Background The aim of this study is to report the experience with a program of Intensive Care to facilitate Organ Donation (ICOD) in 2 Spanish centers based on a common protocol. Methods Retrospective review of clinical charts of patients with a devastating brain injury whose families were approached to discuss the possibility of ICOD once further treatment was deemed futile by the treating team. Study period: 1/1/2011-12/31/2015. Results ICOD was discussed with families of 131 patients. Mean age of possible donors was 75 (SD=11) years. The main cause of brain injury was an intracranial hemorrhage (72%). Interviews with families were held after the decision had been made not to intubate/ventilate in 50% of cases, and after the decision not to continue with invasive ventilation in the remaining cases. Most interviews (66%) took place in the emergency department. The majority of families (95%) consented to ICOD. Of the 125 consented cases, 101 (81%) developed brain death (BD), most in ≤72 hours. Ninety-nine patients (98%) transitioned to actual donation after BD, with 1.2 organs transplanted per donor. Of patients who did not evolve to BD, 4 died following an unexpected cardiac arrest and 18 after the withdrawal of life-sustaining measures. ICOD contributed to 33% of actual donors registered at both centers. Conclusions ICOD is well accepted by families. Most patients evolve to BD within a short period of time. The practice substantially contributes to increasing organ donation and offers more patients the chance of donating their organs after death. CORRESPONDENCE INFORMATION: Beatriz Domínguez-Gil, MD, PhD. Director General, Organización Nacional de Trasplantes. C/Sinesio Delgado 6, pabellón 3, 28029 Madrid, Spain, Email: bdominguez@msssi.es AUTHORSHIP PAGE: FMS, JMPV and BDG conceived and designed the study. FMS, LMC and JMPV contributed with the data required for the study. EC and BDG coordinated the data collection and undertook the statistical analysis. JLM, AFC and PM participated in the performance of the research. FMS, JMPV and BDG drafted the first version of the paper, with contributions from the rest of the authors. The authors declare no conflict of interests. The study received no external funding. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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Τετάρτη 4 Ιουλίου 2018
Donor Derived Viral Infections in Liver Transplantation
Donor-derived infections are defined as any infection present in the donor that is transmitted to 1 or more recipients. Donor-derived infections can be categorized into 2 groups: 'expected' and 'unexpected' infections. Expected transmissions occur when the donor is known to have an infection, such as positive serology for CMV, EBV or hepatitis B core antibody, at the time of donation. Unexpected transmissions occur when a donor has no known infection prior to donation, but 1 or more transplant recipients develop an infection derived from the common donor. Unexpected infections are estimated to occur in far less than 1% of solid organ transplant recipients. We will review the epidemiology, risk factors and approaches to prevention and management of donor-derived viral infectious disease transmission in liver transplantation. *Co-First Authors Corresponding Author: Michael G. Ison, MD MS FIDSA FAST, Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, 645 N Michigan Avenue Suite 900, Chicago, Illinois 60611, 312-695-4186 (Office), 312-695-5088 (Fax). mgison@northwestern.edu Authorship Page Hannah Nam, MD and Kathy M Nilles, MD are co-first authors. Both have made substantial contributions in gathering information necessary in drafting the article, participated in writing the article, and revised it critically for important intellectual content. Josh Levitsky, MD MS and Michael G Ison, MD MS have revised the article critically for important intellectual content and gave final approval of the version to be submitted, as well as any revised versions. Disclosures: HN and KMN have nothing to disclose. JL is a paid speaker for Gilead and Novartis. MGI has received support for research, paid to Northwestern University from Beckman Coulter, Cephied, Chimerix, Emergent BioScience, Gilead, Janssen, and Shire; compensated consultation from Chimerix, Celltrion, Genentech/Roche, MediVector, Seqirus, Shionogi, and VirBio; and paid membership of DSMB from GlaxoSmithKlein, Shionogi. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2KxdXFY
https://ift.tt/2KxdXFY
Incidence, Risk Factors and Outcomes of Early Acute Kidney Injury After Heart Transplantation: An 18-year Experience
Background Little is known about the incidence of acute kidney injury (AKI), as defined using the Kidney Disease Improving Global Outcome (KDIGO) classification, after heart transplantation (HT). Objective. Our objective was to evaluate the impact of AKI in a cohort of HT recipients. (Setting: University Hospital.) Methods We studied 310 consecutive HT recipients from 1999 to 2017, with AKI being defined according to the KDIGO criteria. Risk factors were analyzed by multivariable analyses, and survival by Kaplan-Meier curves and a risk-adjusted Cox proportional hazards regression model. Results 125 patients (40.3%) developed AKI, with 73 (23.5%), 18 (5.8%) and 34 (11%) patients having AKI stage 1, 2 and 3, respectively. Cardiac tamponade (OR: 16.82; 95% CI: 1.06–138), acute right ventricular failure (OR: 3.54; 95% CI: 1.82–6.88), and major bleeding (OR: 2.46; 95% CI: 1.18–5.1) were the principal risk factors for AKI. Patients with AKI had a greater hospital mortality (3.8% vs. 16%, P
https://ift.tt/2IUR8Ge
https://ift.tt/2IUR8Ge
Cardiac output response to exercise in patients before allogenic hematopoietic stem cell transplantation
Abstract
Introduction
High-dose chemotherapy for remission induction can induce cardiac toxicity prior to hematopoietic stem cell transplantation (HSCT). However, the details of cardiac function in patients undergoing HSCT are unclear, particularly during exercise. The aim of present study was to evaluate cardiac output responses to exercise in patients after high-dose chemotherapy before HSCT compared with in age-matched healthy controls.
Methods
Twenty-nine patients before HSCT (age 44.6 ± 15.2 years) and 13 controls (45.8 ± 16.0 years) performed the 6-min walk test (6MWT). Cardiac output (CO), stroke volume (SV), heart rate (HR), and cardiac index (CI) were continuously measured during the 6MWT using the noninvasive thoracic impedance method.
Results
No significant difference was observed in the six-minute walk distance (6MD) between the two groups. SV, CO, and CI both at rest and the end of the 6MWT in the patients were significantly lower, compared with the controls, but there was no significant difference in HR. In all subjects, the 6MD was positively correlated with SV, CO, CI, and HR after the 6MWT.
Conclusion
These findings suggest that cardiac output response to exercise indicates exercise intolerance, which may not be detected by 6MD in patients before HSCT.
https://ift.tt/2lVM3Vp
Targeting tumor-associated acidity in cancer immunotherapy
Abstract
Checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1) monoclonal antibodies have changed profoundly the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma, and bladder cancer. Currently, they are tested in various tumor entities as monotherapy or in combination with chemotherapies or targeted therapies. However, only a subgroup of patients benefit from checkpoint blockade (combinations). This raises the question, which all mechanisms inhibit T cell function in the tumor environment, restricting the efficacy of these immunotherapeutic approaches. Serum activity of lactate dehydrogenase, likely reflecting the glycolytic activity of the tumor cells and thus acidity within the tumor microenvironment, turned out to be one of the strongest markers predicting response to checkpoint inhibition. In this review, we discuss the impact of tumor-associated acidity on the efficacy of T cell-mediated cancer immunotherapy and possible approaches to break this barrier.
https://ift.tt/2Nt4Vr9
Postoperative imatinib in patients with intermediate risk gastrointestinal stromal tumor
Future Oncology, Ahead of Print.
https://ift.tt/2KOR0Kv
SMYD3 promoter hypomethylation is associated with the risk of colorectal cancer
Future Oncology, Ahead of Print.
https://ift.tt/2NsqCaW
Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy
Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy
Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy, Published online: 05 July 2018; doi:10.1038/s41416-018-0168-9
Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy
https://ift.tt/2zdz4HS
Level and factors associated with birth preparedness and complication readiness among semi-pastoral pregnant women in southern Ethiopia, 2016
The objective of this study was to determine the level of birth preparedness and complication readiness (BPCR) and associated factors among semi-pastoral pregnant women in southern, Ethiopia.
https://ift.tt/2lSBAtz
Detection of Clostridium botulinum group III in environmental samples from farms by real-time PCR using four commercial DNA extraction kits
Few studies have tested DNA extraction methods to optimize the detection of Clostridium botulinum in environmental samples that can be collected during animal botulism outbreaks. In this study, we evaluated four ...
https://ift.tt/2zi6Fke
Prevalence of intestinal helminths and associated factors among school children of Medebay Zana wereda; North Western Tigray, Ethiopia 2017
To assess the prevalence of intestinal helminth infections and associated factors among primary school children of Medebay Zana wereda, a northwestern zone of Tigray, northern Ethiopia from March to April 2017.
https://ift.tt/2lSBylr
Screening, purification and characterization of cellulase from cellulase producing bacteria in molasses
This study was conducted to isolate, screening and purification of cellulase from bacteria present in sugar industry waste (molasses) and characterization by morphological and biochemical analysis.
https://ift.tt/2u5HQ58
Rational prescribing of antibiotics in children under 5 years with upper respiratory tract infections in Kintampo Municipal Hospital in Brong Ahafo Region of Ghana
The aim of the study was to assess the rational use of antibiotics in children with URTIs in the Kintampo Municipal Hospital in Ghana.
https://ift.tt/2lSBuCd
Are We Going Nuts on Coconut Oil?
Abstract
Purpose of Review
Sales and consumption of coconut oil have been on the raise due to effective marketing strategies. Coconut oil is stated to offer various benefits including weight loss, improvement in immunity, heart health support, and memory enhancement. Also, it is often portrayed as an excellent source of medium chain triglycerides (MCTs). Here, we review the evidence behind the clinical utility of coconut oil consumption.
Recent Findings
Several studies consistently showed consumption of coconut oil increases low-density lipoprotein cholesterol (LDL-C) and thereby could increase adverse cardiovascular health. Even though coconut oil has relatively high MCT concentration, the clinical benefits of commercial MCT oils cannot be generalized to coconut oil.
Summary
Until the long-term effects of coconut oil on cardiovascular health are clearly established, coconut oil should be considered as a saturated fat and its consumption should not exceed the USDA's daily recommendation (less than 10% of total calorie intake).
https://ift.tt/2lV1HjP
A Randomized Controlled Trial of a Barrier Dressing to Reduce Nasal Injury in Preterm Infants Receiving Binasal Noninvasive Respiratory Support
To determine whether the use of a hydrocolloid nasal barrier dressing during binasal continuous positive airway pressure (CPAP) therapy, compared with no barrier dressing, reduces the rate of nasal injury in very preterm and/or very low birth weight infants.
https://ift.tt/2KzG3Ak
Electrophysiological Evidence of an Attentional Bias towards Appetitive and Aversive Words in Adults with Attention-Deficit/Hyperactivity Disorder
The emotional symptom domain of Attention-Deficit/Hyperactivity Disorder (ADHD) has received increasing attention in the past decade (see Shaw et al., 2014; Retz et al., 2012 for reviews). Moving beyond the traditionally studied symptom domains of hyperactivity, impulsivity, and inattention is particularly important, considering the findings of significant and independent impairments associated with emotion dysregulation (ED) in patients with ADHD (Barkley and Murphy, 2010; Bunford et al., 2014).
https://ift.tt/2lTP8F9
Doing it the other way round – mapping motor function by intrinsic activity
The first neurosurgeons were already known for their aim to localize areas indispensable for motor function. Among them, Krause injected small currents in what became known as primary motor cortex (M1) and noted movements in specific parts of the body (Krause, 1908). Another great leap forward came as Penfield and Jasper laid the foundations for the sensorimotor homunculi, by which time technology had evolved with the advent of EEG so that cortical stimulation could be complemented by electrocorticography (ECoG) recordings of intrinsic brain activity.
https://ift.tt/2zdppRC
Diagnostic accuracy of quantitative EEG to detect delayed cerebral ischemia after subarachnoid hemorrhage: A preliminary study
Case fatality and morbidity of aneurysmal subarachnoid hemorrhage (SAH) decreased during the past decades (Nieuwkamp et al., 2009). Despite improvement of both its prevention (Pickard et al., 1989) and management strategies (Nieuwkamp et al., 2009; Connolly et al., 2012), delayed cerebral ischemia (DCI), which occurs between three to 21 days after bleeding (Charpentier et al., 1999), is the most important and preventable cause of SAH morbidity (Francoeur and Mayer, 2016). DCI pathophysiology is still debated and encompass proximal vasospasm, capillary vasospasm, and spreading depolarizations (Dreier, 2011; Francoeur and Mayer, 2016).
https://ift.tt/2lX86Lg
Delayed high-frequency suppression after automated single-pulse electrical stimulation identifies the seizure onset zone in patients with refractory epilepsy
Twenty to thirty percent of patients with epilepsy are pharmacoresistent (Tonini et al. , 2004). Epilepsy surgery, in which the seizure focus is removed, is an option for some patients and leads to seizure freedom in ∼55-70% of temporal resections and 30-50% of neocortical resections (Tonini et al. , 2004). Many patients require surgical implantation of intracranial electrocorticography (ECoG) electrodes for seizure monitoring to estimate the seizure onset zone (SOZ). Because ECoG is invasive and involves prolonged hospitalization, some patients are hesitant to undergo the procedure, and some neurologists are reluctant to refer patients despite the possibility of seizure freedom.
https://ift.tt/2z9Zv17
Cervical dystonia: Normal auditory mismatch negativity and abnormal somatosensory mismatch negativity
Dystonia is characterized by abnormal postures of the affected body part (Marsden, 1976). This motor dysfunction is the visible part of dystonia, but there is a significant body of evidence suggesting that failures in sensorimotor integration and pure sensory abnormalities
https://ift.tt/2lRQhNs
Long-Term Outcomes of Out-of-Hospital Cardiac Arrest Care at Regionalized Centers
It is unknown whether regionalization of postarrest care by interfacility transfer to cardiac arrest receiving centers reduces mortality. We seek to evaluate whether treatment at a cardiac arrest receiving center, whether by direct transport or early interfacility transfer, is independently associated with long-term outcome.
https://ift.tt/2Ns202b
Use of Interpreter Services in the Emergency Department
People with limited English proficiency cannot speak, read, or write English well enough to communicate effectively in the language.1 Approximately 8% of the US population older than 5 years have limited English proficiency; this number is increasing overall.2 This group includes not only those whose primary language was not English but also those who have sensory impairments: diminished hearing or deafness, partial sight or blindness, or physical inability to speak. Limited English proficiency is associated with disparities in access to health care, lower health literacy, and poorer health care outcomes.
https://ift.tt/2zd733g
Potentially Avoidable Emergency Department Use: When Policy Expects Patients to be Physicians
Identifying and preventing avoidable use of the emergency department (ED) may provide substantial cost savings. One study suggested approximately one fifth of US ED visit episode costs could be avoidable, with an annual estimated expense of greater than $60 billion.1 Considering the cost associated with ED use, payers have embarked on policies with the goal of reducing what is perceived as inappropriate ED visits. These strategies have put patients at greater financial risk and have faced scrutiny from the medical community.
https://ift.tt/2tV5CS2
Preoperative EUS-guided fine-needle aspiration: effects on peritoneal recurrence and survival in patients with pancreatic cancer
Endoscopic ultrasound-guided fine-needle aspiration (EUS-guided FNA) is an accurate and relatively safe tissue confirmation method for pancreatic cancer. However, there is concern that this procedure may spread tumor cells along the needle track or within the peritoneum. We aimed to estimate the effect of preoperative EUS-guided FNA on the risk of peritoneal recurrence and long-term outcomes in resected pancreatic cancer.
https://ift.tt/2lYXDiB
Exploring the combination and modular characteristics of herbs for alopecia treatment in traditional Chinese medicine: an association rule mining and network analysis study
Although alopecia affects the quality of life, its pathogenesis is unknown, because cellular interactions in the hair follicle are complex. Several authors have suggested using herbal medicine to treat alopeci...
https://ift.tt/2lVRGCV
Oleanolic acid attenuates TGF-β1-induced epithelial-mesenchymal transition in NRK-52E cells
Epithelial-to-mesenchymal transition (EMT) plays an important role in the progression of renal interstitial fibrosis, which finally leads to renal failure. Oleanolic acid (OA), an activator of NF-E2-related fa...
https://ift.tt/2z7o8eZ
Effects of a hydroalcoholic extract of Juglans regia (walnut) leaves on blood glucose and major cardiovascular risk factors in type 2 diabetic patients: a double-blind, placebo-controlled clinical trial
We aimed to evaluate the effects of a hydroalcoholic extract of Juglans regia L. leaves on blood glucose level and cardiovascular risk factors in type 2 diabetic patients.
https://ift.tt/2lVXTyI
Weak HIF-1alpha expression indicates poor prognosis in resectable pancreatic ductal adenocarcinoma
Abstract
Background
HIF-1alpha and CAIX proteins are commonly expressed under hypoxic conditions, but other regulatory factors have been described as well. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and strong stromal reaction and has a dismal prognosis with the currently available treatment modalities.
Methods
We investigated the expression and prognostic role of HIF-1alpha and CAIX in PDAC series from Northern Finland (n = 69) using immunohistochemistry.
Results
In our PDAC cases, 95 and 85% showed HIF-1alpha and CAIX expression, respectively. Low HIF-1alpha expression correlated with poor prognosis, and multivariate analysis identified weak HIF-1alpha intensity as an independent prognostic factor for PDAC-specific deaths (HR 2.176, 95% CI 1.216–3.893; p = 0.009). There was no correlation between HIF-1alpha and CAIX expression levels, and the latter did not relate with survival.
Conclusions
Our findings are in contrast with previous research by finding an association between low HIF-1alpha and poor prognosis. The biological mechanisms remain speculative, but such an unexpected relation with prognosis and absence of correlation between HIF-1alpha and CAIX suggests that the prognostic association of HIF-1alpha may not directly be linked with hypoxia. Accordingly, the role of HIF-1alpha might be more complex than previously thought and the use of this marker as a hypoxia-related prognostic factor should be addressed with caution.
https://ift.tt/2tSOX1m
Correlation of clinical illness with viremia in Zika virus disease during an outbreak in Singapore
The first autochthonous Zika virus (ZIKV) outbreak in Singapore was detected in August 2016. We report an analysis of the correlation of clinical illness with viremia and laboratory parameters in this Asian co...
https://ift.tt/2tWIe6u
Social networks in relation to self-reported symptomatic infections in individuals aged 40–75 - the Maastricht study –
Most infections are spread through social networks (detrimental effect). However, social networks may also lower infection acquisition (beneficial effect). This study aimed to examine associations between soci...
https://ift.tt/2KNYvRV
Extra-haematological manifestations related to human parvovirus B19 infection: retrospective study in 25 adults
To describe extra-haematological manifestations associated with human parvovirus B19 (HPV-B19) infection.
https://ift.tt/2NphhAF
Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy
We have previously shown that 8 weeks' treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D3 (vitD3) (5000 IU/day) as host-directed therapy (HDT) accelerated clinical recovery, sputum cultu...
https://ift.tt/2KNIMlG
Yield of household contact tracing for tuberculosis in rural South Africa
Efficient and effective strategies for identifying cases of active tuberculosis (TB) in rural sub-Saharan Africa are lacking. Household contact tracing offers a potential approach to diagnose more TB cases, an...
https://ift.tt/2NrPorQ
Caenorhabditis Sieve: A Low-tech Instrument and Methodology for Sorting Small Multicellular Organisms
https://ift.tt/2u6tH7s
Objective Nociceptive Assessment in Ventilated ICU Patients: A Feasibility Study Using Pupillometry and the Nociceptive Flexion Reflex
Pain assessment in anesthetized patients who cannot communicate with the outside world in any way remains challenging despite the development of innovative objective pain evaluation tools. In this project, the pupillary dilation reflex and the nociception flexion reflex are assessed in critically ill, mechanically ventilated adult patients.
https://ift.tt/2lRRAvX
Nasal Potential Difference to Quantify Trans-epithelial Ion Transport in Mice
Here, we present a protocol to measure nasal potential difference in mice. The test quantifies the function of transmembrane ion transporters such as the cystic fibrosis transmembrane conductance regulator and the epithelial sodium channel. It is valuable to evaluate the efficacy of novel therapies for cystic fibrosis.
https://ift.tt/2u5sahZ
Risk factors for hospitalized patients with resistant or multidrug-resistant Pseudomonas aeruginosa infections: a systematic review and meta-analysis
Identifying risk factors predicting acquisition of resistant Pseudomonas aeruginosa will aid surveillance and diagnostic initiatives and can be crucial in early and appropriate antibiotic therapy. We conducted a ...
https://ift.tt/2KQNwqz
Frequent Tail-tip Blood Sampling in Mice for the Assessment of Pulsatile Luteinizing Hormone Secretion
Here we present a tail-tip blood sampling protocol for frequent sample collection in unrestrained mice. This method is useful for assessing patterns of pulsatile luteinizing hormone secretion and could be adapted for analysis of other circulating factors.
https://ift.tt/2zdd4go
Assessing the Viability of a Synthetic Bacterial Consortium on the In Vitro Gut Host-microbe Interface
Gut host-microbe interactions were assessed using a novel approach combining a synthetic oral community, in vitro gastrointestinal digestion, and a model of the small intestine epithelium. We present a method that can be adapted to evaluate cell invasion of pathogens and multi-species biofilms, or even to test probiotic formulations' survivability.
https://ift.tt/2lUR5Bx
A study on the value of narrow-band imaging (NBI) for the general investigation of a high-risk population of nasopharyngeal carcinoma (NPC)
Abstract
Background
This study aims to explore the feasibility of narrow-band imaging (NBI) applied for the diagnostic screening of a high-risk population of nasopharyngeal carcinoma (NPC) and increase the accuracy rate of nasopharyngeal biopsy and the diagnosis rate of early-stage patients.
Methods
The positive high-risk population of NPC to EB virus antibody was followed up. At the same time, serological screening and pharyngorhinoscopy were carried out. The specific methods were as follows: (1) all subjects received nasopharyngeal examinations through both the HD endoscopic white light mode (WL) and NBI mode, (2) nasopharyngeal biopsy was conducted on positive subjects with microscopic examination, and, finally, (3) a comparative analysis was conducted between the biopsy pathology results and microscopy results. In addition, the following comparative indicators were recorded under different modes: sensitivity, specificity, accuracy, positive likelihood ratio, and negative likelihood ratio. Then, the area under the ROC curve and the kappa coefficient were calculated.
Results
A total of 115 subjects were detected to be positive by microscopic examination under the WL mode. Among these subjects, 19 subjects were diagnosed with NPC. In addition, 24 subjects were detected to be positive by microscopic examination under the NBI mode. Among these subjects, 23 subjects were diagnosed with NPC. Under the WL mode, the specific values of the comparative indicators were as follows: sensitivity, 82.61%; specificity, 0%; and area under the ROC curve, 0.413. Furthermore, the WL mode in the diagnosis on the high-risk population of NPC exhibited poor consistency with the biopsy pathology results (kappa coefficient = − 0.069). Under the NBI mode, the specific values of the comparative indicators were as follows: sensitivity, 100%; specificity, 98.96%; and area under the ROC curve, 0.995. Furthermore, the NBI mode in the diagnosis on the high-risk population of NPC exhibited relatively satisfactory consistency with the biopsy pathology results (kappa coefficient = 0.973). Therefore, the NBI mode is significantly superior to the WL mode.
Conclusion
NBI endoscopic examinations should be conducted on a routine basis for high-risk populations of NPC. This can decrease the frequency of biopsies and enhance diagnostic effects.
https://ift.tt/2zaleGp
Loss of CaMKI Function Disrupts Salt Aversive Learning in C. elegans
The ability to adapt behavior to environmental fluctuations is critical for survival of organisms ranging from invertebrates to mammals. Caenorhabditis elegans can learn to avoid sodium chloride when it is paired with starvation. This behavior may help animals avoid areas without food. Although some genes have been implicated in this salt-aversive learning behavior, critical genetic components, and the neural circuit in which they act, remain elusive. Here, we show that the sole worm ortholog of mammalian CaMKI/IV, CMK-1, is essential for salt-aversive learning behavior in C. elegans hermaphrodites. We find that CMK-1 acts in the primary salt-sensing ASE neurons to regulate this behavior. By characterizing the intracellular calcium dynamics in ASE neurons using microfluidics, we find that loss of cmk-1 has subtle effects on sensory-evoked calcium responses in ASE axons and their modulation by salt conditioning. Our study implicates the expression of the conserved CaMKI/CMK-1 in chemosensory neurons as a regulator of behavioral plasticity to environmental salt in C. elegans.
SIGNIFICANCE STATEMENT Like other animals, the nematode Caenorhabditis elegans depends on salt for survival and navigates toward high concentrations of this essential mineral. In addition to its role as an essential nutrient, salt also causes osmotic stress at high concentrations. A growing body of evidence indicates that C. elegans balances the requirement for salt with the danger it presents through a process called salt-aversive learning. We show that this behavior depends on expression of a calcium/calmodulin-dependent kinase, CMK-1, in the ASE salt-sensing neurons. Our study identifies CMK-1 and salt-sensitive chemosensory neurons as key factors in this form of behavioral plasticity.
https://ift.tt/2lUO0kG
Nerve Injury-Induced Chronic Pain Is Associated with Persistent DNA Methylation Reprogramming in Dorsal Root Ganglion
Nerve injury-induced hyperactivity of primary sensory neurons in the dorsal root ganglion (DRG) contributes to chronic pain development, but the underlying epigenetic mechanisms remain poorly understood. Here we determined genome-wide changes in DNA methylation in the nervous system in neuropathic pain. Spinal nerve ligation (SNL), but not paclitaxel treatment, in male Sprague Dawley rats induced a consistent low-level hypomethylation in the CpG sites in the DRG during the acute and chronic phases of neuropathic pain. DNA methylation remodeling in the DRG occurred early after SNL and persisted for at least 3 weeks. SNL caused DNA methylation changes at 8% of CpG sites with prevailing hypomethylation outside of CpG islands, in introns, intergenic regions, and repetitive sequences. In contrast, SNL caused more gains of methylation in the spinal cord and prefrontal cortex. The DNA methylation changes in the injured DRGs recapitulated developmental reprogramming at the neonatal stage. Methylation reprogramming was correlated with increased gene expression variability. A diet deficient in methyl donors induced hypomethylation and pain hypersensitivity. Intrathecal administration of the DNA methyltransferase inhibitor RG108 caused long-lasting pain hypersensitivity. DNA methylation reprogramming in the DRG thus contributes to nerve injury-induced chronic pain. Restoring DNA methylation may represent a new therapeutic approach to treat neuropathic pain.
SIGNIFICANCE STATEMENT Epigenetic mechanisms are critically involved in the transition from acute to chronic pain after nerve injury. However, genome-wide changes in DNA methylation in the nervous system and their roles in neuropathic pain development remain unclear. Here we used digital restriction enzyme analysis of methylation to quantitatively determine genome-wide DNA methylation changes caused by nerve injury. We showed that nerve injury caused DNA methylation changes at 8% of CpG sites with prevailing hypomethylation outside of CpG islands in the dorsal root ganglion. Reducing DNA methylation induced pain hypersensitivity, whereas increasing DNA methylation attenuated neuropathic pain. These findings extend our understanding of the epigenetic mechanism of chronic neuropathic pain and suggest new strategies to treat nerve injury-induced chronic pain.
https://ift.tt/2lUmqUV
{alpha}2{delta}-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses
α2-4 is an auxiliary subunit of voltage-gated Cav1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding α2-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of α2-4, we used genome editing to generate an α2-4 knock-out (α2-4 KO) mouse. In male and female α2-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in α2-4 KO retina. In reconstructions of α2-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in α2-4 KO mice correlates with a progressive loss of Cav1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in α2-4 KO mice and better under photopic than scotopic conditions. We conclude that α2-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.
SIGNIFICANCE STATEMENT In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for α2-4, a subunit of voltage-gated Ca2+ channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca2+ channels are progressively lost and that rod and cone synapses are disrupted in mice that lack α2-4. Our results suggest that alterations in presynaptic Ca2+ signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the CACNA2D4 gene encoding α2-4.
https://ift.tt/2lSfIyz
Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking
Activating Transcription Factor 4 (ATF4) has been postulated as a key regulator of learning and memory. We previously reported that specific hippocampal ATF4 downregulation causes deficits in synaptic plasticity and memory and reduction of glutamatergic functionality. Here we extend our studies to address ATF4's role in neuronal excitability. We find that long-term ATF4 knockdown in cultured rat hippocampal neurons significantly increases the frequency of spontaneous action potentials. This effect is associated with decreased functionality of metabotropic GABAB receptors (GABABRs). Knocking down ATF4 results in significant reduction of GABABR-induced GIRK currents and increased mIPSC frequency. Furthermore, reducing ATF4 significantly decreases expression of membrane-exposed, but not total, GABABR 1a and 1b subunits, indicating that ATF4 regulates GABABR trafficking. In contrast, ATF4 knockdown has no effect on surface expression of GABABR2s, several GABABR-coupled ion channels or β2 and 2 GABAARs. Pharmacologic manipulations confirmed the relationship between GABABR functionality and action potential frequency in our cultures. Specifically, the effects of ATF4 downregulation cited above are fully rescued by transcriptionally active, but not by transcriptionally inactive, shRNA-resistant, ATF4. We previously reported that ATF4 promotes stabilization of the actin-regulatory protein Cdc42 by a transcription-dependent mechanism. To test the hypothesis that this action underlies the mechanism by which ATF4 loss affects neuronal firing rates and GABABR trafficking, we downregulated Cdc42 and found that this phenocopies the effects of ATF4 knockdown on these properties. In conclusion, our data favor a model in which ATF4, by regulating Cdc42 expression, affects trafficking of GABABRs, which in turn modulates the excitability properties of neurons.
SIGNIFICANCE STATEMENT GABAB receptors (GABABRs), the metabotropic receptors for the inhibitory neurotransmitter GABA, have crucial roles in controlling the firing rate of neurons. Deficits in trafficking/functionality of GABABRs have been linked to a variety of neurological and psychiatric conditions, including epilepsy, anxiety, depression, schizophrenia, addiction, and pain. Here we show that GABABRs trafficking is influenced by Activating Transcription Factor 4 (ATF4), a protein that has a pivotal role in hippocampal memory processes. We found that ATF4 downregulation in hippocampal neurons reduces membrane-bound GABABR levels and thereby increases intrinsic excitability. These effects are mediated by loss of the small GTPase Cdc42 following ATF4 downregulation. These findings reveal a critical role for ATF4 in regulating the modulation of neuronal excitability by GABABRs.
https://ift.tt/2zkQ6Ej
Perineuronal Nets in the Deep Cerebellar Nuclei Regulate GABAergic Transmission and Delay Eyeblink Conditioning
Perineuronal nets (PNNs), composed mainly of chondroitin sulfate proteoglycans, are the extracellular matrix that surrounds cell bodies, proximal dendrites, and axon initial segments of adult CNS neurons. PNNs are known to regulate neuronal plasticity, although their physiological roles in cerebellar functions have yet to be elucidated. Here, we investigated the contribution of PNNs to GABAergic transmission from cerebellar Purkinje cells (PCs) to large glutamatergic neurons in the deep cerebellar nuclei (DCN) in male mice by recording IPSCs from cerebellar slices, in which PNNs were depleted with chondroitinase ABC (ChABC). We found that PNN depletion increased the amplitude of evoked IPSCs and enhanced the paired-pulse depression. ChABC treatment also facilitated spontaneous IPSCs and increased the miniature IPSC frequency without changing not only the amplitude but also the density of PC terminals, suggesting that PNN depletion enhances presynaptic GABA release. We also demonstrated that the enhanced GABAergic transmission facilitated rebound firing in large glutamatergic DCN neurons, which is expected to result in the efficient induction of synaptic plasticity at synapses onto DCN neurons. Furthermore, we tested whether PNN depletion affects cerebellar motor learning. Mice having received the enzyme into the interpositus nuclei, which are responsible for delay eyeblink conditioning, exhibited the conditioned response at a significantly higher rate than control mice. Therefore, our results suggest that PNNs of the DCN suppress GABAergic transmission between PCs and large glutamatergic DCN neurons and restrict synaptic plasticity associated with motor learning in the adult cerebellum.
SIGNIFICANCE STATEMENT Perineuronal nets (PNNs) are one of the extracellular matrices of adult CNS neurons and implicated in regulating various brain functions. Here we found that enzymatic PNN depletion in the mouse deep cerebellar nuclei (DCN) reduced the paired-pulse ratio of IPSCs and increased the miniature IPSC frequency without changing the amplitude, suggesting that PNN depletion enhances GABA release from the presynaptic Purkinje cell (PC) terminals. Mice having received the enzyme in the interpositus nuclei exhibited a higher conditioned response rate in delay eyeblink conditioning than control mice. These results suggest that PNNs regulate presynaptic functions of PC terminals in the DCN and functional plasticity of synapses on DCN neurons, which influences the flexibility of adult cerebellar functions.
https://ift.tt/2u6yhme
Neural Network Interactions Modulate CRY-Dependent Photoresponses in Drosophila
Light is one of the chief environmental cues that reset circadian clocks. In Drosophila, CRYPTOCHROME (CRY) mediates acute photic resetting of circadian clocks by promoting the degradation of TIMELESS in a cell-autonomous manner. Thus, even circadian oscillators in peripheral organs can independently perceive light in Drosophila. However, there is substantial evidence for nonautonomous mechanisms of circadian photoreception in the brain. We have previously shown that the morning (M) and evening (E) oscillators are critical light-sensing neurons that cooperate to shift the phase of circadian behavior in response to light input. We show here that light can efficiently phase delay or phase advance circadian locomotor behavior in male Drosophila even when either the M- or the E-oscillators are ablated, suggesting that behavioral phase shifts and their directionality are largely a consequence of the cell-autonomous nature of CRY-dependent photoreception. Our observation that the phase response curves of brain and peripheral oscillators are remarkably similar further supports this idea. Nevertheless, the neural network modulates circadian photoresponses. We show that the M-oscillator neurotransmitter pigment dispersing factor plays a critical role in the coordination between M- and E-oscillators after light exposure, and we uncover a potential role for a subset of dorsal neurons in the control of phase advances. Thus, neural modulation of autonomous light detection might play an important role in the plasticity of circadian behavior.
SIGNIFICANCE STATEMENT Input pathways provide circadian rhythms with the flexibility needed to harmonize their phase with environmental cycles. Light is the chief environmental cue that synchronizes circadian clocks. In Drosophila, the photoreceptor CRYPTOCHROME resets circadian clocks cell-autonomously. However, recent studies indicate that, in the brain, interactions between clock neurons are critical to reset circadian locomotor behavior. We present evidence supporting the idea that the ability of flies to advance or delay their rhythmic behavior in response to light input essentially results from cell-autonomous photoreception. However, because of their networked organization, we find that circadian neurons have to cooperate to reset the phase of circadian behavior in response to photic cues. Our work thus helps to reconcile cell-autonomous and non-cell-autonomous models of circadian entrainment.
https://ift.tt/2u0CMyE
Glial {beta}II Spectrin Contributes to Paranode Formation and Maintenance
Action potential conduction along myelinated axons depends on high densities of voltage-gated Na+ channels at the nodes of Ranvier. Flanking each node, paranodal junctions (paranodes) are formed between axons and Schwann cells in the peripheral nervous system (PNS) or oligodendrocytes in the CNS. Paranodal junctions contribute to both node assembly and maintenance. Despite their importance, the molecular mechanisms responsible for paranode assembly and maintenance remain poorly understood. βII spectrin is expressed in diverse cells and is an essential part of the submembranous cytoskeleton. Here, we show that Schwann cell βII spectrin is highly enriched at paranodes. To elucidate the roles of glial βII spectrin, we generated mutant mice lacking βII spectrin in myelinating glial cells by crossing mice with a floxed allele of Sptbn1 with Cnp-Cre mice, and analyzed both male and female mice. Juvenile (4 weeks) and middle-aged (60 weeks) mutant mice showed reduced grip strength and sciatic nerve conduction slowing, whereas no phenotype was observed between 8 and 24 weeks of age. Consistent with these findings, immunofluorescence microscopy revealed disorganized paranodes in the PNS and CNS of both postnatal day 13 and middle-aged mutant mice, but not in young adult mutant mice. Electron microscopy confirmed partial loss of transverse bands at the paranodal axoglial junction in the middle-aged mutant mice in both the PNS and CNS. These findings demonstrate that a spectrin-based cytoskeleton in myelinating glia contributes to formation and maintenance of paranodal junctions.
SIGNIFICANCE STATEMENT Myelinating glia form paranodal axoglial junctions that flank both sides of the nodes of Ranvier. These junctions contribute to node formation and maintenance and are essential for proper nervous system function. We found that a submembranous spectrin cytoskeleton is highly enriched at paranodes in Schwann cells. Ablation of βII spectrin in myelinating glial cells disrupted the paranodal cell adhesion complex in both peripheral and CNSs, resulting in muscle weakness and sciatic nerve conduction slowing in juvenile and middle-aged mice. Our data show that a spectrin-based submembranous cytoskeleton in myelinating glia plays important roles in paranode formation and maintenance.
https://ift.tt/2zbkeSn
Supportive effect of interferential current stimulation on susceptibility of swallowing in guinea pigs
Abstract
Sensory-motor control of the pharyngeal swallow requires sensory afferent inputs from the pharynx and larynx evoked by introducing bolus into the pharynx. Patients with reduced sensitivity of the pharynx and larynx are likely to have a swallowing impairment, such as pre-swallow aspiration due to delayed swallow triggering. Interferential current stimulation applied to the neck is thought to improve the swallowing function of dysphagic patients, although the mechanism underlying the facilitatory effect of such stimulation remains unknown. In the present study, we examined the changes in the elicitability of swallowing due to the stimulation and the responses of the swallowing-related neurons in the nucleus tractus solitarius and in the area adjacent to the stimulation in decerebrate and paralyzed guinea pigs. The swallowing delay time was shortened by the stimulation, whereas the facilitatory effect of eliciting swallowing was attenuated by kainic acid injection into the nucleus tractus solitarius. Approximately half of the swallowing-related neurons responded to the stimulation. These data suggest that the interferential current stimulation applied to the neck could enhance the sensory afferent pathway of the pharynx and larynx, subserving excitatory inputs to the neurons of the swallowing pattern generator, thereby facilitating the swallowing reflex.
https://ift.tt/2KwLwYA
Coherence in general and personal semantic knowledge: functional differences of the posterior and centro-parietal N400 ERP component
Abstract
A growing body of scientific literature investigated the difference between general and personal semantic knowledge. In contrast to general world knowledge, personal semantics comprises highly individual knowledge about oneself. The present study aimed to differentiate processes of integration into personal as opposed to general semantic knowledge. For that purpose, participants were presented with pictures of themselves (Self-condition) or unknown persons (Other-condition) superimposed on a congruent or incongruent background. We hypothesized that self-referential processing is based on automatic retrieval of personal information as opposed to the processing of unknown persons, which requires voluntary, i.e., strategic, attention demanding processing. The topography of the N400 effect varied as a function of the type of semantic knowledge. We found a centro-parietal N400 effect within the Self-condition and a posterior effect within the Other-condition. The voluntary integration of facial expressions of unknown persons within the Other-condition was, furthermore, indexed by an N170 effect. The unresolved tension in personal semantics was reflected by the N500. Our study thus provides new impulses for interpretation of the N400's functional properties and extends our knowledge about the N500. Implications for the functional properties of the self as an organizational structure are discussed.
https://ift.tt/2MML19j
Oscillatory Encoding of Visual Stimulus Familiarity
Familiarity of the environment changes the way we perceive and encode incoming information. However, the neural substrates underlying this phenomenon are poorly understood. Here we describe a new form of experience-dependent low-frequency oscillations in the primary visual cortex (V1) of awake adult male mice. The oscillations emerged in visually evoked potentials and single-unit activity following repeated visual stimulation. The oscillations were sensitive to the spatial frequency content of a visual stimulus and required the mAChRs for their induction and expression. Finally, ongoing visually evoked (4–8 Hz) oscillations boost the visually evoked potential amplitude of incoming visual stimuli if the stimuli are presented at the high excitability phase of the oscillations. Our results demonstrate that an oscillatory code can be used to encode familiarity and serves as a gate for oncoming sensory inputs.
SIGNIFICANCE STATEMENT Previous experience can influence the processing of incoming sensory information by the brain and alter perception. However, the mechanistic understanding of how this process takes place is lacking. We have discovered that persistent low-frequency oscillations in the primary visual cortex encode information about familiarity and the spatial frequency of the stimulus. These familiarity evoked oscillations influence neuronal responses to the oncoming stimuli in a way that depends on the oscillation phase. Our work demonstrates a new mechanism of visual stimulus feature detection and learning.
https://ift.tt/2lWBscG
Isolation of Peritoneum-derived Mast Cells and Their Functional Characterization with Ca2+-imaging and Degranulation Assays
Here, we present a protocol to isolate and cultivate murine peritoneal mast cells. We also describe two protocols for their functional characterization: a fluorescent imaging of intracellular free Ca2+ concentration and a degranulation assay based on colorimetric quantification of the released β-hexosaminidase.
https://ift.tt/2zbXJfT
In Vivo Monitoring of Circadian Clock Gene Expression in the Mouse Suprachiasmatic Nucleus Using Fluorescence Reporters
This newly developed fluorescence-based technology enables long-term monitoring of the transcription of circadian clock genes in the suprachiasmatic nucleus (SCN) of freely moving mice in real-time and at a high temporal resolution.
https://ift.tt/2lSSc4w
Clinical impact of upper gastrointestinal endoscopy in critically ill patients with suspected bleeding
Upper gastrointestinal endoscopies' (UGE) profitability is undisputable in patients admitted for an overt upper digestive tract bleeding. In critically ill subjects admitted for other causes, its performances ...
https://ift.tt/2KOzBBx
Preclinical Evaluation of In Vitro and In Vivo Antiviral Activities of KCT-01, a New Herbal Formula against Hepatitis B Virus
Hepatitis B virus (HBV) infectious diseases currently remain incurable due to limitations of conventional antivirals such as incapability of eradicating HBV DNA, prolonged use, drug resistance, and virological relapse. KCT-01, a 30% ethanol extract consisting of Artemisia capillaris, Sanguisorba officinalis, and Curcuma longa, was newly developed. The objective of this study was to investigate pharmacological activities of KCT-01 against HBV using HepG2.2.15 cells and a hydrodynamic injection model. KCT-01 significantly lowered antigen secretion, virion production, and pgRNA synthesis in HepG2.2.15 cells without affecting cell viability. KCT-01 administration also resulted in significant decrease of serum virion production, liver covalently closed circular (ccc) DNA levels, and mRNA synthesis of cytokines in the liver of mice injected with HBV DNA hydrodynamically. Interestingly, coadministration of KCT-01 with entecavir enhanced its in vitro and in vivo antiviral activities. Moreover, safety of KCT-01 was assured up to 5000 mg/kg in rats in both single and repeated-dose preclinical studies. Taken together, our findings demonstrate that KCT-01 is capable of suppressing HBV replication and inflammatory cytokine production in in vitro and in vivo models without showing toxicity, suggesting the potential of using KCT-01 alone or in combination with entecavir as antiviral agent.
https://ift.tt/2u3J8xn
Probiotic Cell-Free Supernatants Exhibited Anti-Inflammatory and Antioxidant Activity on Human Gut Epithelial Cells and Macrophages Stimulated with LPS
The incidence of inflammatory bowel disease is increasing all over the world, especially in industrialized countries. The aim of the present work was to verify the anti-inflammatory activity of metabolites. In particular, cell-free supernatants of Lactobacillus acidophilus, Lactobacillus casei, Lactococcus lactis, Lactobacillus reuteri, and Saccharomyces boulardii have been investigated. Metabolites produced by these probiotics were able to downregulate the expression of PGE-2 and IL-8 in human colon epithelial HT-29 cells. Moreover, probiotic supernatants can differently modulate IL-1β, IL-6, TNF-α, and IL-10 production by human macrophages, suggesting a peculiar anti-inflammatory activity. Furthermore, supernatants showed a significant dose-dependent radical scavenging activity. This study suggests one of the mechanisms by which probiotics exert their anti-inflammatory activity affecting directly the intestinal epithelial cells and the underlying macrophages. This study provides a further evidence to support the possible use of probiotic metabolites in preventing and downregulating intestinal inflammation as adjuvant in anti-inflammatory therapy.
https://ift.tt/2za4AXv
Cancers, Vol. 10, Pages 224: Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance
Cancers, Vol. 10, Pages 224: Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance
Cancers doi: 10.3390/cancers10070224
Authors: Zachary Schrank Gagan Chhabra Leo Lin Tsatsral Iderzorig Chike Osude Nabiha Khan Adijan Kuckovic Sanjana Singh Rachel J. Miller Neelu Puri
Lung cancer is treated with many conventional therapies, such as surgery, radiation, and chemotherapy. However, these therapies have multiple undesirable side effects. To bypass the side effects elicited by these conventional treatments, molecularly-targeted therapies are currently in use or under development. Current molecularly-targeted therapies effectively target specific biomarkers, which are commonly overexpressed in lung cancers and can cause increased tumorigenicity. Unfortunately, several molecularly-targeted therapies are associated with initial dramatic responses followed by acquired resistance due to spontaneous mutations or activation of signaling pathways. Acquired resistance to molecularly targeted therapies presents a major clinical challenge in the treatment of lung cancer. Therefore, to address this clinical challenge and to improve lung cancer patient prognosis, we need to understand the mechanism of acquired resistance to current therapies and develop additional novel therapies. This review concentrates on various lung cancer biomarkers, including EGFR, ALK, and BRAF, as well as their potential mechanisms of drug resistance.
https://ift.tt/2MM5iMg
The Hog1 positive regulated YCT1 Gene Expression under Cadmium tolerance of budding yeast
Abstract
Cadmium is a heavy metal that cause irreversible hazard to the living organisms. Cadmium ion can induces the phosphorylation of MAPKs pathway molecules, such as Hog1 and Slt2, but downstream effectors and potential activation pathway were still unclear. In this study, the RNA-seq data analysis in cadmium-stressed yeast was performed to predict and screen the signal transduction pathway and the potential effect molecules regulated by MAPKs. Based on DEGs and Venn diagram, 31 genes regulated by Hog1p and 2 genes induced by Slt2p, which related to carbohydrate metabolism, oxidative damage, DNA replication stress and detoxification were characterized under Cd exposure yeast. A cysteine-specific transporter (Yct1) modulated by Hog1 was confirmed via RNA-seq result. Meanwhile, we tested the cadmium sensitivity, intracellular cadmium concentrations and β-galactosidase assay, the results indicated that the hypersensitivity of the hog1 mutant to Cd was partly abrogated in YCT1 gene deletion, and induction of YCT1 was dependent on Hog1 and its transcription factors. Yct1p would be epistatic to the Hog1p in Cd tolerance, The investigation of the transcriptome of MAPKs under Cd stress provided valuable information for future molecular studies of cadmium tolerance.https://ift.tt/2NqYDsj
pH level has a strong impact on population dynamics of the yeast Yarrowia lipolytica and oil micro-droplets in multiphasic bioreactor
Abstract
The oleaginous yeast Yarrowia lipolytica has the ability to use oils and fats as carbon source, making it a promising cell factory for the design of alternative bioprocesses based on renewable substrates. However, such a multiphasic bioreactor design is rather complex and leads to several constraints when considering emulsification of the oil-in-water mixture, foaming and cell growth/physiology on hydrophobic substrate. This study aims to shed light on the effect of pH changes on the physico-chemical properties of the cultivation medium and on cell physiology. It was indeed observed that at a pH value of 6, cell growth rate and intracellular lipid accumulation were optimized. Additionally, foaming was significantly reduced. In order to avoid over foaming in bioreactor, without impairing cell physiology, the use of alternative processes that can only act on the physical structure of culture medium, seems to be an effective alternative to usual chemical antifoam agents.https://ift.tt/2IQS8vl
Effects of solid-state fermentation with three higher fungi on the total phenol contents and antioxidant properties of diverse cereal grains
Abstract
Three culinary-medicinal fungi and mushrooms (Agaricus bisporus AS2796, Helvella lacunosa X1 and Fomitiporia yanbeiensis S.Guo & L.Zhou) were individually inoculated into different cereal grains (wheat, rice, oat, corn, millet, quinoa, buckwheat, soybean, pea and sorghum) and the antioxidant properties of fungus-fermented products after solid-state fermentation (SSF) (0, 7, 14, 21, 28 and 35 days; 25°C) were studied.The results showed that the total phenol contents (TPCs) of the fermented cereals varied with fermentation time and the starter organisms. According to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging capacity, reducing power, ferrous ion chelating ability and superoxide anion radical scavenging ability of ethanolic extracts from the fungus-fermented products (35 days), it was shown that the antioxidant properties of all the products were significantly stronger than uninoculated grains. It revealed that solid-state fermentation (SSF) on cereal grains by dietary fungi is a biotechnological strategy, which may enhance the antioxidant properties of the substrate. The three medicinal mushroom and fungi-fermented products were relatively effective in the antioxidant properties assayed and might be potential antioxidants for application in food products.https://ift.tt/2KMPFnk
In Vitro Antidiabetic Activity and Mechanism of Action of Brachylaena elliptica (Thunb.) DC
In South Africa, the number of people suffering from diabetes is believed to be rising steadily and the current antidiabetic therapies are frequently reported to have adverse side effects. Ethnomedicinal plant use has shown promise for the development of cheaper, cost-effective antidiabetic agents with fewer side effects. The aim of this study was to investigate the antidiabetic activity and mechanism of action of aqueous leaf extract prepared from Brachylaena elliptica. The potential of the extract for cytotoxicity was evaluated using MTT assay in HepG2 cells. The effects of the plant extract on glucose utilization in HepG2 cells and L6 myotubes, triglyceride accumulation in 3T3-L1, INS-1 proliferation, glucose metabolism in INS-1 cells, and NO production in RAW macrophages were also investigated using cell culture procedures. The inhibitory effects of the extract on the activities of different enzymes including alpha-amylase, alpha-glucosidase, pancreatic lipase, dipeptidyl peptidase IV (DPP-IV), collagenase, and CYP3A4 enzymes were evaluated. The extract also tested against protein glycation using standard published procedure. The plant extract displayed low level of toxicity, where both concentrations tested did not induce 50% cell death. The extract caused a significant increase in glucose uptake in HepG2 liver cells, with efficacy significantly higher than the positive control, berberine. The crude extract also displayed no significant effect on muscle glucose uptake, triglyceride accumulation in 3T3-L1, glucose metabolism in INS-1 cells, alpha-amylase, alpha-glucosidase, DPP-IV, lipase, protein glycation, and collagenase compared to the respective positive controls. The extract displayed a proliferative effect on INS-1 cells at 25 μg/ml when compared to the negative control. The plant also produced a concentration-dependent reduction in NO production in RAW macrophages and also demonstrated weak significant inhibition on CYP3A4 activity. The findings provide evidence that B. elliptica possess antidiabetic activity and appear to exact its hypoglycemic effect independent of insulin.
https://ift.tt/2ISjiC5
Electroacupuncture at Hua Tuo Jia Ji Acupoints Reduced Neuropathic Pain and Increased GABAA Receptors in Rat Spinal Cord
Chronic constriction injury- (CCI-) induced neuropathic pain is the most similar model to hyperalgesia in clinical observation. Neuropathic pain is a neuronal dysfunction in the somatosensory system that may lead to spontaneous pain. In this study, electroacupuncture (EA) was applied at bilateral L4 and L6 of Hua Tuo Jia Ji points (EX-B2) for relieving neuropathic pain in rats. Eighteen Sprague-Dawley rats were randomly assigned to three groups: sham, 2-Hz EA, and 15-Hz EA groups. Following von Frey and cold plate tests, both the 2- and the 15-Hz EA groups had significantly lower mechanical and thermal hyperalgesia than the sham group. Western blot analysis results showed that γ-aminobutyric acid A (GABAA), adenosine A1 receptor (A1R), transient receptor potential cation channel subfamily V member 1 (TRPV1), TRPV4, and metabotropic glutamate receptor 3 (mGluR3) were similar in the dorsal root ganglion of all three groups. Furthermore, levels of GABAA receptors were higher in the spinal cord of rats in the 2- and 15-Hz EA groups compared with the sham control group. This was not observed for A1R, TRPV1, TRPV4, or mGluR3 receptors. In addition, all the aforementioned receptors were unchanged in the somatosensory cortex of the study rats, suggesting a central spinal effect. The study results provide evidence to support the clinical use of EA for specifically alleviating neuropathic pain.
https://ift.tt/2tRER0U
Gender Variation in the Shape of Superior Talar Dome: A Cadaver Measurement Based on Chinese Population
Understanding the shape of superior talar dome is essential for a better size compatibility between talar component of ankle implant and bone. The purpose of this study was to determine whether there were gender variations in (1) width (TW) and length (TL) of talus, as well as anterior width (DAW), middle width (DMW), posterior width (DPW), and length (DL) of superior talar dome; (2) differences between the DAW, DMW, and DPW; (3) the ratios between these parameters. Fifty-one cadaveric ankle specimens were included. Two observers measured all the specimens using vernier caliper. Intraclass correlation coefficients (ICCs) were used for intraobserver and interobserver reliability analysis and the reliability was thought to be good if the ICC>0.75. A two-tailed unpaired t-test or the rank-sum test was used to investigate gender variations. A single-factor ANOVA was utilized to identify the differences between the width of the superior talar dome surface and p value of
https://ift.tt/2ISZqi1
Compliance to prehospital trauma triage protocols worldwide: a systematic review
Publication date: Available online 3 July 2018
Source:Injury
Author(s): Eveline A.J. van Rein, Rogier van der Sluijs, Antoine M.R. Raaijmakers, Luke P.H. Leenen, Mark van Heijl
BackgroundEmergency medical services (EMS) providers must determine the injury severity on-scene, with the use of a prehospital trauma triage protocol, and decide on the most appropriate hospital destination for the patient. Many severely injured patients are not transported to higher-level trauma centres. An accurate triage protocol is the base of prehospital trauma triage; however, ultimately the quality is dependent on the destination decision by the EMS provider. The aim of this systematic review is to describe compliance to triage protocols and evaluate compliance to the different categories of triage protocols.MethodsAn extensive search of MEDLINE/Pubmed, Embase, CINAHL and Cochrane library was performed to identify all studies, published before January 2018, describing compliance to triage protocols in a trauma system. The search terms were a combination of synonyms for 'compliance,' 'trauma,' and 'triage'.ResultsAfter selection, 11 articles were included. The studies showed a variety in compliance rates, ranging from 21% to 93% for triage protocols, and 41% to 94% for the different categories. The compliance rate was highest for the criterion: penetrating injury. The category of the protocol with the lowest compliance rate was: vital signs. Compliance rates were lower for elderly patients, compared to adults under the age of 55. The methodological quality of most studies was poor. One study with good methodological quality showed that the triage protocol identified only a minority of severely injured patients, but many of whom were transported to higher-level trauma centres.ConclusionsThe compliance rate ranged from 21% to 94%. Prehospital trauma triage effectiveness could be increased with an accurate triage protocol and improved compliance rates. EMS provider judgment could lower the undertriage rate, especially for severely injured patients meeting none of the criteria. Future research should focus on the improvement of triage protocols and the compliance rate.
https://ift.tt/2IT1MNU
A Sickening Tale
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. A 44-year-old man presented to the…
https://ift.tt/2KNBd1s
Will You Forgive Me for Saving You?
I remember the day I first met you. It was a quiet Sunday, early in the morning. I heard a commotion out by the check-in desk, and your mom's scream: "My baby's not breathing!" The first time I saw you was in your mom's arms. Heartbreakingly, you weren't snuggled like a baby should be, or even…
https://ift.tt/2MJenFN
Effects of Surface Nanotopography and Calcium Chemistry of Titanium Bone Implants on Early Blood Platelet and Macrophage Cell Function
Early responses of blood platelets and immunoinflammatory cells (macrophages) to titanium (Ti) bone implants affect the subsequent biological healing of implants by modulating early tissue healing-microenvironments via the formation of temporary fibrin matrix scaffolds for stem cell migration and production of growth factors and cytokines. This study investigated the effects of nanoscale surface topography and calcium ion (Ca2+) modification of Ti surfaces on biocompatibility regulated by blood platelets and macrophages, for the future surface design of Ti bone implants with enhanced early osteogenic capacity. A nanostructured Ti surface with or without Ca2+ enrichment was prepared using the hydrothermal treatment. Immediate and early functions of platelets and macrophages modulated by modified Ti surfaces were investigated by morphological observation of platelet spreading and fibrin matrix formation, platelet growth factor release, immunostaining of macrophage phenotypes, and macrophage inflammatory cytokine production. The results showed that surface nanoscale topographical modification of Ti promotes blood platelet activation and suppresses the inflammatory response of macrophages. In addition, surface chemistry modifications with Ca2+ enhanced the platelet response-modulating function of the nanostructured Ti surface, which accelerated immediate fibrin matrix formation and platelet-derived growth factor-AB release. Thus, nanotopographical and Ca2+ modifications of implant surfaces are expected to be effective approaches that favor the initial phase of wound healing around the Ti bone implants through positive modulation of immediate blood platelet function and early macrophage immunoinflammatory response.
https://ift.tt/2ISZwGp
The Effect of Different Implant Surfaces and Photodynamic Therapy on Periodontopathic Bacteria Using TaqMan PCR Assay following Peri-Implantitis Treatment in Dog Model
Introduction. Peri-implantitis is one of the late complications that leads to implant failure and is associated with specific microorganisms identified as periodontopathic bacteria. The objective of this study was to evaluate the relationship between the different implant surfaces and number of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola using TaqMan PCR assay after peri-implantitis treatment using photodynamic therapy. Method. Forty-eight dental implants with four different surface treatments (M: machined; SA: sandblasted acid-etched; S: 1 µm sputter HA-coated; and P: plasma spraying HA-coated) were inserted in six beagle dogs. After nine months of peri-implantitis induction, a split mouth design was used; on control side decontamination was performed using open flap mechanical debridement OFD with plastic curette, while photodynamic therapy PDT using diode laser (Ga Al As 830-nm) was used in the test side. For the following 2 weeks low-level laser therapy LLLT (10mW) was applied for the test side on alternative days for 6 sec on each implant side. Peri-implant microbial samples were collected using paper points and analyzed using TaqMan PCR before peri-implantitis treatment, immediately after treatment and 5 months posttreatment. Results. Both treatment modalities showed significant decrease in all bacterial count from baseline to immediately after treatment (P
https://ift.tt/2KE9uR5
A Look Forward — The Frontiers in Medicine Series
This week we introduce Frontiers in Medicine, a series of review articles that showcases the ways in which new technologies are influencing contemporary medicine and highlights the synergistic relationship between medicine and science. The series covers a number of advanced diagnostics and…
https://ift.tt/2u5a3Zz
Moving Addiction Care to the Mainstream — Improving the Quality of Buprenorphine Treatment
More than 40,000 Americans died from opioid overdoses in 2016 — more than the number killed in motor vehicle accidents. The stunning increase in overdose deaths since the 1990s has revealed a pervasive lack of capability to meet the need for treatment in the 2.1 million Americans who have an opioid…
https://ift.tt/2z4EPaT
Primary Care and the Opioid-Overdose Crisis — Buprenorphine Myths and Realities
Despite widespread awareness of the opioid-overdose crisis, the epidemic continues to worsen. In 2016, there were 42,249 opioid-overdose deaths in the United States, a 28% increase from the previous year. According to the National Center for Health Statistics, life expectancy in the United States…
https://ift.tt/2lMFKmR
Methadone in Primary Care — One Small Step for Congress, One Giant Leap for Addiction Treatment
The opioid-overdose epidemic has had a devastating impact throughout the United States and currently claims an average of 115 lives a day. Federal, state, and local public health officials, health care agencies, and community partners are working hard to stem the tide of deaths. Opioid use…
https://ift.tt/2lM2WSi
Methadone in Primary Care — One Small Step for Congress, One Giant Leap for Addiction Treatment
The opioid-overdose epidemic has had a devastating impact throughout the United States and currently claims an average of 115 lives a day. Federal, state, and local public health officials, health care agencies, and community partners are working hard to stem the tide of deaths. Opioid use…
https://ift.tt/2lM2WSi
Chronic Occlusion of the Superior Vena Cava
An 89-year-old man presented to the outpatient clinic for evaluation of a right inguinal hernia. He had a history of hypertension and also reported having abdominal-wall varices that had been increasing in size for 20 years. He had no history of central venous catheterization. On physical…
https://ift.tt/2z8FCaJ
Disseminated Cutaneous Blastomycosis
A 44-year-old man presented to the dermatology clinic with nonpruritic skin lesions over his body, including the face, chest, back, arms, and legs. Six months earlier, he had had fever, cough, and vomiting for 1 week. Subsequently, multiple nodules had appeared over his body. He worked in…
https://ift.tt/2KwPkcb
Cancers, Vol. 10, Pages 223: Measuring Surgery Outcomes of Lung Cancer Patients with Concomitant Pulmonary Fibrosis: A Review of the Literature
Cancers, Vol. 10, Pages 223: Measuring Surgery Outcomes of Lung Cancer Patients with Concomitant Pulmonary Fibrosis: A Review of the Literature
Cancers doi: 10.3390/cancers10070223
Authors: Taichiro Goto
Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonias, often progresses to restrictive respiratory disturbance and mortality, typically within 10 years. IPF frequently coexists with lung cancer, and the combination of these two disease entities is far more difficult to treat than either lung cancer or IPF alone. In particular, surgery for lung cancer with IPF in the background increases postoperative morbidity and mortality by exacerbating pre-existing IPF, i.e., acute exacerbation of IPF (AEIPF). Furthermore, the long-term outcome after lung cancer surgery is considerably worsened by the presence of IPF. We present here a comprehensive review of AEIPF and the long-term outcomes after surgery.
https://ift.tt/2u3eVyA
Platelet Counts during Pregnancy
Beginning in 1993, three large studies documented that 5 to 10% of women who had uncomplicated pregnancies had a platelet count of less than 150,000 per cubic millimeter at the time of delivery, which was described as gestational thrombocytopenia. The normal distribution of platelet counts at the…
https://ift.tt/2KId0Ke
Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma
The rate of death from liver cancer is rising faster than the rate of death from any other cancer in the United States. The systemic treatment options available for most cases are limited. Despite several advances, outcomes in the majority of patients remain poor, and additional treatment options…
https://ift.tt/2IPljP7
Chimeric Antigen Receptor Therapy
The aim of cancer immunotherapy is to enhance the immune response against tumor cells. The emergence of immuno-oncology as the first broadly successful strategy to treat metastatic cancer will require clinicians to integrate this new type of medicine with chemotherapy, surgery, radiation therapy,…
https://ift.tt/2KAdt0Z
Direct Thrombectomy versus Bridging for Patients with Emergent Large-Vessel Occlusions
Intervent Neurol 2018;7:403–412
https://ift.tt/2IQWFOl
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Hereditary transthyretin amyloidosis is an autosomal dominant, multisystemic, progressive, life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The liver is the primary source of circulating tetrameric transthyretin protein. In hereditary transthyretin amyloidosis,…
https://ift.tt/2MNkKI3
Methadone in Primary Care — One Small Step for Congress, One Giant Leap for Addiction Treatment
The opioid-overdose epidemic has had a devastating impact throughout the United States and currently claims an average of 115 lives a day. Federal, state, and local public health officials, health care agencies, and community partners are working hard to stem the tide of deaths. Opioid use…
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Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis
Autosomal dominant mutations in the gene encoding transthyretin (TTR) cause a rare systemic disorder known as hereditary transthyretin amyloidosis. The single amino-acid changes that result from these mutations destabilize the tetrameric transthyretin protein complex to cause aggregation of…
https://ift.tt/2MK1v22
Oligonucleotide Drugs for Transthyretin Amyloidosis
In this issue of the Journal, Adams et al. and Benson et al. report the results of two randomized, double-blind, controlled trials testing the therapeutic efficacy of two different chemically modified oligonucleotides to treat transthyretin amyloidosis, which is an autosomal dominant hereditary…
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Will You Forgive Me for Saving You?
I remember the day I first met you. It was a quiet Sunday, early in the morning. I heard a commotion out by the check-in desk, and your mom's scream: "My baby's not breathing!" The first time I saw you was in your mom's arms. Heartbreakingly, you weren't snuggled like a baby should be, or even…
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A Sickening Tale
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. A 44-year-old man presented to the…
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Primary Care and the Opioid-Overdose Crisis — Buprenorphine Myths and Realities
Despite widespread awareness of the opioid-overdose crisis, the epidemic continues to worsen. In 2016, there were 42,249 opioid-overdose deaths in the United States, a 28% increase from the previous year. According to the National Center for Health Statistics, life expectancy in the United States…
https://ift.tt/2lMFKmR
Oligonucleotide Drugs for Transthyretin Amyloidosis
In this issue of the Journal, Adams et al. and Benson et al. report the results of two randomized, double-blind, controlled trials testing the therapeutic efficacy of two different chemically modified oligonucleotides to treat transthyretin amyloidosis, which is an autosomal dominant hereditary…
https://ift.tt/2KwQPaB
Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis
Autosomal dominant mutations in the gene encoding transthyretin (TTR) cause a rare systemic disorder known as hereditary transthyretin amyloidosis. The single amino-acid changes that result from these mutations destabilize the tetrameric transthyretin protein complex to cause aggregation of…
https://ift.tt/2MK1v22
Epigenetic Control of Interleukin-9 in Asthma
Interleukin-9 is a pleiotropic cytokine associated with allergic inflammation and is a therapeutic target in patients with asthma. Its expression and that of the interleukin-9 receptor are greater in the lungs of persons with asthma than in those of healthy persons. In murine models of allergic…
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Chimeric Antigen Receptor Therapy
The aim of cancer immunotherapy is to enhance the immune response against tumor cells. The emergence of immuno-oncology as the first broadly successful strategy to treat metastatic cancer will require clinicians to integrate this new type of medicine with chemotherapy, surgery, radiation therapy,…
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A Look Forward — The Frontiers in Medicine Series
This week we introduce Frontiers in Medicine, a series of review articles that showcases the ways in which new technologies are influencing contemporary medicine and highlights the synergistic relationship between medicine and science. The series covers a number of advanced diagnostics and…
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Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Hereditary transthyretin amyloidosis is an autosomal dominant, multisystemic, progressive, life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The liver is the primary source of circulating tetrameric transthyretin protein. In hereditary transthyretin amyloidosis,…
https://ift.tt/2MNkKI3
Expanding the phenotype of the X-linked BCOR microphthalmia syndromes
Abstract
Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.
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What Have We Learned from Recent Clinical Studies in Low-Grade Gliomas?
Abstract
Purpose of review
The management of low-grade gliomas (grade II WHO) is still controversial, due to the rarity of these tumors and continuous advances in molecular diagnosis and new technologies for treatment. This article reviews the current understanding of management of grade II gliomas in light of the recent clinical and translational studies.
Recent findings
The role of an extensive surgery at onset is now fully recognized. Recent clinical trials in the USA and Europe have demonstrated the importance of chemotherapy either in association with radiotherapy or as initial treatment to delay the risk of cognitive defects following radiation. Molecular factors, such as IDH1 or 2 mutations and 1p/19q codeletion, are favorable prognostic factors, and seem to predict a better response to chemotherapy as well.
Summary
The role of conventional therapeutic options (surgery, radiotherapy, chemotherapy), in various combinations or sequences, has been better defined by clinical trials, but still there are areas of controversy. A future challenge is to reevaluate the role of these options within the different molecular subgroups of prognostic significance according to the last WHO classification of CNS tumors of 2016.
https://ift.tt/2zc75Zk
Levels of peripheral blood polymorphonuclear myeloid-derived suppressor cells and selected cytokines are potentially prognostic of disease progression for patients with non-small cell lung cancer
Abstract
Polymorphonuclear-MDSC (PMN-MDSC) have emerged as an independent prognostic factor for survival in NSCLC. Similarly, cytokine profiles have been used to identify subgroups of NSCLC patients with different clinical outcomes. This prospective study investigated whether the percentage of circulating PMN-MDSC, in conjunction with the levels of plasma cytokines, was more informative of disease progression than the analysis of either factor alone. We analyzed the phenotypic and functional profile of peripheral blood T-cell subsets (CD3+, CD3+CD4+ and CD3+CD8+), neutrophils (CD66b+) and polymorphonuclear-MDSC (PMN-MDSC; CD66b+CD11b+CD15+CD14-) as well as the concentration of 14 plasma cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, IL-17A, IL-27, IL-29, IL-31, and IL-33, TNF-α, IFN-γ) in 90 treatment-naïve NSCLC patients and 25 healthy donors (HD). In contrast to HD, NSCLC patients had a higher percentage of PMN-MDSC and neutrophils (P < 0.0001) but a lower percentage of CD3+, CD3+CD4+ and CD3+CD8+ cells. PMN-MDSC% negatively correlated with the levels of IL1-β, IL-2, IL-27 and IL-29. Two groups of patients were identified according to the percentage of circulating PMN-MDSC. Patients with low PMN-MDSC (≤ 8%) had a better OS (22.1 months [95% CI 4.3–739.7]) than patients with high PMN-MDSC (9.3 months [95% CI 0–18.8]). OS was significantly different among groups of patients stratified by both PMN-MDSC% and cytokine levels. In sum, our findings provide evidence suggesting that PMN-MDSC% in conjunction with the levels IL-1β, IL-27, and IL-29 could be a useful strategy to identify groups of patients with potentially unfavorable prognoses.
https://ift.tt/2KEKoS3
EMCrit CQIR – The Conundrum of Reversing Anticoagulants for Mechanical Heart Valves in Intracranial Hemorrhage
Mechanical Heart Valve + Warfarin = Reversal? a CQiR:
EMCrit Project by Ashley Mogul.
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Extraction of Amana edulis Induces Liver Cancer Apoptosis
HCC is one of the fastest-rising causes of cancer-related death. Novel therapeutic approaches for treatment are warranted. The goal of this study is to find effective components from Chinese herbal medicines, which is an important alternative source of anticancer medicine. To this end, six different herbs were selected from various traditional literatures. Soxhlet extractor was used to distill the strong polar and weak polar components of each herb. The inhibitive effect of each component was determined using liver cancer cells BEL7404. From total of 12 extractions, it was found that the combined crude lysate of Amana edulis from water and ethanol system had the best efficacy. At the concentration of 0.1 mg/mL, this component has the highest inhibition rate up to 70%. To investigate the underlying molecular reasons, we observed that the component can significantly induce the liver cancer cells apoptosis and retard the cell reproduction at G2/M stage. Verification experiments showed that this component also has apparent inhibitive effects on other liver cancer cells, such as HepG2 and Huh7. On the other hand, it has less effectiveness on another cell line HepaRG, which retains many characteristics of primary human hepatocytes. The results suggested that there might be highly efficient antihepatoma ingredient in the water and ethanol extraction of Amana edulis. The pure substances remain to be isolated and further research on their targets is required.
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A Comprehensive Review on Phytochemistry and Pharmacological Activities of Clinacanthus nutans (Burm.f.) Lindau
Clinacanthus nutans (Burm.f.) Lindau (Acanthaceae), commonly known as Sabah snake grass, is a vegetable and a well-known herb that is considered an alternative medicine for insect bites, skin rashes, herpes infection, inflammation, and cancer and for health benefits. Current review aims to provide a well-tabulated repository of the phytochemical screening, identification and quantification, and the pharmacological information of C. nutans according to the experimental design and the plant preparation methods which make it outstanding compared to existing reviews. This review has documented valuable data obtained from all accessible library databases and electronic searches. For the first time we analyzed the presence of flavonoids, triterpenoids, steroids, phytosterols, and glycosides in C. nutans based on the results from phytochemical screening which are then further confirmed by conventional phytochemical isolation methods and advanced spectroscopic techniques. Phytochemical quantification further illustrated that C. nutans is a good source of phenolics and flavonoids. Pharmacological studies on C. nutans revealed that its polar extract could be a promising anti-inflammation, antiviral, anticancer, immune and neuromodulating, and plasmid DNA protective agent; that its semipolar extract could be a promising antiviral, anticancer, and wound healing agent; and that its nonpolar extract could be an excellent anticancer agent.
https://ift.tt/2KPDrdt
A Meta-Analysis of Therapeutic Efficacy and Safety of Gabapentin in the Treatment of Postherpetic Neuralgia from Randomized Controlled Trials
Objective. The study aims to systematically evaluate the clinical effect of gabapentin in the treatment of postherpetic neuralgia (PHN). Method. Data were retrieved electronically from PubMed, Embase, CNKI, the China Biomedical Database, and the Library of Clinical Database, beginning from the time of inception to April 2017, in order to collect data on randomized controlled trials (RCTs) of gabapentin and placebo in PHN treatment. Results. A total of 11 RCTs (2376 people) were retrieved. The gabapentin group reported significantly reduced pain intensity [MD=−0.91, 95% CI −1.32 to −0.51, P
https://ift.tt/2u52RwH
Effects of Fine Particulate Matter on Pseudomonas aeruginosa Adhesion and Biofilm Formation In Vitro
Respiratory infections of Pseudomonas aeruginosa are a major cause of mortality and morbidity for hospitalized patients. Fine particulate matter (FPM) is known to have interactions with some bacterial infection in the respiratory system. In this report, we investigate the effect of different concentration of FPM on P. aeruginosa attachment and biofilm formation using in vitro cell culture systems. P. aeruginosa were cultured to form mature biofilms on hydroxyapatite-coated peg and the number of bacteria in the biofilms was enumerated. Morphology of biofilm was imaged with scanning electron microscopy and confocal laser scanning microscopy. Bacterial affinity change to the cell membrane was evaluated with attached colony counting and fluorescence microscopy images. Alteration of bacterial surface hydrophobicity and S100A4 protein concentration were explored as mechanisms of P. aeruginosa adhesion to human cells. There were a concentration-dependent increase of thickness and surface roughness of biofilm mass. P. aeruginosa adherence to respiratory epithelial cells was increased after FPM treatment. Bacterial surface hydrophobicity and S1000A4 protein concentration were increased with proportionally the dose of FPM in media. FPM in the airway could enhance both the adhesion of P. aeruginosa to epithelial cells and biofilm formation. Bacterial surface hydrophobicity and human cell plasma membrane injury are associated with binding of P. aeruginosa on airway epithelial cells and biofilm formation.
https://ift.tt/2u2XfTK
Pyrethroid Acaricide Resistance Is Proportional to P-450 Cytochrome Oxidase Expression in the Cattle Tick Rhipicephalus microplus
The goal of the present study was to assess the gene expression of xenobiotic metabolizing enzymes (XMEs) Cytochrome P-450 (CYP) and carboxylesterase (CE) related to detoxification of synthetic pyrethroids, plus acetylcholinesterase (AChE), in field isolates of acaricide-resistant Rhipicephalus microplus. The XMEs expression levels were assessed by mRNA measurement using quantitative reverse transcription PCR. The XME expression levels of field-isolated acaricide-resistant ticks were compared against acaricide-susceptible reference ticks used in this study as a gene expression baseline and represented as relative expression units (REU). Field isolates were subjected to toxicological bioassays and determined resistant to all the Pyr acaricides (Pyr), whereas most of them were found susceptible to organophosphorous acaricides (OP), with the exception of three isolates, which exhibited moderate resistance to Diazinon. Significantly higher levels of CYP were detected in pyrethroid-resistance ticks when compared to Su ticks (P
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Clinical Significance of the Decreased Expression of hsa_circ_001242 in Oral Squamous Cell Carcinoma
Background. Circular RNAs (circRNAs) are a type of covalently closed loop structure of endogenous RNAs. Recent studies have shown that circular RNAs may play an important role in human cancer. However, there is limited information on the function of circRNA in oral squamous cell carcinoma (OSCC). Methods. Hsa_circ_001242 expression levels in 40 paired OSCC tissues and four OSCC cell lines were selected using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of hsa_circ_001242 in OSCC. Results. Hsa_circ_001242 was significantly downregulated in OSCC tissues compared to paired adjacent normal tissues (). Hsa_circ_001242 expression levels were significantly downregulated in four OSCC cell lines (SCC-9, SCC-15, SCC25, and CAL-27) than in human normal oral keratinocyte (HOK) cell lines. Moreover, the expression level of hsa_circ_001242 was negatively correlated with tumor size and T stage (). The area under the ROC curve was 0.784. Conclusion. This study showed that hsa_circ_001242 was significantly downregulated in OSCC and may act as a potential novel biomarker for the diagnosis and treatment of OSCC.
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Targeting CD36 as Biomarker for Metastasis Prognostic: How Far from Translation into Clinical Practice?
Metastasis requires cellular changes related to cell-to-cell and cell-to-matrix adhesion, immune surveillance, activation of growth and survival signalling pathways, and epigenetic modifications. In addition to tumour cells, tumour stroma is also modified in relationship to the primary tumour as well as to distant metastatic sites (forming a metastatic niche). A common denominator of most stromal partners in tumour progression is CD36, a scavenger receptor for fatty acid uptake that modulates cell-to-extracellular matrix attachment, stromal cell fate (for adipocytes, endothelial cells), TGFβ activation, and immune signalling. CD36 has been repeatedly proposed as a prognostic marker in various cancers, mostly of epithelial origin (breast, prostate, ovary, and colon) and also for hepatic carcinoma and gliomas. Data gathered in preclinical models of various cancers have shown that blocking CD36 might prove beneficial in stopping metastasis spread. However, targeting the receptor in clinical trials with thrombospondin mimetic peptides has proven ineffective, and monoclonal antibodies are not yet available for patient use. This review presents data to support CD36 as a potential prognostic biomarker in cancer, its current stage towards achieving bona fide biomarker status, and knowledge gaps that must be filled before further advancement towards clinical practice.
https://ift.tt/2lTdHSV
Intraoperative Tracheal Obstruction Management among Patients with Anterior Mediastinal Masses
Background. Patients suffering from undiagnosed obstruction of the central airways: the trachea and main stem bronchi are at increased risk for perioperative and postoperative complications, especially if general anesthesia is performed. Case Description. This report discusses a 30-year-old asymptomatic Caucasian female who faced recurrent distal airway collapse during mediastinoscopy for biopsy of an anterior mediastinal mass, which led to the inability to extubate her. This case examines the necessity of a thorough preoperative assessment especially in patients with undiagnosed tracheal obstruction and a precise coordination between anesthesiologist and surgeon in being able to perform a safe and smooth anesthesia, in order to avoid life-threatening complications and to reduce further morbidity. Methods. The scope of this case report is restricted to publications in all surgical and anesthesiological specialties among adult patient population. Main search key words were as follows: "tracheal obstruction," "general anesthesia," "mediastinum," and "tumors" Results. The literature supports an increased perioperative risk of airway obstruction with the use of general anesthesia in patients with anterior mediastinal masses. This case report suggests a perioperative anesthetic management modality for patients presenting with anterior mediastinal masses and who are at high risk of cardiovascular compression and tracheal obstruction. Thus, it is highly important to note that evidence-based recommendations are not available in the literature. Conclusions. This case report suggests perioperative management modalities performed by anesthesiologists in order to minimize the risk of airway obstruction among patients having anterior mediastinal masses and shed the lights on the importance of proper anesthetic and surgical planning in order to prevent intraoperative complications and improve the quality of healthcare provided to patients presenting critical cases.
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Neurobiological Effects of Binge Drinking Help in Its Detection and Differential Diagnosis from Alcohol Dependence
The prevalence of binge drinking in the general population is 3-4 times higher than that of alcohol dependence. Neuroimaging studies show that binge drinking in adolescence impairs brain development and white matter integrity. Regions with reduced functional activity include the limbic system, ventral diencephalon, frontal lobe, and middle and inferior temporal lobes, whereas the right superior frontal and parietal lobes are typically hyperactivated. The observed activation of the frontoparietal areas might reflect the alternative memory system operating, whereas the reduced occipito-hippocampal response is associated with impaired visual and linguistic processing/learning. Some other findings from literature research include a decrease of N-acetylaspartate (NAA) in the frontal lobe and its increase in the parietal lobes, as well as the reduced components of event-related potentials, reflecting deficit in attention, working memory, inhibition, and executive functioning. Animal studies show that even a single day of binge drinking results in a neurodegeneration and reactive gliosis in the limbic cortex as well as in gene expression dysregulation and histone acetylation. Another biological evidence on binge drinking effect include inflammatory response, oxidative stress, formation of toxic ceramides, activation of caspase 3, and secretion of corticoliberin. Some of the binge drinking-induced cognitive abnormalities can be reversible after three weeks of abstinence. Although binge drinkers have a similar pattern of neuropsychological deficits with chronic alcohol consumers (mainly memory deficits), binge drinkers have prominent impairment of inhibitory control, which may be a marker of binge pattern of alcohol drinking. The optimal therapeutic strategies should target the inhibitory control processes to facilitate discontinuation of alcohol consumption and to block its possible progression to the alcohol dependence syndrome.
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Correlation between miR-200 Family Overexpression and Cancer Prognosis
The correlation between miR-200 family overexpression and cancer prognosis remains controversial. Therefore, we conducted a systematic review and meta-analysis by searching PubMed, Embase, Cochrane Library, China Biology Medicine disc (CBM), and China National Knowledge Infrastructure (CNKI) to identify eligible studies. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate the strength of the correlations. Additionally, different subgroup analyses and publication bias test were performed. Eventually, we analyzed 23 articles that included five tumor types and 3038 patients. Consequently, high expression of miR-200 family in various tumors was associated with unfavorable overall survival (OS) in both univariate (, 95% CI: 1.14–1.54, ) and multivariate (, 95% CI: 1.16–1.49, ) analyses. Likewise, a similar result was found in different subgroups of the patient source, cancer type, test method, sample source, miR-200 component, and sample size. However, no association of miR-200 family was detected with recurrence- or relapse-free survival (RFS) (univariate: , 95% CI: 0.96–1.09, ; multivariate: , 95% CI: 1.00–1.14, ), progression-free survival (PFS) (univariate: , 95% CI: 0.54–1.70, ; multivariate: , 95% CI: 0.86–1.61, ), and disease-free survival (DFS) (univariate: , 95% CI: 0.74–1.09, ; multivariate: , 95% CI: 0.68–1.41, ). Our findings have provided convincing evidence that miR-200 family overexpression suggested poor prognosis of various cancer types, which efforts may raise the potential use of miR-200 family for cancer prognosis in clinical practice.
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Functional maturation and in vitro differentiation of neonatal porcine islet grafts
Background There is a strong rationale to pursue the use of neonatal porcine islets (NPIs) as an unlimited source of islets for clinical xenotransplantation. Since NPIs are composed of immature insulin producing beta (ß) cells and ductal precursor cells, they provide an ideal model to examine culture conditions to enhance ß cell proliferation and/or ß cell neo-formation from ductal cells. In an attempt to optimize the potential of NPIs as a source of ß cell grafts, we utilized an in vitro differentiation protocol and measured its effect on the functional maturation and differentiation of NPIs. Methods Pancreata from 1 to 3-day old neonatal pigs were digested and cultured in standard Ham's-F10 media for 5 days. Each independent preparation was then further cultured in DMEM-F12 differentiation media containing growth factors added in a stepwise fashion, or cultured in control Ham's-F10 media. After 20 days in culture, islets were assessed for insulin secretory capacity, cellular composition, gene expression and metabolic activity after transplantation in immunedeficient diabetic mice. Results Compared to control islets, differentiated islets exhibited a significantly higher proportion of endocrine cells, proliferating cell nuclear antigen double positive ß cells, and an enhanced glucose stimulated insulin secretory activity. Mice transplanted with differentiated islets had significantly lower blood glucose values at weeks 18 and 20 compared to nondifferentiated controls and were shown to be more glucose tolerant. Conclusions Culturing NPIs in a 20-day step-wise differentiation media increases the proportion of endocrine cells and augments both in vitro and in vivo function of the islets. Received 13 February 2018. Revision received 13 June 2018. Accepted 26 June 2018. * Contributed equally Corresponding Author Dr. Gregory S. Korbutt, Alberta Diabetes Institute, 5-002 Li Ka Shing Center, University of Alberta, Edmonton, Alberta, Canada, T6G 2E1. T: (780) 492-4657 F: (780) 492-5501. Email: korbutt@ualberta.ca Authorship TH and LKS performed experiments, presented and analyzed the data and contributed to writing the manuscript. BS conducted all transplants and glucose tolerance tests. GSK designed the study, financial support, data interpretation, manuscript review and final editing of manuscript. Disclosure The authors declare no conflicts of interest associated with this manuscript. Funding This study is supported by the Canadian Institutes of Health Research (Grant #MOP 119500). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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