Our recent report showed that curcumin, polyphenolic compound isolated from the herb Curcuma longa, upregulated the gene expression of human GD3 synthase (hST8Sia I) responsible for ganglioside GD3 synthesis with autophagy induction in human lung adenocarcinoma A549 cells. In this study, on the contrary to this finding, we demonstrated that curcumin downregulated the gene expression of human GM3 synthase (hST3Gal V) catalyzing ganglioside GM3 synthesis with autophagy induction in human colon carcinoma HCT116 cells. To clarify the mechanism leading to the downregulation of hST3Gal V gene expression in curcumin-treated HCT116 cells, we analyzed the curcumin-inducible promoter of the hST3Gal V gene by luciferase reporter assays. Promoter deletion analysis demonstrated that the -177 to -83 region, which includes putative binding sites for transcription factors NFY, CREB/ATF, SP1, EGR3, and MZF1, acts as the curcumin-responsive promoter of the hST3Gal V gene. Site-directed mutagenesis and chromatin immunoprecipitation analysis demonstrated that the CREB/ATF binding site at -143 is pivotal for curcumin-induced downregulation of hST3Gal V gene in HCT116 cells. The transcriptional activation of hST3Gal V in HCT116 cells was significantly repressed by an inhibitor of AMP-activated protein kinase (AMPK). These results suggest that AMPK signal pathway mediates hST3Gal V gene expression in HCT116 cells.
https://ift.tt/2QxLzSN
Σάββατο 10 Νοεμβρίου 2018
Curcumin Downregulates Human GM3 Synthase (hST3Gal V) Gene Expression with Autophagy Induction in Human Colon Carcinoma HCT116 Cells
Effect of Osteopathic Visceral Manipulation on Pain, Cervical Range of Motion, and Upper Trapezius Muscle Activity in Patients with Chronic Nonspecific Neck Pain and Functional Dyspepsia: A Randomized, Double-Blind, Placebo-Controlled Pilot Study
Previous studies have reported that visceral disturbances can lead to increased musculoskeletal tension and pain in structures innervated from the corresponding spinal level through viscerosomatic reflexes. We designed a pilot randomised placebo-controlled study using placebo visceral manipulation as the control to evaluate the effect of osteopathic visceral manipulation (OVM) of the stomach and liver on pain, cervical mobility, and electromyographic activity of the upper trapezius (UT) muscle in individuals with nonspecific neck pain (NS-NP) and functional dyspepsia. Twenty-eight NS-NP patients were randomly assigned into two groups: treated with OVM (OVMG; n = 14) and treated with placebo visceral manipulation (PVMG; n = 14). The effects were evaluated immediately and 7 days after treatment through pain, cervical range, and electromyographic activity of the UT muscle. Significant effects were confirmed immediately after treatment (OVMG and PVMG) for numeric rating scale scores (p 0.05). This study demonstrated that a single visceral mobilisation session for the stomach and liver reduces cervical pain and increases the amplitude of the EMG signal of the UT muscle immediately and 7 days after treatment in patients with nonspecific neck pain and functional dyspepsia.
https://ift.tt/2PpZ8rf
Three-Dimensional Morphological Characteristics of Lower Lumbar Intervertebral Foramen with Age
Intervertebral foramen is the doorway of nerve root and it plays an important role of radiculopathy and surgical treatment of intervertebral foramen diseases. The purpose of the study is to obtain three-dimensional (3D) morphological characteristics of lumbar intervertebral foramen and their relationship with age. Pedicle-superior articular process (P-SAP), disc height between adjacent vertebra (DH), pedicle-inferior vertebrae (P-IV), inferior posterior vertebrae-superior articular process (IPV-SAP), and bony boundary area (BBA) were measured in entrance, middle slice, and exit of lumbar intervertebral foramen for 25 males of different age groups. Spinous process to intervertebral foramen entrance (SP-IFE) was measured for 25 males of different age groups. Overall, P-SAP and P-IV decreased and IPV-SAP increased from the entrance to the exit of intervertebral foramen for L3/4-L5S1. DH decreased at entrance slice, middle slice, and exit slice for L3/4-L5S1 with age. Significant difference with aging was found only at the middle slice of L3/4 and L4/5 for P-SAP. And the significant decrease of IPV-SAP was observed at middle slice of L3/4, entrance slice of L4/5 and L5S1, and exit slice of L5S1. SP-IFE is not consistent for all subjects. In addition, the decrease of BBA at L3/4 and L4/5 was observed earlier than at L5S1. The present study described detailed information of intervertebral foramen, which may be of benefit for better understanding of the pathology and surgical planning for intervertebral foramen diseases.
https://ift.tt/2zKDtiN
Association between physical activity and sub-types of cardiovascular disease death causes in a general population cohort
Abstract
Physical activity is thought to be cardioprotective, but associations with different subtypes of cardiovascular disease (CVD) are poorly understood. We examined associations between physical activity and seven major CVD death causes. The sample comprised 65,093 adults (aged 58 ± 12 years, 45.4% men) followed up over mean [SD] 9.4 ± 4.5 years, recruited from The Health Survey for England and the Scottish Health Surveys. A CVD diagnosis was reported in 9.2% of the sample at baseline. Physical activity was self-reported. Outcomes were subtypes of CVD death; acute myocardial infarction; chronic ischaemic heart disease; pulmonary heart disease; a composite of cardiac arrest, arrhythmias, and sudden cardiac death; heart failure; cerebrovascular; composite of aortic aneurysm and other peripheral vascular diseases. There were 3050 CVD deaths (30.8% of all deaths). In Cox proportional hazards models adjusted for confounders, physical activity was associated with reduced relative risk of all CVD outcomes; compared with the lowest, the highest physical activity quintile was associated with reduced risk of acute myocardial infarction (Hazard ratio 0.66: 95% CI 0.50, 0.89), chronic ischaemic heart disease (0.49: 0.38, 0.64), pulmonary heart disease (0.48: 0.22, 1.07), arrhythmias (0.18: 0.04, 0.76); heart failure (0.35: 0.20, 0.63), cerebrovascular events (0.53: 0.38, 0.75); aneurysm and peripheral vascular diseases (0.54: 0.34, 0.93). Results were largely consistent across participants with and without existing CVD at baseline. Physical activity was associated with reduced risk of seven major CVD death causes. Protective benefits were apparent even at levels of activity below the current recommendations.
https://ift.tt/2AWZr3B
The VAD Scheme versus Thalidomide plus VAD for Reduction of Vascular Endothelial Growth Factor in Multiple Myeloma: A Meta-Analysis
The VAD (vincristine-doxorubicin-dexamethasone) regimen has been used for decades to treat multiple myeloma (MM). Based on reports that vascular endothelial growth factor- (VEGF-) mediated angiogenesis is critical for MM pathogenesis, the antiangiogenic compound thalidomide has been added to VAD (T-VAD). However, it remains unclear whether T-VAD is more efficacious than VAD for serum VEGF reduction or if the difference influences clinical outcome. Pubmed, Cochrane library, China Biomedical Literature (CBM) database, China National Knowledge Infrastructure (CNKI) database, Vip database, and Wanfang database were searched for relevant studies published up to June 2017. RevMan5.2 was used for methodological quality evaluation and data extraction. Thirteen trials (five randomized, seven nonrandomized, and one historically controlled) involving 815 cases were included. Serum VEGF was significantly higher in MM cases than non-MM controls (MD=353.01, [95%CI 187.52–518.51], P
https://ift.tt/2zK4S4b
The Expression of lncRNA NEAT1 in Human Tuberculosis and Its Antituberculosis Effect
Increasing evidence suggests that lncRNA is important in innate immune responses. Recent study has demonstrated that lncRNA NEAT1 (which has two subtypes: NEAT1_1 and NEAT1_2) nuclear-enriched abundant transcript 1 (NEAT1) is essential in immune regulation, but the expression and clinical significance in tuberculosis are still unclear. In this work, we aimed to discuss the expression and clinical significance of NEAT1 in tuberculosis patients. Quantitative real-time polymerase chain reaction was performed to detect the expression of NEAT1 (both NEAT1_1 and NEAT1_2) in peripheral blood mononuclear cells (PBMCs) of patients with tuberculosis and healthy controls and analyze the association of NEAT1 with the development, progression, and outcome of tuberculosis. Then NEAT1 was silenced in THP-1 cells using siRNA. The expression of tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6 was detected after Mycobacterium tuberculosis (Mtb) infection, and the change in bactericidal capacity against Mtb was assessed. We demonstrated that the relative expression of NEAT1 (both NEAT1_1 and NEAT1_2) in patients with tuberculosis was higher than that in the control. However, the expression of NEAT1 (both NEAT1_1 and NEAT1_2) in the new case and relapse groups had insignificant differences. The level of NEAT1 (both NEAT1_1 and NEAT1_2) in PBMCs declined gradually with treatment and was restored to the normal level. The expression of NEAT1 (both NEAT1_1 and NEAT1_2) in THP-1 cells increased markedly after Mtb infection. The levels of IL-6 but not TNF-α in Mtb-infected THP-1 cells declined after the NEAT1 (both NEAT1_1 and NEAT1_2) knockout. The survival of Mtb in NEAT1-knockout (both NEAT1_1 and NEAT1_2) THP-1 cells reached its peak 72 h after infection, taking 0 h after Mtb infection as the baseline data; the difference was statistically significant compared with the control. Thus, our results indicate that the expression of NEAT1 increased during Mtb infection, and it might be associated with the outcome of tuberculosis. The decreased expression of NEAT1 might weaken the clearance of intracellular Mtb by macrophages.
https://ift.tt/2T31NFh
Digital versus Traditional Workflow for Posterior Maxillary Rehabilitations Supported by One Straight and One Tilted Implant: A 3-Year Prospective Comparative Study
Objectives. The aim of the study was to evaluate and compare digital and traditional prosthetic workflow for posterior maxillary restorations supported by an upright and a distally tilted implant at 3-year follow-up. Materials and Methods. Twenty-four patients were treated in the posterior maxilla with 24 immediately loaded axial and 24 distally tilted implants supporting 3-unit or 4-unit screw-retained prostheses. Three months after initial loading patients were randomly stratified into two groups: definitive traditional impressions were carried out in the control group, while digital impressions were performed in the test group. The framework-implant connection accuracy was evaluated by means intraoral digital radiographs at 3, 6, 12, and 36 months of follow-up examinations. Outcome considerations comprised implant and prosthetic survival and success rates, marginal bone level changes, and required clinical time to take impressions. Results. A total of 24 patients received immediately loaded screw-retained prostheses supported by an upright and a distally tilted implant (total 48 implants). No implant dropouts occurred, showing an overall survival rate of 100% for both groups. None of the 24 fixed prostheses were lost during the observation period (prosthetic survival rate of 100%). No statistically significant differences in marginal bone loss were found between control and test groups. The digital impression procedure required on average less clinical time than the conventional procedure. Conclusions. Clinical and radiologic results suggest that digital impression is a predictable procedure for posterior maxillary restorations supported by an upright and a distally tilted implant.
https://ift.tt/2T3D3wI
Can environment or allergy explain international variation in prevalence of wheeze in childhood?
Abstract
Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8–12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother's smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence.
https://ift.tt/2JYdsBe
Fluorescence In Situ Hybridization, a complementary molecular tool for the clinical diagnosis of infectious diseases by intracellular and fastidious bacteria
https://ift.tt/2FfZEDo
Bacterial diversity in the marine sponge Halichondria panicea from Icelandic waters and host-specificity of its dominant symbiont “Candidatus Halichondribacter symbioticus”
https://ift.tt/2T0TjOV
A rapid and non-pathogenic assay for association of Mycobacterium tuberculosis gyrBA mutations and fluoroquinolone resistance using recombinant Mycobacterium smegmatis
https://ift.tt/2JSO9Ag
Bone Marrow Molecular Markers Associated with Relapsed/Refractory Activated B-Cell-Like Diffuse Large B-Cell Lymphoma
Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a common subtype of non-Hodgkin's lymphoma and is very likely to infiltrate the bone marrow. Over 30% of patients are converted to relapsed/refractory DLBCL after first-line rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, with a poor prognosis. Our aim was to identify molecular markers that might be utilized to predict relapsed/refractory ABC-DLBCL patients. Hence, we collected bone marrow aspirate smears from 202 patients with ABC-DLBCL and detected expression of bone marrow molecular marker proteins by immunocytochemistry. Signal transducer and activator of transcription (Stat)3, nuclear factor (NF)-κB p65, Syk, Bruton's tyrosine kinase (BTK), and Bcl2 proteins were strongly expressed in bone marrow aspirate smears of ABC-DLBCL patients. The same smear could present positive expression of multiple proteins simultaneously. Positive combinations of protein expression were associated with resistance. The most significant finding was that the Stat3+NF-κB+ group developed resistance, which was significantly higher than that of the NF-κgroup (80 vs. 14%). There was a significant difference in two-year relapse-free survival between protein-positive and protein-negative combinations of Stat3-NF-κB (P = 0.005), Bcl2-Stat3 (P = 0.009), Bcl2-Pax5 (P = 0.003), and BTK-Syk (P
https://ift.tt/2Df6sOX
Hard Tissue Preservation in Minimally Invasive Mandibular Third Molar Surgery Using In Situ Hardening TCP Bone Filler
Background. Maintenance of hard tissue in the case of impacted third molars (M3M) with close relationship to the mandibular canal is still a surgical challenge which may be overcome using the inward fragmentation technique. Methods. A consecutive case series of 12 patients required the extraction of 13 impacted M3M with a close relationship to the inferior alveolar nerve (IAN). Via occlusal miniflaps, M3M were exposed occlusal under endoscopic vision and removed by inward fragmentation. All patients received socket preservation with resorbable in situ hardening TCP particles to reduce the risk of pocket formation at the second molar. Results. All 13 sites healed uneventfully. Bone height was assessed using CBCT cross-sectional reformats pre- and 3 months postoperatively. The bone height was reduced by 1.54 mm lingual (SD 0.88), 2.91 mm central (SD 0.93), and 2.08 mm buccal (SD 1.09). Differences were significant at a 0.05% level. No tissue invagination at the extraction sites was observed. Conclusions. Major bone defects can be avoided safely using inward fragmentation surgery. The self-hardening bone filler appears to enhance the mineralization of the intrabony defect.
https://ift.tt/2PTz8ns
Neutrophil Lymphocyte Ratio and Cardiovascular Disease Risk: A Systematic Review and Meta-Analysis
Objective. This systematic review aimed to measure the association between neutrophil lymphocyte ratio (NLR) and cardiovascular disease (CVD) risk. Methods. Relevant studies were identified from Medline and Scopus databases. Observational studies with NLR as a study factor were eligible for review. The outcomes of interest were any type of CVD including acute coronary syndrome, coronary artery disease, stroke, or a composite of these cardiovascular events. Mean differences in NLR between CVD and non-CVD patients were pooled using unstandardized mean difference (USMD). Odds ratios of CVD between high and low NLR groups were pooled using a random effects model. Results. Thirty-eight studies (n=76,002) were included. High NLR was significantly associated with the risks of CAD, ACS, stroke, and composite cardiovascular events with pooled ORs of 1.62 (95% CI: 1.38-1.91), 1.64 (95% CI: 1.30, 2.05), 2.36 (95% CI: 1.44, 2.89), and 3.86 (95% CI: 1.73, 8.64), respectively. In addition, mean NLRs in CAD, ACS, and stroke patients were significantly higher than in control groups. Conclusion. High NLR was associated with CAD, ACS, stroke, and composite cardiovascular events. Therefore, NLR may be a useful CVD biomarker.
https://ift.tt/2Df6lD1
Intelligence Algorithms for Protein Classification by Mass Spectrometry
Mass spectrometry (MS) is an important technique in protein research. Effective classification methods by MS data could contribute to early and less-invasive diagnosis and also facilitate developments in the bioinformatics field. As MS data is featured by high dimension, appropriate methods which can effectively deal with the large amount of MS data have been widely studied. In this paper, the applications of methods based on intelligence algorithms have been investigated. Firstly, classification and biomarker analysis methods using typical machine learning approaches have been discussed. Then those are followed by the Ensemble strategy algorithms. Clearly, simple and basic machine learning algorithms hardly addressed the various needs of protein MS classification. Preprocessing algorithms have been also studied, as these methods are useful for feature selection or feature extraction to improve classification performance. Protein MS data growing with data volume becomes complicated and large; improvements in classification methods in terms of classifier selection and combinations of different algorithms and preprocessing algorithms are more emphasized in further work.
https://ift.tt/2PT5hLL
A Study of Machine-Learning Classifiers for Hypertension Based on Radial Pulse Wave
Objective. In this study, machine learning was utilized to classify and predict pulse wave of hypertensive group and healthy group and assess the risk of hypertension by observing the dynamic change of the pulse wave and provide an objective reference for clinical application of pulse diagnosis in traditional Chinese medicine (TCM). Method. The basic information from 450 hypertensive cases and 479 healthy cases was collected by self-developed H20 questionnaires and pulse wave information was acquired by self-developed pulse diagnostic instrument (PDA-1). H20 questionnaires and pulse wave information were used as input variables to obtain different machine learning classification models of hypertension. This method was aimed at analyzing the influence of pulse wave on the accuracy and stability of machine learning model, as well as the feature contribution of hypertension model after removing noise by K-means. Result. Compared with the classification results before removing noise, the accuracy and the area under the curve (AUC) had been improved. The accuracy rates of AdaBoost, Gradient Boosting, and Random Forest (RF) were 86.41%, 86.41%, and 85.33%, respectively. AUC were 0.86, 0.86, and 0.85, respectively. The maximum accuracy of SVM increased from 79.57% to 83.15%, and the AUC stability increased from 0.79 to 0.83. In addition, the features of importance on traditional statistics and machine learning were consistent. After removing noise, the features with large changes were h1/t1, w1/t, t, w2, h2, t1, and t5 in AdaBoost and Gradient Boosting (top10). The common variables for machine learning and traditional statistics were h1/t1, h5, t, Ad, BMI, and t2. Conclusion. Pulse wave-based diagnostic method of hypertension has significant value in reference. In view of the feasibility of digital-pulse-wave diagnosis and dynamically evaluating hypertension, it provides the research direction and foundation for Chinese medicine in the dynamic evaluation of modern disease diagnosis and curative effect.
https://ift.tt/2Df6feD
Toxoplasma Encephalitis following Tandem Autologous Hematopoietic Stem Cell Transplantation: A Case Report and Review of the Literature
Infection with Toxoplasma gondii is a rare but often fatal complication in hematopoietic stem cell transplantation (HSCT) recipients. Most cases have been reported in allogeneic (allo-) HSCT recipients, with only narrative reports following autologous HSCT (ASCT). We report the case of a 58-year-old Caucasian male presenting with toxoplasma encephalitis following tandem ASCT for myeloma and successfully treated with diagnosis by polymerase chain reaction analysis of cerebrospinal fluid. He was treated with sulfadiazine and pyrimethamine (with leucovorin) followed by pyrimethamine and atovaquone as secondary prophylaxis while receiving subsequent therapy for progressive multiple myeloma. Toxoplasmosis is a potential complication in allo-HSCT as well as ASCT recipients and should be considered in any post-HSCT patient with neurological dysfunction. Rapid diagnosis and immediate antimicrobial treatment are essential to avoid morbidity and mortality.
https://ift.tt/2z3ZtW1
Pharmacokinetic and pharmacodynamic considerations in the design of therapeutic antibodies
Abstract
The design and development of therapeutic monoclonal antibodies through optimizing their pharmacokinetic (PK) and pharmacodynamic (PD) properties is crucial to improve efficacy while minimizing adverse events. Many of these properties are interdependent, which highlights the inherent challenges in therapeutic antibody design, where improving one antibody property can sometimes lead to changes in others. Here, we discuss optimization approaches for PK/PD properties of therapeutic mAbs.
This article is protected by copyright. All rights reserved.
https://ift.tt/2QyTeAe
Comparison of Electrocardiographic Biomarkers for Differentiating Drug‐induced Single vs. Multiple Cardiac Ion Channel Block
Abstract
Since introduction of the ICH proarrhythmia guidelines in 2005, no new marketed drugs have been associated with unacceptable risk of TdP. Although cardiac safety improved, these guidelines had the unintended consequence of eliminating potentially beneficial drugs from pipelines early in development. More recently, it has been shown that a QTc prolonging drug may be safe if it impacts multiple ion channels vs. only hERG and that this effect can be discriminated using QT subintervals. We compared the predictive power of four ECG repolarization metrics to discriminate single vs. multichannel block: a) traditional 10‐sec signal‐averaged triplicates, and b) three metrics that employed increasing density of automatically measured beat‐to‐beat (btb) intervals. Predictive power was evaluated using logistic regression and quantified with receiver operating characteristic area under the curve. Compared to the traditional 10‐sec signal averaged triplicates, the reduction in classification error ranged from two to six with increasing density of btb measurements.
This article is protected by copyright. All rights reserved.
https://ift.tt/2qHq86F
Updates in the Diagnosis and Treatment of Paraneoplastic Neurologic Syndromes
Abstract
The disorders of the central nervous system associated with cancer by remote immune-mediated mechanisms are a heterogeneous group. These disorders encompass the classic paraneoplastic disorders and the recently recognized autoimmune encephalitis associated with antibodies against neuronal cell surface or synaptic proteins that occur with or without cancer association. In the last decade, the new surge of interest in neuronal diseases associated with anti-neuronal antibodies led to the rapid discovery of new forms of disease that have different manifestations and were not previously suspected to be immune mediated. The recognition of these syndromes is important because it may lead to early detection of an underlying malignancy and prompt initiation of treatment, improving chances for a better outcome.
https://ift.tt/2Pjq77H
Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy
Abstract
COX20/FAM36A encodes a mitochondrial complex IV assembly factor important for COX2 activation. Only one homozygous COX20 missense mutation has been previously described in two separate consanguineous families. We report four subjects with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Exome sequencing in all four subjects identified the same novel COX20 variants. One variant affected the splice donor site of intron‐one (c.41A>G), while the other variant (c.157+3G>C) affected the splice donor site of intron‐two. cDNA and protein analysis indicated that no full‐length cDNA or protein was generated. These subjects expand the phenotype associated with COX20 deficiency.
https://ift.tt/2Qv48Hu
New Alert Criteria for Intraoperative Somatosensory Evoked Potential Monitoring
Forty years ago, anesthesiologist Betty Grundy and engineer Richard Brown, working with spine surgeon Clyde Nash, began recording somatosensory evoked potentials (SEPs) from the scalp during spine surgery. Their goal was to identify SEP changes in time to avert post-operative neurologic impairment. Their early methods were crude by today's standards. They measured 512 msec long-latency SEPs with filters 1-100 Hz. They followed scalp signals' presence or absence without identifying particular peaks of interest.
https://ift.tt/2JUx5de
Down‐regulation of lncRNA XIST ameliorates podocytes apoptosis in membranous nephropathy via miR‐217/TLR4 pathway
New Findings
What is the central question of this study?
Up‐regulation of lncRNA XIST in injured podocytes and membranous nephropathy has been noted, but its implication in membranous nephropathy pathogenesis has not been elucidated in detail.
What is the main finding and its importance?
We demonstrated that XIST was up‐regulated in kidney tissue of membranous nephropathy and in injured podocytes. Down‐regulation of XIST inhibited podocytes apoptosis. XIST negatively regulated miR‐217, and miR‐217 controlled TLR4. XIST modulated TLR4 through miR‐217 and inhibition of XIST suppressed podocytes apoptosis induced by Angiotensin II via miR‐217.
Abstract
Background
Membranous nephropathy is often characterized by glomerular podocyte injury. Up‐regulation of lncRNA XIST has been verified in membranous nephropathy and in injured podocytes; hence the role of XIST in podocyte injury and membranous nephropathy was explored.
Methods
QRT‐PCR and western blot were performed to detect the expression XIST, miR‐217, and TLR4 protein respectively. Podocyte apoptosis was evaluated with flow cytometry. Interaction between XIST and miR‐217 was analyzed by RIP and RNA pull‐down assay, respectively. Dual luciferase reporter assay was used to exam the interplay between miR‐217 and TLR4.
Results
LncRNA XIST and Ang II up‐regulation, kidney and podocyte injury were indicated in kidney tissue of patients with membranous nephropathy. Increase of XIST and apoptosis were induced by Ang II in podocytes. Down‐regulation of XIST inverted podocytes apoptosis induced by Ang II. MiR‐217 was negatively regulated by XIST. MiR‐217 controlled TLR4 by targeting its 3′‐UTR. XIST modulated TLR4 through miR‐217 and inhibition of XIST inverted podocytes apoptosis induced by Ang II via regulating miR‐217.
Conclusion
Down‐regulation of XIST ameliorates podocytes apoptosis via the miR‐217/TLR4 pathway, which may improve membranous nephropathy.
This article is protected by copyright. All rights reserved
https://ift.tt/2OC02LK
EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK‐eIF2α‐GRP94 and IRE1α‐XBP1‐GRP78
EGFR conferred radioresistance in OSCC cells by activating ERS signalling PERK‐eIF2α‐GRP94 and IRE1α‐XBP1‐GRP78. Knockdown of EGFR in OSCC cells inhibited DNA double‐strand break repair and autophagy mediated by ERS. Co‐expression of EGFR and PERK was associated with poor prognosis of OSCC.
Abstract
The activation of epidermal growth factor receptor (EGFR) is associated with radioresistance in malignant tumors. Specifically, radiation can destroy endoplasmic reticulum (ER) homeostasis to induce ER stress (ERS). However, the effect of EGFR‐mediated regulation of ERS signaling pathway on radiosensitivity has not yet been reported. The present study showed that silencing EGFR increased radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells by inhibiting ER stress signaling (PERK‐eIF2α‐GRP94 and IRE1α‐XBP1‐GRP78). This effect was abolished by pretreatment with EGF, however. In addition, knockdown of EGFR in OSCC cells inhibited DNA double‐stand break repair and autophagy while increased radiation‐induced apoptosis. Conversely, activating ERS inhibited the aforementioned functions. Furthermore, EGF increased ER stress‐independent ERK and AKT signaling upon irradiation of OSCC cells. Immunohistochemical analysis of 80 tissue samples from OSCC patients showed that co‐expression of EGFR and PERK was associated with poor prognosis. It thus appears EGFR confers radioresistance in OSCC by activating ER stress signaling. These results suggested that the cooperative effects of radiotherapy and EGFR‐targeted inhibitor therapy can be further improved by inhibiting PERK‐eIF2α‐GRP94 and IRE1α‐GRP78 in non‐response oropharyngeal carcinoma patients.
https://ift.tt/2qGMaGE
Emergency Medical Services Administration of Systemic Corticosteroids for Pediatric Asthma: A Statewide Study of Emergency Department Outcomes
Abstract
Background
For children with an asthma exacerbation, systemic corticosteroids (CS) administered in the emergency department (ED) decrease hospital admission rates and ED length‐of‐stay (LOS).1‐4 Time‐dependent effects favor earlier CS administration, ideally within the first hour of ED arrival.2,3 Only one pediatric study has examined if earlier, EMS administration of CS improves patient outcomes.5 That study found decreased hospital admission rates and ED LOS after adding dexamethasone to intravenous (IV) methylprednisolone as options for pediatric asthma. However, the study was of a single EMS agency and overall EMS CS use was low (<20%).5 To date, no large study has examined pediatric asthma outcomes after EMS treatment. This study's objective was to examine a statewide population of pediatric asthma patients to determine the effects of EMS administration of CS on ED outcomes.
This article is protected by copyright. All rights reserved.
https://ift.tt/2Pjl0o1
Estimated GFR Decline and Tubular Injury Biomarkers With Intensive Blood Pressure Control
Current clinical practice guidelines recommend a blood pressure (BP) target of 130/80mm Hg in those with and without chronic kidney disease (CKD) to reduce morbidity and mortality.1 These guidelines are supported by recent evidence from clinical trials, including the Systolic Blood Pressure Intervention Trial (SPRINT), which showed reduced cardiovascular events and all-cause mortality with more intensive systolic BP (SBP) control in this high-risk population.2 Commendably, the investigators thoroughly investigated and reported adverse effects associated with intense BP control.
https://ift.tt/2yYf2i4
Kidney Function and Hospital-Acquired Infections: Worth a Deeper Look
Hospital-acquired infections impose a tremendous health care burden in increased length of hospitalization, morbidity, and mortality, as well as consumption of resources, with some estimates suggesting an annual cost to the United States and Europe of $28 to $45 billion and €7 billion, respectively.1,2 Given that hospital-acquired infections are frequently preventable, identifying strategies to reduce them, particularly in those at highest risk, is of critical importance. Appropriately, hospital-acquired infections are not only of interest in individual patient care, but are also a focus of health care systems and government oversight; surveillance and reporting of hospital-acquired infections has become the standard in health care facilities in the developed world.
https://ift.tt/2OCMJe5
Oncology Scan: Reirradiation in Pediatric Patients With Recurrent Brain Tumors: A Last Hope, But One With Greatly Feared Consequences
Over the decades there has been a trend to use radiation therapy less frequently for treatment of pediatric brain tumors (1). The effort to avoid radiation is not the result of a lack of efficacy but rather a fear of long-term side effects of radiation, including neurocognitive delay and other life-altering consequences. For many pediatric brain tumors, omission of radiation therapy significantly compromises tumor control rates; thus, radiation therapy remains an essential component of first-line therapy for many pediatric brain tumors, including medulloblastoma, diffuse intrinsic pontine glioma (DIPG), high-grade gliomas, germ cell tumors, and ependymoma.
https://ift.tt/2SZrHtw
Intestinal immune dysregulation driven by dysbiosis promotes barrier disruption and bacterial translocation in rats with cirrhosis
Abstract
In cirrhosis, intestinal dysbiosis, intestinal barrier impairment and systemic immune system abnormalities lead to gut bacterial translocation (GBT) and bacterial infection. However, intestinal immune system dysfunction and its contribution to barrier damage are poorly understood. This study correlates immune system dysregulation in the intestines of rats at different stages of CCl4‐induced cirrhosis with barrier function and pathogenic microbiota. The following variables were addressed in the small intestine: intraepithelial and lamina propria lymphocyte (IEL, LPL) activation status and cytokine production (flow cytometry), cytokine mRNA and protein expression (real‐time quantitative PCR (qPCR) and immunofluorescence), microbiota composition of ileum content (16SrDNA massive sequencing), permeability (fecal albumin loss) and epithelial junctions (immunohistochemistry and immunofluorescence). The intestinal mucosa in cirrhotic rats showed a proinflammatory pattern of immune dysregulation in IEL and LPL, which featured the expansion of activated lymphocytes, switch to a Th1 regulatory pattern and Th17 reduction. In cirrhotic rats with ascites, this state was associated with epithelial junction protein disruption, fecal albumin loss, and GBT. Direct correlations (p<0.01) were observed between elevated IFNγ‐expressing T cytotoxic LPL and fecal albumin, and between inflammatory taxa abundance and IFNγ−producing immune cells in the ileum. Bowel decontamination led to redistributed microbiota composition, reduced proinflammatory activation of mucosal immune cells, normalized fecal albumin levels and diminished GBT, but there were no modifications in Th17 depletion. Conclusion: The intestinal mucosa of rats with cirrhosis acquires a proinflammatory profile of immune dysregulation that parallels the severity of cirrhosis. This impaired intestinal immune response is driven by gut dysbiosis and leads to disrupted barrier function, promoting GBT.
This article is protected by copyright. All rights reserved.
https://ift.tt/2AXEyFw
Interneuronal gap junctions increase synchrony and robustness of hippocampal ripple oscillations
Abstract
Sharp wave‐ripples (SWRs) are important for memory consolidation. Their signature in the hippocampal extracellular field potential can be decomposed into a ≈ 100 ms long sharp wave superimposed by ≈ 200 Hz ripple oscillations. How ripple oscillations are generated is currently not well understood. A promising model for the genesis of ripple oscillations is based on recurrent interneuronal networks (INT‐INT). According to this hypothesis, the INT‐INT network in CA1 receives a burst of excitation from CA3 that generates the sharp wave, and recurrent inhibition leads to an ultrafast synchronization of the CA1 network causing the ripple oscillations; fast‐spiking parvalbumin‐positive basket cells (PV+BCs) may constitute the ripple‐generating interneuronal network. PV+BCs are also coupled by gap junctions (GJs) but the function of GJs for ripple oscillations has not been quantified. Using simulations of CA1 hippocampal networks of PV+BCs, we show that GJs promote synchrony beyond a level that could be obtained by only inhibition. GJs also increase the neuronal firing rate of the interneuronal ensemble, while they affect the ripple frequency only mildly. The promoting effect of GJs on ripple oscillations depends on fast GJ transmission (≲ 0.5 ms), which requires proximal GJ coupling (≲ 100 μm from soma), but is robust to variability of the delay and the amplitude of GJ coupling.
This article is protected by copyright. All rights reserved.
https://ift.tt/2DdEh2S
Multi‐gene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non‐CDKN2A/CDK4 melanoma families
Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10‐40% of melanoma‐prone families. In this study we comprehensively characterized 488 melanoma cases from 451 non‐CDKN2A/CDK4 families for mutations in 30 established and candidate melanoma susceptibility genes using a custom‐designed targeted gene panel approach. We identified (likely) pathogenic variants in established melanoma susceptibility genes in 18 families (n=3 BAP1, n=15 MITF p.E318K; diagnostic yield 4.0%). Among the three identified BAP1‐families, there were no reported diagnoses of uveal melanoma or malignant mesothelioma. We additionally identified two potentially deleterious missense variants in the telomere maintenance genes ACD and TERF2IP, but none in the POT1 gene. MC1R risk variants were strongly enriched in our familial melanoma cohort compared to healthy controls (R variants: OR 3.67, 95% CI 2.88‐4.68, p<0.001). Several variants of interest were also identified in candidate melanoma susceptibility genes, in particular rare (pathogenic) variants in the albinism gene OCA2 were repeatedly found. We conclude that multi‐gene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non‐CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test.
This article is protected by copyright. All rights reserved.
https://ift.tt/2T2u1jw
Glioblastoma endothelium drives bevacizumab‐induced infiltrative growth via modulation of PLXDC1
Bevacizumab, a VEGF‐targeting monoclonal antibody, may trigger an infiltrative growth pattern in glioblastoma. We investigated this pattern using both a human specimen and rat models. In the human specimen, a substantial fraction of infiltrating tumor cells were located along perivascular spaces in close relationship with endothelial cells. Brain xenografts of U87MG cells treated with bevacizumab were smaller than controls (p=0.0055; Student‐t test), however, bands of tumor cells spread through the brain farther than controls (p<0.001; Student‐t test). Infiltrating tumor cells showed tropism for vascular structures and propensity to form tubules and niches with endothelial cells. Molecularly, bevacizumab triggered an epithelial to mesenchymal transition with over‐expression of the receptor Plexin Domain Containing 1 (PLXDC1). These results were validated using brain xenografts of patient‐derived glioma stem‐like cells. Enforced expression of PLXDC1 in U87MG cells promoted brain infiltration along perivascular spaces. Importantly, PLXDC1 inhibition prevented perivascular infiltration and significantly increased the survival of bevacizumab‐treated rats. This study indicates that bevacizumab‐induced brain infiltration is driven by vascular endothelium and depends on PLXDC1 activation of tumor cells.
This article is protected by copyright. All rights reserved.
https://ift.tt/2zHT3LS
Newly developed anti‐S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis
The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9‐mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45‐Fab and human IgG2‐Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings.
This article is protected by copyright. All rights reserved.
https://ift.tt/2SZpvlM
Demographic Trends and KRAS/BRAFV600E Mutations in Colorectal Cancer Patients of South China: a Single‐site Report
The incidence of colorectal cancer (CRC) is increasing in China. Here, we aimed to evaluate the latest demographic trends and KRAS/BRAF mutations status of Chinese CRC. 5546 CRC patients diagnosed from 2010 to 2017 were involved. KRAS exon 2 and BRAF V600E mutations were detected by Sanger sequencing and high‐resolution melting analysis or allelic‐specific probe method. Gene mutation profiles and clinicopathologic characteristics of 5495 patients were analyzed. The joinpoint regression model was used to predict the demographic data in 2018. We found KRAS exon 2 and BRAF V600E mutation rates were 37.7% and 2.8% in CRC patients. Tumors with KRAS exon 2 mutations were more likely to be present in female and patients aged older than 75 years, right colon and have well‐differentiated histology. Tumors with BRAF V600E mutations were more likely to be present in the female, right colon and have poorly differentiated histology. From 2010 to 2017, the percentage of colon cancer and tubular adenocarcinoma in CRC increased substantially (from 39.3% to 51.8%, from 78.6% to 93.4%, respectively). The percentage of right colon cancer increased from 18.3% to 20.5%, which predictively may keep at 22.6% in 2018. The rise trends for patients with moderate differentiation tumor or KRAS exon 2 mutated tumor were apparent (from 50.3% to 78.6%, from 32.8% to 39.7%, respectively). In conclusion, in recent eight years, there is a shift to the colon, especially right colon in the incidence of Chinese CRC. Moreover tubular adenocarcinoma is becoming the primary histology type.
This article is protected by copyright. All rights reserved.
https://ift.tt/2zHI5Gd
Assessment of 16S rRNA gene primers for studying bacterial community structure and function of aging flue-cured tobaccos
Selection of optimal primer pairs in 16S rRNA gene sequencing is a pivotal issue in microorganism diversity analysis. However, limited effort has been put into investigation of specific primer sets for analysi...
https://ift.tt/2zHsMxq
Erysipelas, the opportunistic zoonotic disease: history, epidemiology, pathology, and diagnosis—a review
Abstract
Due to the recent multidisciplinary collaborations towards 'One Health', it was necessary to review this important zoonotic disease, erysipelas. Swine erysipelas also referred to as diamond skin disease has since become one of the most serious hazards of swine production worldwide. Erysipelothrix rhusiopathiae, the aetiology of erysipelas could affect pigs, turkeys, sheep, chickens, ducks, and emus. The most important animal reservoir of E. rhusiopathiae is the domestic swine. The organism is shed by diseased animals in faeces, urine, saliva, and nasal secretions, which can contaminate food, water, and soil. Swine erysipelas is made up of the hyperacute form, the septicaemia, and cutaneous (diamond) forms (acute), and the chronic form, characterised in pigs by joint lesions (arthritis), vegetative endocarditis, alopecia, and dermatitis. These signs are accompanied by poor fertility, increased prevalence of abortions, stillbirths, and small litter size. Reports of human cases are related to occupational exposure placing fishermen, butchers, slaughterhouse workers, veterinarians, housewives, poultry industry workers, and other agricultural based workers at higher risk. Diagnosis of erysipelas is based on clinical signs, gross lesions, response to antimicrobial therapy, and demonstration of the bacterium using bacterial culturing, mouse protection test, microscopy and mass spectrometry or demonstration of bacterial DNA in tissues from affected animals using PCR assays, immunohistochemical methods, and other serological methods. Swine erysipelas as an opportunistic zoonotic disease is on the increase hence, a synergistic effort should be garnered towards reducing the negative influence of this disease, through enhanced awareness of this disease amongst farmers, butchers, housewives, veterinarians, and drug researchers.
https://ift.tt/2FfJr10
Integrated treatment for autonomic paraneoplastic syndrome improves performance status in a patient with small lung cell carcinoma: a case report
Paraneoplastic neurological syndromes (PNS) are rare disorders associated with cancer and are believed to be immune mediated. Patients with autonomic PNS suffer from variable combinations of parasympathetic an...
https://ift.tt/2z1J1Wm
One-anastomosis Gastric Bypass (OAGB) in Rats
This protocol is for the performance of one-anastomosis gastric bypass (OAGB) on rat. The operator performs a long and tubular-stapled gastric pouch followed by hand-sewn anastomosis. For this model, the operator reproduces the same ratio between biliopancreatic and common limb in humans; therefore, the biliopancreatic limb measures 35 cm.
https://ift.tt/2Dxclb8
Detection of Tilapia Lake Virus Using Conventional RT-PCR and SYBR Green RT-qPCR
https://ift.tt/2RLAsFY
Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study
Objectives
Early placement of transjugular intrahepatic portosystemic shunt (TIPS) has been shown to improve survival in high-risk patients (Child-Pugh B plus active bleeding at endoscopy or Child-Pugh C 10–13) with cirrhosis and acute variceal bleeding (AVB). However, early TIPS criteria may overestimate the mortality risk in a significant proportion of patients, and the survival benefit conferred by early TIPS in such patients has been questioned. Alternative criteria have been proposed to refine the criteria used to identify candidates for early TIPS. Nevertheless, the true survival benefit provided (or not) by early TIPS compared with standard treatment in the different risk categories has not been investigated in specifically designed comparative studies.
DesignWe collected data on 1425 consecutive patients with cirrhosis and AVB who were admitted to 12 university hospitals in China between December 2010 and June 2016. Of these, 206 patients received early TIPS, and 1219 patients received standard treatment. The Fine and Gray competing risk regression model was used to compare the outcomes between the two groups that were stratified based on the currently available risk stratification systems after adjusting for liver disease severity and other potential confounders.
ResultsOverall, early TIPS was associated with an 80% relative risk reduction (RRR) in mortality at 6 weeks (adjusted HR=0.20; 95% CI: 0.10 to 044; p<0.001) and 51% RRR at 1 year (adjusted HR=0.49, 95% CI: 0.32 to 0.73; p<0.001) compared with standard treatment. In stratification analyses, the RRRs in mortality did not significantly differ among the risk categories. However, the absolute risk reductions (ARRs) of mortality were more pronounced in high-risk patients. The ARRs at 6 weeks were –2.1%, –10.2% and –32.4% in Model for End-stage Liver Disease (MELD) ≤11, 12–18 and ≥19 patients and were –1.5%, –9.1% and –23.2% in Child-Pugh A, B and C patients, respectively (interaction tests, p<0.001 for both criteria). The ARRs for mortality at 1 year were –1.7%, –5.4% and –32.7% in MELD ≤11, 12–18 and ≥19 patients, respectively, and –3.6%, –5.2% and –20.3% in Child-Pugh A, B and C patients, respectively (interaction tests, p<0.001 for both criteria). After adjusting for liver disease severity and other potential confounders, a survival benefit was observed in MELD ≥19 or Child-Pugh C patients but not in MELD ≤11 or Child-Pugh A patients. In MELD 12–18 patients, a survival benefit was observed within 6 weeks but not at 1 year. In Child-Pugh B patients, a survival benefit was observed in those with active bleeding but not those without active bleeding. However, the evaluation of active bleeding was associated with a high interobserver variability. Furthermore, early TIPS was associated with a significantly reduced incidence of failure to control bleeding or rebleeding and new or worsening ascites, without increasing the risk of overt hepatic encephalopathy.
ConclusionsEarly TIPS was associated with improved survival in patients with MELD ≥19 or Child-Pugh C cirrhosis but not in patients with MELD ≤11 or Child-Pugh A cirrhosis. For MELD 12–18 or Child-Pugh B patients, future studies addressing optimal selection criteria for early TIPS remain highly warranted.
https://ift.tt/2OD9T47
Stromal protein {beta}ig-h3 reprogrammes tumour microenvironment in pancreatic cancer
Objective
Pancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.
DesignWe performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.
ResultsWe identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.
ConclusionsOur data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.
https://ift.tt/2z4tCom
Effects of Tiotropium Combined with Theophylline on Stable COPD Patients of Group B, D and its Impact on Small Airway Function: A Randomized Controlled Trial
Abstract
Introduction
Tiotropium bromide has been widely used in clinical practice, while theophylline is another treatment option for chronic obstructive pulmonary disease (COPD). However, only a few relevant studies have investigated the long-term outcomes and efficacy of both in patients with COPD. We evaluated the effects of tiotropium and low-dose theophylline on stable COPD patients of groups B and D.
Methods
Eligible participants (n = 170) were randomized and received either tiotropium 18 µg once daily with theophylline 100 mg twice daily (Group I) or tiotropium 18 µg once daily (Group II) for 6 months. COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scores and pulmonary function tests were measured before randomization and during the treatment.
Results
After 6 months of treatment, the CAT scores in both groups decreased significantly (11.41 ± 3.56 and 11.08 ± 3.05, p < 0.0001). The changes of CAT (p = 0.028) and mMRC scores (p = 0.049) between the two groups differed after 1 month of treatment. In Group I, forced expiratory flow after 25% of the FVC% predicted (MEF25% pred) was significantly improved after 3 months (4.84 ± 8.73%, p < 0.0001) and 6 months (6.21 ± 8.65%, p < 0.0001). There was a significant difference in small airway function tests (MEF50% pred, MEF25% pred, and MMEF% pred) between the two groups after 6 month of treatment (p = 0.003, p < 0.0001, and p = 0.021, respectively).
Conclusions
Tiotropium combined with low-dose theophylline significantly improved the symptoms and general health of patients with stable COPD of groups B and D after 6 months of follow-up. Additionally, this therapy also improved the indicators of small airway function.
Trial Registration
Chinese Clinical Trial Registry (Registry ID: ChiCTR1800019027).
https://ift.tt/2RKTLPP
Successful and safe long‐term treatment of cerebral aspergillosis with high‐dose voriconazole guided by therapeutic drug monitoring
We report the case of a patient who had cerebral aspergillosis after otorhinolaryngologic surgery and who was successfully and safely treated with high‐dose voriconazole (200 mg q6h) for more than 1 year thanks to a TDM‐guided approach coupled with pharmacological review and with genotyping of CYP2C19 polymorphisms. The findings support the idea that personalized medicine based on TDM coupled with the need of avoiding drug–drug interactions may be helpful for maximizing the net benefit (probability of efficacy vs. probability of adverse events) of voriconazole in the management of long‐term treatment of cerebral aspergillosis.
https://ift.tt/2qE4Era
Systematic review of single-incision versus conventional multiport laparoscopic surgery for sigmoid colon and rectal cancer
Abstract
Objectives
To explore whether single-incision laparoscopic surgery (SILS) has the better short-term clinical and pathological outcomes than conventional multiport laparoscopic surgery (CLS) for sigmoid colon and rectal cancer.
Methods
A literature investigation of MEDLINE, PubMed, Ovid, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Chinese Biological Medicine (CBM), and Wanfang databases for relevant researches was performed. Fixed effects and random effects models were used to calculate the corresponding outcomes. Standardized mean difference and risk ratio were calculated for continuous and dichotomous variables separately.
Results
Nine clinical controlled trials were composed of two randomized clinical trials and seven non-randomized clinical trials with a total of 829 patients. Two hundred ninety-nine (36.1%) patients underwent SILS, and 530 (63.9%) patients underwent CLS. The meta-analysis showed that SILS had more lymph node resection (SMD − 0.25, 95% CI − 0.50 to − 0.002) and less defecation time (SMD − 0.46, 95% CI − 0.75 to − 0.17), exhaust time (SMD − 0.46, 95% CI − 0.75 to − 0.18), and hospital stay (SMD − 0.30, 95% CI − 0.45 to − 0.15 than CLS. SILS was also accompanied with shorter incision length (SMD − 2.46, 95% CI − 4.02 to − 0.90), less pain score (SMD − 0.56, 95% CI − 0.91 to − 0.21), and lower complication rate (RR 0.66, 95% CI 0.47 to 0.91). Blood loss, operative time, distal margin, conversion rate, anastomotic fistula, readmission, local recurrence, and distant metastasis showed no statistical differences in two groups. In all subgroup analysis, SILS also had advantages of incision length, operative time, defecation time, exhaust time, and hospitalization time than CLS.
Conclusion
SILS could be a more safe and reliable surgical technique than CLS for sigmoid colon and rectal cancer. However, further high-quality studies between these two techniques need to be further developed.
https://ift.tt/2PLuXtR
Role of Stereotactic Body Radiation Therapy in Early Stage Small Cell Lung Cancer in the Era of Lung Cancer Screening: A Systematic Review
https://ift.tt/2z0snqk
A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib With Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients
https://ift.tt/2OC1JZy
Iliac screws may not be necessary in long segment constructs with L5-S1 ALIF: Cadaveric study of stability and instrumentation strain
Publication date: Available online 9 November 2018
Source: The Spine Journal
Author(s): Randall J. Hlubek, Jakub Godzik, Anna G.U.S. Newcomb, Jennifer N. Lehrman, Bernardo de Andrada Pereira, Michael A. Bohl, S. Harrison Farber, Brian P. Kelly, Jay D. Turner
ABSTRACT
Background Context
Lumbosacral pseudoarthrosis and instrumentation failure is common with long segment constructs. Optimizing lumbosacral construct biomechanics may help to reduce failure rates. The influence of iliac screws and interbody type on range of motion (ROM), rod strain (RS), sacral screw strain (SS) is not well-established.
Purpose
Investigate the effects of TLIF, ALIF, and iliac screws on long segment lumbosacral construct biomechanics.
Study Design
Biomechanical study
Patient Sample
Fourteen human cadaveric spine specimens
Outcome Measures
Lumbosacral ROM, RS, and SS
Methods
Specimens were potted at L1 and the ilium. Specimens were equally divided into either an L5-S1 ALIF or TLIF group and underwent testing in the following conditions: 1) intact 2) L2-S1 pedicle screw rod fixation(PSR-S) 3) L2-ilium (PSR-I) 4) PSR-S+ALIF (ALIF-S) or TLIF (TLIF-S) 5) PSR-I + ALIF (ALIF-I) or TLIF (TLIF-I). Pure moment bending (7.5Nm) in flexion, extension, lateral bending, axial rotation and compressive loads (400N) were applied and ROM, SS, and RS were measured. Comparisons were performed using a one-way ANOVA (p<0.05).
Results
ALIF-S and TLIF-S provided similar decreases in ROM as TLIF-I (p>0.05). Compared to PSR-S, PSR-I significantly decreased SS during bending in all directions (p<0.02) but increased RS in flexion and extension (p≤0.02). ALIF-S provided similar decreases in SS as TLIF-I in all directions (p>0.40) but had significantly less RS than TLIF-I in flexion, extension, compression (p<0.01). TLIF-S had more SS than TLIF-I in flexion, extension, axial rotation (p<0.02), while TLIF-S had less RS only in flexion (p=0.03). Compared to PSR-I, ALIF-I decreased the RS (p<0.02) but TLIF-I did not (p>0.67).
Conclusions
Iliac screws were protective of SS but increased RS at the lumbosacral junction. Constructs with ALIF and no iliac screws result in comparable SS as constructs with TLIF and iliac screws with significantly reduced RS. If iliac screws are utilized, ALIF but not TLIF reduces the iliac screw-induced RS.
Clinical Significance
There is a relatively high incidence of lumbosacral instrumentation failure in adult spinal deformity. Optimizing lumbosacral construct biomechanics may help to reduce failure rates. Iliac screws induce lumbosacral rod strain and may be responsible for instrumentation failure. Constructs with lumbosacral ALIF reduce iliac-screw induced rod strain and may obviate the need for fixation to the ilium.
https://ift.tt/2OAUCAQ
FRAGILE X SYNDROME AND CONNECTIVE TISSUE CONNECTIVE TISSUE DEFICITS IN FRAGILE X SYNDROME
Fragile X Syndrome is the most common cause of inherited intellectual disabilities and autism spectrum disorders and it is an X‐linked disorder in which there is a deficiency of the Fragile X Mental Retardation 1 protein. This protein is crucial in regulating translation of mRNAs related to dendritic maturation and cognitive development. The phenotype of FXS is characterized by neurobehavioral alterations, social deficits, communication difficulties, and findings which suggest an alteration of connective tissue, especially in the ligaments and muscles, cardiovascular system and genitourinary system. Connective tissue connects and supports all other tissues of the body, and is composed of cells and extracellular matrix. Severalproteins have been involved in the connective tissue abnormalities associated with the FXS, such as matrix metalloproteinase 9, which plays an important role in the homeostasis of the extracellular matrix, being a potential therapeutic target for certain tetracycline antibiotics that have shown beneficial effects in FXS.Here we review connective tissue problems described in Fragile X Syndrome.
This article is protected by copyright. All rights reserved.
https://ift.tt/2Pj39xi
Qualitative and Quantitative Assessment of Patient and Carer Experience of Chemotherapy (Docetaxel) in Combination with Androgen Deprivation Therapy (ADT) for the Treatment of Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
Abstract
Introduction
Recent studies suggest that docetaxel plus androgen deprivation therapy can prolong survival among men with metastatic hormone-sensitive prostate cancer (mHSPC). However, as a cytotoxic therapy, there is a need to understand the experiences of men with mHSPC receiving docetaxel and their carers in a real-world setting.
Methods
During phase 1, semi-structured qualitative interviews were conducted with men with mHSPC (n = 31) and their carers (n = 14) in Europe to elicit in-depth data concerning their experiences with docetaxel. Eighteen men were also asked to record their experiences in a diary for 7 days. During phase 2, men with mHSPC (n = 161) and carers of men with mHSPC (n = 135) completed an online survey comprising self-report questionnaires including the Cancer Therapy Satisfaction Questionnaire, Brief Fatigue Inventory, Functional Assessment of Cancer Therapy-Prostate, EuroQol-5-Dimensions and the Burden Scale for Family Caregivers (carers only).
Results
At the outset of therapy, men reported a willingness to take docetaxel to prolong their life, despite being fearful of the potential side effects and impacts on their daily lives. Patient and carer experiences were generally consistent with pre-treatment expectations. However, variations in individual experiences and their ability to tolerate side effects were evident. Fatigue emerged as a prominent symptom with the majority (n = 98, 60.9%) of men reporting experiencing moderate-severe fatigue in the past 24 h. Participant ratings of fatigue were strongly correlated with health-related quality of life (r = − 0.82). Nausea, diarrhoea and sore mouth were also among the most bothersome symptoms for participants.
Conclusions
Findings from this study highlight that real-world experience of docetaxel may differ from that observed in clinical trials and that care must be taken to ensure that treatment options are tailored to the needs of individual patients to promote not only how long patients survive but also the quality of that survival.
Funding
Janssen
https://ift.tt/2OzkQDF
Cognitive-perceptual load modulates hand selection in left-handers to a greater extent than in right-handers
Abstract
Previous studies have proposed that selecting which hand to use for a reaching task appears to be modulated by a factor described as "task difficulty," defined by either the requirement for spatial precision or movement sequences. However, we previously reported that analysis of the movement costs associated with even simple movements plays a major role in hand selection. We further demonstrated, in right-handers, that cognitive-perceptual loading modulates hand selection by interfering with the analysis of such costs. It has been reported that left-handers tend to show less dominant hand bias in selecting which hand to use during reaching. We, therefore, hypothesized that hand selection would be less affected by cognitive-perceptual loading in left-handers than in right-handers. We employed a visual search task that presented different levels of difficulty (cognitive-perceptual load), as established in previous studies. Our findings indicate that left-handed participants tend to show greater modulation of hand selection by cognitive-perceptual loading than right-handers. Left-handers showed lower dominant hand reaction times than right-handers, and greater high-cost movements that reached to extremes of the contralateral workspace under the most difficult task conditions. We previously showed in this task that midline crossing has high-energy and time costs and that they occur more frequently under cognitively demanding conditions. The current study revealed that midline crossing was associated with the lowest reaction times, in both handedness groups. The fact that left-handers showed lower dominant hand reaction times, and a greater number of high-cost cross-midline reaches under the most cognitively demanding conditions suggests that these actions were erroneous.
https://ift.tt/2Ffl6Zf
Evaluation of effectiveness of palliative radiotherapy for bone metastases: a prospective cohort study
Abstract
Objective
Radiotherapy is the standard local treatment for patients with painful bone metastases, but effectiveness has primarily been evaluated in trial populations. The aim of this study was to study pain response to palliative radiotherapy in a prospective cohort of unselected patients with bone metastases.
Methods
Patients with painful bone metastases referred to the UMC Utrecht for radiotherapy and enrolled in the PRESENT cohort were included in this study. For all patients, pain response to radiotherapy was assessed, and responders were defined as patients with a complete or partial pain response. Patients with stable pain scores, pain increase, or undetermined response were regarded non-responders. Pain scores obtained at baseline and after 2, 4, 6, 8, and 12 weeks following radiotherapy were obtained. Pain response rates of the total treated population, as well as response rates of the assessable patients, were calculated. To measure the percentage of the remaining time spent with pain relief, the net pain relief (NPR) was calculated by dividing the period of pain relief by the period of survival.
Results
Of the 432 patients enrolled in this study, 262 patients (61%) experienced a complete or partial response. In the 390 assessable patients, this percentage was 67%. Median time to response was 4 weeks (range 1–15 weeks), and the NPR was 64%.
Conclusion
Compared to randomized trial populations, palliative radiotherapy in our unselected patients with bone metastases showed similar pain response rates (61%), with a reasonable duration of this effect.
https://ift.tt/2z3oCjX
Clinicopathological significance of miR-27b targeting Golgi protein 73 in patients with hepatocellular carcinoma
https://ift.tt/2Fg9CVa
Hydroxychavicol sensitizes imatinib-resistant chronic myelogenous leukemia cells to TRAIL-induced apoptosis by ROS-mediated IAP downregulation
https://ift.tt/2qFTJ0k
Leptin stimulates the release of pro-inflammatory cytokines in hypothalamic astrocyte cultures from adult and aged rats
Abstract
Leptin is an adipose tissue-derived hormone that acts on the hypothalamus in order to maintain energy homeostasis. However, leptin can also induce an inflammatory response. Increasing evidence has highlighted a critical role of astrocytes in the effects of leptin on the hypothalamus. In addition, astrocytes participate in neuroinflammation by producing and releasing a wide range of inflammatory mediators. In this study, we aimed to investigate the age-dependent effect of leptin on pro- and anti-inflammatory cytokines released by the hypothalamic astrocyte cultures obtained from newborn, adult, and aged Wistar rats. In hypothalamic astrocytes from newborn rats, leptin did not change the release of pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). On the other contrary, leptin increased the release of both TNF-α and IL-1β in astrocyte cultures from adult and aged animals. Regarding the anti-inflammatory cytokine interleukin 10 (IL-10), we did not observe any change in response to leptin. In conclusion, our data suggests a pro-inflammatory action of leptin on the hypothalamus during aging. This in turn may be related to the triggering of metabolic disorders, as both of these conditions are associated with neuroinflammation.
https://ift.tt/2z2oC3z
Carvacrol mitigates proconvulsive effects of lipopolysaccharide, possibly through the hippocampal cyclooxygenase-2 inhibition
Abstract
Systemic injection of LPS changes neuronal excitability and increase susceptibility for convulsions. Carvacrol exerts neuroprotective and antiepileptic effects in animal models. Herein, we investigated the anticonvulsive effect of carvacrol on LPS induced seizure severity and possible involvement of the hippocampal COX-1 and -2 activities in this effect. Adult male wistar rats were used. LPS was injected (400 μg/kg; i.p.) four hours before the PTZ (80 mg/kg; i.p.) injection. Carvacrol was injected (100 mg/kg; i.p.) immediately after the LPS injection. Following the PTZ injection, behavioral seizures were observed for 30 min. Latency and duration for each stage were recorded for analysis. Rats divided into seven groups: (1) PTZ, (2) LPS + PTZ, (3) carvacrol + PTZ, (4) LPS + carvacrol + PTZ, (5) LPS, (6) carvacrol, (7) intact. At the end of the experimental procedure the hippocampus of all animals were extracted to measure COX- 1 and 2 levels using the ELISA. LPS injection four hours before the PTZ injection were significantly reduced latency to seizure stages 3–5 and increased duration of the stage 5 in compare with PTZ group (p < 0.05). Carvacrol significantly reduced these effects of LPS on seizure susceptibility (p < 0.05). However, injection of carvacrol alone before the PTZ injection did not significantly affect seizure indexes in compare with PTZ group. Additionally, LPS significantly increased hippocampal level COX-2 but not COX-1 (p < 0.01) and carvacrol significantly attenuates this effect of LPS (p < 0.001). Carvacrol prevents the proconvulsant effect of LPS possibly through the inhibition of the COX-2 increased activity.
https://ift.tt/2OBSNDu
Impact of missense mutations in survival motor neuron protein (SMN1) leading to Spinal Muscular Atrophy (SMA): A computational approach
Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the mutations in survival motor neuron 1 gene (SMN1). The molecular pathology of missense mutations in SMN1 is not thoroughly investigated so far. Therefore, we collected all missense mutations in the SMN1 protein, using all possible search terms, from three databases (PubMed, PMC and Google Scholar). All missense mutations were subjected to in silico pathogenicity, conservation, and stability analysis tools. We used statistical analysis as a QC measure for validating the specificity and accuracy of these tools. PolyPhen-2 demonstrated the highest specificity and accuracy. While PolyPhen-1 showed the highest sensitivity; overall, PolyPhen2 showed better measures in comparison to other in silico tools. Three mutations (D44V, Y272C, and Y277C) were identified as the most pathogenic and destabilizing. Further, we compared the physiochemical properties of the native and the mutant amino acids and observed loss of H-bonds and aromatic stacking upon the cysteine to tyrosine substitution, which led to the loss of aromatic rings and may reduce protein stability. The three mutations were further subjected to Molecular Dynamics Simulation (MDS) analysis using GROMACS to understand the structural changes. The Y272C and Y277C mutants exhibited maximum deviation pattern from the native protein as compared to D44V mutant. Further MDS analysis predicted changes in the stability that may have been contributed due to the loss of hydrogen bonds as observed in intramolecular hydrogen bond analysis and physiochemical analysis. A loss of function/structural impact was found to be severe in the case of Y272C and Y277C mutants in comparison to D44V mutation. Correlating the results from in silico predictions, physiochemical analysis, and MDS, we were able to observe a loss of stability in all the three mutants. This combinatorial approach could serve as a platform for variant interpretation and drug design for spinal muscular dystrophy resulting from missense mutations.
https://ift.tt/2z2oAst
MEDNIK syndrome with a frame shift causing mutation in AP1S1 gene and literature review of the clinical features
Abstract
MEDNIK syndrome is an autosomal recessive rare disease as one of the most recently described copper metabolism disorder characterized by intellectual disability, ichthyosis, hearing loss, peripheral neuropathy, enteropathy and keratodermia. Here in, we reported a case presented with ichthyosis and intellectual disability with MEDNIK syndrome that confirmed by mutation analysis in a Turkish child. She was finally diagnosed with MEDNIK syndrome by clinical findings, which were confirmed by molecular genetic testing. Sequencing of AP1S1 gene showed a homozygous insertion c.364dupG (NM_001283.4), which is predicted to cause a frameshift of the reading frame (p.D122Gfs*18). To our knowledge, this is the first case of MEDNIK syndrome from Turkey. Diagnosis of MEDNIK syndrome is still challenging and we hope that this case will contribute to further understanding.
https://ift.tt/2OBSMzq
Standardized Citrus unshiu peel extract ameliorates dexamethasone-induced neurotoxicity and depressive-like behaviors in mice
Abstract
Dried Citrus unshiu peel, also known as Chinpi, have been commonly used as a traditional medicine to improve for allergy, inflammation and hepatopathy. Many previously studies have reported that citrus flavonoids show neuroprotective activities. However, the antidepressant-related effects of C. unshiu peels have not been well characterized. Here, the antidepressant-like effects of standardized C. unshiu peel extract (SCP) were evaluated in in vivo and in vitro depression models induced by dexamethasone (DEX), a synthetic glucocorticoid. Male ICR mice (9-week-old) were injected the DEX (40 mg/kg) and were orally given SCP daily (30, 100, and 300 mg/kg) for 14 consecutive days. The depressive-like behaviors were determined by use of open filed test (OFT), sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST). We show that treatment with SCP significantly alleviated DEX-induced depressive-like behaviors and reduced neurotoxicity in a concentration dependent manner in SH-SY5Y cells. Additionally, repeated DEX injection markedly decreased brain derived neurotrophic factor (BDNF) level, tropomyosin receptor kinase B (TrkB), and cyclic AMP-response element-binding protein (CREB), while SCP treatment improved these levels in the cerebral cortex and hippocampus regions. Our findings suggest that SCP exhibits significant antidepressant-like effects in the DEX-induced depressive animal model, and this activity may be mediated by preventing corticosterone-induced neurotoxicity.
https://ift.tt/2z0Wxtc
Gradual common carotid artery occlusion as a novel model for cerebrovascular Hypoperfusion
Abstract
Chronic cerebrovascular hypoperfusion results in vascular dementia and increases predisposition to lacunar infarcts. However, there are no suitable animal models. In this study, we developed a novel model for chronic irreversible cerebral hypoperfusion in mice. Briefly, an ameroid constrictor was placed on the right carotid artery to gradually occlude the vessel, while a microcoil was placed on the left carotid artery to prevent compensation of the blood flow. This procedure resulted in a gradual hypoperfusion developing over a period of 34 days with no cerebral blood flow recovery. Histological analysis of the brain revealed neuronal and axonal degeneration as well as necrotic lesions. The most severely affected regions were located in the hippocampus and the corpus callosum. Overall, our paradigm is a viable model to study brain pathology resulting from gradual cerebrovascular hypoperfusion.
https://ift.tt/2z10TRp
Oxymatrine attenuates brain hypoxic-ischemic injury from apoptosis and oxidative stress: role of p-Akt/GSK3β/HO-1/Nrf-2 signaling pathway
Abstract
To investigate the potential neuroprotection of oxymatrine in hypoxic-ischemic injury in rat's brain and the associated underlying mechanisms, modified neurological severity scores (mNSS) for neurological functional deficits, 2,3,5-triphenyl-tetrazolium chloride (TTC) staining for infarct volume, TUNEL assay and flow cytometry analysis for apoptosis were assessed. The expressions of Akt, glycogen synthase kinase 3 beta (GSK3β), phosphorylated Akt (p-Akt), phosphorylated GSK3β (p-GSK3β), nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were measured by western blot. Our results showed that infarct volume and the apoptosis of NeuN-positive cells were significantly reduced in rats that administrated oxymatrine, with a corresponding improvement in neurological function after H/I. Upregulated p-Akt, p-GSK3β, Nrf-2 and HO-1 expressions were observed in response to oxymatrine treatment. Moreover, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 counteracted the protective effect of oxymatrine, evidenced by western blot and histological outcomes. To conclude, our results suggested that oxymatrine could exert efficacious neuroprotective effect against H/I injury by inhibiting apoptosis and oxidative stress, which might be related to the activation of Akt and GSK3β and modulation of Nrf-2/HO-1 signaling pathway.
https://ift.tt/2OBSHM8
Contemporary scope of inborn errors of metabolism involving epilepsy or seizures
Abstract
Many inborn errors of metabolism may present with epilepsy or seizures, however, current scope of these diseases is unknown. Due to available precision medicine approaches in many inborn errors of metabolism and sophisticated traditional diagnostics, this group of disorders is of special relevance to clinicians. Besides, as current treatment is challenging and unsuccessful in more than 30% of all epilepsy patients, these diseases may provide valuable models for ictogenesis and epileptogenesis studies and potentially pave the ways to identification of novel treatments. The aim of this study was to elucidate genetic architecture of inborn errors of metabolism involving epilepsy or seizures and to evaluate their diagnostic approaches. After extensive search, 880 human genes were identified with a considerable part, 373 genes (42%), associated with inborn errors of metabolism. The most numerous group comprised disorders of energy metabolism (115, 31% of all inborn errors of metabolism). A substantial number of these diseases (26%, 97/373) have established specific treatments, therefore timely diagnosis comes as an obligation. Highly heterogenous, overlapping and non-specific phenotypes in most of inborn errors of metabolism presenting with epilepsy or seizures usually preclude phenotype-driven diagnostics. Besides, as traditional diagnostics involves a range of specialized metabolic tests with low diagnostic yields and is generally inefficient and lengthy, next-generation sequencing-based methods were proposed as a cost-efficient one-step way to shorten "diagnostic odyssey". Extensive list of 373 epilepsy- or seizures-associated inborn errors of metabolism genes may be of value in development of gene panels and as a tool for variants' filtration.
https://ift.tt/2z2aUxt
Correlation of PICALM polymorphism rs3851179 with Alzheimer’s disease among Caucasian and Chinese populations: a meta-analysis and systematic review
Abstract
The rs3851179 which located at upstream of PICALM was reported to be associated with Alzheimer's disease (AD); however, the relationship is still undefined. To gain a more precise understanding of the association, we conducted a meta-analysis: a comprehensive survey of 16 case-control studies that evaluated the role of rs3851179 gene variants in AD patients. The overall analysis revealed a significant association between the polymorphism and AD in the allelic, homozygote, heterozygote, dominant, and recessive models (p < 0.05). When stratified by ethnicity, a significant association was observed between AD development in Caucasian populations and the five-genetic models; Asian populations, however, featured a significant association in only the allelic, homozygote, and recessive models. We did not observe any influence of APOE ε4 carrier status on the incidence of AD and rs3851179 (p > 0.05). Our meta-analysis thus suggested that the PICALM rs3851179 polymorphism was associated with AD; the APOE ε4 status did not influence the relationship. Nevertheless, considering the limitations of our meta-analysis, further large-scale studies should be conducted to gain a more comprehensive understanding.
https://ift.tt/2OBSHf6
Clinical and molecular characteristics of 11 Chinese probands with GM1 gangliosidosis
Abstract
GM1 gangliosidosis is an autosomal recessive lysosomal storage disease caused by the deficiency of β-galactosidase activity, precisely due to mutations in the GLB1 gene. To explore the clinical and molecular characteristics of GM1 gangliosidosis patients from China, GLB1 gene were analyzed in 11 probands with GM1 gangliosidosis by exploiting direct Sanger-sequencing. Among them, five patients were classified as the infantile type and the remaining six as the late-infantile or juvenile type. In these probands, eight novel mutations p.Y50N, p.Y237C, p.S267F, p.G453R, p.K578 N, c.618delC, c.475_478delGACA and c.1979_1980insG have been identified. Among them, three novel missense mutations p.Y50N, p.S267F and p.G453R were transiently transfected in COS-7 cells by plasmid system for functional verification. In vitro GLB1 activities carrying the aforesaid missense mutants p.Y50N, p.S267F and p.G453R were 0.11%, 0 and 0.55% of wild-type, respectively. Mutation c.495_497delTCT and p.S149F accounted for 22.7 and 13.6% of the mutant alleles, respectively. Our results expand the spectrum of GLB1 gene, provide new insights into the clinical and molecular characteristics of GM1 gangliosidosis in China.
https://ift.tt/2OBSFE0
Nicotinamide reverses behavioral impairments and provides neuroprotection in 3˗nitropropionic acid induced animal model ofHuntington’s disease: implication of oxidative stress˗ poly(ADP˗ ribose) polymerase pathway
Abstract
Huntington's disease (HD) is characterized by cognitive and psychiatric impairment caused by neuronal degeneration in the brain. Several studies have supported the hypothesis that oxidative stress is the main pathogenic factor in HD. The current study aims to determine the possible neuroprotective effects of nicotinamide on 3-nitropropionic acid (3-NP) induced HD. Male Wistar albino rats were divided into six groups. Group I was the vehicle-treated control, group II received 3-NP (20 mg/kg, intraperitoneally (i.p.) for 4 days, group III received nicotinamide (500 mg/kg, i.p.). The remaining groups received a combination of 3-NP plus nicotinamide 100, 300 or 500 mg/kg, i.p. respectively for 8 days. Afterward, the motor function and hind paw activity in the limb withdrawal were tested; rats were then euthanized for biochemical and histopathological analyses. Treatment of rats with 3-NP altered the motor function, elevated oxidative stress and caused significant histopathological changes in the brain. The treatment of rats with nicotinamide (100, 300 and 500 mg/kg) improved the motor function tested by locomotor activity test, movement analysis, and limb withdrawal test, which was associated with decreased oxidative stress markers (malondialdehyde, nitrites) and increased antioxidant enzyme (glutathione) levels. In addition, nicotinamide treatment decreased lactate dehydrogenase and prevented neuronal death in the striatal region. Our study, therefore, concludes that antioxidant drugs like nicotinamide might slow progression of clinical HD and may improve the motor functions in HD patients. To the best of our knowledge, this study is the first to explore the neuroprotective effects of nicotinamide on 3-NP-induced HD.
https://ift.tt/2z1csbf
Astrogliosis and decreased neural viability as consequences of early consumption of aspartame and acesulfame potassium in male Wistar rats
Abstract
Artificial sweeteners are mainly used as substitutes for sucrose derivates. In this study, we analyzed if the chronic consumption of aspartame or acesulfame potassium at an early age, produces histological alterations, astrogliosis and decreased neuronal viability, in hippocampus, prefrontal cortex, amygdala and hypothalamus of male Wistar rats. A histological analysis was performed on male Wistar rats that consumed aspartame or acesulfame potassium during 90 days, initiating the consumption of sweeteners immediately after weaning. The evaluation of neuronal morphology in different areas of the brain was performed with hematoxylin - eosin staining. To measure astrogliosis and neuronal viability, we used the immunohistochemical technique, with the glial fibrillary acidic protein immunomodulators (GFAP) and with neuronal-specific enolase (NSE). The consumption of aspartame or acesulfame potassium promoted morphological changes of neurons including increased pyknotic nuclei and vacuolization in all the brain areas studied. In hippocampus, prefrontal cortex, amygdala and hypothalamus, astrogliosis and reduction of neural viability were observed in sweeteners consumers in comparison with the control group. Chronic consumption of ASP and ACK from early stages of development and during long periods, may promote neural modifications, astrogliosis and decrease neuronal viability in prefrontal cortex, amygdala, hippocampus, and hypothalamus.
https://ift.tt/2Oy8Imh
A polymer model for the quantitative reconstruction of chromosome architecture from HiC and GAM data
It is widely believed that the folding of the chromosome in the nucleus has a major effect on genetic expression. For example co-regulated genes in several species have been shown to colocalize in space despite being far away on the DNA sequence. In this manuscript, we present a new method to model the three-dimensional structure of the chromosome in live cells, based on DNA-DNA interactions measured in high-throughput chromosome conformation capture experiments (Hi-C and GAM). Our approach incorporates a polymer model, and uses directly the contact probabilities measured in Hi-C and GAM experiments rather than estimates of average distances between genomic loci.
https://ift.tt/2yZov8U
-
Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
-
Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
-
heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
