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Background Asthma prevalence is 339 million globally. ‘Severe asthma’ (SA) comprises subjects with uncontrolled asthma despite proper management. Objectives To compare asthma from diverse ethnicities and environments. Methods A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED. Results Among SA subjects, age, weight, proportion of former smokers and FEV1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/μl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV1/FVC pre- and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%. Conclusions ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management.

BackgroundAlthough several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.ObjectiveWe sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.MethodsAn IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS–specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.ResultsActivation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the absence of systemic inflammation. The IL-6TS–high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.ConclusionsLocal lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.

Background The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

Background: Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous samples. Objective: We sought to identify gene profiles associated with adult-onset severe asthma. Methods: This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (

Laparoscopic cholecystectomy is commonly performed, and several factors increase the risk of open conversion, prolonging operating time and hospital stay. Preoperative stratification would improve consent, scheduling and identify appropriate training cases. The aim of this study was to develop a validated risk score for conversion for use in clinical practice.Preoperative patient and disease-related variables were identified from a prospective cholecystectomy database (CholeS) of 8820 patients, divided into main and validation sets. Preoperative predictors of conversion were identified by multivariable binary logistic regression. A risk score was developed and validated using a forward stepwise approach.Some 297 procedures (3.4%) were converted. The risk score was derived from six significant predictors: age (p = 0.005), sex (p 0.001), indication for surgery (p 0.001), ASA (p 0.001), thick-walled gallbladder (p = 0.040) and CBD diameter (p = 0.004). Testing the score on the validation set yielded an AUROC = 0.766 (p 0.001), and a score6 identified patients at high risk of conversion (7.1% vs. 1.2%).This validated risk score allows preoperative identification of patients at six-fold increased risk of conversion to open cholecystectomy.

Emission spectrum of Tm3+ doped tellurite glasses for the 3H4–3F4 transition at 1.46 μm has been measured at room temperature and at 5 K. The glass compositions have a major influence on the spectral change, especially in the longer wavelength part of the emission. The effect of different Tm3+ concentrations on the upper and lower level lifetimes and on the emission spectrum has also been reported for designing a broadband multi-channel S-band TDFA.

Tellurium oxide glass hosts have exceptionally large solubility for RE-ions. In this paper, the relationship between the host glass composition and spectroscopic properties of Er 3+ -doped and Tm 3+ -doped tellurite glasses and fibres has been examined in detail. In particular, the effect of compositional modification on the line-shapes of the transitions: 4 I 13/2 → 4 I 15/2 in Er 3+ -doped and 3 H 4 → 3 F 4 in Tm 3+ -doped tellurite glasses is analysed and discussed. The presence of co-dopants, namely Tb 3+ and Ho 3+ ions in Tm 3+ -doped glasses on the lifetimes of the upper ( 3 H 4 ) and the lower ( 3 F 4 ) levels have also been discussed for shortening the lifetime of the transition between the 3 F 4 level and the ground state in thulium. The spectroscopic properties of Nd 3+ -doped glasses for designing amplifiers operating in the 1330- to 1370-nm region has also been explained for demonstrating a continuous gain spectrum from 1310- to 1610-nm. The fibre loss measurements demonstrate that the Er-doped fibres have less than 880 dB km –1 attenuation in the 1200- to 1400-nm range. An explanation is given to determine the suitability of such RE-doped tellurite fibres for designing broadband amplifiers.

Bare-root seedlings of Eucalyptus nitens frequently exhibit water stress after planting resulting in leaf lamina damage and reduced leaf area. Two trials examined effects of root exposure and desiccation between lifting and transplanting on post-planting water relations, leaf retention and root growth. Plants with roots exposed on a glasshouse bench initially lost water rapidly. In one trial ψ1 declined to around −2.0 MPa within 2.5 h, after which there was no further change with exposure up to 7.5 h. In the second trial, the initial decline in ψ1 was more rapid, reaching below −2.0 MPa in the first hour, before remaining stable with continuing exposure up to 4.5 h. A further decline then continued to −4.0 MPa after 7.5 h.

The objective of this experiment was to determine the effects of controlled heat stress on ovarian function of dairy heifers. Estrus was synchronized in Holstein heifers (estrus = d 0), and heifers then were randomly assigned to either heat stress (n = 10; 33 degrees C, 60% relative humidity) or thermoneutral (n = 11; 21 degrees C, 60% relative humidity) treatment. For heat-stressed heifers, ambient temperature was increased from thermoneutrality to heat stress (33 degrees C) between d 9 and 14 (2.4 degrees C/d increase) after the synchronized estrus and remained between 31 and 33.5 degrees C until d 22. From d 11 to 21, the growth and regression of ovarian follicles and corpora lutea were measured by using ultrasonography, and blood was collected daily for serum progesterone and estradiol analyses. The second wave dominant follicle was larger for the heifers in the thermoneutral environment than for heat-stressed heifers, and ovulation of the second wave dominant follicle occurred in 9 of 11 thermoneutral heifers. For 6 of 10 heat-stressed heifers, the second wave dominant follicle regressed and was replaced by an ovulatory third wave dominant follicle. Smaller follicular size in heat stressed heifers was associated with decreased serum estradiol concentrations between d 11 and 21. Serum concentrations of progesterone during the luteal phase were similar, but luteolysis was delayed in heat-stressed heifers compared with onset in heifers in the thermoneutral treatment. Conclusions were that heat stress inhibited the growth and function of the dominant follicle so that most of the heat-stressed heifers had three follicular waves and a delay in corpus luteum regression.

The objective of this experiment was to determine the effects of controlled heat stress on ovarian function of lactating dairy cows. Estrus was synchronized (estrus = d 0), and cows were randomly assigned to either heat stress (n = 11; 29 degrees C, 60% relative humidity) or thermoneutral (n = 11; 19 degrees C, 60% relative humidity) treatment. For cows undergoing heat stress, ambient temperature (19 degrees C) was increased from d 11 to 13 of the estrous cycle (3.3 degrees C/d increase) and remained at 29 degrees C until d 21. Beginning on d 11, the growth and regression of ovarian follicles and corpora lutea were measured by using ultrasonography. Blood was collected daily by coccygeal venipuncture for measurement of serum concentrations of progesterone and estradiol. The second wave dominant follicle was more likely to ovulate in cows in the thermoneutral treatment than in cows undergoing heat stress (91 vs. 18% ovulation, respectively). Patterns of follicular growth in cows under-going heat stress were associated with decreased serum estradiol from d 11 to 21 and on the day of luteolysis. The average day of luteolysis was delayed by 9 d in heat-stressed cows. Conclusions were that follicular growth and development and luteolytic mechanisms were compromised in heat-stressed cows; as a result, luteolysis was delayed, and second wave dominant follicles did not ovulate.

Field symptoms of transplanting shock in Eucalyptus nitens open rooted (1/2 + 1/2) transplants suggest water stress. To identify stages in the development of symptoms, changes in water relations were monitored from undisturbed seedlings growing in a commercial nursery through lifting, transplanting into pots and re-establishment of normal water relations. Hydraulic resistance measured as leaf specific resistivity increased with each step in the transplanting process. Resistivity after lifting was double that measured on undisturbed plants in the nursery and subsequently doubled with each of the two successive stages, root trimming and planting out. Resistivity fell after the initial rise, returning to the values recorded in the nursery in two stages. An initial rapid decrease, which was not accompanied by any measurable root growth, was followed by a seven day period without a change in resistivity before a further gradual decrease as root volume increased with new root growth. All water relations measurements were taken on trees which had not suffered any permanent leaf damage as a result of transplanting. For a small group of trees which did suffer damage there was a significant relationship between root volume at planting and the retained healthy leaf area. Before shoot growth had recommenced the final ratio of turgid leaf area to initial root volume was comparable with plants immediately after lifting and before trimming. The results are discussed in terms of the changes in predawn leaf water potential, leaf water potential and the leaf damage or defoliation symptoms occuring in plantations.

The accuracy of three models for the interpretation of moisture redistribution experiments with fiber glass slabs is investigated. The initial quasi-steady state of the evaporation-condensation process is well predicted by all three models. The quasi-steady model and the numerical model predict much faster changes in the heat flux and temperature distribution during the final drying-redistribution process. The semi-empirical model which incorporates the ‘falling rate’ evaporation period gives more accurate predictions of the experimental data. This model is used to obtain additional physical information on the moisture redistribution and drying process in the slab.

A method for the incorporation of chlorhexidine into acrylic resin using monomer together with the pattern of release of chlorhexidine from treated resin into water at 37 degrees C is described. Release from polished and unpolished resin, and from acrylic prepared by short-curing and dry-curing processes are investigated. The pattern of release in all cases was of an exponential nature, showing a rapid release within the first 10 days becoming almost constant at a level of 0.4-1.5 micrograms cm-2 at about 20 days. Release was still evident at the end of the test period in all cases. Release of chlorhexidine into water from the short-cure specimens was accompanied by release of monomer, evident from the odour of the test solutions, indicating that polymerization was not complete.

The role of motor innervation in supporting and regulating muscle development was studied using aneural muscles in the hindlimb of the mouse mutant peroneal muscular atrophy (pma). This is a single-locus autosomal mutation where homozygous animals lack the common peroneal nerve, so that muscles in the anterolateral compartment of the lower leg develop entirely without innervation. In adults, these muscles are extremely atrophied, and the mice display a clubfoot deformity. The mutant animals provide a preparation in which aspects of muscle formation can be studied in muscles that have never been exposed to direct contact with somatic motor or sensory axons, without pharmacological or surgical intervention. Using quantitative electron microscopy, we found that normal numbers of primary myotubes formed in aneural pma EDL muscles, but a greater than normal proportion degenerated during the first 2 days after their formation. Secondary myotubes appeared at their normal time and position within the muscle, initially in normal numbers, so that the ratio of secondary to primary myotubes initially was greater in pma than in CF1 control strain mice. No abnormalities in ultrastructure were seen until the time of birth, when retardation in development was obvious, together with invading macrophages and degenerating myofibres. The results show that secondary myotube formation in the mouse, as in the chick (B. J. Fredette and L. T. Landmesser, Dev. Biol. 143, 19-35, 1991) is not directly dependent on innervation. In control muscles, secondary myotubes first form in the vicinity of endplates on primary myotubes. No aggregations of ACh receptors or acetylcholinesterase were present in the aneural muscles, showing that these are neurally induced in the mouse, but secondary myotubes formed in their normal position indicating that positional information related to endplate formation is present in aneural muscles.

A simple method of estimating traces of chlorhexidine in water using bromothymol blue is described. The procedure involves the extraction of the chlorhexidine/bromothymol blue complex into carbon tetrachloride from a buffered neutral solution and measurement of the absorbances of the extracts in a spectrophotometer. The extracted complex has good colour stability, and the method is accurate, reproducible, and very sensitive, with concentrations of chlorhexidine down to 0.05 micrograms ml-1 measurable.

Valproic acid (VPA)-induced hyperammonaemia, with or without clinical or laboratory evidence of hepatoxicity, is well-documented. This study was designed to assess the prevalance of hyperammonaemia in institutionalised patients treated with VPA chronically and to identify contributing factors. Eight-two refractory patients (60 men and 22 women; mean age, 39 years; mean weight, 70.1 kg), were studied. Ten patients were on VPA monotherapy, and 72 were on antiepileptic drug (AED) polytherapy. Fourteen epileptic patients on AED polytherapy excluding VPA (patient controls) and 10 volunteers (healthy controls) were also evaluated. VPA dose ranged between 7.1 and 71.4 mg/kg/day and was associated with VPA plasma concentrations of 114–753 and 77–1,315 μmol/L pre-and postprandially, respectively. A plasma ammonium (NH 4 + ) concentration of 50 μmol/L is considered the upper normal limit in healthy adult subjects. Pre- and postprandial plasma NH 4 + concentrations >50 μmol/L were seen in 20% and 30% of VPA-treated patients, respectively. In contrast, all healthy and patient controls had plasma NH 4 + concentrations 4 + concentration. The highest VPA dose (71.4 mg/kg/day) was associated with the highest (95 μmol/L) plasma NH 4 + concentration. There was a significant correlation ( r = 0.61; p 4 + and VPA concentration postprandially in male patients taking VPA and carbamazepine in combination. It is concluded that, although VPA medication can be associated with elevated plasma NH 4 + concentrations that are not clinically significant in many patients, caution is necessary when prescribing VPA.

A new broad-band amplifier topology that provides a continuous gain across 75 nm (1528-1603 nm) of optical bandwidth using Er/sup 3+/-doped SiO/sub 2/ fiber is demonstrated. The noise figure is low and does not present any discontinuity across the entire amplification bandwidth. The topology has a buried 1550/1585-nm splitter to reduce input signal loss and to provide amplified spontaneous emission suppression. The topology has been optimized using hybrid fiber; Er/sup 3+/-doped SiO/sub 2/ for the first stage and Er/sup 3+/-doped TeO/sub 2/ for the second stage, achieving 82 nm (1526-1618 nm) of optical bandwidth.

We present theoretical and experimental verification of an optimized erbium-doped fiber amplifiers model in the extended band with an emission coefficient derived from a dynamic gain tilt technique. The validity of the method has been verified with two different erbium fibers.

Radiative transfer in absorbing, emitting, linearly anisotropically scattering, inhomogeneous solid spheres with reflecting boundaries is considered. Thynell and Ozisik have reformulated this problem as a set of coupled integral equations and Thynell has solved the homogeneous case using Galerkin's method. A collocation method is proposed by us to solve the coupled integral equations. This procedure may also be used to handle the inhomogeneous case. The results for the homogeneous case with isotropic scattering are compared with exact values by El-Wakil et al. The results for the homogeneous case with anisotropic scattering are compared with those obtained by Thynell. The results for the inhomogeneous case with isotropic scattering are compared with those of El-Wakil et al.

On the basis of an analysis of coupling between single-mode optical fibres, the optimum geometries for 1× N and N × N couplers, which rely on radiative coupling between tapered single-mode fibres, are described. Examples are given of the loss performance, output uniformity and bandwidth to be expected from the proposed devices. The couplers have attractive benefits, particularly at large values of N , when compared with alternative technologies.

The isothermal viscous flow properties of two fluorozirconate glass compositions have been studied by parallel plate rheometry at temperatures approaching the fibre-drawing viscosity region. An unusual flow behaviour has been found, in which sharp end points occur where deformation ceases under load. This behaviour has been characterised in terms of a threshold yield stress with hysteresis effects. The materials are prone to crystallisation, but no obvious direct link has been found between such effects and the flow behaviour, which may thus be intrinsic.

The use of the technique of parallel plate rheometry for providing viscosity data as a function of temperature in the range 105 to 109 poise is described. Results obtained for a standard reference glass are compared with previous data.

We present results on spectral gain changes resulting from small changes of pump wavelength in erbium-doped fiber amplifiers (EDFAs). While conventional-band EDFAs exhibit a significant effect with 980-nm pumping and a smaller effect with 1480 nm, it is absent for extended-band EDFAs operating around 1585 nm.

A new method to determine the Er-fiber gain coefficient is presented using a dynamic gain tilt technique. Results demonstrate that this method is very simple, highly accurate, and especially useful for long-wavelength erbium-doped fiber amplifier.

An improvement in amplifier efficiency resulting from pump wavelength tuning is shown to occur in extended band (L-band) EDFAs. We investigate the effects for different EDFA configurations and for 980 nm and 1480 nm pumping.

Publisher Summary This chapter discusses all the anthropocentric definitions of sustainability and focuses on sustaining an acceptable level of human quality of life (QOL). Within the dominant ideology of free market capitalism, reducing wealth and resource consumption also reduces QOL within a generation. It appears that excessive resource consumption on the part of the current generation threatens dramatic reductions to the QOL of future generations. Continued economic growth substantially increases this threat. Current levels of QOL depends on current consumption levels, as this means ensuring sustainability for fixture generations requires a reduction in QOL for at least some of the people alive today. Above a certain level, greater wealth, and resource consumption are not tightly linked to QOL. Thus, a more fair distribution of resources and wealth within and among generations need not require a sacrifice in QOL for the current generation, increasing the feasibility of policies directed towards this outcome.

The advantages of tellurite glass hosts for Tm-doped S-band gain media are investigated. Comparisons are made with fluoride hosts and the ability to control bandwidth. by choice of tellurite glass composition is demonstrated.

This work reports a substantial optical gain in Tm doped fiber in the region of 1450-1500 nm, with dual wavelength pumps in 980 nm and 1550 nm ranges. Pump sources employedare semiconductor lasers and all passive components in the amplifier are commonly found in EDFAs.

One component of polarization-dependent gain (PDG) in optical amplifiers has been shown to originate from polarization hole burning (PHB) in the erbium fibers.1 In this paper we quantify its magnitude for copumped amplifiers under operating conditions typical of those used in long-haul amplified systems. We find that PDG can be significant, even when the polarization state of the signal is circular, and that hole burning due to the polarization of the 1480-nm pump laser contributes significantly to the overall polarization-dependent gain of the fiber.

Skeletal muscles formed in the absence of innervation are deficient in number of fibers, atrophic, and prone to degeneration. We and others have suggested that primary myotubes form autonomously, and the major effect of embryonic denervation is to halt the formation of secondary myotubes by removing the mitotic stimulus for generation of their precursor myoblasts. This hypothesis has recently been put into question by the results of work by Condon et al. (Dev. Biol., 138, 275-295, 1990) and by B. J. Fredette and L. T. Landmesser (Dev. Biol. 143, 19-35, 1991) who propose that lowered secondary myotube numbers are at least in part due to absence of the primary myotubes which would normally serve as scaffold for their formation. We distinguish between these hypotheses by studying generation and degeneration of primary myotubes and formation of secondary myotubes in fetal rat muscles denervated by injection of beta-bungarotoxin at different times between Embryonic Days (E) 14 and 17. Denervation at any of these times reduced primary myotube numbers on E18 to about 80% of control. Despite this modest decrease in primary myotube numbers, secondary myotube generation fell to below 3% of normal in extensor digitorum longus (EDL) muscles denervated on E14 or E15 and to below 12% of control in soleus muscles denervated on E14-E16. Secondary myotubes were associated with degenerating as well as intact primary myotubes. More secondary myotubes were generated only if nerves had been present up until E16 for EDL or E17 for soleus. We suggest that these observations of a critical period until E16 (EDL) or E17 (soleus) during which innervation is an absolute prerequisite for secondary myotube formation reflect the presence of a nerve-dependent population of myoblasts which must be activated before secondary myotube formation can commence.