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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.
Glyphodes pyloalis Walker (Lepidoptera: Pyralididae) is a common pest in sericulture and has developed resistance to different insecticides. However, the mechanisms involved in insecticide resistance of G. pyloalis are poorly understood. Here, we present the first whole-transcriptome analysis of differential expression genes in insecticide-resistant and susceptible G. pyloalis. Clustering and enrichment analysis of DEGs revealed several biological pathways and enriched Gene Ontology terms were related to detoxification or insecticide resistance. Genes involved in insecticide metabolic processes, including cytochrome P450, glutathione S-transferases and carboxylesterase, were identified in the larval midgut of G. pyloalis. Among them, CYP324A19, CYP304F17, CYP6AW1, CYP6AB10, GSTs5, and AChE-like were significantly increased after propoxur treatment, while CYP324A19, CCE001c, and AChE-like were significantly induced by phoxim, suggesting that these genes were involved in insecticide metabolism. Furthermore, the sequence variation analysis identified 21 single nucleotide polymorphisms within CYP9A20, CYP6AB47, and CYP6AW1. Our findings reveal many candidate genes related to insecticide resistance of G. pyloalis. These results provide novel insights into insecticide resistance and facilitate the development of insecticides with greater specificity to G. pyloalis.
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.
Respiratory syncytial virus infection is the most frequent cause of acute lower respiratory tract disease in infants. A few reports have suggested that pulmonary hypertension is associated with increased severity of respiratory syncytial virus infection. We sought to determine the association between the pulmonary hypertension detected by echocardiography during respiratory syncytial virus bronchiolitis and clinical outcomes.
We retrospectively reviewed 154 children admitted with respiratory syncytial virus bronchiolitis who had an echocardiography performed during the admission. The association between pulmonary hypertension and clinical outcomes including mortality, intensive care unit (ICU) admission, prolonged ICU stay (>10 days), tracheal intubation, and need of high frequency oscillator ventilation was evaluated.
Echocardiography detected pulmonary hypertension in 29 patients (18.7%). Pulmonary hypertension was observed more frequently in patients with congenital heart disease (CHD) (n = 11/33, 33%), chronic lung disease of infancy (n = 12/25, 48%), prematurity (<37 weeks gestational age, n = 17/59, 29%), and Down syndrome (n = 4/10, 40%). The presence of pulmonary hypertension was associated with morbidity (p < 0.001) and mortality (p = 0.02). However, in patients without these risk factors (n = 68), pulmonary hypertension was detected in five patients who presented with shock or poor perfusion. Chronic lung disease was associated with pulmonary hypertension (OR = 5.9, 95% CI 2.2–16.3, p = 0.0005). Multivariate logistic analysis demonstrated that pulmonary hypertension is associated with ICU admission (OR = 6.4, 95% CI 2.2–18.8, p = 0.0007), intubation (OR = 4.7, 95% CI 1.8–12.3, p = 0.002), high frequency oscillator ventilation (OR = 8.4, 95% CI 2.95–23.98, p < 0.0001), and prolonged ICU stay (OR = 4.9, 95% CI 2.0–11.7, p = 0.0004).
Pulmonary hypertension detected by echocardiography during respiratory syncytial virus infection was associated with increased morbidity and mortality. Chronic lung disease was associated with pulmonary hypertension detected during respiratory syncytial virus bronchiolitis. Routine echocardiography is not warranted for previously healthy, haemodynamically stable patients with respiratory syncytial virus bronchiolitis.
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 aims of this study were to investigate risk factors for the development of postoperative chylothorax following paediatric congenital heart surgery and to investigate the impact of a management guideline on management strategies and patient outcome.
All patients with chylothorax following cardiac surgery at the Royal Children’s Hospital, Melbourne, over a 48-month period beginning in January 2008 were identified. A control group, matched for age, date of surgery, and sex, was identified. To investigate potential risk factors, univariable and multivariable logistic regression models were constructed with paired analysis. To examine the effect of a standardised management protocol, data before and after the implementation of the guideline were compared.
In total, 121 cases of chylothorax were identified, with 121 controls, matched for age at surgery, date of surgery, and sex. The incidence of chylothorax was 5.23%. Increasing surgical complexity (univariable OR 0.17 for the least complex versus the most complex group, p=0.02), closed-heart surgeries (OR 0.07 for open versus closed, p<0.001), and redo chest incisions (OR 10.0 for redo versus virgin, p<0.001) were significantly associated with chylothorax. The standardised management protocol had no significant impact on either drainage duration or management strategy.
We have replicated the previously reported association between surgical complexity and chylothorax risk, and have shown, for the first time, that redo chest openings are also associated with a significantly increased risk. The implementation of a standardised management protocol in our institution did not result in a significant change in either chylothorax drainage duration or management strategy.
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.
Various environmental factors have been associated with the timing of eruption of primary dentition, but the evidence to date comes from small studies with limited information on potential risk factors. We aimed to investigate associations between tooth emergence patterns and pre-conception, pregnancy and postnatal influences. Dentition patterns were recorded at ages 1 and 2 years in 2915 children born to women in the Southampton Women’s Survey from whom information had been collected on maternal factors before conception and during pregnancy. In mutually adjusted regression models we found that: children were more dentally advanced at ages 1 and 2 years if their mothers had smoked during pregnancy or they were longer at birth; mothers of children whose dental development was advanced at age 2 years tended to have poorer socioeconomic circumstances, and to have reported a slower walking speed pre-pregnancy; and children of mothers of Asian ethnicity had later tooth development than those of white mothers. The findings add to the evidence of environmental impacts on the timing of the eruption of primary dentition in indicating that maternal smoking during pregnancy, socio-economic status and physical activity (assessed by reported walking speed) may influence the child’s primary dentition. Early life factors, including size at birth are also associated with dentition patterns, as is maternal ethnicity.