Journals
2018 UN
Kim H.J. · Zeidi M. · Bonciani D.
+4 more
Summary 皮肌炎患者通常会出现瘙痒,但是发病机理尚不清楚。本研究的作者来自美国、韩国和意大利开展,研究目的是查明皮肌炎患者出现瘙痒有多普遍以及受影响的皮肤中IL‐31细胞因子是否会增加。细胞因子是免疫系统中的细胞产生的蛋白质,细胞因子必须保持微妙平衡才能维持身体健康。而在某些皮肤病(比如异位性湿疹)患者体内,这种平衡被打破,产生了过多的促炎细胞因子(即导致炎症的细胞因子)。本研究调查了191名皮肌炎患者,作者采集了皮肤病变的活检样本,与四个健康对照样本(无皮肌炎之人)进行对比。他们发现半数患者存在中度至重度瘙痒,而瘙痒与疾病严重程度有关。在瘙痒皮肌炎患者的皮肤病变中,IL‐31及其受体的基因表达增加(即释放出更多IL‐31和帮助其发挥作用的受体),患者瘙痒越严重,这种表达越强烈。针对皮肌炎正在研究的一种新药lenabasum能够减少或“下调”IL‐31的表达,因此作者得出结论,该药可能在治疗皮肌炎瘙痒方面具有价值。
Journals
2018 EN
Friedman Ben J. · Sahu Joya · Solomides Charalambos C.
+2 more
Background Syringocystadenoma papilliferum (SCAP) is an uncommon cutaneous adnexal proliferation. There have been several reports describing collision lesions of SCAP and verruca, although little is known about the frequency of this association. Molecular testing has revealed the BRAFV600E mutation in a large proportion of SCAP cases, although its expression pattern has not been previously evaluated. Methods In this retrospective analysis, we explored the potential histopathological association between verruca and SCAP. We also evaluated mutation‐specific BRAFV600E expression in these lesions by immunohistochemistry. Cases of SCAP diagnosed over a 7‐year period were closely reviewed for the presence of contiguous verrucous proliferations. Additional sections were cut and stained using the BRAFV600E‐specific clone VE1 antibody. Results Contiguous verrucous proliferations were identified in 9 out of 12 identified cases. Furthermore, expression of the BRAFV600E mutation was identified in 7 out of 12 cases. Interestingly, in SCAP associated with endophytic verrucous proliferations ( n = 4), expression of BRAFV600E was found in both the glandular and the contiguous hyperplastic squamous epithelium. Conclusion Overall, these findings suggest that contiguous verrucous proliferations in SCAP are common. Both components of the neoplasm may express the BRAFV600E mutation, which is suggestive of a common origin.
Journals
2018 EN
Tiwari Richa · Sahu Indrajit · Soni Bihari Lal
+11 more
Keratin 8/18, the predominant keratin pair of simple epithelia, is often aberrantly expressed in various squamous cell carcinomas ( SCC s) including skin SCC . Its aberrant expression is correlated with increased invasiveness and poor prognosis of the same, although the underlying mechanism is still unclear. A previous report from our laboratory has shown K8‐mediated regulation of α6β4 integrin signaling and thereby tumorigenic potential of oral SCC ‐derived cells. Another study on transgenic mouse model has shown that during skin carcinogenesis, K8 favors conversion of papillomas toward malignancy. In order to understand the role of K8 and allied mechanism in skin SCC , K8 was stably knocked down in a skin epidermoid carcinoma‐derived A431 cells. K8 downregulation significantly reduced the tumorigenic potential of these cells. In agreement with our phenotypic data, differential quantitative proteomics followed by IPA analysis showed altered expression of many proteins associated with biological functions including ‘Cancer’, ‘Cellular movement’, ‘Cell death and survival’, and ‘Cellular morphology’. Some of these proteins were TMS 1, MARCKSL 1, Ran BP 1, 14‐3‐3γ, Rho‐ GDI 2, etc. Furthermore, to our surprise, there was a significant reduction in K17 protein stability upon loss of K8, probably due to its caspase‐mediated degradation. This was supported by altered TMS 1‐ NF ‐κB signaling, leading to increased apoptotic sensitivity of A431 cells which in turn affected ‘Cell death and survival’. Moreover, MARCKSL 1‐Paxillin1‐Rac axis was found to be deregulated bestowing a possible mechanism behind altered ‘Cellular movement’ pathway. Altogether our study unravels a much broader regulatory role of K8, governing multiple signaling pathways and consequently regulating oncogenic potential of skin SCC ‐derived cells. Database Proteome Xchange Consortium via PRIDE database (dataset identifier PXD007206).
Journals
2018 EN
Gurjar Bahadur Singh · Manikanta Sriharsha Tholu · Bhasym Angika
+16 more
Summary We previously reported that Indian paediatric patients with atypical haemolytic–uraemic syndrome ( aHUS ) showed high frequencies of anti‐complement factor H ( FH ) autoantibodies that are correlated with homozygous deletion of the genes for FH ‐related proteins 1 and 3 ( FHR 1 and FHR 3) ( FHR 1/3 –/– ). We now report that Indian paediatric aHUS patients without anti‐ FH autoantibodies also showed modestly higher frequencies of the FHR 1/3 –/– genotype. Further, when we characterized epitope specificities and binding avidities of anti‐ FH autoantibodies in aHUS patients, most anti‐ FH autoantibodies were directed towards the FH cell‐surface anchoring polyanionic binding site‐containing C‐terminal short conservative regions ( SCR s) 17–20 with higher binding avidities than for native FH . FH SCR 17–20‐binding anti‐ FH autoantibodies also bound the other cell‐surface anchoring polyanionic binding site‐containing region FH SCR 5–8, at lower binding avidities. Anti‐ FH autoantibody avidities correlated with antibody titres. These anti‐ FH autoantibody characteristics did not differ between aHUS patients with or without the FHR 1/3 –/– genotype. Our data suggest a complex matrix of interactions between FHR 1 ‐ FHR 3 deletion, immunomodulation and anti‐ FH autoantibodies in the aetiopathogenesis of aHUS .
Journals
2018 EN
Gupta S. · Rout G. · Patel A. H.
+9 more
Summary Novel direct‐acting antivirals ( DAA s) are now the standard of care for the management of hepatitis C virus ( HCV ) infection. Branded DAA s are associated with high sustained virological response at 12 weeks post‐completion of therapy ( SVR 12), but are costly. We aimed to assess the efficacy of generic oral DAA s in a real‐life clinical scenario. Consecutive patients with known HCV infection who were treated with generic‐oral DAA regimens (May 2015 to January 2017) were included. Demographic details, prior therapy and SVR 12 were documented. Four hundred and ninety patients (mean age: 38.9 ± 12.7 years) were treated with generic DAA s in the study time period. Their clinical presentations included chronic hepatitis ( CHC ) in 339 (69.2%) of cases, compensated cirrhosis in 120 (24.48%) cases and decompensated cirrhosis in 31 (6.32%) cases. Genotype 3 was most common (n = 372, 75.9%) followed by genotype 1 (n = 97, 19.8%). Treatment naïve and treatment‐experienced (defined as having previous treatment with peginterferon and ribavirin) were 432 (88.2%) and 58 (11.8%), respectively. Generic DAA treatment regimens included sofosbuvir in combination with ribavirin (n = 175), daclatasvir alone (n = 149), ribavirin and peginterferon (n = 80), ledipasvir alone (n = 43), daclatasvir and ribavirin (n = 37), and ledipasvir and ribavirin (n = 6). Overall SVR 12 was 95.9% (470/490) for all treatment regimens. SVR 12 for treatment naïve and experienced patients was 97.0% (419/432) and 87.9% (51/58), respectively, P = .005. High SVR 12 was observed with various regimens, irrespective of genotype and underlying liver disease status. There were no differences in SVR 12 with 12 or 24 weeks therapy. No major adverse event occurred requiring treatment stoppage. Generic oral DAA s are associated with high SVR rates in patients with HCV infection in a real‐life clinical scenario.
Journals
2018 EN
Liang Yuhu · Dong Xiao · Ni Xuemei
+6 more
Genotyping by sequencing ( GBS ) has been applied to identify genetic markers in crops for trait association and breeding purposes. Here, we applied GBS technology to study a natural population of 270 Indica rice strains, which resulted in identification of 79,545 genomewide single nucleotide polymorphisms. Using these SNP s, we found the close relationship between the 270 Indica rice strains. Furthermore, we tested the feasibility of using these 270 Indica strains in studying important rice traits by analysing the cadmium and other metal accumulation of these strains and correlating the traits with genetic markers. We identified 32 SNP s to be associated with cadmium (Cd) accumulation, explaining 61.25% of the Cd concentration variances in grains. The genetic markers provided here are valuable resources for future rice studies, and further characterization of the candidate loci identified in this study can also aid the development of low Cd‐accumulating rice varieties.
Journals
2018 EN
Zheng Ping · Wu JianXin · Sahu Sunil Kumar
+5 more
Sphingolipids, a class of bioactive lipids found in cell membranes, can modulate the biophysical properties of the membranes and play a critical role in signal transduction. Sphingolipids are involved in autophagy in humans and yeast, but their role in autophagy in plants is not well understood. In this study, we reported that the AtACER , an alkaline ceramidase that hydrolyses ceramide to long‐chain base (LCB), functions in autophagy process in Arabidopsis. Our empirical data showed that the loss of AtACER inhibited autophagy, and its overexpression promoted autophagy under nutrient, salinity, and oxidative stresses. Interestingly, nitrogen deprivation significantly affected the sphingolipid's profile in Arabidopsis thaliana , especially the LCBs. Furthermore, the exogenous application of LCBs also induced autophagy. Our findings revealed a novel function of AtACER , where it was found to involve in the autophagy process, thus, playing a crucial role in the maintenance of a dynamic loop between sphingolipids and autophagy for cellular homeostasis under various environmental stresses.
Journals
2018 EN
Mukhopadhyay Sabyasachi · Sahu Sujit K.
Summary Estimation of long‐term exposure to air pollution levels over a large spatial domain, such as the mainland UK, entails a challenging modelling task since exposure data are often only observed by a network of sparse monitoring sites with variable amounts of missing data. The paper develops and compares several flexible non‐stationary hierarchical Bayesian models for the four most harmful air pollutants, nitrogen dioxide and ozone, and PM 10 and PM 2.5 particulate matter, in England and Wales during the 5‐year period 2007–2011. The models make use of observed data from the UK's automatic urban and rural network as well as output of an atmospheric air quality dispersion model developed recently especially for the UK. Land use information, incorporated as a predictor in the model, further enhances the accuracy of the model. Using daily data for all four pollutants over the 5‐year period we obtain empirically verified maps which are the most accurate among the competition. Monte Carlo integration methods for spatial aggregation are developed and these enable us to obtain predictions, and their uncertainties, at the level of a given administrative geography. These estimates for local authority areas can readily be used for many purposes such as modelling of aggregated health outcome data and are made publicly available alongside this paper.
Royal Statistical Society
Journals
2018 EN
Yoo JeungKi · Sun DanDan · Parker Rosemary S.
+7 more
New FindingsWhat is the central question of this study? The venoarteriolar response (VAR) contributes substantially to the maintenance of orthostatic tolerance in humans. Despite its importance in haemodynamic homeostasis, the impact of ageing on the VAR remains understudied.What is the main finding and its importance? Older adults exhibit an augmented VAR in response to leg dependency. The age‐related augmentation of the VAR might be linked with progressive increases of peripheral vascular resistance with ageing. We found a modest but significant correlation between the leg VAR and the morning blood pressure surge in older adults. Augmented leg VAR might contribute to the blood pressure elevation in the early morning.Abstract The venoarteriolar response (VAR) is a non‐adrenergic, non‐baroreflex‐mediated mechanism of vasoconstriction, which has been proposed to contribute ∼45% of the increase in total peripheral resistance during orthostasis. Despite its importance in human cardiovascular control during orthostatic stress, there is no information available regarding the impact of age and sex on the VAR or its role in diurnal blood pressure (BP) variation. We studied 33 (15 women) young (mean ± SD; 28 ± 4 years old) and 26 (12 women) older (71 ± 3 years old) healthy individuals. Brachial and femoral blood flow were measured using Doppler ultrasound. The percentage reduction in vascular conductance (blood flow/mean BP) during 4 min of limb dependency (35–40 cm below the heart level) was used to assess the VAR. The morning surge in BP was assessed using 24 h ambulatory BP monitoring. Peak VAR in the lower limb, but not in the upper limb, was significantly higher in the older than the younger adults (33 ± 4 versus 26 ± 6%, older versus young; P < 0.05). There was no sex difference in the VAR in either the young or the older group. A greater leg VAR was related to a greater morning surge in BP in older adults ( r = −0.4, P = 0.02) but not in the young adults ( r = −0.26, P = 0.1). Thus, advancing age enhances the VAR in the lower limb and is associated with the morning blood pressure surge in older adults. Sex does not affect this local axonal reflex in healthy humans.
Journals
2018 EN
Petersen Lonnie G. · Lawley Justin S. · LiljaCyron Alexander
+9 more
Key points During long‐term missions, some astronauts experience structural and functional changes of the eyes and brain which resemble signs/symptoms experienced by patients with intracranial hypertension. Weightlessness prevents the normal cerebral volume and pressure ‘unloading’ associated with upright postures on Earth, which may be part of the cerebral and ocular pathophysiology. By placing the lower body in a negative pressure device (LBNP) that pulls fluid away from cranial compartments, we simulated effects of gravity and significantly lowered pressure within the brain parenchyma and ventricle compartments. Application of incremental LBNP demonstrated a non‐linear dose–response curve, suggesting 20 mmHg LBNP as the optimal level for reducing pressure in the brain without impairing cerebral perfusion pressure. This non‐invasive method of reducing pressure in the brain holds potential as a countermeasure in space as well as having treatment potential for patients on Earth with traumatic brain injury or other pathology leading to intracranial hypertension.Abstract Patients with elevated intracranial pressure (ICP) exhibit neuro‐ocular symptoms including headache, papilloedema and loss of vision. Some of these symptoms are also present in astronauts during and after prolonged space‐flight where lack of gravitational stress prevents daily lowering of ICP associated with upright posture. Lower body negative pressure (LBNP) simulates the effects of gravity by displacing fluid caudally and we hypothesized that LBNP would lower ICP without compromising cerebral perfusion. Ten cerebrally intact volunteers were included: six ambulatory neurosurgical patients with parenchymal ICP‐sensors and four former cancer patients with Ommaya‐reservoirs to the frontal horn of a lateral ventricle. We applied LBNP while recording ICP and blood pressure while supine, and during simulated intracranial hypertension by 15° head‐down tilt. LBNP from 0 to 50 mmHg at increments of 10 mmHg lowered ICP in a non‐linear dose‐dependent fashion; when supine ( n = 10), ICP was decreased from 15 ± 2 mmHg to 14 ± 4, 12 ± 5, 11 ± 4, 10 ± 3 and 9 ± 4 mmHg, respectively ( P < 0.0001). Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure at midbrain level minus ICP, was unchanged (from 70 ± 12 mmHg to 67 ± 9, 69 ± 10, 70 ± 12, 72 ± 13 and 74 ± 15 mmHg; P = 0.02). A 15° head‐down tilt ( n = 6) increased ICP to 26 ± 4 mmHg, while application of LBNP lowered ICP (to 21 ± 4, 20 ± 4, 18 ± 4, 17 ± 4 and 17 ± 4 mmHg; P < 0.0001) and increased CPP ( P < 0.01). An LBNP of 20 mmHg may be the optimal level to lower ICP without impairing CPP to counteract spaceflight‐associated neuro‐ocular syndrome in astronauts. Furthermore, LBNP holds clinical potential as a safe, non‐invasive method for lowering ICP and improving CPP for patients with pathologically elevated ICP on Earth.