect multiple physiological signals, such as pulse signal, breathing rhythm, and real-time beat-to-beat cuffless blood pressure. All of these signals can be obtained simultaneously for detailed health detection and monitoring. The fabrication method does not involve complex expensive equipment or complicated operational processes, so it is especially suitable for the fabrication of large-area, complex flexible electronics. We believe this approach will pave the way for the application of flexible electronics in biomedical detection and health monitoring.


Reversal of microvascular rarefaction and reduced renal mass hypertension.
This study examined the microcirculatory and renin-angiotensin system changes following the reversal of hypertension in reduced renal mass rats. Nine-week-old Sprague-Dawley reduced renal mass rats were placed on a low or high sodium diet for 4 or 8 weeks or a combination of 4 weeks of high sodium followed by 4 weeks of low sodium. Blood pressure was directly measured during the development of hypertension and its reversal. Plasma renin activity, angiotensin-converting enzyme activity, and angiotensin II concentrations were measured throughout the experiment. The cremaster and hindlimb muscles were removed, and microvascular density was determined by quantitative stereology. Four weeks of high sodium increased blood pressure (152+/-7 mm Hg) and reduced microvessel density (13.7%). Reduced renal mass hypertension was rapidly reversed after the rats were returned to a low sodium diet (124+/-7 mm Hg after 3 days), and microvascular density returned to control levels. After 4 weeks of high sodium, circulating plasma renin activity and angiotensin II fell by 94% and 82%, respectively. Plasma angiotensin-converting enzyme activity was increased after 2 weeks of high sodium but returned to control levels after 4 weeks of high sodium. This study demonstrates that microvascular density is reduced in reduced renal mass hypertensive rats following exposure to high sodium diet and this is associated with a fall in circulating plasma renin activity and angiotensin II levels. Microvascular density can return to normal levels after a reactivation of the circulating renin-angiotensin system. This study provides further evidence for the hypothesis that modulation of the renin-angiotensin system is important in the regulation of microvascular structure.


Selective Emitter with Engineered Anisotropic Radiation to Minimize Dual-Band Thermal Signature for Infrared Stealth Technology.
Selective emitters comprising plasmonic resonators have been exploited for cooling devices or infrared stealth technology. While selective emitters have been designed using odd-order resonances, even-order resonances also emit anisotropic thermal radiation signals. Thermal radiation by even-order resonances in selective emitters can be experimentally detected by thermal imaging cameras, and such thermal emissions often degrade the observability of infrared detectors, rendering them inapplicable to infrared stealth technology. Here, a selective emitter with extremely low thermal radiation signature in a dual-band range, a detection range by an infrared detector, is proposed with engineering anisotropic thermal radiation by even-order resonances. To minimize infrared signature in a dual-band range, the characterization of even-order resonances of gap plasmon metasurfaces is achieved based on vectorial diffraction within a relative error of 10%. Thermal radiation by even-order resonance has been shown to be highly directional and can be experimentally measured using mid-wave infrared images. Based on model prediction, the proposed selective emitter reduces mid-wave infrared signatures and long-wave infrared signatures by factors of 37.95 and 38.06, respectively, compared with those of blackbody surfaces. In addition, numerically confirmed thermal signature reduction and captured mid-wave infrared images indicate excellent thermal camouflage performance of the selective emitter with background medium. Thus, the characterization of even-order resonances provides a basis for the design of metasurfaces that can be employed for multispectral applications, especially infrared stealth technology.


Comparative Genomic Analysis of Two Vibrio toranzoniae Strains with Different Virulence Capacity Reveals Clues on Its Pathogenicity for Fish.
Vibrio toranzoniae is a Gram-negative bacterium of the Splendidus clade within the Vibrio genus. V. toranzoniae was first isolated from healthy clams in Galicia (Spain) but recently was also identified associated to disease outbreaks of red conger eel in Chile. Experimental challenges showed that the Chilean isolates were able to produce fish mortalities but not the strains isolated from clams. The aim of the present study was to determine the differences at the genomic level between the type strain of the species (CECT 7225T) and the strain R17, isolated from red conger eel in Chile, which could explain their different virulent capacity. The genome-based comparison showed high homology between both strains but differences were observed in certain gene clusters that include some virulence factors. Among these, we found that iron acquisition systems and capsule synthesis genes were the main differential features between both genomes that could explain the differences in the pathogenicity of the strains. Besides, the studied genomes presented genomic islands and toxins, and the R17 strain presented CRISPR sequences that are absent on the type strain. Taken together, this analysis provided important insights into virulence factors of V. toranzoniae that will lead to a better understanding of the pathogenic process.


A computer-controlled conformal radiotherapy system. I: Overview.
Equipment developed for use with computer-controlled conformal radiotherapy (CCRT) treatment techniques, including multileaf collimators and/or computer-control systems for treatment machines, are now available. The purpose of this work is to develop a system that will allow the safe, efficient, and accurate delivery of CCRT treatments as routine clinical treatments, and permit modifications of the system so that the delivery process can be optimized. The needs and requirements for a system that can fully support modern computer-controlled treatment machines equipped with multileaf collimators and segmental or dynamic conformal therapy capabilities have been analyzed and evaluated. This analysis has been used to design and then implement a complete approach to the delivery of CCRT treatments. The computer-controlled conformal radiotherapy system (CCRS) described here consists of a process for the delivery of CCRT treatments, and a complex software system that implements the treatment process. The CCRS system described here includes systems for plan transfer, treatment delivery planning, sequencing of the actual treatment delivery process, graphical simulation and verification tools, as well as an electronic chart that is an integral part of the system. The CCRS system has been implemented for use with a number of different treatment machines. The system has been used clinically for more than 2 years to perform CCRT treatments for more than 200 patients. A comprehensive system for the implementation and delivery of computer-controlled conformal radiation therapy (CCRT) plans has been designed and implemented for routine clinical use with multisegment, computer-controlled, multileaf-collimated conformal therapy. The CCRS system has been successfully implemented to perform these complex treatments, and is considered quite important to the clinical use of modern computer-controlled treatment techniques.


Aqueous reactions of U(VI) at high chloride concentrations: syntheses and structures of new uranyl chloride polymers.
The reactions of UO(3) with acidic aqueous chloride solutions resulted in the formation of two new polymeric U(VI) compounds. Single crystals of Cs(2)[(UO(2))(3)Cl(2)(IO(3))(OH)O(2)].2H(2)O (1) were formed under hydrothermal conditions with HIO(3) and CsCl, and Li(H(2)O)(2)[(UO(2))(2)Cl(3)(O)(H(2)O)] (2) was obtained from acidic LiCl solutions under ambient temperature and pressure. Both compounds contain pentagonal bipyramidal coordination of the uranyl dication, UO(2)(2+). The structure of 1 consists of infinite [(UO(2))(3)Cl(2)(IO(3))(mu(3)-OH)(mu(3)-O)(2)](2-) ribbons that run down the b axis that are formed from edge-sharing pentagonal bipyramidal [UO(6)Cl] and [UO(5)Cl(2)] units. The Cs(+) cations separate the chains from one another and form long ionic contacts with terminal oxygen atoms from iodate ligands, uranyl oxygen atoms, water molecules, and chloride anions. In 2, edge-sharing [UO(3)Cl(4)] and [UO(5)Cl(2)] units build up tetranuclear [(UO(2))(4)(mu-Cl)(6)(mu(3)-O)(2)(H(2)O)(2)](2-) anions that are bridged by chloride to form one-dimensional chains. These chains are connected in a complex network of hydrogen bonds and interactions of uranyl oxygen atoms with Li(+) cations. Crystal data: 1, orthorhombic, space group Pnma, a = 8.2762(4) A, b = 12.4809(6) A, c = 17.1297(8) A, Z = 4; 2, triclinic, space group P1, a = 8.110(1) A, b = 8.621(1) A, c = 8.740(1) A, Z = 2.


Risk of Dementia in Patients with Depression or Parkinson's Disease: A Retrospective Cohort Study.
This study aimed to clarify whether Parkinson's disease (PD) and depression were independent risk factors or with synergic effects in dementia. Newly diagnosed PD (n = 1213) patients and control subjects (n = 4852) were selected from the Taiwan National Health Insurance Research Database from January 2001 through December 2008. Follow-up ended in 2011 with an outcome of dementia occurring or not. This cohort was divided into controls with or without depression, PD only, and PD with depression. The incident rate of dementia and hazard ratio (HR) using Cox's regression analysis were calculated for each group. When compared with controls without depression as HR 1.00, the adjusted HR for dementia was 3.29 (p < 0.001) in the PD only group, 2.77 (p < 0.001) in the PD with depression group, and 1.55 (p=0.024) in the depression only group. The incident rate of dementia was 29.2 (per 1000 person-years) in the PD only group and 13.2 in the PD with depression group. The effect of PD on dementia in the depression group produced a HR of 0.97 (p=0.905). Parkinson's disease served as a risk factor for dementia. By comparison, depression was not a risk factor for dementia in PD patients, although it did act as a risk factor for dementia.


Redundant Postsynaptic Functions of SynCAMs 1-3 during Synapse Formation.
Investigating the roles of synaptogenic adhesion molecules during synapse formation has proven challenging, often due to compensatory functions between additional family members. The synaptic cell adhesion molecules 1-3 (SynCAM1-3) are expressed both pre- and postsynaptically, share highly homologous domains and are synaptogenic when ectopically presented to neurons; yet their endogenous functions during synaptogenesis are unclear. Here we report that SynCAM1-3 are functionally redundant and collectively necessary for synapse formation in cultured hippocampal neurons. Only triple knockdown (KD) of SynCAM1-3 using highly efficient, chained artificial microRNAs (amiRNAs) reduced synapse density and increased synapse area. Electrophysiological recordings of quantal release events supported an increase in synapse size caused by SynCAM1-3 depletion. Furthermore, a combinatorial, mosaic lentiviral approach comparing wild type (WT) and SynCAM1-3 KD neurons in the same culture demonstrate that SynCAM1-3 set synapse number and size through postsynaptic mechanisms. The results demonstrate that the redundancy between SynCAM1-3 has concealed their synaptogenic function at the postsynaptic terminal.


The lack of effect of progestogen on bone.
Several critical issues surround the possible effects of progestogens in postmenopausal women. No comparative studies of the effects of estrogen and progestogens on bone loss have been conducted to date, but a review of the available evidence suggests that endogenous progesterone has little effect on endometrial secretory homeostasis. The evidence also suggests that when used alone at normally prescribed dosages, progestogens have neither a direct effect on osteoporosis nor an additive effect when used as a component of hormone replacement therapy (HRT). The positive effects of HRT on bone seen in postmenopausal women are more likely a direct result of the estrogen component.


myo-Inositol Trisphosphate Mobilizes Calcium from Fusogenic Carrot (Daucus carota L.) Protoplasts.
To determine whether or not inositol trisphosphate (IP(3)) mobilizes calcium in higher plant cells, we investigated the effect of IP(3) on Ca(2+) fluxes in fusogenic carrot (Daucus carota L.) protoplasts. The protoplasts were incubated in (45)Ca(2+)-containing medium and the (45)Ca(2+) associated with the protoplasts was monitored with time. Addition of IP(3) (20 micromolar) caused a 17% net loss of the accumulated (45)Ca(2+) within 4 minutes. There was a reuptake of (45)Ca(2+) and the protoplasts recovered to their initial value by 10 minutes. Phytic acid (IP(6)), also stimulated (45)Ca(2+) efflux from the protoplasts. Both the IP(3(-) ) and the IP(6(-) )induced (45)Ca(2+) efflux were inhibited by the calmodulin antagonist, trifluoperazine.


[Malformative giant emphysema bulla. Report of a case in childhood].
Bullous pneumopathy is considered a surgical disease, although her treatment is still discussed. The initial attempts of surgical treatment were founded on erroneous physiopathological concepts and date back to early years of 1900. These surgical treatments intended to external drainage of giant bullae, their marsupialized or to reduction of extension of bullae by pneumoperitonaeum, section of phrenic nerve or thoracoplasty. The definition of emphysematous bullae has been much improved with the development of computed tomography. A precise study of their size, of their position and of condition of residual pulmonary parenchyma may be considered important to decide the surgical treatment: this must determine the removal of bulla and the reexpansion of compressed pulmonary parenchyma. The Authors report a case of giant bulla, initially wrong interpreted as pneumothorax, of exceptional observation for her malformative origin, diagnoses and surgical treated on an eleven years old child.


Ethanol: Novel Actions on Nerve Cell Physiology Explain Impaired Functions.
Molecular biological tools have revealed receptor proteins for excitatory and inhibitory neurotransmitters on cell membranes as targets of ethanol action. Behavioral and pharmacogenetic assays using rodent lines have supported this neurotransmitter theory of ethanol action and given a firm basis for future identification of the relevant genes and the central physiological processes vulnerable to ethanol.


Crystal structure of bovine trypsin and wheat germ trypsin inhibitor (I-2b) complex (2:1) at 2.3 a resolution.
The Bowman-Birk trypsin inhibitor (BBI) from wheat germ (I-2b) consists of 123 amino acid residues with two inhibitory loops. The crystal structure of a bovine trypsin-wheat germ trypsin inhibitor (I-2b) complex (2:1) has been determined at 2.3 A resolution to a final R-factor of 0.177. A distance of 37.2 A between the contiguous contact loops allows them to bind and inhibit two trypsin molecules simultaneously and independently. Each domain shares the same overall fold with 8 kDa BBIs. The five disulfide bridges in each domain are a subset of seven disulfide bridges in the 8 kDa BBIs. I-2b consists of ten beta-strands and the loops connecting these strands but it lacks alpha-helices. The conformations of the contiguous contact loops of I-2b are in a heart-like structure. The reactive sites in both domains, Arg 17 and Lys 76, are located on the loop connecting anti-parallel beta-strands, beta 1/beta 2 and beta 6/beta 7. Strands beta 1 and beta 6 are in direct contact with trypsin molecules and form stable triple stranded beta-sheet structures via hydrogen bonds.


Pleural fluid and serum soluble interleukin-2 receptors in pleural effusions.
Pleural fluid and serum soluble Interleukin-2 receptors (sIL-2R) were measured by an enzyme-immunoassay in 13 patients with tuberculous pleurisy, in 28 patients with carcinomatous pleurisy and in 17 transudates from patients with congestive heart failure. Significantly higher values of sIL-2R were observed in exudative than in transudative (mean +/- SEM = 713 +/- 111 U/ml) pleural fluid samples, the highest being found in tuberculous (3777 +/- 501 U/ml) and the intermediate in carcinomatous exudates (1981 +/- 160 U/ml) (p less than 0.0001; on way ANOVA). Serum sIL-2R were significantly higher in carcinomatous and transudative groups than in age- and sex- matched controls (p less than 0.002; one way ANOVA), while there was no significant difference between the tuberculous group and controls. The pleural/serum sIL-2R ratio was significantly higher in tuberculous (5.32 +/- 0.60), than in carcinomatous pleurisy (2.67 +/- 0.20) and higher still than in transudates (0.76 +/- 0.10) (p less than 0.001; one way ANOVA). In conclusion, the pleura/serum sIL-2R ratio may be a helpful parameter in differentiating tuberculous from carcinomatous pleurisy and an additional confirmatory one for distinguishing transudates from exudates.


Implicit Coordination Strategies for Effective Team Communication.
We investigated implicit communication strategies for anticipatory information sharing during team performance of tasks with varying degrees of complexity. We compared the strategies used by teams with the highest level of performance to those used by the lowest-performing teams to evaluate the frequency and methods of communications used as a function of task structure. High-performing teams share information by anticipating the needs of their teammates rather than explicitly requesting the exchange of information. As the complexity of a task increases to involve more interdependence among teammates, the impact of coordination on team performance also increases. This observation motivated us to conduct a study of anticipatory information sharing as a function of task complexity. We conducted an experiment in which 13 teams of four people performed collaborative search-and-deliver tasks with varying degrees of complexity in a simulation environment. We elaborated upon prior characterizations of communication as implicit versus explicit by dividing implicit communication into two subtypes: (a) deliberative/goal information and (b) reactive status updates. We then characterized relationships between task structure, implicit communication, and team performance. We found that the five teams with the fastest task completion times and lowest idle times exhibited higher rates of deliberative communication versus reactive communication during high-complexity tasks compared with the five teams with the slowest completion times and longest idle times (p = .039). Teams in which members proactively communicated information about their next goal to teammates exhibited improved team performance. The findings from our work can inform the design of communication strategies for team training to improve performance of complex tasks.


Perfluorocarbons in the twenty-first century: clinical applications as transfusion alternatives.
The risks of allogeneic transfusion are well known to physicians and have prompted a search for alternatives. Perfluorocarbons were introduced into clinical trials in the early 1980's with the hope that these products would develop into acceptable blood substitutes. Unfortunately, the limited potency, short half-life, and potential toxicity of these early formulations coupled with unrealistic expectations for efficacy prevented the perfluorocarbons from playing a significant role in transfusion medicine. Recent changes in formulation to improve efficacy and eliminate toxicity have stimulated renewed interest in perfluorocarbons as alternatives to allogeneic transfusion. Our recent work has focused on the role of perfluoroctylbromide (PFOB), a second generation perfluorocarbon, as an adjunct to autologous transfusion and acute normovolemic hemodilution (ANH), rather than as a total blood substitute. Initial animal experiments have shown the ability of small doses of PFOB to maintain oxygen delivery without the need for blood transfusion in the setting of hemodilution. Our presentation will focus on subsequent clinical work using PFOB as an alternative to both allogeneic and autologous blood transfusion during ANH. We believe that perfluorocarbons such as PFOB will have a significant role in the future as one of several, additive alternatives to blood transfusion.


Dealing with the spiralling price of medicines: issues and solutions.
Escalating cost of medicines is rapidly becoming a serious threat to patients and health systems. This trend has been documented to impact patient outcomes adversely. As clinicians and tax payers, it is our responsibility to be aware of the potential detrimental effects spiralling costs have on our patients, our community and our health system and to mitigate these effects by exposing this issue to our respective professional societies, representatives of the pharmaceutical companies that we interact with, government regulatory bodies and to patients who we are caring for. Only through understanding and constructive actions will we be able to provide the best quality of care to our patients and continue to enjoy universal healthcare in our country.


Endothelin effects in isolated, perfused lamb lungs: role of cyclooxygenase inhibition and vasomotor tone.
We have determined the sites of action of endothelin-1 (ET) in the lamb pulmonary circulation. The influence of cyclooxygenase inhibition and baseline vasomotor tone on ET effects was also studied. Lungs of 14 lambs (6-9 wk of age, 12.1 +/- 0.6 kg body wt) were isolated and perfused with blood. Group I lungs (n = 5) were untreated, group II lungs (n = 5) were treated with indomethacin to inhibit cyclooxygenase, and group III lungs (n = 4) were treated with indomethacin and a thromboxane A2 analogue, U-46619, to elevate vasomotor tone. All lungs were perfused with constant flow in zone 3, with left atrial and airway pressures being 8 and 6 cmH2O, respectively. We measured pulmonary arterial pressure and, by the micropuncture servo-null method, pressures in 20- to 50-microns diameter subpleural venules, both before and after each dose of ET was infused (50, 100, 250, and 500 ng/kg). Group I lungs, with high baseline vasomotor tone, exhibited a biphasic response to ET; 50-100 ng/kg of ET dilated both arteries and veins, whereas 500 ng/kg of ET constricted both arteries and veins. In group II lungs with low vasomotor tone, all doses of ET caused constriction of arteries only. In group III lungs (indomethacin treated with elevated vasomotor tone), 50-100 ng/kg of ET caused dilation of arteries and veins, whereas 500 ng/kg of ET induced constriction, this time only in arteries. We conclude that ET has both dilator and constrictor effects in arteries and veins of isolated, perfused lamb lungs. ET-induced arterial and venous dilation is dependent on initial vasomotor tone but not on cyclooxygenase metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)


A POSTERIORI ERROR ANALYSIS OF TWO STAGE COMPUTATION METHODS WITH APPLICATION TO EFFICIENT DISCRETIZATION AND THE PARAREAL ALGORITHM.
We consider numerical methods for initial value problems that employ a two stage approach consisting of solution on a relatively coarse discretization followed by solution on a relatively fine discretization. Examples include adaptive error control, parallel-in-time solution schemes, and efficient solution of adjoint problems for computing a posteriori error estimates. We describe a general formulation of two stage computations then perform a general a posteriori error analysis based on computable residuals and solution of an adjoint problem. The analysis accommodates various variations in the two stage computation and in formulation of the adjoint problems. We apply the analysis to compute "dual-weighted" a posteriori error estimates, to develop novel algorithms for efficient solution that take into account cancellation of error, and to the Parareal Algorithm. We test the various results using several numerical examples.


Gender and veterinary medicine: global historical perspectives.
This essay will suggest research methodologies for historians interested in the history of gender and veterinary medicine over the past 200 years. This topic is a very timely one, because we are currently living through a transition in the interactions between gender and veterinary medicine. Traditionally male-dominated, veterinary medicine has recently experienced a world-wide increase in the number of women entering veterinary schools and practicing in all areas of the profession. Understanding this transition requires us to ask historical, cultural, and sociological questions in order to illuminate the roles of gender ideologies and the participation of women in the development of modern veterinary medicine. The following paragraphs outline three specific methodological strategies that historians have used to study the interactions between gender and science and gender and medicine. I will propose ways that we veterinary historians can use these strategies to study gender and veterinary medicine. It is beyond the scope of this paper to summarize the literature on women and veterinary medicine; but it will nonetheless highlight a few studies from nations around the world to illustrate the methodological strategies that I propose. I hope to provide scholars with ideas for future studies in the history of gender and veterinary medicine.


Polio vaccine and retroviruses.
In this paper we consider the main steps in the process of manufacture of oral polio vaccine and assess the probable clearance factor for HIV retrovirus at each step. We conclude that the processes employed would have eliminated retrovirus contamination for all practical purposes.


Generation of induced pluripotent stem cells in rabbits: potential experimental models for human regenerative medicine.
Human induced pluripotent stem (iPS) cells have the potential to establish a new field of promising regenerative medicine. Therefore, the safety and the efficiency of iPS-derived cells must be tested rigorously using appropriate animal models before human trials can commence. Here, we report the establishment of rabbit iPS cells as the first human-type iPS cells generated from a small laboratory animal species. Using lentiviral vectors, four human reprogramming genes (c-MYC, KLF4, SOX2, and OCT3/4) were introduced successfully into adult rabbit liver and stomach cells. The resulting rabbit iPS cells closely resembled human iPS cells; they formed flattened colonies with sharp edges and proliferated indefinitely in the presence of basic FGF. They expressed the endogenous pluripotency markers c-MYC, KLF4, SOX2, OCT3/4, and NANOG, whereas the introduced human genes were completely silenced. Using in vitro differentiating conditions, rabbit iPS cells readily differentiated into ectoderm, mesoderm, and endoderm. They also formed teratomas containing a variety of tissues of all three germ layers in immunodeficient mice. Thus, the rabbit iPS cells fulfilled all of the requirements for the acquisition of the fully reprogrammed state, showing high similarity to their embryonic stem cell counterparts we generated recently. However, their global gene expression analysis revealed a slight but rigid difference between these two types of rabbit pluripotent stem cells. The rabbit model should enable us to compare iPS cells and embryonic stem cells under the same standardized conditions in evaluating their ultimate feasibility for pluripotent cell-based regenerative medicine in humans.


Autocrine regulation of the renal arterial tone by adrenomedullin.
We tested the hypothesis that adrenomedullin (ADM), a recently isolated hypotensive peptide, is an autocrine transmitter in renal arterial smooth muscle cells (RASMCs). Fura-2 fluorometry revealed that ADM decreases both the cytosolic Ca2+ concentration ([Ca2+]i) and tension induced by 0.3 microM phenylephrine (PE) in porcine RASMCs. The expression of ADM mRNA in RASMCs was assessed by the reverse transcription polymerase chain reaction (RT-PCR), using the total RNA from the RASMCs and the specific primers for the porcine ADM mRNA. A band with an expected size could be detected only when the reverse transcriptase was added, thus indicating that the porcine RASMCs express ADM mRNA. These results therefore suggested that ADM plays an important role in the regulation of the renal vascular tone, not only as a circulating hormone, but also as an autocrine transmitter.


Sequence analysis of T-cell repertoires in health and disease.
T-cell antigen receptor (TCR) variability enables the cellular immune system to discriminate between self and non-self. High-throughput TCR sequencing (TCR-seq) involves the use of next generation sequencing platforms to generate large numbers of short DNA sequences covering key regions of the TCR coding sequence, which enables quantification of T-cell diversity at unprecedented resolution. TCR-seq studies have provided new insights into the healthy human T-cell repertoire, such as revised estimates of repertoire size and the understanding that TCR specificities are shared among individuals more frequently than previously anticipated. In the context of disease, TCR-seq has been instrumental in characterizing the recovery of the immune repertoire after hematopoietic stem cell transplantation, and the method has been used to develop biomarkers and diagnostics for various infectious and neoplastic diseases. However, T-cell repertoire sequencing is still in its infancy. It is expected that maturation of the field will involve the introduction of improved, standardized tools for data handling, deposition and statistical analysis, as well as the emergence of new and equivalently large-scale technologies for T-cell functional analysis and antigen discovery. In this review, we introduce this nascent field and TCR-seq methodology, we discuss recent insights into healthy and diseased TCR repertoires, and we examine the applications and challenges for TCR-seq in the clinic.


Relationship between roentgenographic joint destruction in the hands and functional disorders among patients with rheumatoid arthritis.
Although a relationship between joint destruction and functional disorders seems apparent in patients with rheumatoid arthritis (RA), it has not been well proven in the literature. The aims of this study were to clarify the relationship between roentgenographic joint destruction in the hands and functional disorders in patients with RA, and to explore the appropriate assessment measures for functional disorders. Cross-sectional data of the Genant-modified Total Sharp Score (Genant-mTSS), Health Assessment Questionnaire-Disability Index (HAQ-DI), Disabilities of the Arm, Shoulder, and Hand (DASH), and Michigan Hand Outcomes Questionnaire (MHQ) were collected from 50 consecutive RA patients and analyzed. HAQ-DI, DASH, and MHQ had close correlations with Genant-mTSS, with correlation coefficients of 0.69, 0.71, and -0.70, respectively, among patients with low disease activity (DAS28 < 3.2). A floor effect was observed in HAQ-DI, but neither floor nor ceiling effects were observed in DASH and MHQ. Both DASH and MHQ were strongly correlated with HAQ-DI, with correlation coefficients of 0.87 and 0.73, respectively. Functional disorders had significant relationships with roentgenographic joint destruction in the hands among RA patients with low disease activity. As assessment measures of functional disorders, DASH and MHQ had no floor or ceiling effects, being different from HAQ-DI.


Seeing in the deep-sea: visual adaptations in lanternfishes.
Ecological and behavioural constraints play a major role in shaping the visual system of different organisms. In the mesopelagic zone of the deep- sea, between 200 and 1000 m, very low intensities of downwelling light remain, creating one of the dimmest habitats in the world. This ambient light is, however, enhanced by a multitude of bioluminescent signals emitted by its inhabitants, but these are generally dim and intermittent. As a result, the visual system of mesopelagic organisms has been pushed to its sensitivity limits in order to function in this extreme environment. This review covers the current body of knowledge on the visual system of one of the most abundant and intensely studied groups of mesopelagic fishes: the lanternfish (Myctophidae). We discuss how the plasticity, performance and novelty of its visual adaptations, compared with other deep-sea fishes, might have contributed to the diversity and abundance of this family.This article is part of the themed issue 'Vision in dim light'.


Single- and multiple-dose pharmacokinetics of methylphenidate administered as methylphenidate transdermal system or osmotic-release oral system methylphenidate to children and adolescents with attention deficit hyperactivity disorder.
This was a 1-month, multicenter, open-label, randomized study to determine single- and multiple-dose pharmacokinetics of d,l-methylphenidate (MPH) after MPH transdermal system (MTS) and osmotic-release oral system MPH (OROS MPH) dosing in children (6-12 years) and adolescents (13-17 years) who had a diagnosis of attention deficit hyperactivity disorder. The pharmacokinetic population consisted of 33 children and 31 adolescents. Accumulation of d-MPH was 34% in children and 57% in adolescents after multiple fixed doses of MTS for 7 days and 76% and 94%, respectively, after 28 days of dosing. After 7 days of OROS MPH dosing, accumulation was 16% in children and 19% in adolescents; fixed doses of OROS MPH were not studied beyond 7 days. After escalating the doses to 30 mg per 9 hours for MTS, accumulation was 73% in children and 83% in adolescents after allowing for dose escalation. Corresponding values for OROS MPH after dose escalation to 54 mg were 33% in both age groups. Plasma l-MPH concentrations were approximately half those of d-MPH for MTS and negligible for OROS MPH. Overall, MTS accumulation was above that expected for single-dose pharmacokinetics of MTS and OROS MPH in both age groups. As a result of accumulation, systemic exposure to d-MPH in children after multiple escalating doses was 1.4- to 1.6-fold higher for MTS compared with OROS MPH, but similar in adolescents for both formulations. After all dosing, systemic exposure was greater in children compared with adolescents, consistent with lower body weight in children. Adverse events were mild to moderate for both formulations, and MTS dermal responses were mild.


The SPORT-NMR software: a tool for determining relaxation times in unresolved NMR spectra.
A software package which allows the correct determination of individual relaxation times for all the nonequivalent nuclei in poorly resolved NMR spectra is described. The procedure used, based on the fitting of each spectrum in the series recorded in the relaxation experiment, should improve the analysis of relaxation data in terms of quantitative dynamic information, especially in anisotropic phases. Tests on simulated data and experimental examples concerning 1H and 13C T1rho measurement in a solid copolymer and 2H T1Z and T1Q measurement in a liquid crystal are shown and discussed.


Impact of summer drought on isoprenoid emissions and carbon sink of three Scots pine provenances.
Scots pine (Pinus sylvestris L.) provenances cover broad ecological amplitudes. In a greenhouse study, we investigated the impact of drought stress and rewetting on gas exchange for three provenances (Italy: Emilia Romagna; Spain: Alto Ebro; Germany: East-German lowlands) of 2-year old Scots pine seedlings. CO2, water vapour and isoprenoid exchange of stressed and control trees were quantified with a four-chamber dynamic-enclosure system in the controlled environment of a climate chamber. The three provenances showed distinct isoprenoid emission patterns and were classified into a non-Δ3-carene, with either high α-/β-pinene or β-myrcene fraction, and a Δ3-carene dominated type. Isoprenoid emission rates, net-photosynthesis and transpiration were reduced during summer drought stress and significantly recovered after rewetting. A seasonal increase of isoprenoid emission rates towards autumn was observed for all control groups. Compared with the German provenance, the Spanish and Italian provenances revealed higher isoprenoid emission rates and more plastic responses to drought stress and seasonal development, which points to a local adaptation to climate. As a result of drought, net carbon uptake and transpiration of trees was reduced, but recovered after rewetting. We conclude from our study that Scots pine isoprenoid emission is more variable than expected and sensitive to drought periods, likely impacting regional air chemistry. Thus, a provenance-specific emission assessment accounting for reduced emission during prolonged (summer) drought is recommend for setting up biogenic volatile organic compound emission inventories used in air quality models.


Parasite-driven in vitro human lymphocyte cytotoxicity against autologous infected macrophages from mucosal leishmaniasis.
Parasite-specific cytotoxicity in human leishmaniasis was evaluated in an autologous system. PBL from cutaneous leishmaniasis (CL) or mucosal leishmaniasis (ML) patients were exposed to Leishmania amazonensis-infected autologous macrophages for 7 days and then used as effector cells in a cytotoxic assay using 51Cr-labeled autologous infected macrophages as targets. Results are reported as LU per 10(7) PBMC. Cytotoxic activity is present in ML (9.7 +/- 2.1 LU/10(7) PBMC) but not in CL (1.5 +/- 2.4 LU/10(7) PBMC) patients' lymphocytes, and the differences were highly significant (p < 0.0001). Both CD8+ T cells and NK cells exhibited cytotoxic activity. Addition of rIL-12, but not of IFN-gamma, during the generation of effector cells increased cytotoxic responses against infected macrophages. On the other hand, addition of mAb against human IL-12 or IFN-gamma during the stimulation of PBL significantly decreased the cytotoxic responses. Addition of IL-10 led to diminished cytotoxic responses, whereas the addition of anti-IL-10 did not significantly increase the cytotoxic responses. The observation of parasite-driven autologous cytotoxic responses in patients with ML, the destructive form of leishmaniasis, but not in CL, suggests that this phenomenon is involved in tissue pathology rather than in protection. Understanding the regulation of cytotoxic responses in leishmaniasis may be relevant to strategies aimed at limiting pathologic tissue destruction.


Measuring teacher identity during the transition from medical school to residency.
Residents undergo professional identity formation during training, and the integration of a teacher identity into that of a clinician is part of this process. We aimed to measure the teacher identity of incoming interns of various specialties. In this cross-sectional, survey-based study, we modified a validated teacher identity scale and distributed it to residents attending orientation at a large, academic institution. A total of 297 residents took the survey, including 272 interns; 80% (218/272) of interns completed the survey and permitted use of their data. The mean score for global teacher identity was 4.16 (SD 0.67) on a 1 to 5 Likert scale. There were significant differences between interns' current self-assessed teaching abilities and their desired future performance as teachers (P < 0.001 for all domains). Male interns had higher global teacher identity scores (4.27) than female interns (4.05; P = 0.02). There were no differences in global teacher identity between interns in medical, surgical, and supportive specialties. Interns who had participated in a student-as-teacher program in medical school had higher global teacher identity (P < 0.001) than those who had not. In conclusion, teacher identity is high in incoming interns, with higher scores in men and in those who completed student-as-teacher programs in medical school.


Antihyperglycemic profile of erinidine isolated from Hunteria umbellata seed.
Water decoction made from the seed of Hunteria umbellata is widely used in the traditional management of diabetes mellitus by Nigerian herbalists, particularly, in the southwest region of the country. Recently, a new bisindole alkaloid, erinidine, was isolated but its antihyperglycemic profile remains largely un-investigated scientifically. This forms the basis for the current study which is primarily designed at investigating the antihyperglycemic profile of erinidine and other fractions in both in vitro and in vivo models of diabetes mellitus. In the present study, erinidine was isolated and purified using the earlier described methods and its antihyperglycemic potentials tested in in vitro models such as dipeptidylpeptidase (IV), glycogen phosphorylase, HIT-T15 cell insulin secretion, glucose uptake activity, aldose reductase assays and α-glucosidase inhibition assay testings. In addition, 50 mg/kg of erinidine and that of other fractions were evaluated in in vivo models of normal and chemically-induced hyperglycemic rats. Results showed that erinidine was a light yellow, amorphous solid with UV (CHCl3) λ max 256 nm, HRESIMS m/z 382.1881 [(M+H)(+)] (calculated for C22H26N4O2, 382.1876) and melting point of 230 °C. The in vitro study showed the antihyperglycemic action of erinidine to be weakly mediated via α-glucosidase inhibition mechanism as the results for other in vitro tests such as dipeptidylpeptidase (IV), glycogen phosphorylase, HIT-T15 cell insulin secretion, glucose uptake activity and aldose reductase assays were all negative. However, the in vivo results showed 50 mg/kg erinidine given per os to normal and alloxan-induced hyperglycemic rats to significantly (p<0.05, p<0.001) attenuate an increase in their post-absorptive blood glucose concentrations after 3 g/kg glucose loading in the rats, suggesting its antihyperglycemic mechanism to be via α-glucosidase inhibition. This result, although, further corroborated the in vitro findings but also suggests that erinidine needs to be biotransformed in vivo for its inhibitory activity on intestinal glucose absorption to become evident. Thus, the present study suggests erinidine to be the possible antihyperglycemic agent in Hunteria umbellata seed extract mediating its antihyperglycemic action via intestinal glucose uptake inhibition.


Serum 25-hydroxyvitamin D levels in patients with vulvar cancer.
The anticarcinogenic potential of vitamin D 25(OH)D has been attributed to the inhibition of proliferation of cells from different carcinomas. Reduced serum levels of 25(OH)D are associated with an increased incidence of various types of cancer. The influence of serum 25(OH)D on the incidence and outcome of patients with vulvar cancer is unknown. The serum 25(OH)D levels in 24 patients with vulvar cancer and 24 age-matched cancer-free patients was investigated. The blood samples were collected between October 2009 and September 2010 and time of blood collection of each patient and control was matched to avoid seasonal variations between the pairs. The median 25(OH)D serum levels in the under 50 year old group of patients were significantly lower in the vulvar cancer group than the controls. The younger cancer group also had an age-related trend of lower median serum level than the older population. In the control population the trend was vice versa, yet this finding was not statistically significant. Serum 25(OH)D has a possible role in the pathogenesis and progression of vulvar cancer, but further investigations of the association of vitamin D and vulvar cancer as well as regarding its influence on patient survival and quality of life are warranted in the future.


Phase-stabilization of the carrier-envelope-offset frequency of a SESAM modelocked thin disk laser.
We phase-stabilized the carrier-envelope-offset (CEO) frequency of a SESAM modelocked Yb:CaGdAlO₄ (CALGO) thin disk laser (TDL) generating 90-fs pulses at a center wavelength of 1051.6 nm and a repetition rate of 65 MHz. By launching only 2% of its output power into a photonic crystal fiber, we generated a coherent octave-spanning supercontinuum spectrum. Using a standard f-to-2f interferometer for CEO detection, we measured CEO beats with 33 dB signal-to-noise ratio in 100 kHz resolution bandwidth. We achieved a tight lock of the CEO frequency at 26.18 MHz by active feedback to the pump current. The residual in-loop integrated phase noise is 120 mrad (1 Hz-1 MHz). This is, to our knowledge, the first CEO-stabilized SESAM modelocked TDL. Our results show that a reliable lock of the CEO frequency can be achieved using standard techniques in spite of the strongly spatially multimode pumping scheme of TDLs. This opens the door towards fully-stabilized low-noise frequency combs with hundreds of watts of average power from table-top SESAM modelocked thin disk oscillators.


Hydrogen-Deuterium Exchange Profiles of Polyubiquitin Fibrils.
Ubiquitin and its polymeric forms are conjugated to intracellular proteins to regulate diverse intracellular processes. Intriguingly, polyubiquitin has also been identified as a component of pathological protein aggregates associated with Alzheimer's disease and other neurodegenerative disorders. We recently found that polyubiquitin can form amyloid-like fibrils, and that these fibrillar aggregates can be degraded by macroautophagy. Although the structural properties appear to function in recognition of the fibrils, no structural information on polyubiquitin fibrils has been reported so far. Here, we identify the core of M1-linked diubiquitin fibrils from hydrogen-deuterium exchange experiments using solution nuclear magnetic resonance (NMR) spectroscopy. Intriguingly, intrinsically flexible regions became highly solvent-protected in the fibril structure. These results indicate that polyubiquitin fibrils are formed by inter-molecular interactions between relatively flexible structural components, including the loops and edges of secondary structure elements.


Atrium and artwork appeal to the heart.
The new Bristol Heart Institute (BHI), part of University Hospitals Bristol NHS Foundation Trust (UH Bristol), and one of a number of specialist regional cardiology and cardiac surgery centres built in England over the past decade in line with Department of Health regional cardiac provision strategy, opened to its first patients in May. Lead architect at CODA Architects Craig Bennett told Jonathan Baillie the "excellent spirit of collaboration" throughout the facility's design and construction was a major contributor to its completion on time and on budget.


Effect of different interventions on heart rate variability after heart transplantation: non-autonomic vs autonomic factors.
1. The human transplanted heart is initially denervated, hence any fluctuation present in the RR interval variability can be either due to reacquired innervation, or to the effect of some non autonomic activity, such as a direct effect of respiration on atrial (sinus node) stretch. 2. In order to distinguish between sympathetic, vagal and non autonomic factors we examined the effects of various physical and pharmacologic manoeuvres on the respiratory and non-respiratory components of heart rate variability. 3. We found that sinusoidal neck suction appears a useful, noninvasive tool to characterise the relative importance of the different factors, which can influence heart rate variability in the transplanted heart.


Determination of docosahexaenoic acid and n-3 fatty acids in refined fish oils by 1H-NMR spectroscopy: IUPAC interlaboratory study.
A high-resolution proton nuclear magnetic resonance (NMR) method for determining the concentration (mg/g) of docosahexaenoic acid (DHA), the molar proportion (mol%) of DHA, and the molar proportion of total n-3 fatty acids in fish oils was validated by an IUPAC interlaboratory study (the Commission VI-6 on Oils, Fats, and Derivatives WG 3/98). Thirteen laboratories from 5 countries tested 6 pairs of blind duplicate fish oils: a refined tuna oil, 2 extracted tuna oils, an extracted bonito oil, an extracted salmon oil, and an extracted sardine oil ranging from 9 to 30 mol% DHA and from 20 to 35 mol% n-3 fatty acids. Before 1 D-proton NMR measurements with 300-500 MHz instruments, oil samples were weighed and diluted with deuterochloroform solution containing ethylene glycol dimethyl ether as internal standard. To achieve precise performance, a detailed procedure for signal area measurement was described in the protocol, and all participants were instructed about the critical importance of following the protocol. Statistical performances with invalid and outlier data removed were as follows: repeatability relative standard deviations (RSDr) ranged from 0.91 to 2.62% and reproducibility relative standard deviation (RSDR) ranged from 1.73 to 4.27% for DHA concentration (mg/g); RSDr ranged from 0.39 to 2.06%, and RSDR ranged from 0.59 to 3.46% for mol% DHA; RSDr ranged from 0.23 to 0.90% and RSDR ranged from 0.85 to 2.01 % for mol% total n-3 fatty acids. The method is expected to be recommended by IUPAC.


Influence of interleukin-2 on the differentiation of macrophages.
Macrophage precursor cells, enriched in the light fraction of murine bone marrow, were cultured in vitro under the influence of CSF-1 or IL-2 or both cytokines. In the presence of CSF-1 or CSF-1 and IL-2 strong proliferation occurred, whereas in the presence of only IL-2 or medium, cells did not proliferate. Thus all proliferating cells had CSF-1 receptors and thus belonged to the macrophage lineage. IL-2 induced in these cells the formation of cytoplasmic granules and concomitantly NK-like lytic activity. Under high dosage IL-2 cells further differentiated into cells containing abundant amounts of cytoplasmic granules and exerted LAK type cytotoxicity. When IL-2 was withdrawn from the culture medium, cells could be redirected to develop the properties of typical macrophages when CSF-1 was present. Thus the composition of the cytokines surrounding macrophage precursors decides on their differentiation pathway.


Stability and chaotification of vibration isolation floating raft systems with time-delayed feedback control.
This paper presents a systematic study on the stability of a two-dimensional vibration isolation floating raft system with a time-delayed feedback control. Based on the generalized Sturm criterion, the critical control gain for the delay-independent stability region and critical time delays for the stability switches are derived. The critical conditions can provide a theoretical guidance of chaotification design for line spectra reduction. Numerical simulations verify the correctness of the approach. Bifurcation analyses reveal that chaotification is more likely to occur in unstable region defined by these critical conditions, and the stiffness of the floating raft and mass ratio are the sensitive parameters to reduce critical control gain.


Overview of early response assessment in lymphoma with FDG-PET.
Early assessment of response to chemotherapy with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) is becoming a routine part of management in patients with Hodgkin lymphoma (HL) and histologically aggressive non-Hodgkin lymphoma (NHL). Changes in FDG uptake can occur soon after the initiation of therapy and they precede changes in tumour volume. Recent studies in uniform populations of aggressive lymphomas (predominantly diffuse large B cell lymphomas) and HL have clarified the value of early response assessment with PET. These trials show that PET imaging after 2-3 chemotherapy cycles is far superior to CT-based imaging in predicting progression-free survival and can be at least as reliable as definitive response assessment at the end of therapy. This information is of great potential value to patients, but oncologists should be cautious in the use of early PET response in determining choice of therapy until some critical questions are answered. These include: When is the best time to use PET for response assessment? What is the best methodology, visual or quantitative? (For HL at least, visual reading appears superior to an SUV-based assessment). Can early responders be cured with less intensive therapy? Will survival be better for patients treated more intensively because they have a poor interim metabolic response? In the future, early PET will be crucial in developing response-adapted therapy but without further carefully designed clinical trials, oncologists will remain uncertain how best to use this new information.


NXP-1, a human protein related to Rad21/Scc1/Mcd1, is a component of the nuclear matrix.
Nuclear matrix is a complex intranuclear network supposed to be involved in the various nuclear functions. In order to identify the nuclear matrix proteins, we isolated a cDNA clone from a human placenta cDNA library. This clone was partially represented a known cDNA clone HA1237. HA1237 encoded a 631-amino-acid peptide, which we designated NXP-1. NXP-1 was related to yeast Rad21/Scc1/Mcd1, Xenopus XRAD21, and mouse PW29, and identical with HR21spA isolated from a human testis cDNA library. We developed a polyclonal antibody to the purified NXP-1 bacterially expressed as a fusion protein with GST. Western blot analysis with anti-NXP-1 polyclonal antibody showed nuclear matrix localization of NXP-1 in HeLa cells. Indirect immunofluorescence staining also showed nuclear and nuclear matrix localization of the NXP-1. Results of in vitro binding assays employing nuclear matrix preparations indicated that the N-terminal region (16-128 amino acid) of NXP-1 has an important role in nuclear matrix distribution.