On the Role of Mining Exposure in Epigenetic Effects in Parkinson’s Disease

Abstract

To explore the possible influence of heavy metal mining on incidence of Parkinson's disease (PD), global DNA methylation was assessed in blood samples from a population of PD patients (n = 45) and control subjects (n = 52) in Antofagasta neighborhood, a Chilean city built for exclusive use of mining companies. Comparisons were made with PD subjects (n = 52) and control subjects (n = 59) from Santiago Chile, a city having little association with mining. All subjects were assessed by two neurologists and PD diagnosis was based on UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria. From blood samples obtained from each individual, a decrease in global DNA methylation was observed in PD patients either exposed (49% of control, P < 0.001) or not exposed (47% of control, P < 0.001) to mining activity. Although there was no difference in levels of DNA methylation between PD patients from the two cities, there was a lower level of DNA methylation in control subjects from Santiago versus Antofagasta.

http://ift.tt/2qptB7P

Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats

Abstract

Propofol is a general anesthetic commonly used in pediatric clinical practices. Experimental findings demonstrate that anesthetics induce widespread apoptosis and cognitive decline in a developing brain. Although anesthesia-mediated neurotoxicity is the most prominent during intense period of synaptogenesis, the effects of an early anesthesia exposure on the synapses are not well understood. The aim of this study was to examine the effects of neonatal propofol anesthesia on the expression of key proteins that participate in synaptogenesis and synaptic plasticity and to evaluate long-term neurobehavioral abnormalities in the mature adult brain. Propofol-injected 7-day-old rats were maintained under 2-, 4-, and 6-h-long anesthesia and sacrificed 0, 4, 16, and 24 h after the termination of each exposure. We showed that propofol anesthesia strongly influenced spatiotemporal expression and/or proteolytic processing of crucial presynaptic (GAP-43, synaptophysin, α-synuclein), trans-synaptic (N-cadherin), and postsynaptic (drebrin, MAP-2) proteins in the cortex and thalamus. An overall decrease of synaptophysin, α-synuclein, N-cadherin, and drebrin indicated impaired function and structure of the synaptic contacts immediately after anesthesia cessation. GAP-43 and MAP-2 adult and juvenile isoforms are upregulated following anesthesia, suggesting compensatory mechanism in the maintaining of the structural integrity and stabilization of developing axons and dendritic arbors. Neonatal propofol exposure significantly altered spontaneous motor activity (increased stereotypic/repetitive movements) and changed emotional behavior (reduced anxiety-like response) in the adulthood, 6 months later. These findings suggest that propofol anesthesia is synaptotoxic in the developing brain, disturbing synaptic dynamics and producing neuroplastic changes permanently incorporated into existing networks with long-lasting functional consequences.

http://ift.tt/2pUF7bR

Long-Term Clinical Outcomes After Switching from Remicade ® to Biosimilar CT-P13 in Inflammatory Bowel Disease

Abstract

Background

Limited data are available on long-term clinical outcomes regarding the switch from Remicade^® to the infliximab biosimilar CT-P13 in inflammatory bowel disease (IBD) patients.

Aims

To investigate long-term efficacy, safety, pharmacokinetic profile, and immunogenicity.

Methods

We performed a single-center prospective observational cohort study following an elective switch from Remicade^® to CT-P13 in IBD patients.

Results

Eighty-three patients were included (57 Crohn's disease, 24 ulcerative colitis, and 2 IBD unclassified), and 68 patients completed one-year follow-up. Disease activity (Harvey–Bradshaw Index and Simple Clinical Colitis Activity Index) as well as inflammatory markers (CRP, fecal calprotectin) did not change significantly during the 1-year follow-up. In total, 7 out of 83 patients (8%) demonstrated detectable antidrug antibodies during follow-up, and 5 out of 7 antidrug antibody titers were already detectable at baseline prior to switching. Six patients (7%) discontinued CT-P13 due to adverse events.

Conclusions

Following a switch from Remicade^® to CT-P13, 82% of IBD patients continued treatment through 1 year. Disease activity scores and inflammatory markers remained unchanged during follow-up, and no CT-P13-related serious adverse events occurred. These 1-year data suggest that switching to CT-P13 in Remicade^®-treated IBD patients is safe and feasible.

http://ift.tt/2sXzbCb

Design and evaluation of safety operation VR training system for robotic catheter surgery

Abstract

A number of remote robotic catheter systems have been developed to protect physicians from X-ray exposure in endovascular surgery. However, the teleoperation prevents the physicians sensing the force directly which may easily result in healthy vessels injured. To realize the safe operation, a tissue protection-based VR training system has been developed in this paper to prevent collateral damage by collision. The integrated VR simulator cannot only remind the novice possible collisions by visual signs, but also cooperate with the newly designed tissue protection mechanism to remit collision trauma beforehand. Such mechanism exploits the diameter variable pulley in order to implement the safe interaction between catheter and vasculature. To testify the effectiveness of the tissue protection in training system, we invited four non-medical students to participate the successive 5 days training session. The evaluation results show that the average impingement distance (representing tissue damage) to vascular wall has been reduced to 0.6 mm, and the collision frequency is greatly decreased which implies the realization of relative safe catheterization.

http://ift.tt/2tvKOlo

Evaluation of the results of surgery treatment in patients with congenital chest deformity

Abstract

Purpose

Present study is designed to evaluate usefulness of sternochondroplasty and other surgical techniques in repairing congenital chest deformity.

Materials and methods

This study were considered in 51 patients undergoing congenital chest deformity repair with sternochondroplasty and other surgical techniques that had been referred to Thorax surgery ward of Gaem Hospital in Mashhad University of Medical Sciences between 1992 and 2012. Variables included were gender, age, symptoms, complications, recurrence, and cosmetic results.

Results

We studied 51 patients (male/female = 36/15) with mean age of 12.39 years (in 50 patients). The patient with central syndrome is 1 day old. Distribution of patients was 20 cases with pectus excavatum, 14 cases with pectus carinatum, 3 cases with sternal cleft, 3 cases with Poland syndrome, and one case with central syndrome. Congenital anomalies associated with patients included cardiac anomaly in 3 patients, ectopic testis in 1 patient, hand anomaly in 1 patient, skeletal anomaly in 1patient, and ear deformity in 1 patient. Complication after surgery was pneumothorax in 1 patient. Recurrence did not occur in patients. In 96% of cases, cosmetic result was excellent. Two hospital mortalities were reported.

Conclusion

Sternochondroplasty is an appropriate procedure in repairing congenital chest deformity. We did photography for most of patients before and after operation in order to compare results. We measured the distance between the deepest area on sternum and upper area on the chest wall with ruler .This way is simpler than CT scan imaging for measuring the degree of defect in pectus excavatum. Sternochondroplasty has the fewest complications. Cosmetic results are excellent. We had no recurrence after 2 years of follow-up. Patients with upper sternal cleft were repaired with apposition of sternal bars using steel wire, although in one patient we used prosthetic mesh because of extensive defect area. In patients with Poland syndrome we used latissimus dorsi for repairing of defect, and we recommended using autologous tissue for repair of defective area. Cantrell pentad is very rare disease and we have a little experience in treatment.

http://ift.tt/2sXBK7D

„Krankheit“ als theoretischer Begriff der Medizin: Unterschiede zwischen lebensweltlichem und wissenschaftlichem Krankheitsbegriff

Abstract

Der Krankheitsbegriff ist sowohl ein Begriff der Lebenswelt als auch ein theoretischer Begriff der medizinischen Wissenschaft. Das Paper zeigt die wichtigsten Unterschiede auf. Im ersten Teil wird die Grundstruktur der Krankheitslehre anhand von 7 Prinzipien dargestellt. Im zweiten Teil werden einige besonders wichtige Unterschiede in Form von Frage und Antwort explizit erklärt. Prinzipien: (1) Die Krankheitslehre hat das individuelle menschliche Leben unter dem Aspekt von Krankheit und Gesundheit zum Gegenstand. (2) Die Krankheitslehre fasst Krankheiten als abgrenzbare Anteile eines individuellen Lebens auf. (3) Jedes krankhafte Phänomen ist entweder eine Krankheit oder deren Manifestation. (4) Jede einzelne Krankheit ist ein Fall einer allgemeinen Art: einer Krankheitsentität. (5) Krankheitsentitäten werden definiert durch eine Kombination von Erstursachen, Wirkbedingungen, Reaktionen und Folgen im Organismus, Verlaufsformen und Ausgängen. (6) Krankheitsentitäten sind durch sie definierende pathologische Merkmale gekennzeichnet. Die Pathologizität von Merkmalen lässt sich durch ein System von Krankheitskriterien charakterisieren. (7) Ein fraglich pathologischer Lebensvorgang kann durch Rekurs auf die Ätiopathologie der zugehörigen Krankheitsentität theoretisch eingeordnet werden. Fragen (mit Antworten): (1) Gibt es eine scharfe Grenze zwischen Gesundheit und Krankheit? (2) Gibt es zwischen Gesundheit und Krankheit einen neutralen Bereich von Zuständen? (3) Kann die Medizin eine positive Definition von Gesundheit angeben? (4) Kann man Gesundheit mit vollständigem subjektivem Wohlbefinden gleichsetzen? (5) Ist Krankheit etwas Unnatürliches? (6) Können Menschen auch dann gesund sein, wenn sie eine Krankheit oder Behinderung haben? (7) Ist jemand krank, bei dem ein Risikofaktor festgestellt wird? (8) Dürfen gegen eine Krankheit nur Personen mit nachgewiesener Erkrankung behandelt werden? (9) Ist Krankheit immer ein Übel? (10) Welche normativen Implikationen hat der wissenschaftliche Krankheitsbegriff?

http://ift.tt/2tscsyP

Microfluidic device flow field characterization around tumor spheroids with tunable necrosis produced in an optimized off-chip process

Abstract

Tumor spheroids are a 3-D tumor model that holds promise for testing cancer therapies in vitro using microfluidic devices. Tailoring the properties of a tumor spheroid is critical for evaluating therapies over a broad range of possible indications. Using human colon cancer cells (HCT-116), we demonstrate controlled tumor spheroid growth rates by varying the number of cells initially seeded into microwell chambers. The presence of a necrotic core in the spheroids could be controlled by changing the glucose concentration of the incubation medium. This manipulation had no effect on the size of the tumor spheroids or hypoxia in the spheroid core, which has been predicted by a mathematical model in computer simulations of spheroid growth. Control over the presence of a necrotic core while maintaining other physical parameters of the spheroid presents an opportunity to assess the impact of core necrosis on therapy efficacy. Using micro-particle imaging velocimetry (micro-PIV), we characterize the hydrodynamics and mass transport of nanoparticles in tumor spheroids in a microfluidic device. We observe a geometrical dependence on the flow rate experienced by the tumor spheroid in the device, such that the "front" of the spheroid experiences a higher flow velocity than the "back" of the spheroid. Using fluorescent nanoparticles, we demonstrate a heterogeneous accumulation of nanoparticles at the tumor interface that correlates with the observed flow velocities. The penetration depth of these nanoparticles into the tumor spheroid depends on nanoparticle diameter, consistent with reports in the literature.

http://ift.tt/2tqT45J

New Paradigm: Adaptive Approach

http://ift.tt/2tvOHHg

Sorafenib-Induced Acute Pancreatitis: Case Report and Review of the Literature

http://ift.tt/2u5bh6s

A surgical robot with augmented reality visualization for stereoelectroencephalography electrode implantation

Abstract

Purpose

Using existing stereoelectroencephalography (SEEG) electrode implantation surgical robot systems, it is difficult to intuitively validate registration accuracy and display the electrode entry points (EPs) and the anatomical structure around the electrode trajectories in the patient space to the surgeon. This paper proposes a prototype system that can realize video see-through augmented reality (VAR) and spatial augmented reality (SAR) for SEEG implantation. The system helps the surgeon quickly and intuitively confirm the registration accuracy, locate EPs and visualize the internal anatomical structure in the image space and patient space.

Methods

We designed and developed a projector-camera system (PCS) attached to the distal flange of a robot arm. First, system calibration is performed. Second, the PCS is used to obtain the point clouds of the surface of the patient's head, which are utilized for patient-to-image registration. Finally, VAR is produced by merging the real-time video of the patient and the preoperative three-dimensional (3D) operational planning model. In addition, SAR is implemented by projecting the planning electrode trajectories and local anatomical structure onto the patient's scalp.

Results

The error of registration, the electrode EPs and the target points are evaluated on a phantom. The fiducial registration error is \(0.25 \pm 0.23\) mm (max 1.22 mm), and the target registration error is \(0.62\pm 0.28\) mm (max 1.18 mm). The projection overlay error is \(0.75\pm 0.52\) mm, and the TP error after the pre-warped projection is \(0.82\pm 0.23\) mm. The TP error caused by a surgeon's viewpoint deviation is also evaluated.

Conclusion

The presented system can help surgeons quickly verify registration accuracy during SEEG procedures and can provide accurate EP locations and internal structural information to the surgeon. With more intuitive surgical information, the surgeon may have more confidence and be able to perform surgeries with better outcomes.

http://ift.tt/2tvjrb4

Axillary Advancement Suture to Minimize Post-Implantation Deformity in Implant: Based Breast Reconstruction

http://ift.tt/2tpBjDZ

Re: “The Role of Lipofilling After Breast Reconstruction: Evaluation of Outcomes and Patient Satisfaction with BREAST-Q”

http://ift.tt/2s6V1R0

Comment on: “Surgical Masculinization of the Breast: Clinical Classification and Surgical Procedures”

http://ift.tt/2s6zeJ8

Response to: Comment to “The Characteristics and Short-Term Surgical Outcomes of Adolescent Gynecomastia”

http://ift.tt/2tpLLvf

Lymphocele Following Liposuction in the Thigh

Abstract

Lymphocele has not been reported as a complication after liposuction. In this study, we present the case of a patient who developed a cystic lesion after liposuction in her right thigh. The cyst could contract and evolve. The diagnosis of pseudobursa seroma (late seroma) was first considered. However, lymphoscintigraphy showed that lymphatic fluid accumulated in the cyst, and lymphatic vessel connected with it. The final diagnose was a lymphocele. After interventional therapy and conservative treatment failed, the lymphocele was resected. The subcutaneous soft tissue around the cyst was divided into bundles and then ligated with the purpose of blocking lymph leakage from the lymphatic duct.

Level of Evidence V

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

http://ift.tt/2tv8TJ3

Axillary Advancement Suture to Minimize Post-Implantation Deformity in Implant-Based Breast Reconstruction

Abstract

Patients who have undergone implant-based breast reconstruction after skin-sparing mastectomy often complain about bulging on the upper flank or inferior axillary area. This is most likely because the subcutaneous tissue layer of the upper flank, which is continuous with the breast tissue, tends to show inferolateral drooping once the subcutaneous tissue becomes loose after eliminating the breast parenchyma. In addition, one of the weaknesses of implant surgery is that implants cannot completely replace the tissue removed during skin-sparing mastectomy (SSM). This leads to the formation of a depression and a stepping effect superior and lateral to the implant on both sides. Notably, because the pectoralis major muscle is quite thin, when there is a depression around the superolateral area of the implant, it acts as a band, which then leads to tissue bulging and serious aesthetic problems. Here, we describe a simple advancement suture technique that can be used to resolve these two aesthetic problems in direct-to-implant breast reconstruction. The advancement sutures are performed after the implant and drains are inserted following SSM and before closing the incision. First, the surgeon confirms the depression in the superolateral area of the implant insertion site by redraping a skin flap lateral to the margin. If a depression is suspected, the surgeon uses forceps to pull the subcutaneous tissue in the lateral flank pocket over to the lateral border of the pectoralis major muscle, superolateral to the implant. At this point, correction of the lateral flank bulging and depression on the superolateral border is verified. If the result is not satisfactory, the surgeon may attempt advancing the subcutaneous fat from different areas; the more posterior the tissue is advanced, the better it eliminates the lateral bulging and superolateral depression. However, too much advancement may cause extra tension, potentially resulting in tearing of the tissue. A round needle is used to suture two to three stitches, before completing wound closure. By performing this simple advancement suture, we were able to successfully minimize post-implantation deformity—bulging on the lateral flank and depression at the superolateral implant margin.

Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

http://ift.tt/2tpYSMO

Comparative Quantitative Lymph Node Assessment in Localized Esophageal Cancer Patients After R0 Resection With and Without Neoadjuvant Chemoradiation Therapy

Abstract

Introduction

The effects of neoadjuvant chemoradiation therapy on lymph node retrieval during esophagectomy for patients with esophageal cancer are unclear. The aim of this study was to quantify lymph node retrieval after R0 esophagectomy and to assess its impact on overall survival in induction therapy patients.

Methods

One hundred seventy-four consecutive patients underwent esophagectomy with or without induction therapy from 2008 to 2015 for esophageal cancer. Total lymph nodes, positive lymph nodes, and lymph node ratios were compared between two groups of patients: those treated with either upfront surgery or those treated with neoadjuvant chemoradiation therapy followed by surgery. Comparisons were made using Student's t test. Overall survival was obtained and compared using Kaplan Meier survival curves.

Results

Total lymph node counts were less in the induction therapy group (p = 0.027), while positive lymph node counts and lymph node ratios did not differ between groups (p = 0.262 and p = 0.310, respectively). In the neoadjuvant chemoradiation followed by surgery group, overall survival was significantly shorter for patients who had any positive lymph nodes in the pathologic specimen (p = 0.0065).

Conclusions

Total lymph node counts were significantly lower in the induction therapy group, while positive lymph node counts and lymph node ratios did not differ from the upfront surgery group. Although overall survival was not different between groups, it was decreased within the induction therapy cohort among those who had any positive lymph nodes retrieved at surgery. This study confirms that unstratified gross lymph node counts do not substantially relate to prognosis in the heterogeneous population of locally advanced esophageal cancer patients who may or may not have had neoadjuvant chemoradiation.

http://ift.tt/2tujS5z

Hospital Volume and the Costs Associated with Surgery for Pancreatic Cancer

Abstract

Background

Data evaluating the financial implications of volume-based referral are lacking. This study sought to compare in-hospital costs for pancreatic surgery by annual hospital volume.

Methods

Eleven thousand and eighty-one patients aged ≥18 years undergoing an elective pancreatic resection for cancer were identified using the Nationwide Inpatient Sample 2002–2011. Multivariable regression analysis was performed to compare length-of-stay (LOS), postoperative morbidity and mortality, failure-to-rescue (FTR), and inpatient costs by annual hospital volume group.

Results

Patients undergoing surgery at high-volume hospitals (HVH) demonstrated 23% lower odds (odds ratio [OR] = 0.77, 95% confidence interval [95%CI] 0.63–0.95) of developing a postoperative complication, 59% lower odds of experiencing an LOS > 14 days (OR = 0.41, 95%CI 0.34–0.50), 51% lower odds of postoperative mortality (OR = 0.49, 95%CI 0.34–0.71), and 47% lower odds of FTR (OR = 0.53, 95%CI 0.37–0.76; all p<0.05). The overall mean in-hospital cost was $39,012 (SD = $15,214) with minimal differences observed across hospital volume groups. Rather, postoperative complications (no complication vs. complication $26,686 [SD = $5762] vs. $44,633 [SD = $11,637]) and FTR (rescue vs. FTR $42,413 [SD = $8481] vs. $69,546 [SD = $13,131]) were determinant of higher in-hospital costs. While this pattern was observed at all hospital volume groups, costs varied minimally between hospital volume groups after this stratification.

Conclusions

Annual hospital surgical volume was not associated with in-hospital costs among patients undergoing pancreatic surgery.

http://ift.tt/2u3Zvci

Blood Flow in Idealized Vascular Access for Hemodialysis: A Review of Computational Studies

Abstract

Although our understanding of the failure mechanism of vascular access for hemodialysis has increased substantially, this knowledge has not translated into successful therapies. Despite advances in technology, it is recognized that vascular access is difficult to maintain, due to complications such as intimal hyperplasia. Computational studies have been used to estimate hemodynamic changes induced by vascular access creation. Due to the heterogeneity of patient-specific geometries, and difficulties with obtaining reliable models of access vessels, idealized models were often employed. In this review we analyze the knowledge gained with the use of computational such simplified models. A review of the literature was conducted, considering studies employing a computational fluid dynamics approach to gain insights into the flow field phenotype that develops in idealized models of vascular access. Several important discoveries have originated from idealized model studies, including the detrimental role of disturbed flow and turbulent flow, and the beneficial role of spiral flow in intimal hyperplasia. The general flow phenotype was consistent among studies, but findings were not treated homogeneously since they paralleled achievements in cardiovascular biomechanics which spanned over the last two decades. Computational studies in idealized models are important for studying local blood flow features and evaluating new concepts that may improve the patency of vascular access for hemodialysis. For future studies we strongly recommend numerical modelling targeted at accurately characterizing turbulent flows and multidirectional wall shear disturbances.

http://ift.tt/2slWsit

Stratification of disease progression in a broad spectrum of degenerative cerebellar ataxias with a clustering method using MRI-based atrophy rates of brain structures

Abstract

Background

The rate of disease progression differs among patients with degenerative cerebellar ataxia. The uncertain natural course in individual patients hinders clinical trials of promising treatments. In this study, we analyzed atrophy changes in brain structures with cluster analysis to find sub-groups of patients with homogenous symptom progression in a broad spectrum of degenerative cerebellar ataxias.

Methods

We examined 48 patients including 21 cases of spinocerebellar ataxia (SCA), 17 cases of the cerebellar type of multiple system atrophy (MSA-C), and 10 cases of cortical cerebellar ataxia (CCA). In all patients, at least two sets of evaluations including magnetic resonance imaging (MRI) and the International Cooperative Ataxia Rating Scale (ICARS) scoring were performed. The median number (min-max) of follow-up studies in each patient was three (2–6), and the mean follow-up period was 3.1 ± 1.6 years. The area of the corpus callosum on midsagittal images and the cerebellar volume were measured using MRI, and these values were divided by the cranial antero-posterior diameter of each patient to correct for individual head size differences as an area index (Adx) and a volume index (Vdx), respectively. The annual changes in Adx, Vdx, and ICARS score were calculated in each patient, and atrophy patterns in patients were categorized with cluster analysis.

Results

The annual atrophy rates for the corpus callosum (Adx) and cerebellum (Vdx) and symptom progression differed significantly by subtype of cerebellar ataxia (p = 0.026, 0.019, and 0.021, respectively). However, neither the annual atrophy rate of Adx nor Vdx was significantly correlated with the annual increase in the ICARS score. When the patients were categorized into three clusters based on the annual changes in Adx and Vdx, the annual increase in the ICARS score was significantly different among clusters (2.9 ± 1.7/year in Cluster 1, 4.8 ± 3.2/year in Cluster 2, and 8.7 ± 6.1/year in Cluster 3; p = 0.014).

Conclusions

The annual increase in the ICARS score can be stratified by cluster analysis based on the atrophy rates of the corpus callosum and cerebellum. Further studies are warranted to explore whether these simple MRI methods could be used for random allocation of a broad spectrum of patients with degenerative cerebellar ataxia in clinical trials.

http://ift.tt/2sm0wQ4

Correlation Between Expression of Recombinant Proteins and Abundance of H3K4Me3 on the Enhancer of Human Cytomegalovirus Major Immediate-Early Promoter

Abstract

Role of epigenetic regulation in the control of gene expression is well established. The impact of several epigenetic mechanisms, such as DNA methylation and histone acetylation, on recombinant protein production in mammalian cells has been investigated recently. Here we investigate the correlation between the selected epigenetic markers and five trastuzumab biosimilar-producing Chinese hamster ovary (CHO) cell lines in which the expression of trastuzumab is driven by human cytomegalovirus (HCMV) major immediate-early (MIE) promoter. We chose the producing clones in which transcription was the determinative step for the production of recombinant trastuzumab. We found that the abundance of trimethylation of histone 3 at lysine 4 (H3K4Me3) on the enhancer of HCMV MIE promoter correlated well with the relative titers of recombinant trastuzumab among the clones. Such close correlation was not observed between the recombinant protein and other epigenetic markers examined in our study. Our results demonstrate that the HCMV MIE enhancer-bound H3K4Me3 epigenetic marker may be used as the epigenetic indicator to predict the relative production of recombinant proteins between the producing CHO cell lines.

http://ift.tt/2srygqk

Signal of Miscarriage with Aripiprazole: A Disproportionality Analysis of the Japanese Adverse Drug Event Report Database

Abstract

Introduction

With recent advances in medicines, many patients with schizophrenia have become able to conceive. One common second-generation antipsychotic given to patients with schizophrenia is aripiprazole. The label information of aripiprazole in Japan states that according to one case report "there is a report of miscarriage in clinical trial".

Objective

The aim of this study was to evaluate the relationship between aripiprazole and miscarriage by conducting a disproportionality analysis of an adverse drug event report database.

Methods

We conducted a disproportionality analysis of second-generation antipsychotic exposure during pregnancy using the Japanese Adverse Drug Event Report database, which is a spontaneous reporting database in Japan. We investigated aripiprazole and other approved second-generation antipsychotics in Japan. In accordance with the previous report, we created a data set for analysis consisting of pregnancy-related reports.

Results

A potential signal for miscarriage was detected for aripiprazole [proportional reporting ratio: 2.39, χ ²: 13.77, reporting odds ratio (95% confidence interval): 2.76 (1.62–4.69); n = 18]. In contrast, no potential signal for miscarriage was detected for other second-generation antipsychotics.

Conclusion

Through our analysis of the Japanese Adverse Drug Event Report database, we found a potential signal for miscarriage for aripiprazole. Safety information on the use of aripiprazole during pregnancy is very limited. Therefore, we suggest that the potential signal detected in our analysis be explored further.

http://ift.tt/2t5uGE5

The impact of growth hormone on proteomic profiles: a review of mouse and adult human studies

Abstract

Growth hormone (GH) is a protein that is known to stimulate postnatal growth, counter regulate insulin's action and induce expression of insulin-like growth factor-1. GH exerts anabolic or catabolic effects depending upon on the targeted tissue. For instance, GH increases skeletal muscle and decreases adipose tissue mass. Our laboratory has spent the past two decades studying these effects, including the effects of GH excess and depletion, on the proteome of several mouse and human tissues. This review first discusses proteomic techniques that are commonly used for these types of studies. We then examine the proteomic differences found in mice with excess circulating GH (bGH mice) or mice with disruption of the GH receptor gene (GHR^−/−). We also describe the effects of increased and decreased GH action on the proteome of adult patients with either acromegaly, GH deficiency or patients after short-term GH treatment. Finally, we explain how these proteomic studies resulted in the discovery of potential biomarkers for GH action, particularly those related with the effects of GH on aging, glucose metabolism and body composition.

http://ift.tt/2sVA4eO

Factors associated with antithrombotic treatment decisions for stroke prevention in atrial fibrillation in the Stockholm region after the introduction of NOACs

Abstract

Purpose

The purpose of this study was to investigate the influence of patient characteristics such as age and stroke and bleeding risks on decisions for antithrombotic treatment in patients with atrial fibrillation (AF).

Methods

This was a retrospective, population-based study including AF patients initiated with either warfarin, dabigatran, rivaroxaban, apixaban, or low-dose aspirin (ASA) between March 2015 and February 2016. Multivariate models were used to calculate adjusted odds ratios (aOR) for factors associated with treatment decisions.

Results

A total of 6765 newly initiated patients were included, most with apixaban (46.4%) and least with ASA (6.7%). There were more comorbidities in patients initiated with ASA or warfarin compared to the cohort average. Patients with high stroke risks had higher chances of receiving ASA (CHA₂DS₂-VASc ≥5 vs 0; aOR 2.01; 95% confidence interval (CI) 1.12–3.33). Among patients receiving oral anticoagulants, patients with high bleeding risks more often received warfarin (ATRIA score 5–10 vs 0–3; aOR 1.40; CI 1.20–1.64). Among NOACs, apixaban was preferred for patients with higher stroke risks (aOR 1.78; CI 1.31–2.41), high bleeding risks (aOR 1.54; CI 1.26–1.88) and high age (age group ≥85 vs 0–65; aOR 1.84; CI 1.44–2.35). Conversely, dabigatran treatment was associated with lower ages and lower risks.

Conclusions

High stroke and bleeding risks favored choices of warfarin or ASA. Among patients receiving NOACs, apixaban was favored for elderly and high-risk patients whereas dabigatran was used in lower risk patients. The inadvertent use of ASA, especially among those with high stroke risks, should be further discouraged.

http://ift.tt/2s5XmvD

Modified Well-Field Configurations for Improved Performance of Contaminant Elution and Tracer Tests

Abstract

Contaminant elution and tracer (CET) tests are one method for characterizing the impact of mass transfer, transformation, and other attenuation processes on contaminant transport and mass removal for subsurface systems. The purpose of the work reported herein is to explore specific well-field configurations for improving CET tests by reducing the influence of preferential flow and surrounding plume effects. Three injection-extraction well configurations were tested for different domain conditions using a three-dimensional numerical model. The three configurations were the traditional configuration with a single pair of injection-extraction wells, modified configuration I with one extraction well located between two injection wells, and modified configuration II with two pairs of injection-extraction couplets (one nested within the other). Elution curves for resident contaminant and breakthrough curves from simulated tracer tests were examined for specific landmarks such as the presence and extent of steady state (relatively high concentrations) and asymptotic (asymptotic decrease to low concentrations) phases, as well as distinct changes in slope. Temporal moment analysis of the breakthrough curves was conducted to evaluate mass recovery. Effective diffusion coefficients were obtained by fitting selected functions to the elution curves. Based on simulation results for a homogeneous domain, full isolation of the inner extraction well from the surrounding plume was obtained for the modified configuration II, whereas the extraction wells are impacted by the surrounding plume for the other two configurations. Therefore, configuration II was used for additional simulations conducted with layered and heterogeneous domains. Tracer test simulations for homogeneous and layered domains indicate 100% mass recovery for the inner extraction well. For the heterogeneous domain, decreasing the distance between the inner injection-extraction well couplet and adjusting the pumping rate distribution between the two extraction wells increased the mass recovery from 69 to 99%.

http://ift.tt/2t5yRQv

Pine Bark Amendment to Promote Sustainability in Cu-Polluted Acid Soils: Effects on Lolium perenne Growth and Cu Uptake

Abstract

The establishment of a complementary grass cover on vineyard soils can promote sustainability of the affected environment. In this work, we used an acid vineyard soil with total Cu concentration 188 mg kg⁻¹ to study the influence of pine bark amendment on Lolium perenne growth and Cu uptake. The results indicate that the pine bark amendment did not cause a significant increase in the mass of the shoots of Lolium perenne, but favored the root biomass: 0.034 g for control and 0.061 g for soil samples amended with 48 g kg⁻¹ of pine bark. Moreover, the pine bark amendment decreased Cu concentration in both, shoots (50 mg kg⁻¹ for control soil and 29 mg kg⁻¹ for soil amended with 48 g kg⁻¹ pine bark) and roots (250 mg kg⁻¹ for control soil and 64 mg kg⁻¹ for soil amended with 48 g kg⁻¹ pine bark). The main factor responsible for these results was a significant decrease of the most mobile fractions of Cu in the soil. Those fractions were extracted using ammonium acetate, ammonium chloride, sodium salt of ethylene-diamine-tetraacetic acid (EDTA-Na), and diethylene-triamine-pentaacetic acid (DTPA).

http://ift.tt/2slaeSR

PTEN is a negative regulator of mitotic checkpoint complex during the cell cycle

Abstract

Nuclear PTEN plays an important role during mitosis. To understand the molecular basis by which PTEN mediates mitotic progression, we examined whether PTEN regulated the formation of mitotic checkpoint complex (MCC). We observed that arsenic trioxide, a mitotic inducer, stimulated nuclear translocation of PTEN in a time-dependent manner. PTEN physically interacted with Cdc20 and Mad2, two important components of MCC. Arsenic treatment diminished the physical association of PTEN with BubR1 and Bub3 but not with Cdc20 and Mad2. Our further studies revealed that downregulation of PTEN via RNAi enhanced formation of MCC during the cell cycle. Moreover, PTEN silencing induced chromosomal instability. Given the crucial role of PTEN in suppressing tumor development, our study strongly suggests that PTEN also functions to maintain chromosomal stability, partly through suppressing unscheduled formation of MCC.

http://ift.tt/2t5e1AK

Effect of vitamin E on oxidative stress level in blood, synovial fluid, and synovial tissue in severe knee osteoarthritis: a randomized controlled study

Abstract

Background

This study was performed to evaluate the antioxidative and anti-inflammatory effects of vitamin E on oxidative stress in the plasma, synovial fluid, and synovial tissue of patients with knee osteoarthritis.

Methods

Seventy-two patients with late-stage knee osteoarthritis scheduled for total knee arthroplasty were randomized to take oral placebo (Group A) or 400 IU of vitamin E (Group B) once a day for 2 months before undergoing surgery. The blood levels of endpoints indicating oxidative stress or antioxidant capacity, Knee Society Score (KSS), Western Ontario and McMaster Universities Osteoarthritis Index score (WOMAC), and adverse effects were compared before and after the intervention between the two groups. At surgery, these redox endpoints and histological findings were compared between the synovial fluid and synovial tissue.

Results

In blood samples, the pre-intervention of oxidative stress and antioxidative capacity were not different between Group A and Group B. In post-intervention blood samples, the Malondialdehyde (Group A 1.34 ± 0.10, Group B 1.00 ± 0.09, p < 0.02), Alpha tocopherol (Group A 15.92 ± 1.08, Group B 24.65 ± 1.47, p < 0.01) and Trolox equivalent antioxidant capacity (Group A 4.22 ± 0.10, Group B 5.04 ± 0.10, 0 < 0.01) were significantly different between Group A and Group B. In synovial fluid samples, the Malondialdehyde (Group A 1.42 ± 0.12, Group B 1.06 ± 1.08, p 0.01), Alphatocopherol (Group A 4.51, Group B 7.03, p < 0.01), Trolox equivalent antioxidant capacity (Group A, 1.89 ± 0.06, Group B 2.19 ± 0.10) were significantly different between Group A and Group B. The pre-intervention WOMAC score and KSS score were not different between Group A and Group B. The post-intervention WOMAC score was significantly improved in all categories in Group B (Pain: Group A 27.26 ± 0.89, Group B 19.19 ± 1.43, p < 0.01; Stiffness: Group A 8.23 ± 0.79, Group B 5.45 ± 0.73, p 0.01; Function: Group A 94.77 ± 4.22, Group B 72.74 ± 6.55, p < 0.01). The post-intervention KSS score was significantly improved in all categories in Group B (Clinical: Group A 25.31 ± 14.33, Group B 33.52 ± 16.96, p < 0.01; Functional: Group A 41.43 ± 16.11, Group B 51.61 ± 19.60, p 0.02). Significantly fewer synovial tissue cells were stained with nitrotyrosine and hematoxylin–eosin in Group B than in Group A. There were no differences in adverse effects or surgical complications between the groups.

Conclusion

Vitamin E is an effective antioxidant that can improve clinical symptoms and reduce oxidative stress conditions in patients with late-stage knee osteoarthritis.

Trial registration

This research project had been approved for registration at Thai Clinical Trials Registry (TCTR) since 2016–08-28 11:26:32 (Retrospective registered). The TCTR identification number is TCTR20160828001.

http://ift.tt/2ttOPXK

Validation of three-dimensional models of the distal femur created from surgical navigation point cloud data for intraoperative and postoperative analysis of total knee arthroplasty

Abstract

Purpose

Despite the success of total knee arthroplasty, there continues to be a significant proportion of patients who are dissatisfied. One explanation may be a shape mismatch between pre- and postoperative distal femurs. The purpose of this study was to investigate methods suitable for matching a statistical shape model (SSM) to intraoperatively acquired point cloud data from a surgical navigation system and to validate these against the preoperative magnetic resonance imaging (MRI) data from the same patients.

Methods

A total of 10 patients who underwent navigated total knee arthroplasty also had an MRI scan <2 months preoperatively. The standard surgical protocol was followed which included partial digitization of the distal femur. Two different methods were employed to fit the SSM to the digitized point cloud data, based on (1) iterative closest points and (2) Gaussian mixture models. The available MRI data were manually segmented and the reconstructed three-dimensional surfaces used as ground truth against which the SSM fit was compared.

Results

For both approaches, the difference between the SSM-generated femur and the surface generated from MRI segmentation averaged less than 1.7 mm, with maximum errors occurring in less clinically important areas.

Conclusion

The results demonstrated good correspondence with the distal femoral morphology even in cases of sparse datasets. Application of this technique will allow for measurement of mismatch between pre- and postoperative femurs retrospectively on any case done using the surgical navigation system and could be integrated into the surgical navigation unit to provide real-time feedback.

http://ift.tt/2ttH5EQ

Role of DISC1 in Neuronal Trafficking and its Implication in Neuropsychiatric Manifestation and Neurotherapeutics

Abstract

Disrupted-in-schizophrenia 1 (DISC1) was initially identified as a gene disrupted by a translocation mutation co-segregating with a variety of psychotic and mood disorders in a Scottish pedigree. In agreement with this original finding, mouse models that perturb Disc1 display deficits of behaviors in specific dimensions, such as cognition and emotion, but not a motor dimension. Although DISC1 is not a risk gene for sporadic cases of specific psychiatric disorders defined by categorical diagnostic criteria (e.g., schizophrenia and major depressive disorder), DISC1 is now regarded as an important molecular lead to decipher molecular pathology for specific dimensions relevant to major mental illnesses. Emerging evidence points to the role of DISC1 in the regulation of intracellular trafficking of a wide range of neuronal cargoes. We will review recent progress in this aspect of DISC1 biology and discuss how we could utilize this body of knowledge to better understand the pathophysiology of mental illnesses.

http://ift.tt/2s5O1nA

A case of incisional hernia repair using Composix mesh prosthesis after antethoracic pedicled jejunal flap reconstruction following an esophagectomy

Abstract

Background

An incisional hernia in a case of antethoracic pedicled jejunal flap esophageal reconstruction after esophagectomy is a very rare occurrence, and this hernia was distinctive in that the reconstructed jejunum had passed through the hernial orifice; a standard surgical treatment for such a presentation has not been established. Herein, we describe a case of repair using mesh prosthesis for an atypical and distinctive incisional hernia after antethoracic pedicled jejunal flap esophageal reconstruction.

Case presentation

A 77-year-old woman with a history of subtotal esophagectomy who had undergone antethoracic pedicled jejunal flap reconstruction complained of epigastric prominence and discomfort without pain. On examination, she had an abdominal protrusion between the xiphoid process and the umbilicus that contained the small bowel. Computed tomography showed that the fenestration of the abdominal wall that was intentionally created for jejunum pull-up was dehisced in a region measuring 9 × 15 cm and the small intestine protruded through it into the subcutaneous space without strangulation. Because the hernial orifice was too large and the reconstructed jejunum was passing through the hernial orifice in this case, we applied a parastomal hernia repair method that was modified from the inguinal hernia repair using the Lichtenstein technique. After 3 years and 5 months following surgery, the patient has recovered without hernia recurrence or other complications.

Conclusion

We consider this to be the first case of repair using Composix mesh prosthesis for repair of an atypical and distinctive incisional hernia after an antethoracic pedicled jejunal flap reconstruction. This method seems to be useful and could potentially be widely adopted as the surgical treatment for this condition.

http://ift.tt/2sqyxtt

Effects of Mindfulness Practice on Performance-Relevant Parameters and Performance Outcomes in Sports: A Meta-Analytical Review

Abstract

Background

Mindfulness as a present-oriented form of mental training affects cognitive processes and is increasingly considered meaningful for sport psychological training approaches. However, few intervention studies have examined the effects of mindfulness practice on physiological and psychological performance surrogates or on performance outcomes in sports.

Objective

The aim of the present meta-analytical review was to examine the effects of mindfulness practice or mindfulness-based interventions on physiological and psychological performance surrogates and on performance outcomes in sports in athletes over 15 years of age.

Data Sources

A structured literature search was conducted in six electronic databases (CINAHL, EMBASE, ISI Web of Knowledge, PsycINFO, MEDLINE and SPORTDiscus). The following search terms were used with Boolean conjunction: (mindful* OR meditat* OR yoga) AND (sport* OR train* OR exercis* OR intervent* OR perform* OR capacity OR skill*) AND (health* OR adult* OR athlete*).

Study Selection

Randomized and non-randomized controlled studies that compared mindfulness practice techniques as an intervention with an inactive control or a control that followed another psychological training program in healthy sportive participants were screened for eligibility.

Data Extraction

Eligibility and study quality [Physiotherapy Evidence Database (PEDro)] scales were independently assessed by two researchers. A third independent researcher was consulted to achieve final consensus in case of disagreement between both researchers. Standardized mean differences (SMDs) were calculated as weighted Hedges' g and served as the main outcomes in comparing mindfulness practice versus control. Statistical analyses were conducted using a random-effects inverse-variance model.

Results

Nine trials of fair study quality (mean PEDro score 5.4, standard deviation 1.1) with 290 healthy sportive participants (athletics, cyclists, dart throwers, hammer throwers, hockey players, hurdlers, judo fighters, rugby players, middle-distance runners, long-distance runners, shooters, sprinters, volleyball players) were included. Intervention time varied from 4 weeks to over 2 years. The practice frequency lasted from twice daily to just once a week, and the mean session time covered 50–60 min. In favor of mindfulness practice compared with the control condition, large effects with narrow confidence limits and low heterogeneity were found for mindfulness scores [SMD 1.03, 90% confidence interval (CI) 0.67–1.40, p < 0.001, I ² = 17%]. Physiological performance indices depicted wide confidence limits accompanied with very large heterogeneity. However, the effect sizes remained very large, with confidence limits that did not overlap zero (SMD 3.62, 90% CI 0.03–7.21, p = 0.10, I ² = 98%). Moderate to large effects were observed for both psychological performance surrogates (SMD 0.72, 90% CI 0.46–0.98, p < 0.001, I ² = 14%) and performance outcomes in shooting and dart throwing (SMD 1.35, 90% CI 0.61–2.09, p = 0.003, I ² = 82%).

Conclusions

Mindfulness practice consistently and beneficially modulates mindfulness scores. Furthermore, physiological and psychological surrogates improved to a meaningful extent following mindfulness practice, as well as performance outcomes in shooting and dart throwing. It seems reasonable to consider mindfulness practice strategies as a regular complementary mental skills training approach for athletes, at least in precision sports; however, more high-quality, randomized, controlled trials on mindfulness practice and performance improvements in diverse sport settings are needed.

http://ift.tt/2sV9GBD

Netzwerke für motorische Kognition

Zusammenfassung

Unter dem Begriff Apraxie werden unterschiedliche Störungen höherer motorischer Fähigkeiten zusammengefasst, die nicht durch elementare sensomotorische Defizite (z. B. Paresen oder Ataxie) erklärt werden. Charakteristische, im klinischen Alltag gut zu erfassende Merkmale sind Schwierigkeiten bei pantomimisch dargestelltem oder tatsächlichem Werkzeuggebrauch sowie bei der Imitation bedeutungsloser Gesten. Apraxien sind bilaterale, deshalb kognitiv-motorische Störungen, die meist (jedoch nicht ausschließlich) nach linkshemisphärischen Läsionen auftreten; zudem gibt es Apraxien bei neurodegenerativen Erkrankungen (z. B. kortikobasales Syndrom, M. Alzheimer). Apraktische Defizite können zu gravierenden Einschränkungen bei den Aktivitäten des täglichen Lebens führen, weshalb die Diagnose von großer Bedeutung ist. Auf funktionell-anatomischer Ebene werden unterschiedliche kognitiv-motorische Fähigkeiten durch zumindest teilweise verschiedene Netzwerke ermöglicht. Hier werden ein ventraler Verarbeitungspfad für semantische Handlungskomponenten wie Zuordnungen zwischen Handlungen und Objekten, ein ventrodorsaler Pfad für sensomotorische Programme erlernter Bewegungen sowie ein dorsodorsales System für Bewegungskontrolle und wahrscheinlich auch Imitation bedeutungsloser Gesten unterschieden. Hierbei kommt es zu partiellen Überlappungen mit sprachrelevanten Regionen, während sich zwischen apraktischen und räumlichen Aufmerksamkeitsdefiziten deutlichere Dissoziationen finden. Bei der Therapie apraktischer Störungen rücken neben rein verhaltensbasierten Therapieansätzen zunehmend nichtinvasive neuromodulatorische Verfahren sowie auch computerbasierte Assistenzsysteme in den Fokus.

http://ift.tt/2sqw7Ll

S100A6 protein: functional roles

Abstract

S100A6 protein belongs to the A group of the S100 protein family of Ca²⁺-binding proteins. It is expressed in a limited number of cell types in adult normal tissues and in several tumor cell types. As an intracellular protein, S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors. S100A6 can be secreted/released by certain cell types which points to extracellular effects of the protein. RAGE (receptor for advanced glycation endproducts) and integrin β1 transduce some extracellular S100A6's effects. Dosage of serum S100A6 might aid in diagnosis in oncology.

http://ift.tt/2u2iRPf

BACE2 suppression promotes β-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression

Abstract

BACE2 (β-site APP-cleaving enzyme 2) is a protease expressed in the brain, but also in the pancreas, where it seems to play a physiological role. Amyloidogenic diseases, including Alzheimer's disease and type 2 diabetes (T2D), share the accumulation of abnormally folded and insoluble proteins that interfere with cell function. In T2D, islet amyloid polypeptide (IAPP) deposits have been shown to be a pathogenic key feature of the disease. The aim of the present study was to investigate the effect of BACE2 modulation on β-cell alterations in a mouse model of T2D induced by IAPP overexpression. Heterozygous mice carrying the human transcript of IAPP (hIAPP-Tg) were used as a model to study the deleterious effects of IAPP upon β-cell function. These animals showed glucose intolerance and impaired insulin secretion. When crossed with BACE2-deficient mice, the animals presented a significant improvement in glucose tolerance accompanied with an enhanced insulin secretion, as compared to hIAPP-Tg mice. BACE2 deficiency also partially reverted gene expression changes observed in islets from hIAPP-Tg mice, including a set of genes related to inflammation. Moreover, homozygous hIAPP mice presented a severe hyperglycemia and a high lethality rate from 8 weeks onwards due to a massive destruction of β-cell mass. This process was significantly reduced when crossed with the BACE2-KO model, improving the survival rate of the animals. Altogether, the absence of BACE2 ameliorates glucose tolerance defects induced by IAPP overexpression in the β-cell and promotes β-cell survival. Thus, targeting BACE2 may represent a promising therapeutic strategy to improve β-cell function in T2D.

http://ift.tt/2tt947B

Development of anticancer agents targeting the Hedgehog signaling

Abstract

Hedgehog signaling is an evolutionarily conserved pathway which is essential in embryonic and postnatal development as well as adult organ homeostasis. Abnormal regulation of Hedgehog signaling is implicated in many diseases including cancer. Consequently, substantial efforts have made in the past to develop potential therapeutic agents that specifically target the Hedgehog signaling for cancer treatment. Here, we review the therapeutic agents for inhibition of the Hedgehog signaling and their clinical advances in cancer treatment.

http://ift.tt/2tthGvd

Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production

Abstract

Intracellular accumulation of α-synuclein (α-syn) are hallmarks of synucleinopathies, including Parkinson's disease (PD). Exogenous addition of preformed α-syn fibrils (PFFs) into primary hippocampal neurons induced α-syn aggregation and accumulation. Likewise, intrastriatal inoculation of PFFs into mice and non-human primates generates Lewy bodies and Lewy neurites associated with PD-like neurodegeneration. Herein, we investigate the putative effects of synthetic human PFFs on cultured rat ventral midbrain dopamine (DA) neurons. A time- and dose-dependent accumulation of α-syn was observed following PFFs exposure that also underwent phosphorylation at serine 129. PFFs treatment decreased the expression levels of synaptic proteins, caused alterations in axonal transport-related proteins, and increased H2AX Ser139 phosphorylation. Mitochondrial impairment (including modulation of mitochondrial dynamics-associated protein content), enhanced oxidative stress, and an inflammatory response were also detected in our experimental paradigm. In attempt to unravel a potential molecular mechanism of PFFs neurotoxicity, the expression of inducible nitric oxide synthase was blocked; a significant decline in protein nitration levels and protection against PFFs-induced DA neuron death were observed. Combined exposure to PFFs and rotenone resulted in an additive toxicity. Strikingly, many of the harmful effects found were more prominent in DA rather than non-DA neurons, suggestive of higher susceptibility to degenerate. These findings provide new insights into the role of α-syn in the pathogenesis of PD and could represent a novel and valuable model to study DA-related neurodegeneration.

http://ift.tt/2tt6MW4

Mechanisms of collective cell movement lacking a leading or free front edge in vivo

Abstract

Collective cell movement is one of the strategies for achieving the complex shapes of tissues and organs. In this process, multiple cells within a group held together by cell–cell adhesion acquire mobility and move together in the same direction. In some well-studied models of collective cell movement, the mobility depends strongly on traction generated at the leading edge by cells located at the front. However, recent advances in live-imaging techniques have led to the discovery of other types of collective cell movement lacking a leading edge or even a free edge at the front, in a diverse array of morphological events, including tubule elongation, epithelial sheet extension, and tissue rotation. We herein review some of the developmental events that are organized by collective cell movement and attempt to elucidate the underlying cellular and molecular mechanisms, which include membrane protrusions, guidance cues, cell intercalation, and planer cell polarity, or chirality pathways.

http://ift.tt/2u2jR5U

The acidic microenvironment as a possible niche of dormant tumor cells

Abstract

Although surgical excision, chemo-, and radio-therapy are clearly advanced, tumors may relapse due to cells of the so-called "minimal residual disease". Indeed, small clusters of tumor cells persist in host tissues after treatment of the primary tumor elaborating strategies to survive and escape from immunological attacks before their relapse: this variable period of remission is known as "cancer dormancy". Therefore, it is crucial to understand and consider the major concepts addressing dormancy, to identify new targets and disclose potential clinical strategies. Here, we have particularly focused the relationships between tumor microenvironment and cancer dormancy, looking at a re-appreciated aspect of this compartment that is the low extracellular pH. Accumulating evidences indicate that acidity of tumor microenvironment is associated with a poor prognosis of tumor-bearing patients, stimulates a chemo- and radio-therapy resistant phenotype, and suppresses the tumoricidal activity of cytotoxic lymphocytes and natural killer cells, and all these aspects are useful for dormancy. Therefore, this review discusses the possibility that acidity of tumor microenvironment may provide a new, not previously suggested, adequate milieu for "dormancy" of tumor cells.

http://ift.tt/2u2dcbY

Ethnic differences in the +405 and −460 vascular endothelial growth factor polymorphisms and peripheral neuropathy in patients with diabetes residing in a North London, community in the United Kingdom

Abstract

Background

There are marked ethnic differences in the susceptibility to the long-term diabetic vascular complications including sensory neuropathy. The vascular endothelial growth factor (VEGF) +405 (C/G) and −460 (T/C) polymorphisms are associated with retinopathy and possibly with nephropathy, however no information is available on their relationship with peripheral neuropathy. Therefore, we examined the prevalence of these VEGF genotypes in a multi-ethnic cohort of patients with diabetes and their relationship with evident peripheral diabetic neuropathy.

Methods

In the current investigation, we studied 313 patients with diabetes mellitus of African-Caribbean, Indo-Asian and Caucasian ethnic origin residing in an inner-city community in London, United Kingdom attending a single secondary care centre. Genotyping was performed for the VEGF +405 and VEGF −460 polymorphisms using a pyrosequencing technique.

Results

Forty-nine patients (15.6%) had clinical evidence of peripheral neuropathy. Compared to Caucasian patients, African-Caribbean and Indo-Asian patients had lower incidence of neuropathy (24.6%, 14.28%, 6.7%, respectively; P = 0.04). The frequency of the VEGF +405 GG genotype was more common in Indo-Asian patients compared to African-Caribbean and Caucasian patients (67.5%, 45.3%, 38.4%, respectively; p ≤ 0.02). The G allele was more common in patients with type 2 diabetes of Indo-Asian origin compared to African-Caribbean and Caucasian origin (p ≤ 0.02). There was no difference between the ethnic groups in VEGF −460 genotypes. The distributions of the VEGF +405 and VEGF −460 genotypes were similar between the diabetic patients with and without neuropathy.

Conclusions

In this cohort of patients, VEGF +405 and VEGF −460 polymorphisms were not associated with evident diabetic peripheral neuropathy, however an association was found between VEGF +405 genotypes and Indo-Asian which might have relevance to their lower rates of ulceration and amputation. This finding highlights the need for further investigation of any possible relationship between VEGF genotype, circulating VEGF concentrations and differential vulnerability to peripheral neuropathy amongst diabetic patients of different ethnic backgrounds.

http://ift.tt/2sq7BtO

Thrombocytopenia induced by dabigatran: two case reports

Abstract

Background

Vitamin K inhibitors (e.g. warfarin) and indirect thrombin inhibitors (e.g. heparin) are widely used to prevent thromboembolic disorders (e.g. myocardial infarction, venous thromboembolism, and stroke). These agents have been mainstays of anticoagulation for people older than 60 years. However, their administration is associated with a risk of bleeding and requires careful monitoring of patients. Novel oral anticoagulants (NOACs), such as dabigatran, are significantly safer in preventing thromboembolism than warfarin and heparin (sporadically causes thrombocytopenia) and are more specific for their target protein, thrombin. The major advantage of dabigatran, a direct thrombin inhibitor, is that it reversibly inhibits both free and clot-bound thrombin by tight binding affinity and the predictable pharmacodynamic effect. A few studies, however, reported that dabigatran can cause thrombocytopenia, although the underlying mechanism remains unclear. Thus, an antidote for dabigatran was developed to prevent thrombocytopenia.

Case presentation

In this report, we discuss two cases of thrombocytopenia and purpura after dabigatran treatment. A 73-year-old man showed hemorrhagic necrotic skin lesions on his neck and right hand. He was administered dabigatran (220 mg/day) for cerebral infarction for three days and his platelet count decreased abruptly (6000/μL). This suggested that dabigatran had caused thrombocytopenia and purpura; therefore, dabigatran administration was discontinued. The results of a blood test, performed 14 days after stopping dabigatran treatment, showed that the platelet count had recovered to the normal range of more than 150,000/μL. A 75-year-old woman had taken warfarin continuously for 8 years. However, she had a new cerebral infarction. Therefore, warfarin treatment was replaced with dabigatran (300 mg/day). Her platelet count decreased (41,000/μL) significantly and dabigatran treatment was discontinued. The blood test results show that platelet counts gradually recovered to the normal range.

Conclusions

Dabigatran application may cause bleeding; therefore, careful monitoring during dabigatran treatment is required to prevent thrombocytopenia. An explanation is that the interaction of dabigatran with thrombin, because of its strong binding affinity, may cause the observed thrombocytopenia.

http://ift.tt/2sV6PbY

A case of neuropsychiatric lupus Erythematosus characterized by the Owl’s eye sign: a case report

Abstract

Background

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder characterized by multiple affected systems. More than half of SLE patients will suffer from neuropsychiatric lupus erythematosus (NPSLE) during the course of their disease. Although nearly half of the NPSLE patients have normal MRI manifestations, the abnormalities found in the remainder can be located anywhere in the brain, and especially in the subcortical white matter of the frontal and temporal lobe. However, NPSLE involving the medulla oblongata and spinal cord which presents as the "owl's eye" sign has to our best knowledge not been reported to date.

Case presentation

A 19-year-old girl presented at our hospital with a 7-day history of fever and headache since a one day's exertion, accompanied by 2 days of weakness. The patient had slurred speech. Neurological examination revealed the presence of horizontal nystagmus and a limitation of bilateral eye movement when looking up and down. At the same time, she showed difficulty in raising the jaw, accompanied by a weak pharyngeal reflex. Muscle strength was remarkably decreased in all four extremities: the MRCS grade of the upper limbs was 4/5, while in the lower limbs it was 0/5. Hypotonia was apparent in the lower extremities. Regarding subjective sensation, the patient appeared to be experiencing an increased sense of pain in the whole body, and especially in the cervical region, abdomen, and feet. An examination of shallow reflex documented the reinforcement of the abdominal reflex. Deep tendon reflexes were symmetric: absent in lower, normal in upper extremities. The patient also had a stiff neck with a positive Kernig's sign. The laboratory examination showed elevated C - reactive protein and rheumatoid factor, as well as complement components 3 and 4. Symptomatic treatments were applied, but she did not respond well, after which we did immunological laboratory examinations. The results showed the presence of anti-nRNP/Sm, anti-dsDNA and anti-AMA M2 antibodies. An MRI scan and enhancement of the cervical and thoracic regions displayed abnormal signs in the medulla and bilateral anterior horn of the lower thoracic spine. Following the exclusion of other possible diseases, neuropsychiatric lupus was diagnosed. High-dose intravenous gamma-globulin combined with methylprednisolone gradually improved her condition.

Conclusion

We report the first case of NPSLE presenting with medulla oblongata and spinal cord involvement, manifesting as the "owl's eye" sign in MRI.

http://ift.tt/2sq7AWM

HLA B27 antigen in Middle Eastern and Arab countries: systematic review of the strength of association with axial spondyloarthritis and methodological gaps

Abstract

Background

Axial spondyloarthritis (AxSpA) is a relatively frequent and debilitating disease, with a prevalence ranging from 0.1 to 2% in the Caucasian population. Current Assessment of Spondyloarthritis International Society (ASAS) classification criteria of AxSpA rely either on sacroiliitis on imaging plus one SpA feature or positive HLAB27 antigen plus two SpA features, in a patient with chronic low back pain and age at onset of less than 45 years. Therefore, HLA-B27 is a central feature in SpA classification and plays a pivotal role in referral strategies and early diagnosis. The primary objective of the study is to review the prevalence of HLA-B27 in normal and AxSpA populations in Middle Eastern and Arab Countries and to assess the strength of association between HLA-B27 antigen and AxSpA. The secondary objective is to identify the gaps in the methodology of the studies and suggest a framework for future research.

Methods

Studies were included in the analysis if they reported prevalence of HLA-B27 in AxSpA and/or general population and if they covered geographical location in the Middle East or Arab countries in the Mediterranean basin. Odds ratios (OR) were calculated for each country, as a measure of the strength of association between HLA-B27 and AxSpA, compared to the normal population, using the two-by-two frequency table. Available data from the literature were analyzed according to the following quality indicators: sample size, method of HLA-B27 testing, presence of control group and external validity.

Results

Twenty-seven studies were analyzed. HLAB27 prevalence in the normal population ranged from 0.3% (Oman) to 6.8% (Turkey). HLA-B27 prevalence in AxSpA ranged from 26.2% (Lebanon) to 91% (Turkey). HLA-B27 prevalence in all SpA ranged from 13.87% (Lebanon) to 69.43% (Kuwait). Peripheral SpA was less associated with HLA-B27 than AxSpA, indicating the need of differentiating between the two entities when calculating prevalence. When available (8 studies), the OR ranged from 21.63 (Morocco) to 105.6 (Syria). The high heterogeneity between the results can be due to differences in methodology: study sample size, different classification criteria, absence of control groups, HLA-B27 testing method.

Conclusions

The prevalence of HLA-B27 in the normal population is significantly lower in the Middle Eastern and Arab countries than in Western Countries. However, HLA-B27 testing can be useful for AxSpA positive diagnosis, given the high OR. Heterogeneity between countries may be due to methodological differences.

http://ift.tt/2sq0B0i

Comparison of fixed and mobile-bearing total knee arthroplasty in terms of patellofemoral pain and function: a prospective, randomised, controlled trial

Abstract

Background

Despite growing evidence in the literature, there is still a lack of consensus regarding the use of the mobile-bearing (MB) design total knee arthroplasty (TKA).

Methods

In a prospective, comparative, randomised, single centre trial, 106 patients with end-stage osteoarthritis of the knee were randomised to either an MB or fixed-bearing (FB) group to receive posterior stabilised (PS)-TKA using a standard medial parapatellar approach and patellar resurfacing with follow-up (FU) for 5 years. The primary outcome was anterior knee pain (AKP) during the chair rise test and the stair climb test 5 years after surgery. The secondary outcome was the ability to rise from a chair and to climb stairs, range of motion (ROM), Knee Society Score (KSS), RAND-36 scores and radiological analysis of the patellar tilt.

Results

No statistically significant difference was found between the two groups at 5 years FU in terms of median AKP during the chair rise test and the stair climb test (p = 0.5 and p = 0.8, respectively). There was no significant difference in any of the other secondary outcome parameters between the groups at 5 years FU.

Conclusion

A mobile-bearing TKA does not decrease AKP compared to fixed bearings.

Trial registration number

ClinicalTrials.gov NCT02892838.

Level of evidence

II

http://ift.tt/2sV4zl0

Impact of Medicine Withdrawal on Reporting of Adverse Events Involving Therapeutic Alternatives: A Study from the French Spontaneous Reporting Database

Abstract

Introduction

The consequences of the withdrawal of marketing authorisation of drugs have mostly been studied considering drug prescription patterns for the therapeutic alternatives of the withdrawn drugs. The potential concomitant changes in the reporting of adverse reactions concerning these alternatives have been studied less often.

Objective

The objective of this study was to analyse the changes in the reporting of adverse events (AEs) for therapeutic alternatives after the withdrawal of three medicines (dextropropoxyphene, pioglitazone and tetrazepam) from the market for safety reasons.

Methods

This study was performed using both the French pharmacovigilance database and the Echantillon Généraliste des Bénéficiaires (a random sample of French health insurance affiliates). For dextropropoxyphene, pioglitazone and tetrazepam alternatives, the number and types of case reports were studied for both the year preceding the first official safety warning and the year following the withdrawal. Reporting rates expressed per 10,000 reimbursements (RR_Reimb) and per 10,000 treated patients (RR_Pat) were also compared for the two periods.

Results

After dextropropoxyphene withdrawal, case reports and reimbursements increased for tramadol (case reports: +23%, reimbursements: +13%) and codeine (case reports: +74%, reimbursements: +47%), RR_Pat being significantly increased for tramadol (0.92 vs. 1.06, p = 0.02). After pioglitazone withdrawal, case reports increased for dipeptidyl peptidase-4 (DPP-4) inhibitors, glinides, and glucagon-like peptide 1 (GLP-1) analogues (+84%, +22% and +5%, respectively) and reimbursements (+55, +11 and +50%, respectively); both decreased for sulfonylureas (case reports: −6%, reimbursements: −2%). RR_Pat increased for DPP-4 inhibitors (1.63 vs. 2.26, p = 0.008). After tetrazepam withdrawal, case reports increased for diazepam, methocarbamol and thiocolchicoside (+110, +86 and +157%, respectively), as lesser did reimbursements. RR_Pat increased for diazepam (1.78 vs. 2.41, p = 0.054) and thiocolchicoside (0.14 vs. 0.24, p = 0.013).

Conclusion

For the three drug withdrawals investigated, the number of case reports involving alternatives increased to a larger extent than the numbers of prescriptions. This could relate to a higher occurrence of AEs in new users of alternatives who switched from the withdrawn medicines or to an increased awareness of possible AEs.

http://ift.tt/2s5Ms8Y

Using Multiple Pharmacovigilance Models Improves the Timeliness of Signal Detection in Simulated Prospective Surveillance

Abstract

Introduction

Prospective pharmacovigilance aims to rapidly detect safety concerns related to medical products. The exposure model selected for pharmacovigilance impacts the timeliness of signal detection. However, in most real-life pharmacovigilance studies, little is known about which model correctly represents the association and there is no evidence to guide the selection of an exposure model. Different exposure models reflect different aspects of exposure history, and their relevance varies across studies. Therefore, one potential solution is to apply several alternative exposure models simultaneously, with each model assuming a different exposure–risk association, and then combine the model results.

Methods

We simulated alternative clinically plausible associations between time-varying drug exposure and the hazard of an adverse event. Prospective surveillance was conducted on the simulated data by estimating parametric and semi-parametric exposure–risk models at multiple times during follow-up. For each model separately, and using combined evidence from different subsets of models, we compared the time to signal detection.

Results

Timely detection across the simulated associations was obtained by fitting a set of pharmacovigilance models. This set included alternative parametric models that assumed different exposure–risk associations and flexible models that made no assumptions regarding the form/shape of the association. Times to detection generated using a simple combination of evidence from multiple models were comparable to those observed under the ideal, but unrealistic, scenario where pharmacovigilance relied on the single 'true' model used for data generation.

Conclusions

Simulation results indicate that, if the true model is not known, an association can be detected in a more timely manner by first fitting a carefully selected set of exposure–risk models and then generating a signal as soon as any of the models considered yields a test statistic value below a predetermined testing threshold.

http://ift.tt/2tooc5Z

A case of protein-losing enteropathy caused by sclerosing mesenteritis diagnosed with capsule endoscopy and double-balloon endoscopy

Abstract

A 75-year-old man presented with abdominal distension, hypoproteinemia, ascites and a 35-mm mass in the small bowel mesentery. Laparotomy was performed, and he was diagnosed with sclerosing mesenteritis. His clinical condition improved, with computed tomography (CT) showing tumor shrinkage and decreasing ascites after administration of prednisolone; however, on drug withdrawal, abdominal fullness recurred and CT revealed an enlarging tumor and increasing ascites. Capsule endoscopy (CE) and double-balloon enteroscopy (DBE) were performed to further investigate hypoalbuminemia, which revealed white villi, white nodules, white debris, and mucosal edema in the jejunum. Biopsies from the jejunal mucosa demonstrated infiltration by chronic inflammatory cells consisting mostly of lymphocytes and plasma cells, with marked lymphangiectasia of the lamina propria and submucosa. A fecal alpha-1-antitrypsin clearance test revealed abnormal leakage from the gastrointestinal tract, confirming that hypoalbuminemia was secondary to protein-losing enteropathy (PLE). The incidence of sclerosing mesenteritis accompanied by PLE is very rare. Only six cases have been reported so far. CE and DBE were helpful for diagnosing this condition, and should be performed in patients in whom the cause of hypoalbuminemia is unknown, and in those with PLE.

http://ift.tt/2t4KZ3Y

Impact of brown rice-specific γ-oryzanol on epigenetic modulation of dopamine D2 receptors in brain striatum in high-fat-diet-induced obesity in mice

Abstract

Aims/hypothesis

Overeating of dietary fats causes obesity in humans and rodents. Recent studies in humans and rodents have demonstrated that addiction to fats shares a common mechanism with addiction to alcohol, nicotine and narcotics in terms of a dysfunction of brain reward systems. It has been highlighted that a high-fat diet (HFD) attenuates dopamine D2 receptor (D2R) signalling in the striatum, a pivotal regulator of the brain reward system, resulting in hedonic overeating. We previously reported that the brown rice-specific bioactive constituent γ-oryzanol attenuated the preference for an HFD via hypothalamic control. We therefore explored the possibility that γ-oryzanol would modulate functioning of the brain reward system in mice.

Methods

Male C57BL/6J mice fed an HFD were orally treated with γ-oryzanol, and striatal levels of molecules involved in D2R signalling were evaluated. The impact of γ-oryzanol on DNA methylation of the D2R promoter and subsequent changes in preferences for dietary fat was examined. In addition, the effects of 5-aza-2′-deoxycytidine, a potent inhibitor of DNA methyltransferases (DNMTs), on food preference, D2R signalling and the levels of DNMTs in the striatum were investigated. The inhibitory effects of γ-oryzanol on the activity of DNMTs were enzymatically evaluated in vitro.

Results

In striatum from mice fed an HFD, the production of D2Rs was decreased via an increase in DNA methylation of the promoter region of the D2R. Oral administration of γ-oryzanol decreased the expression and activity of DNMTs, thereby restoring the level of D2Rs in the striatum. Pharmacological inhibition of DNMTs by 5-aza-2′-deoxycytidine also ameliorated the preference for dietary fat. Consistent with these findings, enzymatic in vitro assays demonstrated that γ-oryzanol inhibited the activity of DNMTs.

Conclusions/interpretation

We demonstrated that γ-oryzanol ameliorates HFD-induced DNA hypermethylation of the promoter region of D2R in the striatum of mice. Our experimental paradigm highlights γ-oryzanol as a promising antiobesity substance with the distinct property of being a novel epigenetic modulator.

http://ift.tt/2ttbymJ

Delayed diffuse cerebellar swelling after resection of medulloblastoma: case report and review of literature

Abstract

Introduction

Delayed diffuse cerebellar swelling is a rare life-threatening complication following medulloblastoma resection.

Presentation

We present our experience of managing a 4-year-old who developed diffuse cerebellar swelling with upward herniation 41 days after resection of a large cell anaplastic medulloblastoma.

Conclusion

Emergency chemotherapy alone was sufficient in promoting regression of swelling and recovery from coma. Reports of similar cases are scant. Chemotherapy may be a critical component of treatment.

http://ift.tt/2ttkiJn

The significance of polymorphisms in genes encoding Il-1β, Il-6, TNFα, and Il-1RN in the pathogenesis of intraventricular hemorrhage in preterm infants

Abstract

Introduction

Intraventricular hemorrhage (IVH) is a significant morbidity seen in very low birth weight infants. Genes related to inflammation may be risk factors for IVH.

Material and methods

We examined five polymorphisms for an association with IVH in 100 preterm infants born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroid therapy, and without congenital abnormalities. These polymorphisms include interleukin-1β 3953 C>T, interleukin-6 −174G>C and −596G>A, tumor necrosis factor −308 G>A, and 86 bp variable number tandem repeat polymorphism of interleukin-1 receptor antagonist (Il -1RN 86 bp VNTR).

Results

In our study population, 45 (45%) infants developed IVH, including 15 (33.33%) with stage 1, 19 (42.22%) with stage 2, 8 (17.77%) with stage 3, and 3 (6.66%) with stage 4. In contrast to the previously published data, the prevalence of IVH did not vary between infants with different IL-6 and TNFα alleles and genotypes. Our novel investigations in Il-1 +3953 C>T and Il-1RN 86 bp VNTR polymorphism did not show any significant link between those alleles or genotypes and IVH.

Conclusions

IVH is a significant problem for preterm infants. In addition to little progress in preventing IVH in preterm babies, substantial research that are focused on understanding the etiology, mechanism and risk factors for IVH are imperative. In the era of personalized medicine, identification of genetic risk factors creates opportunities to generate preventative strategies. Further studies should be performed to confirm the role of genetic factors in etiology and pathogenesis of IVH.

http://ift.tt/2u2x12H

A congenital external carotid artery-external jugular vein arteriovenous fistula was successfully treated by coil embolization (case report and literature review)

Abstract

Object

Congenital arteriovenous fistula involving the external carotid system is rare.

Methods

This paper reports a case of congenital external carotid artery-external jugular vein arteriovenous fistula admitted to Xuanwu Hospital, and reviews the literature.

Results

The patient was a boy, 9 years old, with a history of pulsatile mass and thrill in the right neck since his birth. External carotid artery-external jugular vein fistula was confirmed by the digital subtraction angio-graphy. And coil embolization was done later. Postoperative immediate angiography confirmed the complete occlusion of the fistula, and partial branch of the external carotid artery can be seen. The abnormal clinical manifestation disappeared after the procedure without any complications.

Conclusion

This case and relevant literatures remind us that congenital external carotid artery-external jugular vein arteriovenous fistula has its unique features, and it can be treated by coil embolization safely and effectively.

http://ift.tt/2ttkgBf

Response criteria of tolvaptan for the treatment of hepatic edema

Abstract

Background

Although tolvaptan is an effective treatment for hepatic edema, there are no established criteria for assessment of the therapeutic effect. The present study evaluates the association between body weight change and clinical symptoms to identify an effective indicator of tolvaptan response.

Methods

The study comprised 460 patients. The first data set contained 147 patients with hepatic edema who received tolvaptan in Kagoshima Kouseiren Hospital, a representative institution of this study. From these data, an optimal cutoff value of body weight change, which accurately indicated symptom reduction, was identified. The response rates obtained based on the cutoff value were evaluated by receiver-operating characteristic (ROC) analysis and kappa coefficients. The kappa coefficient was then validated internally using the bootstrap method and externally using the validation data set of 313 patients from four other hospitals.

Results

A cutoff value for body weight loss of 1.5 kg/week produced the largest area under the ROC curve (0.961; sensitivity, 89.8%; specificity, 92.0%) and a high kappa coefficient (0.831). The correlation between symptom reduction and body weight loss of 1.5 kg/week was evaluated internally and externally, and the cutoff value was validated.

Conclusions

The cutoff value of body weight change that most accurately reflected symptom reduction was 1.5 kg/week; this value is expected to be an effective indicator of response to tolvaptan in clinical practice.

http://ift.tt/2umRy1y

Effect of resolution recovery using graph plots on regional cerebral blood flow in healthy volunteers

Abstract

Purpose

We evaluated the effect of resolution recovery (RR) using graph plots on regional cerebral blood flow (rCBF) in brain perfusion single-photon emission computed tomography (SPECT) images derived from healthy volunteers and patients diagnosed with probable Alzheimer's disease.

Method

We acquired brain perfusion SPECT images with scatter correction (SC), computed tomography-based attenuation correction (CTAC), and RR from a three-dimensional brain phantom and from healthy volunteers. We then compared contrast-to-noise ratio, count density ratios, increase maps, and rCBF using statistical parametric mapping 8.

Results

Regional brain counts were significantly increased from 20–24% with SC, CTAC, and RR compared with SC and CTAC. Mean CBF in healthy volunteers was 42.5 ± 5.4 mL/100 g/min. Average rCBF determined using SC, CTAC and RR increased 7.5, 2.0, and 3.7% at the thalamus, posterior cingulate, and whole brain, respectively, compared with SC and CTAC.

Conclusion

Resolution recovery caused variations in normal rCBF because counts increased in cerebral regions.

http://ift.tt/2tpBsa9

The largest empty circle with location constraints in spatial databases

Abstract

Given a set S of points in the two-dimensional space, which are stored in a spatial database, this paper presents an efficient algorithm to find, in the area delimited by those points, the empty circle with the largest area that contains only a query point q. Our algorithm adapts previous work in the field of computational geometry to be used in spatial databases, which requires to manage large amounts of data. To achieve this objective, the basic idea is to discard a large part of the points of S, in such a way that the problem can be solved providing only the remaining points to a classical computational geometry algorithm that, by processing a smaller collection of points, saves main memory resources and computation time. The correctness of our algorithm is formally proven. In addition, we empirically show its efficiency and scalability by running a set of experiments using both synthetic and real data.

http://ift.tt/2t4Agqm

Early Use of Ceftaroline Fosamil in the United States Veterans Health Care System

Abstract

Background

Ceftaroline fosamil is US Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, but it is not known how ceftaroline is being used in real-world settings or how adverse effects (AEs) and mortality compare to clinical trials.

Objective

This study describes ceftaroline use, AEs, and mortality in US Veterans Health Administration (VHA) hospital patients.

Methods

This phase IV, population-based, epidemiologic study analyzed patients ≥18 years old who received one or more ceftaroline doses within 14 days of admission to 69 VHA hospitals in 41 US states/territories from 1 October 2010 to 30 September 2014. VHA repository data were linked using unique patient identifiers. Diagnoses and AEs were determined using ICD9-CM and CSS codes. Demographics, AEs within 30 days of therapy initiation, and all-cause in-hospital mortality were summarized using descriptive statistics.

Results

764 Patients met study criteria. Patients were 97% male and 56% White, with a median age of 61 years and a Charlson score of 6. Diagnoses included skin (40%), sepsis (30%), osteomyelitis (25%), diabetic foot (22%), pneumonia (16%), bacteremia (11%), endocarditis (6%), meningitis (2%), and device (2%) infections. Ceftaroline was used first-line (37%), second-line (56%), and third-line or greater (7%). Patients received ceftaroline a median of 3 days after hospital admission. All-cause in-hospital mortality rates were: overall (5%), skin (2%), sepsis (9%), osteomyelitis (3%), diabetic foot (1%), pneumonia (13%), bacteremia (6%), endocarditis (11%), meningitis (6%), and device (13%). Eosinophilia, leukopenia, leukocytosis, fibromyalgia, myalgia and myositis, and polymyalgia rates were <1% each.

Conclusions

Ceftaroline is used in VHA hospitals for various diagnoses. Mortality was low and comparable with rates from clinical trials. Additional studies comparing ceftaroline to other drugs used in similar situations are needed.

http://ift.tt/2sUqFEg

Bone Metastasis from Solid Tumors: Biologic and Clinical State of the Art

Abstract

Bone metastases are a frequent and debilitating consequence for many tumors, of which breast, lung, prostate, and kidney cancer are the most common. The dialog among cancer cells, bone microenvironment, and immune system regulates bone metastasis formation. Indeed, bone and immune system are strictly linked to each other because bone regulates the hematopoietic stem cells from which all cells of the immune system derive. Many immunoregulatory cytokines influence the fate of bone cells and promote the growth of tumor cells in bone, contributing to sustain the vicious cycle of bone metastasis. Bone is an attractive soil for cancer cells, which can remain dormant for years or directly form bone lesions. The fate of cancer cells after their arrival to bone marrow depends on a complex cross-talk among cancer, bone, and immune cells in the microenvironment. This review provides an overview of the different steps occurring during bone metastatic process, with particular attention to the osteoimmunology field. Furthermore, we will revise the current available clinical approaches for the therapy of bone metastatic patients.

http://ift.tt/2spSWPp

The influence of pregnancy on women with adolescent idiopathic scoliosis

Abstract

Purpose

The study's aim was to address three fundamental questions related to pregnancy and adolescent idiopathic scoliosis (AIS), and provide clinically applicable answers to spine specialists and general practitioners alike.

Methods

The authors performed a systematic literature review using MEDLINE, EMBASE, Google Scholar, and Cochrane Database of Systematic Reviews to identify articles published between 1980 and 2015 that described pregnancy-related characteristics and outcomes in AIS patients. The search was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and evidence was classified according to the Oxford CEBM (Centre for Evidence-Based Medicine) appraisal tool.

Results

Twenty-two articles incorporating more than 3125 AIS patients were included. All studies concluded level 2b evidence or lower. Nulliparity rates were slightly higher among AIS patients, and more frequent infertility treatment was required. Pregnancy-related back pain was common, and while non-disabling, may have been more severe than in healthy women. Minor curve progression often occurred during pregnancy, though its permanence was questioned and significance unknown. Back pain and curve progression occurred independent of AIS treatment modality. With modern technology, anesthetic and obstetric complications in the perinatal period were not elevated in AIS mothers.

Conclusions

Women with AIS experience slightly elevated rates of nulliparity, infertility treatment, prepartum back pain, and peripartum curve progression. However, most women are able to have children and are not at increased risk of pregnancy-related complications. Higher quality evidence is needed to better define these relationships and allow more guided counseling and treatment.

http://ift.tt/2u1JILb

Efficacy of Vonoprazan-Based Triple Therapy for Helicobacter pylori Eradication: A Multicenter Study and a Review of the Literature

Abstract

Background

Eradication therapies for Helicobacter pylori infection are advancing as new acid inhibitory reagents approved. The aim of this study was to assess the efficacy and safety of vonoprazan-based triple treatment.

Materials and Methods

Triple therapy with vonoprazan and two antibiotics (amoxicillin and clarithromycin or metronidazole) received focus in this analysis. We performed a multicenter retrospective study of patients who received vonoprazan-based eradication therapy between February 2015 and February 2016 and conducted a review of the literature.

Results

The eradication rate among the 799 patients in our multicenter study was 94.4% (95% confidence interval [CI] 92.6–96.2%) in the per-protocol analysis for first-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg, twice a day for 7 days) and 97.1% (95% CI 93.0–101.1%) for second-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and metronidazole 250 mg, twice a day for 7 days). The overall incidence of adverse events was 4.4% in an intention-to-treat analysis with no patients hospitalized. In a literature review, six reports, in which 1380 patients received vonoprazan-based first-line eradication therapy, were included and were all reported by Japanese researchers. The eradication success rates in per-protocol analysis were between 85 and 93%, which was roughly the same among the studies.

Conclusions

Vonoprazan-based triple therapy was effective and safe for Helicobacter pylori eradication in real-world experience, confirmed by a multicenter study and a review of the pertinent literature.

http://ift.tt/2toIYlo

Direct measurement of interaction forces between a platinum dichloride complex and DNA molecules

Abstract

The interaction forces between a platinum dichloride complex and DNA molecules have been studied using atomic force microscopy (AFM). The platinum dichloride complex, di-dimethylsulfoxide-dichloroplatinum (II) (Pt(DMSO)₂Cl₂), was immobilized on an AFM probe by coordinating the platinum to two amino groups to form a complex similar to Pt(en)Cl₂, which is structurally similar to cisplatin. The retraction forces were measured between the platinum complex and DNA molecules immobilized on mica plates using force curve measurements. The histogram of the retraction force for λ-DNA showed several peaks; the unit retraction force was estimated to be 130 pN for a pulling rate of 60 nm/s. The retraction forces were also measured separately for four single-base DNA oligomers (adenine, guanine, thymine, and cytosine). Retraction forces were frequently observed in the force curves for the DNA oligomers of guanine and adenine. For the guanine DNA oligomer, the most frequent retraction force was slightly lower than but very similar to the retraction force for λ-DNA. A higher retraction force was obtained for the adenine DNA oligomer than for the guanine oligomer. This result is consistent with a higher retraction activation energy of adenine with the Pt complex being than that of guanine because the kinetic rate constant for retraction correlates to exp(FΔx – ΔE) where ΔE is an activation energy, F is an applied force, and Δx is a displacement of distance.

http://ift.tt/2sU6zdn

Pro-apoptotic cationic host defense peptides rich in lysine or arginine to reverse drug resistance by disrupting tumor cell membrane

Abstract

Host defense peptides have been demonstrated to exhibit prominent advantages in cancer therapy with selective binding ability toward tumor cells via electrostatic attractions, which can overcome the limitations of traditional chemotherapy drugs, such as toxicity on non-malignant cells and the emergence of drug resistance. In this work, we redesigned and constructed a series of cationic peptides by inserting hydrophobic residues into hydrophilic surface or replacing lysine (K) with arginine (R), based on the experience from the preliminary work of host defense peptide B1. In-depth studies demonstrated that the engineered peptides exhibited more potent anti-cancer activity against various cancer cell lines and much lower toxicity to normal cells compared with B1. Further investigation revealed that compounds I-3 and I-7 could act on cancer cell membranes and subsequently alter the permeability, which facilitated obvious pro-apoptotic activity in paclitaxel-resistant cell line (MCF-7/Taxol). The result of mitochondrial membrane potential assay (ΔΨm) demonstrated that the peptides induced ΔΨm dissipation and mitochondrial depolarization. The caspase-3 cellular activity assay showed that the anti-cancer activity of peptides functioned via caspase-3-dependent apoptosis. The study yielded compound I-7 with superior properties for antineoplastic activity in comparison to B1, which makes it a promising potential candidate for cancer therapy.

http://ift.tt/2umkSVX

Transdermally administered proline–arginine-rich host defense peptides show systemic efficacy in a lethal mouse bacteremia model

Abstract

Host defense peptides are preferably administered as topical therapeutic agents. We have investigated whether peptide A3-APO can enter the circulation when applied to the ear skin. Efficacy of peptide monotherapy as transdermal administration option was assessed in a systemic mouse Acinetobacter baumannii model. A3-APO reduced mortality and demonstrated a statistically significant reduction of blood bacterial counts, regardless whether it was administered prior or after bacterial challenge. The peptidic metabolite of A3-APO was efficacious when applied to the ear or tail.

http://ift.tt/2toCraq

Biased selection of propagation-related TUPs from phage display peptide libraries

Abstract

Phage display is rapidly advancing as a screening strategy in drug discovery and drug delivery. Phage-encoded combinatorial peptide libraries can be screened through the affinity selection procedure of biopanning to find pharmaceutically relevant cell-specific ligands. However, the unwanted enrichment of target-unrelated peptides (TUPs) with no true affinity for the target presents an important barrier to the successful screening of phage display libraries. Propagation-related TUPs (Pr-TUPs) are an emerging but less-studied category of phage display-derived false-positive hits that are displayed on the surface of clones with faster propagation rates. Despite long regarded as an unbiased selection system, accumulating evidence suggests that biopanning may create biological bias toward selection of phage clones with certain displayed peptides. This bias can be dependent on or independent of the displayed sequence and may act as a major driving force for the isolation of fast-growing clones. Sequence-dependent bias is reflected by censorship or over-representation of some amino acids in the displayed peptide and sequence-independent bias is derived from either point mutations or rare recombination events occurring in the phage genome. It is of utmost interest to clean biopanning data by identifying and removing Pr-TUPs. Experimental and bioinformatic approaches can be exploited for Pr-TUP discovery. With no doubt, obtaining deeper insight into how Pr-TUPs emerge during biopanning and how they could be detected provides a basis for using cell-targeting peptides isolated from phage display screening in the development of disease-specific diagnostic and therapeutic platforms.

http://ift.tt/2umaTjp

Curcin C, a novel type I ribosome-inactivating protein from the post-germinating cotyledons of Jatropha curcas

Abstract

A novel type I ribosome-inactivating protein (RIP), designated as curcin C, was purified from Jatropha curcas, an important feedback source of bio-fuel. Molecular mass and isoelectric point of curcin C were 31.398 kDa and 7.12 as detected by MALTI-TOF assay and capillary electrophoresis assay, respectively. N-terminal sequence and LC–MS/MS analyses confirmed that curcin C is a type I RIP having high homology, but not the exactly the same with curcin, another type 1 RIP isolated from the endosperm of J. curcas. It exhibited N-glycosidase activity and in vitro translation inhibition activity. Moreover, curcin C displayed a strong selectively anti-tumor activity on human cancer cells. Its cytotoxicity against osteosarcoma cell line U20S is even higher than that of Paclitaxel with IC₅₀ of 0.019 μM. Purification and identification of curcin C not only suggested its potential in natural anticancer drug development, but also provide chance to understanding different cytotoxic action among different RIPs.

http://ift.tt/2toCoeK

Synthesis and morphological insight of new biocompatible smart hydrogels

Abstract

We present a first report for developing stimulus responsive hydrogels via free radical aqueous polymerization technique using Acrylic acid (AAc), methacrylic acid (MAAc) and diethylaminoethyl methacrylate (DEAEMA). The morphological aspects of poly(AAc-co-DEAEMA) (pAcD) and poly(MAAc-co-DEAEMA) (pMcD) were investigated to delineate the relevant mechanism of hydrogel formation for better understanding of their mechanical behaviour. The formulated hydrogels were found to have a structural framework comprising inter-connected nanogels and continuous outer skin with macroporous interiors. An abrupt increase in the peak intensities specific to the polymer and a simultaneous decrease in the water related peaks in the attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra exhibited the phenomenon of phase separation, whereas peaks of proton nuclear magnetic resonance (¹HNMR) revealed hydrogen bonding and electrolytic complexation between the monomers. Biocompatibility is the hallmark for any drug carrier and was evaluated by both in vitro and in vivo testing. Administration of the prepared hydrogels to rat models did not cause any significant affect on the vital organs.

Graphical abstract

Graphical representation showing macroporous interior with interlocked nanoglobules as stable building blocks in pAcD gels with high in-vitro and in-vivo biocompatibility

http://ift.tt/2t4eWBi