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To examine the relationship between the therapeutic effect of intratympanic methylprednisolone perfusion and histone acetylation in refractory sudden sensorineural hearing loss.
Thirty-four refractory sudden sensorineural hearing loss patients were enrolled and treated with intratympanic methylprednisolone perfusion. Pure tone average, acetylated histone H3, acetylated histone H4 and histone deacetylase 2 (HDAC2) were measured in peripheral blood mononuclear cells before and after intratympanic methylprednisolone perfusion. Sixteen healthy volunteers were recruited to obtain normal reference values.
Pure tone average in sudden sensorineural hearing loss patients improved from 84.14 ± 13.54 dB to 73.56 ± 18.45 dB after intratympanic methylprednisolone perfusion. Up-regulations in HDAC2 protein level, and down-regulations in histone H3 and H4 acetylation were observed in the intratympanic methylprednisolone perfusion sensitive group (pure tone average gain of 15 dB or more), while no significant changes were observed in the intratympanic methylprednisolone perfusion insensitive group (pure tone average gain of less than 15 dB).
Intratympanic methylprednisolone perfusion can improve hearing in a considerable number of refractory sudden sensorineural hearing loss patients. The therapeutic effect is closely related to reduced histone acetylation.
Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.
The Chinese white pine beetle Dendroctonus armandi (Coleoptera: Scolytinae) typically displays bivoltinism at altitudes below 1700 m in the Qinling Mountains, China. The periods of host colonization and larval overwintering are two important phases in the life cycle of bark beetles, as it is during these periods that they have to contend with host plant defences and periods of intense cold, respectively. Although during different seasons, the females and males of Chinese white pine beetles show varying tolerances to host plant terpenoids, the sex ratio and survival physiology condition of the two beetle generations are unknown. We investigated the sex ratio of individuals, and also examined the body mass, energy stores, and detoxication enzymes of males and females in each of the two generations in order to determine the overall population stability of each generation. We identified a female-biased sex ratio among adults in both generations. Furthermore, patterns of body mass, energy stores, and detoxication enzymes were found to differ between the two sexes and two seasons. Compared with the males, the females have a larger body mass and higher amounts of stored lipids, which are assumed to be adaptations designed to overcome host resistance and facilitate subsequent oviposition.
Cucumber powdery mildew is a destructive foliar disease caused by Podosphaera xanthii (formerly known as Sphaerotheca fuliginea) that substantially damages the yield and quality of crops. The control of this disease primarily involves the use of chemical pesticides that cause serious environmental problems. Currently, numerous studies have indicated that some plant extracts or products potentially have the ability to act as natural pesticides to control plant diseases. It has been reported that turmeric (Curcuma longa L.) and its extract can be used in agriculture due to their insecticidal and fungicidal properties. However, the most effective fungicidal component of this plant is still unknown. In the current study, the crude extract of C. longa L. was found to have a fungicidal effect against P. xanthii. Afterwards, eight fractions (Fr.1–Fr.8) were gradually separated from the crude extract by column chromatography. Fraction 1 had the highest fungicidal effect against this pathogen among the eight fractions. The active compound, (+)-(S)-ar-turmerone, was separated from Fr 1 by semi-preparative high-performance liquid chromatography and identified based on its 1H nuclear magnetic resonance (NMR) and 13C NMR spectrum data. The EC50 value of (+)-(S)-ar-turmerone was found to be 28.7 µg/ml. The compound also proved to have a curative effect. This is the first study to report that the compound (+)-(S)-ar-turmerone has an effect on controlling this disease. These results provide a basis for developing a new phytochemical fungicide from C. longa L. extract.
In vivo and in vitro trials were conducted to assess the effects of tributyrin (TB) supplementation on short-chain fatty acid (SFCA) concentrations, fibrolytic enzyme activity, nutrient digestibility and methanogenesis in adult sheep. Nine 12-month-old ruminally cannulated Small Tail ewes (initial body weight 55 ± 5.0 kg) without pregnancy were used for the in vitro trial. In vitro substrate made to offer TB at 0, 2, 4, 6 and 8 g/kg on a dry matter (DM) basis was incubated by ruminal microbes for 72 h at 39°C. Forty-five adult Small Tail ewes used for the in vivo trial were randomly assigned to five treatments with nine animals each for an 18-d period according to body weight (55 ± 5.0 kg). Total mixed ration fed to ewes was also used to offer TB at 0, 2, 4, 6 and 8 g/kg on a DM basis. The in vitro trial showed that TB supplementation linearly increased apparent digestibility of DM, crude protein, neutral detergent fibre and acid detergent fibre, and enhanced gas production and methane emissions. The in vivo trial showed that TB supplementation decreased DM intake, but enhanced ruminal fermentation efficiency. Both in vitro and in vivo trials showed that TB supplementation enhanced total SFCA concentrations and carboxymethyl cellulase activity. The results indicate that TB supplementation might exert advantage effects on rumen microbial metabolism, despite having an enhancing effect on methanogenesis.
Multiple human immunodeficiency virus (HIV)-1 genotypes in China were first discovered in Yunnan Province before disseminating throughout the country. As the HIV-1 epidemic continues to expand in Yunnan, genetic characteristics and transmitted drug resistance (TDR) should be further investigated among the recently infected population. Among 2828 HIV-positive samples newly reported in the first quarter of 2014, 347 were identified as recent infections with BED-captured enzyme immunoassay (CEIA). Of them, 291 were successfully genotyped and identified as circulating recombinant form (CRF)08_BC (47.4%), unique recombinant forms (URFs) (18.2%), CRF01_AE (15.8%), CRF07_BC (14.4%), subtype C (2.7%), CRF55_01B (0.7%), subtype B (0.3%) and CRF64_BC (0.3%). CRF08_BC and CRF01_AE were the predominant genotypes among heterosexual and homosexual infections, respectively. CRF08_BC, URFs, CRF01_AE and CRF07_BC expanded with higher prevalence in central and eastern Yunnan. The recent common ancestor of CRF01_AE, CRF07_BC and CRF08_BC dated back to 1983.1, 1992.1 and 1989.5, respectively. The effective population sizes (EPS) for CRF01_AE and CRF07_BC increased exponentially during 1991–1999 and 1994–1999, respectively. The EPS for CRF08_BC underwent two exponential growth phases in 1994–1998 and 2001–2002. Lastly, TDR-associated mutations were identified in 1.8% of individuals. These findings not only enhance our understanding of HIV-1 evolution in Yunnan but also have implications for vaccine design and patient management strategies.
The development of adverse behaviour in group–housed growing/ finishing pigs with intact tails was studied in a straw–flow housing system and in a part–slatted system with a commercial enrichment object. Food intake, body weight and behaviour were monitored over the finishing period, with tail biting outbreaks defined as an occasion where three or more pigs within a group had freshly damaged tails and tail biting behaviour was ongoing. Data from the two systems were analysed to identify tail–biting outbreaks and behavioural changes over time. Levels of pig manipulation were higher in the part–slatted system. Over time, pigs in both systems showed reduced interest in the enrichment provided, but not in each other. Despite the presence of the enrichment device, tail biting occurred in all groups in the part–slatted system, but only 1/12 groups in the straw–flow system. The amount of time occupied by manipulation of the enrichment provided was very significantly higher for straw than for the commercial object. Better design of enrichment strategies is therefore needed and should be based on species–relevant requirements.
The mixing of unfamiliar sows at weaning leads to aggression whilst dominance hierarchies within the group are established (Kay et al, 1999). The objective of this study was to determine whether the presence of a boar would reduce the incidence of aggression and level of skin damage of newly mixed sows. The overall aim of the project was to improve welfare by designing a suitable strategy for mixing groups of newly-weaned sows
UK legislation dictates that all pigs shall have access to straw or other material or object suitable to satisfy their behavioural needs (Welfare of Livestock Regulations, 1994). However, it is unknown how much straw must be provided to be behaviourally rewarding, and whether pigs’ prior experience of straw can impact upon their subsequent behavioural needs. Therefore, the aim of the current experiment was to investigate these issues by exposing pigs which did, or did not, have prior experience of straw to four levels of straw bed depth.
Providing environmental enrichment to farmed animals such as pigs is very important to safeguard their welfare. Current legislation specifies that all pigs must have permanent access to a sufficient quantity of material to enable proper investigation and manipulation activities. Straw has always been regarded as a functional form of enrichment for pigs, but can be difficult to use in slatted housing systems. Alternative enrichment objects might be acceptable substitutes, provided they are designed according to characteristics which pigs find important (Van de Weerd et al., 2003), as pigs may lose interest in simple devices. Most enrichment studies have focussed on immediate effects on behaviour, but it is also important to find out whether there are critical periods where providing enrichment will have effects later in life. The aim of the present study was to investigate whether early life enrichment had an effect on the behavioural development of pigs. To assess this, pigs were tested on an Elevated Plus Maze (EPM) at 10 weeks of age. The EPM is a well-validated anxiety model in rodents, which has more recently been used in pigs. It provides a way to separate fear of novelty (avoidance of open arms) and activity-related elements (entries into closed arms) (Anderson et al., 2000).
Legislation in the United Kingdom states that all pigs should have access to straw or other material or object suitable to satisfy their behavioural needs (Welfare of Livestock Regulations, 1994). However, the use of straw bedding has not been universally adopted as its use is incompatible with housing systems which contain perforated flooring, and 76% of pig producers in the UK currently employ fully- or part-slatted finishing housing systems. The aim of this study was to investigate whether different lengths of chopped straw would achieve enhancements in pig welfare, by exploring the possibility that small quantities of chopped straw, in preference to unchopped straw, could constitute adequate provision in part- and fully-slatted systems, thus avoiding the blockage of perforated flooring.
The general well-being of growing pigs is known to be affected by both the quantity/quality of stockperson input invested and the complexity of their housing environment (Pearce et. al., 1989). However, the nature of the interactions which exist between these two factors is still largely unknown. The aim of this experiment was to investigate the separate and interactive effects of handling and environmental enrichment on the welfare and performance of growing pigs.
By introducing the concept of forming springback anti-coupled systems and considering the influence of the self damping effect, meanwhile establishing higher-order geometrical nonlinear equation of a high strength and low alloy (HSLA) steel plate, then a set of nonlinear dynamic springback governing equations of the plate are obtained. The finite difference method, Newmark method and iterative method are applied to solve the whole problem. Numerical results denote that the boundary conditions, thickness-length ratio of the plate and initial impact velocity of the impactor have great influence on the springback amount of the rectangular HSLA steel plate, besides the natural frequency is affected a lot by the boundary conditions and thickness-length ratio. The effect of higher-order geometrical nonlinearity on the springback amount of the plate can be ignored, considering the first-order geometrical nonlinearity is enough accurate for such similar nonlinear dynamic problems.
In this paper, the dynamical behavior and stability of hanging micropipes conveying fluid with pinned-free boundary conditions are investigated. For a pinned-free rigid micropipe, the dynamical system is found to be stable for various flow velocities. Particular emphasis is placed on the effects of flow velocity, mass ratio and gravity on the dynamics and flutter instability of flexible micropipe system with pinned-free boundary conditions. The governing equations for flexible micropipes are discretized using the differential quadrature method (DQM), yielding a generalized eigenvalue problem which is then solved for various flow velocities, mass ratios and gravity parameters. It is shown that, with increasing flow velocity, the flexible micropipe with pinned-free boundary conditions is stable until it becomes unstable via a Hopf bifurcation leading to flutter. The system may lose stability first in the second or third mode, mainly depending on the selected value of mass ratio. The existence of mode exchange between the second and third modes is possible. The gravity parameter of positive values causes additional restoring force and hence enhances the stability of the micropipe system; however, it can generate the complexity of stability diagrams.
This study aimed to examine the effectiveness of intratympanic methylprednisolone perfusion as salvage treatment for profound idiopathic sudden sensorineural hearing loss.
A retrospective clinical study of 97 patients with unilateral profound idiopathic sudden sensorineural hearing loss was performed. In all, 83 patients who received salvage intratympanic methylprednisolone perfusion plus conventional treatment (except for steroids) as the second-line therapy were assigned to the study group, while 14 patients who received conventional treatment alone were assigned to the comparison group.
In the study group, treatments in patients with a shorter interval from disease onset to intratympanic methylprednisolone perfusion (up to 15 days) had significantly greater improvements in the overall effective rate and pure tone average compared with patients with a longer interval (over 15 days). For patients with a short interval from disease onset to intratympanic methylprednisolone perfusion, those in the study group had significantly greater improvements in the overall effective rate and pure tone average compared with those in the comparison group. In both the study and comparison groups, hearing improvements were greater at low frequencies than at medium and high frequencies.
The interval from disease onset to intratympanic methylprednisolone perfusion was the major factor affecting hearing recovery. Early second-line salvage intratympanic methylprednisolone perfusion significantly improved the degree of hearing recovery in profound idiopathic sudden sensorineural hearing loss patients after failure of systemic steroid treatment.
Rural-to-urban migrant workers are a large marginalised population in urban China. Prevalence estimates of common mental health problems (CMHPs) in previous studies varied widely and very few studies have investigated migration-related factors of CMHPs in migrant workers. The objective of this study was to determine the prevalence and risk factors of CMHPs among Chinese migrant workers.
A random sample of 3031 migrant workers of ten manufacturing factories in Shenzhen, China, completed a standardised questionnaire containing socio-demographic and migration-related variables and the Chinese 12-item General Health Questionnaire (GHQ-12). A GHQ-12 score of three or higher was used to denote the presence of CMHPs.
The prevalence of CMHPs was 34.4% in Chinese migrant workers. In multiple logistic regression, risk factors for CMHPs included being 16–25 years old (odd ratio [OR] 1.65, 95% confidence interval [CI] 1.28, 2.12), being 26–35 years old (OR 1.36, 95% CI: 1.05, 1.75), low monthly income (OR 1.42, 95% CI 1.04, 1.92), poor living condition (OR: 1.76, 95% CI: 1.22, 2.54), physical illness in the past 2 weeks (OR 1.72, 95% CI 1.43, 2.05), having worked in many cities (OR 1.34, 95% CI 1.03, 1.74), infrequently visiting hometown (OR 1.56, 95% CI 1.22, 1.99), poor Mandarin proficiency (OR 1.51, 95%CI 1.13, 2.01), a low level of perceived benefits of migration (OR 1.33, 95% CI 1.14, 1.55) and working more than 8 h/day (OR 1.39, 95% CI 1.14, 1.70).
CMHPs are very prevalent among Chinese migrant workers. Given the large number of Chinese migrant workers, there is an urgent need to address the mental health burden of China's migrant worker population.
Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: Phase 2 and 3 studies of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized. Results: Ataluren nmDMD trials include: a Phase 2a proof-of-concept study (N=38); a Phase 2b randomized controlled trial (RCT) (N=174); an ongoing US-based open-label safety extension study (N=108); an ongoing non-US-based open-label safety/efficacy extension study (N=94); and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail. Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression.
In this paper, transient response analysis of a circular sandwich plate with a functionally graded material (FGM) central disk and two piezoelectric layers is presented. Material properties of the FGM central disk for the circular sandwich plate are assumed to vary through the structural thickness according to a power law and the Poisson’s ratio is assumed as the same constant. Based on the first-order shear deformation theory and geometric nonlinear relationship, the nonlinear motion equations of the circular sandwich plate are formulated by using the Hamilton’s variational principle, then combining with the boundary and initial conditions, the whole problem is solved by adopting the finite difference method, Newmark method and iterative method. Numerical results are presented to illustrate that the volume fraction index, geometric parameters, mechanical and electrical loads have a great influence on transient response of the circular sandwich plate.
Both maternal 25-hydroxyvitamin D (25(OH)D) concentrations during pregnancy and
placental amino acid transporter gene expression have been associated with
development of the offspring in terms of body composition and bone structure.
Several amino acid transporter genes have vitamin D response elements in their
promoters suggesting the possible linkage of these two mechanisms. We aimed to
establish whether maternal 25(OH)D and vitamin D-binding protein (VDBP) levels
relate to expression of placental amino acid transporters. RNA was extracted
from 102 placental samples collected in the Southampton Women's Survey,
and gene expression was analysed using quantitative real-time PCR. Gene
expression data were normalised to the geometric mean of three housekeeping
genes, and related to maternal factors and childhood body composition. Maternal
serum 25(OH)D and VDBP levels were measured by radioimmunoassay. Maternal
25(OH)D and VDBP levels were positively associated with placental expression of
specific genes involved in amino acid transport. Maternal 25(OH)D and VDBP
concentrations were correlated with the expression of specific placental amino
acid transporters, and thus may be involved in the regulation of amino acid
transfer to the fetus. The positive correlation of VDBP levels and placental
transporter expression suggests that delivery of vitamin D to the placenta may
be important. This exploratory study identifies placental amino acid
transporters which may be altered in response to modifiable maternal factors and
provides a basis for further studies.