Παρασκευή 18 Αυγούστου 2017
Population Pharmacokinetic Meta-Analysis of Ramucirumab in Cancer Patients
Aim
Ramucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks binding of VEGF-A, VEGF-C, and VEGF-D. The objective of the analysis was to characterize the clinical pharmacology profile of ramucirumab using a population pharmacokinetic approach.
Methods
A total of 1639 patients with 6427 serum concentrations from 11 Phase 1b, 2, and 3 clinical trials in patients with various cancer indications were included in the analysis. Ramucirumab was administered as an i.v. infusion over 1 hour at 8 mg kg-1 every 2 weeks or 10 mg kg-1 every 3 weeks. A series of pharmacostatistical models were developed to describe the concentration data. The best model was used to evaluate patient factors for their effect on ramucirumab pharmacokinetics.
Results
The pharmacokinetics of ramucirumab were well characterized by a two-compartment model. Mean population estimates of clearance (CL), volume of distribution (Vss), and half-life (t1/2) for a typical 68-kg patient were 0.0148 l h-1, 5.30 l, and 13.4 days, respectively. A modest relationship was observed between body weight and ramucirumab disposition; CL and V1 increased with body weight. No other patient characteristics were shown to influence the disposition of ramucirumab in this patient population.
Conclusions
The final model adequately described the concentration-time profile of ramucirumab in patients with a range of cancer indications. The model confirmed that a weight-normalized dosing regimen is appropriate for ramucirumab therapy. Dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment.
http://ift.tt/2wZr6gl
Response to Editorial, midwifery education
Publication date: Available online 18 August 2017
Source:Women and Birth
Author(s): Kairan A. Meek, Rosannah L. Skufca
http://ift.tt/2vMnjV7
Priapism due to essential thrombocythaemia: a rare causation
Priapism is rarely caused by essential thrombocytosis, a disorder characterised by increased number of megakaryocytes. We report a case of a 21-year-old man who presented with priapism and on investigation was found to have essential thrombocytosis as the cause.
http://ift.tt/2ie6myd
Renal cell carcinoma presenting as a cutaneous horn and nodules on the gingiva and scalp
A 63-year-old man presented with a pulsatile cutaneous horn on the nose and multiple angiomatous nodules on the gingiva and scalp, which appeared over 2 months. He had severe hypercalcaemia, lytic lesions in multiple bones and acute kidney injury. Excision biopsy from the gingival nodule showed a clear cell neoplasm. The bone marrow showed atypical cells with similar morphology. Imaging showed a 7 cmx7.5 cm mass at the upper pole of the left kidney with metastases to the bones, liver and lung. Immunohistochemistry was consistent with metastatic renal cell carcinoma. Renal cell carcinoma presenting as a cutaneous horn is extremely rare and to the best of our knowledge only one other case was found in the literature. There was visible regression in the size of the cutaneous horn and nodules following initiation of pazopanib therapy. However, he succumbed to his illness a month later.
http://ift.tt/2fTZEN4
Bilateral optic disc coloboma
Description
A 5-month-old male child was brought with the history of right-sided corneal opacity noticed for the past 2 months. The baby was immunised until now with an uneventful antenatal and peripartum history. Ocular examination showed normal sized cornea having a paracentral nebular opacity along the inferior and nasal aspect without any discharge or significant exposure keratopathy. The baby was able to fix at the light with each eye separately, the anterior chamber in both the eyes was of normal depth having a clear lens and retinal examination showed a well-defined posteriorly excavated area along the inferior portion of the optic disc in both the eyes. Sleeping intraocular pressures were 10 and 12 mm Hg in right eye and left eye, respectively. Posterior segment B-scan ultrasound showed a well-defined symmetric excavation along the inferior aspect of the optic disc in both the eyes with an axial length of 20 mm...
http://ift.tt/2ie6iyt
Idiopathic spontaneous lesser sac haematoma: a perplexing case of abdominal apoplexy
A 37-year-old woman presented with a 3-hour history of back pain, nausea and vomiting and an episode of syncope. A fluid collection in the lesser sac was detected on ultrasound and CT scan. Emergency laparoscopy and subsequent laparotomy were performed and a large blood clot was evacuated from the lesser sac. No identifiable source or predisposition to bleeding was found. She made a full recovery postoperatively. There are few reported cases of spontaneous intraperitoneal haemorrhage. In a third of cases, there is no identifiable source of bleeding. Unfortunately, patients present late with non-specific symptoms and a prompt diagnosis is difficult to make. The case reiterates the importance of awareness of lesser sac haematoma formation; an unusual clinical entity with a high morbidity and mortality rate. A high index of suspicion, radiological adjuncts and appropriate surgical intervention, especially in unstable patients, is essential for a good outcome.
http://ift.tt/2fU4D02
Successful treatment of direct carotid-cavernous fistula in a patient with Ehlers-Danlos syndrome type IV without arterial puncture: the transvenous triple-overlay embolization (TAILOREd) technique
We report successful transvenous treatment of direct carotid–cavernous fistula in a patient with Ehlers–Danlos syndrome type IV using a novel triple-overlay embolization (TAILOREd) technique without the need for arterial puncture, which is known to be highly risky in this patient group. The TAILOREd technique allowed for successful treatment using preoperative MR angiography as a three-dimensional overlay roadmap combined with cone beam CT and live fluoroscopy, precluding the need for an arterial puncture.
http://ift.tt/2iemobp
Physiologic Considerations in Trauma Patients Undergoing Resuscitative Endovascular Balloon Occlusion of the Aorta
Resuscitative endovascular balloon occlusion of the aorta is a new procedure for adjunctive management of critically injured patients with noncompressible torso or pelvic hemorrhage who are in refractory hemorrhagic shock, ie, bleeding to death. The anesthesiologist plays a critical role in management of these patients, from initial evaluation in the trauma bay to definitive care in the operating room and the critical care unit. A comprehensive understanding of the effects of resuscitative endovascular balloon occlusion of the aorta is essential to making it an effective component of hemostatic resuscitation.
http://ift.tt/2v0eAvK
http://ift.tt/2v0eAvK
Resuscitative Endovascular Balloon Occlusion of the Aorta: Principles, Initial Clinical Experience, and Considerations for the Anesthesiologist
Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an endovascular technique that allows for temporary occlusion of the aorta in patients with severe, life-threatening, trauma-induced noncompressible hemorrhage arising below the diaphragm. REBOA utilizes a transfemoral balloon catheter inserted in a retrograde fashion into the aorta to provide inflow control and support blood pressure until definitive hemostasis can be achieved. Initial retrospective and registry clinical data in the trauma surgical literature demonstrate improvement in systolic blood pressure with balloon inflation and improved survival compared to open aortic cross-clamping via resuscitative thoracotomy. However, there are no significant reports of anesthetic implications and perioperative management in this challenging cohort. In this narrative, we review the principles, technique, and logistics of REBOA deployment, as well as initial clinical outcome data from our level-1 American College of Surgeons–verified trauma center. For anesthesiologists who may not yet be familiar with REBOA, we make several suggestions and recommendations for intraoperative management based on extrapolation from these initial surgical-based reports, opinions from a team with increasing experience, and translated experience from emergency aortic vascular surgical procedures. Further prospective data will be necessary to conclusively guide anesthetic management, especially as potential complications and implications for global organ function, including cerebral and renal, are recognized and described.http://ift.tt/2uZJgNF
Human neural stem cell transplantation into the corpus callosum of Alzheimer's mice
Abstract
The hippocampus has been the target of stem cell transplantations in preclinical studies focused on Alzheimer's disease, with results showing improvements in histological and behavioral outcomes. The corpus callosum is another structure that is affected early in Alzheimer's disease. Therefore, we hypothesize that this structure is a novel target for human neural stem cell transplantation in transgenic Alzheimer's disease mouse models. This study demonstrates the feasibility of targeting the corpus callosum and identifies an effective immunosuppression regimen for transplanted neural stem cell survival. These results support further preclinical development of the corpus callosum as a therapeutic target in Alzheimer's disease.
http://ift.tt/2vR05fa
Evidence based anti-osteoporosis effects of Periplaneta americana L on osteoblasts, osteoclasts, vascular endothelial cells and bone marrow derived mesenchymal stem cells
Kangfuxin (KFX) is the ethanol extract of Periplaneta americana L, which has been widely used in the Traditional Chinese Medicine for the repair and regeneration of injured organ and tissues with long history. Th...
http://ift.tt/2wpL6eo
High prevalence of the mcr-1 gene in retail chicken meat in the Netherlands in 2015
Recently, plasmid-mediated colistin resistance was reported in humans, animals and food. We studied the presence of mcr-1 and mcr-2 in Dutch retail chicken meat. The prevalence of mcr-1 was 24,8% (53/214), wherea...
http://ift.tt/2wpWua5
Optoacoustic detection of early therapy-induced tumor cell death using a targeted imaging agent
Purpose: The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU).<br /><br />Experimental Design: C2Am was labeled with a near infrared (NIR) fluorophore and injected intravenously into mice bearing human colorectal TRAIL-sensitive Colo205 and TRAIL-resistant HT-29 xenografts that had been treated with a potent agonist of TRAILR2 and in Colo205 tumors treated with 5-FU.<br /><br />Results: Three dimensional MSOT images of probe distribution showed development of tumor contrast within 3 h of probe administration and a signal-to-background ratio in regions containing dead cells of >10 after 24 h. A site-directed mutant of C2Am that is inactive in PS binding showed negligible binding. Tumor retention of the active probe was strongly correlated (R2=0.97, P value<0.01) with a marker of apoptotic cell death measured in histological sections obtained post mortem.<br /><br />Conclusions: The rapid development of relatively high levels of contrast suggests that NIR fluorophore-labeled C2Am could be a useful optoacoustic imaging probe for detecting early therapy-induced tumor cell death in the clinic.
http://ift.tt/2vM1c17
p53 non-genotoxic activation and mTORC1 inhibition lead to effective combination for neuroblastoma therapy.
Purpose: mTORC1 inhibitors are promising agents for neuroblastoma therapy, however they have shown limited clinical activity as monotherapy, thus rational drug combinations need to be explored to improve efficacy. Importantly, neuroblastoma maintains both an active p53 and an aberrant mTOR signaling. <br /><br />Experimental Design: Using an orthotopic xenograft model and modulating p53 levels, we investigated the anti-tumor effects of the mTORC1 inhibitor temsirolimus in neuroblastoma expressing normal, decreased, or mutant p53, both as single agent and in combination with first and second generation MDM2 inhibitors to reactivate p53. <p>Results: Non-genotoxic p53 activation suppresses mTOR activity. Moreover, p53 reactivation via RG7388, a second generation MDM2 inhibitor, strongly enhances the in vivo anti-tumor activity of temsirolimus. Single agent temsirolimus does not elicit apoptosis, and tumors rapidly re-grow after treatment suspension. In contrast, our combination therapy triggers a potent apoptotic response in wild-type p53 xenografts and efficiently blocks tumor re-growth after treatment completion. We also found that this combination uniquely led to p53-dependent suppression of survivin whose ectopic expression is sufficient to rescue the apoptosis induced by our combination.</p> <br />Conclusions: Our study supports a novel highly effective strategy that combines RG7388 and temsirolimus in wild-type p53 neuroblastoma, which warrants testing in early-phase clinical trials.
http://ift.tt/2wZnHhO
Synergy of WEE1 and mTOR inhibition in mutant KRAS-driven lung cancers
Purpose: KRAS-activating mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC), but efforts to directly target mutant KRAS have proved a formidable challenge. Therefore, multi-targeted therapy may offer a plausible strategy to effectively treat KRAS-driven NSCLCs. Here, we evaluate the efficacy and mechanistic rationale for combining mTOR and WEE1 inhibition as a potential therapy for lung cancers harboring KRAS mutations. <p>Experimental Design: We investigated the synergistic effect of combining mTOR and WEE1 inhibitors on cell viability, apoptosis, and DNA damage repair response using a panel of human KRAS-mutant and wild type NSCLC cell lines and patient-derived xenograft cell lines. Murine autochthonous and human transplant models were used to test the therapeutic efficacy and pharmacodynamic effects of dual treatment.</p> <p>Results: We demonstrate that combined inhibition of mTOR and WEE1 induced potent synergistic cytotoxic effects selectively in KRAS-mutant NSCLC cell lines, delayed human tumor xenograft growth and caused tumor regression in a murine lung adenocarcinoma model. Mechanistically, we show that inhibition of mTOR potentiates WEE1 inhibition by abrogating compensatory activation of DNA repair, exacerbating DNA damage in KRAS-mutant NSCLC, and that this effect is due in part to reduction in cyclin D1. </p> <p>Conclusions: These findings demonstrate that compromised DNA repair underlies the observed potent synergy of WEE1 and mTOR inhibition and support clinical evaluation of this dual therapy for patients with KRAS-mutant lung cancers.
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Defective cyclin B1 induction in trastuzumab-emtansine (T-DM1) acquired resistance in HER2-positive breast cancer
Purpose: Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2 positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance. <p>Experimental Design: HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3 and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up or down regulate cyclin B1 were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation and apoptosis were assayed in human HER2 positive breast cancer explants.</p> <p>Results: We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells. Cyclin B1 knock-down by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing cdc20, partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation.</p> <p>Conclusion: Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2 positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2 positive breast cancer.
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Dasatinib reversibly disrupts endothelial vascular integrity by increasing non-muscle myosin II contractility in a ROCK-dependent manner
Purpose: Dasatinib is a short-acting dual ABL/SRC family tyrosine kinase inhibitor (TKI), which is frequently used to treat chronic myeloid leukemia. Although very effective, dasatinib often displays severe adverse effects, including pleural effusions and increased risk of bleeding primarily in the gastrointestinal tract. The actual causes of these side effects are currently undetermined. We hypothesize that endothelial cells (ECs) that line the inner walls of blood vessels and control the traffic to the underlying tissues, might be involved. <p>Experimental design: The effects of TKIs on ECs were studied by various assays, such as real-time cell impedance measurements, live-cell microscopy, wound healing, western blot and an in vivo model.</p> <p>Results: Dasatinib uniquely causes a profound, dose-dependent disorganization of the EC monolayers. Dasatinib promoted the disassembly of cell-cell contacts, altered cell-matrix contacts and further altered the wound healing. A key observation is that this effect is fully reversible after drug washout. In line with these in vitro observations, intraperitoneal administration of dasatinib to mice caused significant vascular leakage in the intestine. The underlying molecular mechanism of dasatinib-induced reorganization of the actin involves ROCK activation, which increases the amount of the phosphorylation of myosin light chain and consequently activates the non-muscle myosin II.</p> <p>Conclusions: Our data are consistent with a scenario in which dasatinib triggers a transient increase in vascular leakage that probably contributes to adverse effects such as bleeding diathesis and pleural effusions.
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Selected alkylating agents can overcome drug tolerance of G0-like tumor cells and eradicate BRCA1-deficient mammary tumors in mice.
Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse.<br /><br />Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53-mutant breast cancer. Due to the large intragenic deletion of the Brca1 gene, no restoration of BRCA1 function is possible, and therefore no BRCA1-dependent acquired resistance occurs. To characterize the cell cycle stage from which Brca1-/-;p53-/- mammary tumors arise after cisplatin treatment, we introduced the fluorescent ubiquitination-based cell cycle indicator (FUCCI) construct into the tumor cells.<br /><br />Results: Despite repeated sensitivity to the maximum tolerated dose (MTD) of platinum drugs, the Brca1-mutated mammary tumors are not eradicated, not even by a frequent dosing schedule. We show that relapse comes from single nucleated cells delaying entry into S phase. Such slowly cycling cells, which are present within the drug-naïve tumors, are enriched in tumor remnants. Using the FUCCI construct we identified non-fluorescent G0-like cells as the population most tolerant to platinum drugs. Intriguingly, these cells are more sensitive to the DNA crosslinking agent nimustine resulting in an increased number of multinucleated cells that lack clonogenicity. This is consistent with our in vivo finding that the nimustine MTD, among several alkylating agents, is most effective in eradicating Brca1-mutated mouse mammary tumors.<br /><br />Conclusions: Our data show that targeting G0-like cells is crucial for the eradication of BRCA1/p53-deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine.
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TMPRSS2-ERG Alters the cis-Regulatory Landscape and Activates NOTCH [Research Watch]
In TMPRSS2–ERG-positive prostate tumors, ERG establishes new clusters of regulatory elements (CORE).
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PON2 Promotes Glucose Uptake to Support PDAC Growth and Metastasis [Research Watch]
PON2 promotes GLUT1-mediated glucose transport, is upregulated in PDAC, and is required for PDAC growth.
http://ift.tt/2v9zkAq
Anti-CTLA4 and Anti-PD-1 Act on Distinct T-cell Populations [Research Watch]
Both anti–PD-1 and anti-CTLA4 target subpopulations of exhausted-like CD8+ T cells.
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Crizotinib Has Antitumor Activity in ALK-Positive ALCL and IMT [Research Watch]
Crizotinib has an overall response rate of 90% in ALCL and 86% in IMT at the recommended phase II dose.
http://ift.tt/2uQNsmO
Poncet’s disease after the intravesical instillation of Bacillus Calmette–Guérin (BCG): a case report
Poncet's disease is a rare syndrome characterized by articular impairment in a form of rare tuberculid. One of the theories of its cause involves an autoimmune response induced by the intravesical administrati...
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Second-Order Peer Reviews of Clinically Relevant Articles for the Physiatrist: “Early Physical Therapy Vs Usual Care in Patients with Recent-Onset Low Back Pain” (Fritz JM, Magel JS, McFadden M, et al, JAMA 2015): “Physical Therapy May Not Help Acute Lower Back Pain Sufferers”
No abstract availablehttp://ift.tt/2wij4Cd
Grip Strength on the Unaffected Side as an Independent Predictor of Functional Improvement After Stroke
Objective: The aim of this study was to investigate the association between grip strength on the unaffected side and post-stroke functional improvement. Design: A total of 127 patients with unilateral stroke were included in this study. Demographic data, clinical data on initial grip strength, initial National Institutes of Health Stroke Scale, admission and discharge Modified Barthel Index (MBI), and stroke profiles were retrospectively reviewed. Results: Univariate and multiple linear regression analyses were carried out to evaluate the predictive values of each variable. In the model for discharge MBI, age, initial National Institutes of Health Stroke Scale, grip strength on the unaffected side, lesion side, and admission MBI were shown to be independent predictors. Meanwhile, grip strength on the unaffected side, lesion side, and admission MBI had significant predictive values in the model for difference between admission and discharge MBI. Conclusion: The current study suggests for the first time that grip strength on the unaffected side is an independent predictor for short-term functional gain and outcome after stroke. This result may change post-stroke rehabilitation strategies to emphasize exercises to prevent loss of muscle strength. In addition, this implies the possibility of a relationship between sarcopenia and post-stroke function. Further research is needed to reveal the effect of sarcopenia on stroke patients and its mechanism.http://ift.tt/2uQiMlK
Feasibility of Restoring Walking in Multiple Sclerosis with Multichannel Implanted Electrical Stimulation
Abstract: A patient with multiple sclerosis–related gait dysfunction was followed over the course of his disease. Despite aggressive treatment, he developed significant weakness in ankle dorsiflexors and hip and knee flexors and was no longer capable of consistently taking a step on his own. With electrical stimulation of hip and knee flexors and ankle dorsiflexors using implanted electrodes, he was able to consistently walk short distances as far as 30 m, thus significantly improving his Expanded Disability Status Scale score. This case study supports further exploration into the potential benefits of an implanted pulse generator to ameliorate gait dysfunction and improve quality of life for people with multiple sclerosis.http://ift.tt/2wpjbuZ
Isometric Exercise for the Cervical Extensors Can Help Restore Physiological Lordosis and Reduce Neck Pain: A Randomized Controlled Trial
Objective: The aim of this study was to investigate whether isometric neck extension exercise restores physiological cervical lordosis and reduces pain. Design: Sixty-five patients with loss of cervical lordosis were randomly assigned to exercise (27 women, 7 men; mean age, 32.82 ± 8.83 yrs) and control (26 women, 5 men; mean age, 33.48 ± 9.67 yrs) groups. Both groups received nonsteroidal anti-inflammatory drugs for 10 days. The exercise group received additional therapy as a home exercise program, which consisted of isometric neck extension for 3 mos. Neck pain severity and cervical lordosis were measured at baseline and at 3 mos after baseline. Results: Compared with baseline levels, cervical lordosis angle was significantly improved in the exercise group (Phttp://ift.tt/2uQ9TbX
The State of Disability Awareness in American Medical Schools
Abstract: This study was designed to: (1) determine how many American medical schools include disability awareness in their curriculum, (2) explore the format of disability awareness programs in existence, and (3) understand why some schools do not include disability awareness in their curriculum. An online survey was sent to deans of medical education (or equivalent positions) at accredited allopathic and osteopathic American medical schools (N = 167) in 2015. Seventy-five schools (45%) completed surveys. Fifty-two percent (39/75) reported having a disability awareness program. The most common format was people with disabilities or caregivers speaking in a large group setting. Programs were most likely to focus on adults with physical disabilities. Among schools without a program, the top barriers were no one advocating for inclusion in the curriculum and time constraints. Nearly half of schools without a program expressed interest in adopting an awareness curriculum if one was made available. Such results indicate that efforts should be made to increase the number of schools that provide disability awareness education through increased advocacy and providing additional resources to schools without a curriculum.http://ift.tt/2widEan
Authors' Response to Letter to the Editor “Ultrasound-Guided C7 Cervical Medial Branch Block Using the In-Plane Approach”
No abstract availablehttp://ift.tt/2wpRIsW
Chronic Effects of Different Rest Intervals Between Sets on Dynamic and Isometric Muscle Strength and Muscle Activity in Trained Older Women
Objective: This study investigated the chronic effects of different rest intervals (RIs) between sets on dynamic and isometric muscle strength and muscle activity. Design: We used a repeated-measures design (pretraining and posttraining) with independent groups (different RI). Twenty-one resistance-trained older women (66.4 ± 4.4 years) were randomly assigned to either a 1-minute RI group (G-1 min; n = 10) or 3-minute RI group (G-3 min; n = 11). Both groups completed 3 supervised sessions per week during 8 weeks. In each session, participants performed 3 sets of 15 repetitions of leg press exercise, with a load that elicited muscle failure in the third set. Fifteen maximum repetitions, maximal voluntary contraction, peak rate of force development, and integrated electromyography activity of the vastus lateralis and vastus medialis muscles were assessed pretraining and posttraining. Results: There was a significant increase in load of 15 maximum repetitions posttraining for G-3 min only (3.6%; P 0.05). Conclusions: The findings suggest that different RIs between sets did not influence dynamic and isometric muscle strength and muscle activity in resistance-trained older women.http://ift.tt/2v9hIoe
Can Early Rehabilitation on the General Ward After an Intensive Care Unit Stay Reduce Hospital Length of Stay in Survivors of Critical Illness?: A Randomized Controlled Trial
Objective: The aim of this study was to evaluate if an early rehabilitation program for survivors of critical illness improves functional recovery, reduces length of stay, and reduces hospital costs. Design: This was a prospective randomized controlled trial. Fifty-three consecutive survivors of critical illness were included in the study. After discharge from the intensive care unit, the intervention group received an early rehabilitation program, and the standard-care group received physical therapy as ordered by the primary care team. Length of stay at the general ward after transfer from the intensive care unit was recorded. In addition, Early Rehabilitation Barthel Index, visual analog scale for pain, 3-minute walk test, Beck Depression Inventory, State-Trait Anxiety Inventory, and Medical Research Council scale were used. Results: In the per-protocol analysis, length of stay at the general ward was a median 14 days (interquartile range [IQR], 12–20 days) in the early rehabilitation and 21 days [IQR, 13–34 days) in the standard-care group. This significant result could not be confirmed by the intention-to-treat analysis (16 days [IQR, 13–23 days] vs. 21 days [IQR, 13–34 days]). Secondary outcomes were similar between the groups. Hospital costs were lower in the intervention group. No adverse effects were detected. Conclusions: An early rehabilitation program in survivors of critical illness led to an earlier discharge from the hospital, improved functional recovery, and was also cost-effective and safe. To Claim CME Credits: Complete the self-assessment activity and evaluation online at http://ift.tt/1l80W45 CME Objectives: Upon completion of this article, the reader should be able to (1) delineate the benefits of early rehabilitation on a general medicine ward after an intensive care unit stay, (2) recognize the safety of appropriately implemented early rehabilitation, and (3) incorporate early rehabilitation on the general medical ward as applicable. Level: Advanced Accreditation: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.http://ift.tt/2v9bHry
The Magnitude and Time Course of Muscle Cross-section Decrease in Intensive Care Unit Patients
Objective: Bedriddenness and immobilization of patients at an intensive care unit may result in muscle atrophy and devaluation in quality of life. The exact effect of immobilization on intensive care unit patients is not known. The aim of this study was to investigate the magnitude and time course of muscle cross-section decrease in acute critically ill patients admitted to the intensive care unit. Design: An observational pilot study was performed in intensive care unit patients. Data of bilateral ultrasound muscle cross-section measurements of the knee extensors and the elbow flexors were collected. Thirty-four intensive care unit patients were included in this study; data are presented from 14 patients who were measured at least three times. Results: Repeated measures analysis of variance shows a significant decrease in muscle cross-section over time (F1,13 = 80.40, P ≤ 0.001).The decrease in muscle cross-section of the arms was significantly higher (F1,13 = 5.38, P = 0.037) than the decrease of the legs. Four weeks after intensive care unit admission, the muscle cross-section decrease had not reached an asymptote yet. Conclusions: The muscle cross-section decrease in bedridden intensive care unit patients is significant for a time of 2 to 4 weeks. The decrease in muscle cross-section of the arms is greater than the decrease of the legs.http://ift.tt/2v9E4WO
Massage Therapy for Pain and Function in Patients With Arthritis: A Systematic Review of Randomized Controlled Trials
Background: Massage therapy is gaining interest as a therapeutic approach to managing osteoarthritis and rheumatoid arthritis symptoms. To date, there have been no systematic reviews investigating the effects of massage therapy on these conditions. Design: Systematic review was used. Objectives: The primary aim of this review was to critically appraise and synthesize the current evidence regarding the effects of massage therapy as a stand-alone treatment on pain and functional outcomes among those with osteoarthritis or rheumatoid arthritis. Methods: Relevant randomized controlled trials were searched using the electronic databases Google Scholar, MEDLINE, and PEDro. The PEDro scale was used to assess risk of bias, and the quality of evidence was assessed with the GRADE approach. Results: This review found seven randomized controlled trials representing 352 participants who satisfied the inclusion criteria. Risk of bias ranged from four to seven. Our results found low- to moderate-quality evidence that massage therapy is superior to nonactive therapies in reducing pain and improving certain functional outcomes. It is unclear whether massage therapy is more effective than other forms of treatment. Conclusions: There is a need for large, methodologically rigorous randomized controlled trials investigating the effectiveness of massage therapy as an intervention for individuals with arthritis.http://ift.tt/2w9VW8u
Responsiveness of Myofascial Trigger Points to Single and Multiple Trigger Point Release Massages: A Randomized, Placebo Controlled Trial
Objective: This study aimed to assess the effects of single and multiple massage treatments on pressure-pain threshold (PPT) at myofascial trigger points (MTrPs) in people with myofascial pain syndrome expressed as tension-type headache. Design: Individuals (n = 62) with episodic or chronic tension-type headache were randomized to receive 12 twice-weekly 45-min massage or sham ultrasound sessions or wait-list control. Massage focused on trigger point release (ischemic compression) of MTrPs in the bilateral upper trapezius and suboccipital muscles. PPT was measured at MTrPs with a pressure algometer pre and post the first and final (12th) treatments. Results: PPT increased across the study timeframe in all four muscle sites tested for massage, but not sham ultrasound or wait-list groups (Phttp://ift.tt/2v8TjiQ
Strengthening Rehabilitation in Health Systems Worldwide by Integrating Information on Functioning in National Health Information Systems
Abstract: A complete understanding of the experience of health requires information relevant not merely to the health indicators of mortality and morbidity but also to functioning—that is, information about what it means to live in a health state, "the lived experience of health." Not only is functioning information relevant to healthcare and the overall objectives of person-centered healthcare but to the successful operation of all components of health systems. In light of population aging and major epidemiological trends, the health strategy of rehabilitation, whose aim has always been to optimize functioning and minimize disability, will become a key health strategy. The increasing prominence of the rehabilitative strategy within the health system drives the argument for the integration of functioning information as an essential component in national health information systems. Rehabilitation professionals and researchers have long recognized in WHO's International Classification of Functioning, Disability and Health the best prospect for an internationally recognized, sufficiently complete and powerful information reference for the documentation of functioning information. This paper opens the discussion of the promise of integrating the ICF as an essential component in national health systems to secure access to functioning information for rehabilitation, across health systems and countries.
http://ift.tt/2w9Ynb6
http://ift.tt/2w9Ynb6
Prospective Evaluation of Postural Control and Gait in Pediatric Patients with Cancer After a 4-Week Inpatient Rehabilitation Program
Objective: The aim of the study was to investigate the effects of a 4-wk inpatient rehabilitation program on postural control and gait in pediatric patients with cancer. Design: Eighty-eight patients with brain tumors (n = 59) and bone/soft tissue sarcomas (n = 29) were evaluated. Postural control was assessed examining the velocity of the center of pressure and single-leg stance time on a pressure distribution platform. Walk ratio, a measure of neuromotor control, was used to evaluate intervention effects on gait. Results: Repeated measures analysis of variance showed improvements in postural control measures, indicated by a decrease in velocity of center of pressure of −0.4 cm/sec (F1,80 = 7.175, P = 0.009, ηp2 = 0.082) and increase in single-leg stance time (mean [median] = 1.1 [2.6] sec, respectively; F1,80 = 12.617, P = 0.001, ηp2 = 0.136). Walk ratio increased by 0.2 mm/steps per min (F1,82 = 3.766, P = 0.056, ηp2 = 0.044). Mean changes in dependent variables did not differ between both patient groups (P > 0.05). Conclusions: The results indicate benefits of an inpatient rehabilitation program comprising standard physical therapy as well as aquatic and hippo therapy on postural control and gait after treatment of pediatric patients with cancer.http://ift.tt/2w9VGqc
Ultrasound-Guided C7 Cervical Medial Branch Block Using the In-Plane Approach
No abstract availablehttp://ift.tt/2vQ98gh
The 1-Year Results of Lumbar Transforaminal Epidural Steroid Injection in Patients with Chronic Unilateral Radicular Pain: The Relation to MRI Findings and Clinical Features
Objective: In patients with chronic radicular pain, we aimed to evaluate subgroup differences in 1-yr response to transforaminal epidural steroid injection. Design: In this longitudinal cohort study of 100 subjects, 170 transforaminal epidural steroid injections were performed for 1 yr. The sample was stratified by type of disc herniation (protrusion n = 57, extrusion n = 27), by location of disc herniation (central/subarticular n = 60, foraminal n = 24), by grade of nerve root compression (low-grade compression n = 61, high-grade subarticular nerve compression n = 14, high-grade foraminal nerve compression n = 25), and by positive Slump test (n = 67). Treatment response was evaluated by visual analogue scale leg pain and self-reported disability (Oswestry Disability Index). Logistic regression was used to analyze the predictive value of baseline characteristics including the stratified subgroups. Results: High-grade subarticular nerve compression predicted the 1-yr improvement in both visual analogue scale leg pain (P = 0.046) and Oswestry Disability Index (P = 0.027). Low age (Phttp://ift.tt/2waWPhc
A Rarely Seen Complication That Causes Increase in Morbidity in Tetraplegic Patients: Zenker Diverticula
Abstract: Although spinal cord injury (SCI) damages the spinal cord, physiological changes due to SCI can affect many organs and systems of the human body. While respiratory problems are common following cervical SCI, dysphagia is a relatively uncommon secondary complication that occurs after cervical SCI. We report a case of recurrent aspiration pneumonia due to Zenker diverticulum in 26-year-old tetraplegic patient with a chronic history of silent aspirations and dysphagia contributing to functional disability.http://ift.tt/2waojDF
Radiopaque Line in Front of the Lumbar Spine During a S1 Transforaminal Epidural Injection: Where Is the Contrast?
No abstract availablehttp://ift.tt/2w9kVcg
Methodological factors affecting joint moments estimation in clinical gait analysis: a systematic review
Quantitative gait analysis can provide a description of joint kinematics and dynamics, and it is recognized as a clinically useful tool for functional assessment, diagnosis and intervention planning. Clinicall...
http://ift.tt/2vMdvKT
Colorectal cancer patient’s self-efficacy for managing illness-related problems in the first 2 years after diagnosis, results from the ColoREctal Well-being (CREW) study
Abstract
Purpose
There is a growing emphasis on self-management of cancer aftercare. Little is known about patient's self-efficacy (confidence) to manage illness-related problems and how this changes over time. This paper describes the patterns of self-efficacy for managing illness-related problems amongst colorectal cancer patients in the 2 years following diagnosis.
Methods
In this prospective cohort study, questionnaires were administered at baseline (pre-surgery), 3, 9, 15 and 24 months to 872 colorectal cancer patients. Self-efficacy (confidence to manage illness-related problems), anxiety, social support, affect, socio-demographics, physical symptoms and clinical and treatment characteristics were assessed. Group-based trajectory analysis identified trajectories of self-efficacy up to 24 months and predictors.
Results
Four trajectories of self-efficacy were identified: group 1 (very confident) 16.0% (95% confidence interval (CI) 10.7–21.3%), group 2 (confident) 45.6% (95% CI 40.3–51.0%), group 3 (moderately confident) 29.5% (95% CI 25.1–33.8%) and group 4 (low confidence) 8.9% (95% CI 6.4–11.4%). Greater deprivation, domestic status, more co-morbidities, worse fatigue and pain, lower positivity and greater negativity were significantly associated with lower self-efficacy. There was an increase in mean scores for self-efficacy over time for the whole sample, but this did not reach the cut-off for minimally important differences. At 2 years, the lowest level of confidence to manage was for symptoms or health problems.
Conclusion
Around 40% of patients had suboptimal levels of confidence to manage illness-related problems with little change from the time of diagnosis across the four groups.
Implications for cancer survivors
Screening for self-efficacy at diagnosis would enable targeted, early intervention which could in turn enhance health-related quality of life.
http://ift.tt/2uQd2IM
Seroprevalence of Herpes Simplex Virus type-2 (HSV-2) among pregnant women who participated in a national HIV surveillance activity in Haiti
Herpes simplex virus type 2 (HSV-2), one the most common causes of genital ulcers, appears to increase both the risk of HIV acquisition and HIV transmission. HSV-2/HIV co-infection among pregnant women may inc...
http://ift.tt/2vLMA1R
Incident Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis patients in Brazil
In household contact investigations of tuberculosis (TB), a second tuberculin skin test (TST) obtained several weeks after a first negative result consistently identifies individuals that undergo TST conversio...
http://ift.tt/2wZ1kJd
Cost-effectiveness of Magnetic Resonance Imaging in Cervical Spine Clearance of Neurologically Intact Patients With Blunt Trauma
Use of magnetic resonance imaging (MRI) for cervical clearance after a negative cervical computed tomography (CT) scan result in alert patients with blunt trauma who are neurologically intact is not infrequent, despite poor evidence in regard to its utility. The objective of this study is to evaluate the utility and cost-effectiveness of using MRI versus no follow-up in this patient population.
http://ift.tt/2w9vkVm
Posttraumatic Stress Disorder in Emergency Medicine Residents
The emergency department (ED) is an environment of high intensity and stress for all its staff members. In addition to the daily challenges experienced in the ED, emergency medicine resident physicians are also regularly exposed to trauma, illness, death, and violence, which compose the primary triggers for the development of posttraumatic stress disorder (PTSD). They are confronted with these difficult scenarios and tragedies from the onset of their training, leaving them prone to the emotional effects.
http://ift.tt/2vQaV4V
Lack of Association Between the Use of Nerve Blockade and the Risk of Persistent Opioid Use Among Patients Undergoing Shoulder Arthroplasty: Evidence From the Marketscan Database
BACKGROUND: Persistent opioid use following surgery has received increasing attention from policymakers, researchers, and clinicians. Perioperative nerve blockade has been hypothesized to decrease the risk of persistent opioid use. We examined whether nerve blockade was associated with a decreased risk of persistent opioid use among patients undergoing shoulder arthroplasty, a procedure with high rates of persistent postoperative pain. METHODS: Using health care claims data, we constructed a sample of 6695 patients undergoing shoulder arthroplasty between 2002 and 2012 and used billing data to identify the utilization of nerve blockade. We then used a multivariable logistic regression to estimate the association between nerve blockade and 2 measures of opioid use: having filled at least 1 prescription for an opioid between postoperative days (PODs) 0 and 90, and between POD 91 and 365. This regression adjusted for a variety of potential confounders, such as preoperative opioid use and medical history. RESULTS: There was no association between nerve blockade and our 2 measures of persistent opioid use: adjusted odds ratio, 1.12 (97.5% confidence interval, 0.939–1.34; P = .15) for opioid use between POD 0 and 90, and adjusted odds ratio, 0.997 (97.5% confidence interval, 0.875–1.14; P = .95) for opioid use between POD 91 and 365. CONCLUSIONS: Although the use of perioperative nerve blockade may offer short-term benefits, in this study, it was not associated with a reduction in the risk of persistent opioid use for patients undergoing shoulder arthroplasty.http://ift.tt/2xc0xnp
Do Institution-Level Blood Utilization and Blood Management Initiatives Meaningfully Impact Transfusion Practices in Cardiac Surgery?
No abstract availablehttp://ift.tt/2xczDMk
Patient Characteristics Associated with Quality of Colonoscopy Preparation: A Systematic Review and Meta-analysis
Some features of patients are associated with inadequate bowel preparation, which reduces the effectiveness of colonoscopy examination. We performed a systematic review and meta-analysis of the association between patients' sociodemographic characteristics, health conditions, and medications with inadequate bowel preparation.
http://ift.tt/2ifwcSD
Worldwide Burden of and Trends in Mortality From Gallbladder and Other Biliary Tract Cancers
Gallbladder cancer has a low rate of survival, a unique geographic distribution, and is associated with lifestyle factors that have changed in recent decades. Little is known about the extent to which behavioral patterns have affected global trends in gallbladder cancer. We investigated recent mortality patterns and trends worldwide.
http://ift.tt/2ieRgs2
Palliative Care In Romania
Hospice Casa Sperantei has been pioneering palliative care development in Romania since 1992. The have developed specialist palliative care services in home-based settings, inpatient units, day care centers and as hospital support teams. They have provided national and international education programs for professionals in the palliative care field, as well as promoting palliative care integration in the healthcare system. Legislative improvements were adopted including funding mechanisms for the reimbursement of palliative care services through the health insurance funds, review of opioid policy, and quality standards of care.
http://ift.tt/2wi3LcW
Morus nigra and its major phenolic, syringic acid, have antidepressant-like and neuroprotective effects in mice
Abstract
Depression is a disorder with a high incidence that has been increasing worldwide although the pathophysiology remains unclear. Moreover, some studies revealed a higher concentration of glutamate and oxidative stress in the patients' brain, which causes cell death by excitotoxicity. Morus nigra L. is known as black mulberry and its leaves are popularly used to treat affections related to menopause, obesity and high cholesterol. M. nigra leaves are a rich fount of phenolics which well-known by the antioxidant property. Herein, we examined the phenolic profile and the antidepressant-like effect of the Morus nigra aqueous extract (MN) and its major phenolic constituent, syringic acid (SA). Furthermore, the involvement of antioxidant and neuroprotective activities were further evaluated. Our results show that acute and subchronic MN or SA administration exerted antidepressant-like property in the behavioral testes in mice. The results suggest that the antidepressant-like effect of MN, at least in part, could be due to the SA influence. Moreover, the observed effect involves the nitro-oxidative system modulation in both the serum and brain of mice. Furthermore, MN or SA was able to contain the glutamate-induced cell death in the hippocampal and cortical slices implicating the neuroprotection activity in the antidepressant-like effect.
http://ift.tt/2v9H8SO
Carcinoma of the Urethra
Primary carcinomas of the urethra are rare and poorly understood lesions, hence their clinical and pathologic spectrum is not completely defined. We analyzed a series of 130 primary urethral tumors and classified 106 of them as primary urethral carcinomas. The age at diagnosis of patients with primary urethral carcinomas ranged from 42–97years (mean: 69.4yrs.; median: 70yrs). There were 73 males and 33 female patients with a ratio of 2.2:1. In male patients the tumors most frequently developed in the bulbous-membranous segment of the urethra.
http://ift.tt/2ieIg6z
Sarcomatoid carcinoma associated with small cell carcinoma of the urinary bladder: a series of 28 cases
The association of sarcomatoid carcinoma (SC) with small cell carcinoma (SCC) has not been systematically studied. We identified 39 consult cases between 2001–2016 with available slides for review in 28 cases. There were 19 men and 9 women [mean age: 78years (51–89)]. In 26 (92.8%) cases, the sarcomatoid component had nonspecific malignant spindle cells, 4 (14%) chondrosarcoma, 2 (7%) myxoid sarcomatous, 1 (3.5%) osteosarcoma, and 1 (3.5%) rhabdomyosarcoma. The predominant component was in 11 (39%) cases SCC, 6 (21%) urothelial carcinoma, 3 (10%) sarcomatoid, and 8 (29%) equal sarcomatoid and SCC.
http://ift.tt/2fSSwAA
Sterile Drug Products by Bella Pharmaceuticals: Recall - Lack of Sterility Assurance
Audience: Health Care Professionals [Posted 08/18/2017] ISSUE: Bella Pharmaceuticals is voluntarily recalling all lots of unexpired sterile drug products due to lack of sterility assurance. The recalled products were distributed to health care...
http://ift.tt/2w9UOll
Sterile Drug Products by Bella Pharmaceuticals: Recall - Lack of Sterility Assurance
Audience: Health Care Professionals [Posted 08/18/2017] ISSUE: Bella Pharmaceuticals is voluntarily recalling all lots of unexpired sterile drug products due to lack of sterility assurance. The recalled products were distributed to health care...
http://ift.tt/2w9UOll
O203 Neuromodulation of lower limb motor circuitry with transcutaneous lumbar spinal cord direct current stimulation
The advent of transcranial direct current stimulation (tDCS) introduced growing interest in modulating spinal circuits, altered in many neurologic conditions. Transcutaneous spinal direct current stimulation (tsDCS) of cervical and thoracic spine regions was observed to modulate sensory and motor responses. Combining clinical studies with computational modelling can be a powerful tool to establish tsDCS protocols for specific therapeutic purposes. The aim of this study was to measure the effects of tsDCS delivered on the lumbar region on motor spinal responses and observe if these were consistent with the electric field (E-field) distribution predicted in the spinal cord using a computational model.
http://ift.tt/2xbRjYf
P229 Peripheral nerve injury after nerve blockade
Nerve blockade is a common procedure in peripheral limb surgery. In some cases however the anesthesia is directly followed by distally paresis and/or sensory disturbance.
http://ift.tt/2whUktH
P239 Muscle contraction does not always trigger the appearance of motor evoked potential polyphasia in healthy individuals
Motor evoked potentials (MEP) using magnetic stimulation are a non-invasive method that assesses the integrity of the central motor pathway. A phase is a part of the motor unit action potential that falls between two baseline crossings. Previous studies suggest that voluntary muscle contraction increases the appearance of MEP polyphasia. In this study we examined healthy individuals with the use of MEP, in order to evaluate the probability of polyphasia appearance during both muscle contraction and relaxation.
http://ift.tt/2xbMtu4
P247 Painful laser evoked potential inhibition during high-frequency non-noxious somatosensory stimulation
The inhibition of single nociceptive inputs by single non-painful stimuli was shown to occur at supraspinal level (Testani et al., 2015). However, the neurophysiological mechanism subserving the analgesia induced by rubbing the painful part of the body or during TENS is still unknown. Our aim was to investigate the site of this inhibition.
http://ift.tt/2whH7kL
P230 Ulnar epineural discontinuity and electrophysiological changes in a young girl following ulnar fracture
Electrophysiologic evaluation of traumatic peripheral nerve lesions can be complicated, especially in children where the given diagnosis can have dire consequences especially if not accurate.
http://ift.tt/2xbNPp1
P235 Localizing non-epileptic abnormal brain function in children using high density EEG (HDEEG): Electric source imaging (ESI) of focal slowing
Interictal focal slowing is an important EEG index of brain activity dysfunction, possibly representing an additional tool for presurgical evaluation in pediatric epilepsy. Here, we investigate the accuracy of electric source imaging (ESI) applied to pathological focal EEG slowing (FS) as new neurophysiological index localizing the epileptic focus in children with drug-resistant epilepsy.
http://ift.tt/2wibqYm
P335 Comparison of median nerve distal motor responses in patients with chronic inflammatory demyelinating polyneuropathy and carpal tunnel syndrome
Dispersion of distal compound muscle action potential (CMAP) is a useful finding for showing demyelination. In this study, we aimed to compare the duration and area of CMAP of median nerve between cases with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) and Carpal Tunnel Syndrome (CTS).
http://ift.tt/2xbRcfh
How Loud Is the Sun?
How loud would the sun be measured on Earth if its soundwaves could propagate through space? The answer might surprise you, as solar physicists estimate that the solar surface noise would be approximately 100dB by the time it reaches Earth! The enormity of the sun's surface paired with its capability of generating of tens of thousands of watts of sound energy per meter makes the sun astronomically loud.
http://ift.tt/2xccGZM
Coulomb Explosion Imaging as a Tool to Distinguish Between Stereoisomers
For small chiral species, Coulomb Explosion Imaging provides a new approach to determine the handedness of individual molecules.
http://ift.tt/2uPVY5u
PknB remains an essential and a conserved target for drug development in susceptible and MDR strains of M. Tuberculosis
The Mycobacterium tuberculosis (M.tb) protein kinase B (PknB) which is now proved to be essential for the growth and survival of M.tb, is a transmembrane protein with a potential to be a good drug target. However...
http://ift.tt/2vKMtDM
Nitrogen Cavitation and Differential Centrifugation Allows for Monitoring the Distribution of Peripheral Membrane Proteins in Cultured Cells
Here we present protocols for detergent-free homogenization of cultured mammalian cells based on nitrogen cavitation and subsequent separation of cytosolic and membrane-bound proteins by ultracentrifugation. This method is ideal for monitoring the partitioning of peripheral membrane proteins between soluble and membrane fractions.
http://ift.tt/2v9kpGw
T1-/T2-weighted ratio differs in demyelinated cortex of multiple sclerosis
Abstract
Detecting cortical demyelination in patients with multiple sclerosis (MS) is difficult. Using magnetic resonance imaging (MRI), ratio maps of T1-weighted and T2-weighted images (T1w/T2w) may be sensitive to cortical myelin levels. In this MRI-histological study, postmortem in situ scans were acquired from six cadavers with MS on a 3 Tesla MRI. Immunocytochemistry was used to correlate myelin status and cortical T1w/T2w measures. The results showed that the T1w/T2w values significantly differed between demyelinated and myelinated cortex (p < 0.001). The T1w/T2w ratio maps may be a relatively simple, clinically feasible method to assess cortical demyelination. This article is protected by copyright. All rights reserved.
http://ift.tt/2uPGNcE
Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women’s Health Initiative Observational Study
Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study
British Journal of Cancer advance online publication, August 17 2017. doi:10.1038/bjc.2017.268
Authors: Hannah Oh, Hannah Arem, Charles E Matthews, Nicolas Wentzensen, Kerryn W Reding, Louise A Brinton, Garnet L Anderson, Sally B Coburn, Jane A Cauley, Chu Chen, Deborah Goodman, Ruth M Pfeiffer, Roni T Falk, Xia Xu & Britton Trabert
http://ift.tt/2wUvBJj
MDM2 promotes epithelial–mesenchymal transition and metastasis of ovarian cancer SKOV3 cells
MDM2 promotes epithelial–mesenchymal transition and metastasis of ovarian cancer SKOV3 cells
British Journal of Cancer advance online publication, August 17 2017. doi:10.1038/bjc.2017.265
Authors: Ying Chen, Dan-Dan Wang, Ye-Ping Wu, Dan Su, Tian-Yi Zhou, Ren-Hua Gai, Ying-Ying Fu, Lin Zheng, Qiao-Jun He, Hong Zhu & Bo Yang
http://ift.tt/2vIAIO5
Influence of dietary insulin scores on survival in colorectal cancer patients
Influence of dietary insulin scores on survival in colorectal cancer patients
British Journal of Cancer advance online publication, August 17 2017. doi:10.1038/bjc.2017.272
Authors: Chen Yuan, Ying Bao, Kaori Sato, Katharina Nimptsch, Mingyang Song, Jennie C Brand-Miller, Vicente Morales-Oyarvide, Emilie S Zoltick, NaNa Keum, Brian M Wolpin, Jeffrey A Meyerhardt, Andrew T Chan, Walter C Willett, Meir J Stampfer, Kana Wu, Edward L Giovannucci, Charles S Fuchs & Kimmie Ng
http://ift.tt/2wUKA60
History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report
History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report
British Journal of Cancer advance online publication, August 17 2017. doi:10.1038/bjc.2017.267
Authors: Albina N Minlikeeva, Jo L Freudenheim, Rikki A Cannioto, Kevin H Eng, J Brian Szender, Paul Mayor, John L Etter, Daniel W Cramer, Brenda Diergaarde, Jennifer A Doherty, Thilo Dörk, Robert Edwards, Anna deFazio, Grace Friel, Marc T Goodman, Peter Hillemanns, Estrid Høgdall, Allan Jensen, Susan J Jordan, Beth Y Karlan, Susanne K Kjær, Rüdiger Klapdor, Keitaro Matsuo, Mika Mizuno, Christina M Nagle, Kunle Odunsi, Lisa Paddock, Mary Anne Rossing, Joellen M Schildkraut, Barbara Schmalfeldt, Brahm H Segal, Kristen Starbuck, Kathryn L Terry, Penelope M Webb, Emese Zsiros, Roberta B Ness, Francesmary Modugno, Elisa V Bandera, Jenny Chang-Claude & Kirsten B Moysich
http://ift.tt/2vHUMQI
Evaluating the effect of immune cells on the outcome of patients with mesothelioma
Evaluating the effect of immune cells on the outcome of patients with mesothelioma
British Journal of Cancer advance online publication, August 17 2017. doi:10.1038/bjc.2017.269
Authors: Serena J Chee, Maria Lopez, Toby Mellows, Sharmali Gankande, Karwan A Moutasim, Scott Harris, James Clarke, Pandurangan Vijayanand, Gareth J Thomas & Christian H Ottensmeier
http://ift.tt/2wUKBa4
Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)
Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228)
British Journal of Cancer advance online publication, August 17 2017. doi:10.1038/bjc.2017.278
Authors: Francis Lévi, Abdoulaye Karaboué, Raphaël Saffroy, Christophe Desterke, Valerie Boige, Denis Smith, Mohamed Hebbar, Pasquale Innominato, Julien Taieb, Carlos Carvalho, Rosine Guimbaud, Christian Focan, Mohamed Bouchahda, René Adam, Michel Ducreux, Gérard Milano & Antoinette Lemoine
http://ift.tt/2vHkHYv
FMNL2 destabilises COMMD10 to activate NF-κB pathway in invasion and metastasis of colorectal cancer
FMNL2 destabilises COMMD10 to activate NF-κB pathway in invasion and metastasis of colorectal cancer
British Journal of Cancer advance online publication, August 17 2017. doi:10.1038/bjc.2017.260
Authors: S S Yang, X M Li, M Yang, X L Ren, J L Hu, X H Zhu, F F Wang, Z C Zeng, J Y Li, Z Q Cheng, W T Liao, Y Q Ding, J Guan & L Liang
http://ift.tt/2wUGMS3
Fla. county losing millions of dollars in unpaid ambulance bills
Palm Beach County has $11.8 million in unpaid ambulance fees accrued from taking patients to the hospital
http://ift.tt/2w9yb0l
Epigenetic Regulation of Hepatitis B Virus Covalently Closed Circular DNA: Implications for Epigenetic Therapy against Chronic Hepatitis B
ABSTRACT
Hepatitis B virus (HBV) infection represents a significant public health burden worldwide. Although current therapeutics manage to control the disease progression, lifelong treatment and surveillance are required because drug resistance develops during treatment and reactivations frequently occur following medication cessation. Thus, the occurrence of hepatocellular carcinoma (HCC) is decreased but not eliminated. One major reason for the treatment failure is the inability to eradicate or inactivate the viral covalently closed circular DNA (cccDNA) which is a stable episomal form of viral genome decorated with host histones and non-histone proteins. Accumulating evidence suggests that epigenetic modifications of cccDNA contribute to viral replication and the outcome of chronic HBV infection. Here, we summarize the progress on HBV epigenetics research and the therapeutic implications for chronic HBV infection by learning from the epigenetic therapies for cancer and other viral diseases, which may open a new venue to cure the chronic hepatitis B. This article is protected by copyright. All rights reserved.
http://ift.tt/2uPwHby
A miR-7/GAS6/TYRO3 axis regulates the growth and invasiveness of sorafenib-resistant cells in human hepatocellular carcinoma
Abstract
Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient and patients invariably develop sorafenib resistance (SR). Recently, TYRO3, a member of the TAM family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC, however its role in SR is unknown. In this study, we generated two functionally distinct sorafenib resistant human Huh-7 HCC cell lines, in order to identify new mechanisms to abrogate acquired SR, as well as new potential therapeutic targets in HCC. Initially, we investigated the effects of a microRNA, miR-7, in both in vitro and in vivo preclinical models of human HCC and identified miR-7 as a potent tumour suppressor of human HCC. We identified TYRO3 as a new functional target of miR-7, which regulates proliferation, migration and invasion of Huh-7 cells via the PI3-Kinase/AKT pathway and is markedly elevated upon acquisition of SR. Furthermore, miR-7 effectively silenced TYRO3 expression in both sorafenib-sensitive and sorafenib-resistant Huh-7 cells inhibiting TYRO3/GAS6 mediated cancer cell migration and invasion. In conclusion, we identified a novel mechanism for acquiring SR in HCC which is via the aberrant expression of the TYRO3/PI3-Kinase/AKT signal transduction pathway, a mechanism that can be overcome by miR-7 over-expression. Taken together, these data suggest a potential role for miR-7 as an RNA-based therapeutic to treat refractory and drug resistant HCC. This article is protected by copyright. All rights reserved.
http://ift.tt/2v8KZiO
Radioembolization for Hepatocellular Carcinoma: Statistical Confirmation of Improved Survival in Responders by Landmark Analyses
ABSTRACT
Does imaging response predict survival in hepatocellular carcinoma (HCC)? We studied the ability of post-therapeutic imaging response to predict overall survival. Over 14 years, 948 HCC patients were treated with radioembolization. Patients with baseline metastases, vascular invasion, multifocal disease, Child-Pugh>B7 and transplanted/resected were excluded. This created our homogenous study cohort of 134 Child-Pugh≤B7 patients with solitary HCC. Response (using European Association for Study of the Liver [EASL] and Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1] criteria) was associated with survival using Landmark and risk-of-death methodologies after reviewing 960 scans. In a sub-analysis, survival times of responders were compared to those of patients with stable disease (SD) and progressive disease (PD). Uni/multivariate survival analyses were performed at each Landmark. At the 3-month Landmark, responders survived longer than nonresponders by EASL (HR:0.46; CI:0.26-0.82; P=0.002) but not RECIST 1.1 criteria (HR:0.70; CI:0.37-1.32; P=0.32). At the 6-month Landmark, responders survived longer than nonresponders by EASL (HR:0.32; CI:0.15-0.77; P<0.001) and RECIST 1.1 criteria (HR:0.50; CI:0.29-0.87; P=0.021). At the 12-month Landmark, responders survived longer than nonresponders by EASL (HR:0.34; CI:0.15-0.77; P<0.001) and RECIST 1.1 criteria (HR:0.52;CI 0.27-0.98; P=0.049). At 6 months, risk of death was lower for responders by EASL (P<0.001) and RECIST 1.1 (P=0.0445). In sub-analyses, responders lived longer than patients with SD or PD. EASL response was a significant predictor of survival at 3, 6, and 12 month Landmarks on uni/multivariate analyses. Conclusion: Response to radioembolization in patients with solitary HCC can prognosticate improved survival. EASL necrosis criteria outperformed RECIST 1.1 size criteria in predicting survival. The therapeutic objective of radioembolization should be radiologic response and not solely to prevent progression. This article is protected by copyright. All rights reserved.
http://ift.tt/2uOXIfu
In Situ Characterization of Shewanella oneidensis MR1 Biofilms by SALVI and ToF-SIMS
http://ift.tt/2xbn7N1
Peptide and Protein Quantification Using Automated Immuno-MALDI (iMALDI)
A protocol for the protein quantification in complex biological fluids using automated immuno-MALDI (iMALDI) technology is presented.
http://ift.tt/2xbBXDf
Quality standards in upper gastrointestinal endoscopy: a position statement of the British Society of Gastroenterology (BSG) and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS)
This document represents the first position statement produced by the British Society of Gastroenterology and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, setting out the minimum expected standards in diagnostic upper gastrointestinal endoscopy. The need for this statement has arisen from the recognition that while technical competence can be rapidly acquired, in practice the performance of a high- quality examination is variable, with an unacceptably high rate of failure to diagnose cancer at endoscopy. The importance of detecting early neoplasia has taken on greater significance in this era of minimally invasive, organ- preserving endoscopic therapy. In this position statement we describe 38 recommendations to improve diagnostic endoscopy quality. Our goal is to emphasise practices that encourage mucosal inspection and lesion recognition, with the aim of optimising the early diagnosis of upper gastrointestinal disease and improving patient outcomes.
http://ift.tt/2whuLZJ
Cortical pathology in MS detected by the T1/T2-weighted ratio from routine MRI
Abstract
Objective
In multiple sclerosis, neuropathological studies have shown widespread changes in the cerebral cortex. In vivo imaging is critical since the histopathological substrate of most measurements is unknown.
Method
Using a novel MRI analysis technique, based on the ratio of T1- and T2-weighted signal intensities, we studied the cerebral cortex of a large cohort of patients in early stages of multiple sclerosis. 168 patients with clinically isolated syndrome or relapsing-remitting multiple sclerosis (Expanded Disability Status Scale: median, 1; range, 0-3.5) and 80 age- and sex-matched healthy controls were investigated. We also searched for the histopathological substrate of the T1/T2-weighted ratio by combining post mortem imaging and histopathology in 9 multiple sclerosis brain donors.
Results
Patients showed lower T1/T2-weighted ratio values in parietal and occipital areas. The four most significant clusters appeared in the medial occipital and posterior cingulate cortex (each left and right). The decrease of the T1/T2-weighted ratio in the posterior cingulate was related to performance in attention. Analysis of the T1/T2-weighted ratio values of post mortem imaging yielded a strong correlation with dendrite density but none of the other parameters including myelin.
Interpretation
The T1/T2-weighted ratio decreases in early stages of multiple sclerosis in a widespread manner with a preponderance of posterior areas and with a contribution to attentional performance; it seems to reflect dendrite pathology. As the method is broadly available and applicable to (available) clinical scans, we believe that it is a promising candidate for studying and monitoring cortical pathology or therapeutic effects in multiple sclerosis. This article is protected by copyright. All rights reserved.
http://ift.tt/2woRkLm
Axonal components of nerves innervating the human arm
ABSTRACT
Objective: Axons travelling within the brachial plexus are responsible for the dexterous control of human arm and hand movements. Despite comprehensive knowledge on the topographical anatomy of nerves innervating the human upper limb, the definite quantity of sensory and motor axons within this neural network remains elusive. Our aim was to perform a quantitative analysis of the axonal components of human upper limb nerves based on highly specific molecular features from spinal cord level to the terminal nerves at wrist level.
Methods: Nerve specimen harvest at pre-defined harvesting sites (plexus roots and cords as well as major nerves originating from the brachial plexus innervating the arm and hand) was performed in nine human heart-beating organ donors. Double immunofluorescence staining using antibodies against choline-acetyltransferase and neurofilament was performed to differentiate motor and sensory axons on nerve cross sections.
Results: 350.000 axons emerge from the spinal cord to innervate the human upper limb of which 10% are motor neurons. In all nerves studied sensory axons outnumber motor axons by a ratio of at least 9:1. The sensory axon contribution increases when moving distally while only 1.700 motor axons reach the hand to innervate the intrinsic musculature.
Interpretation: Our results suggest that upper limb motor execution, and particularly dexterous coordination of hand movement require an unexpectedly low number of motor neurons, with a large convergence of afferent input for feedback control. This article is protected by copyright. All rights reserved.
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Persistent seizure control in epileptic mice transplanted with GABA progenitors
Abstract
Objective
A significant proportion of the more than 50 million people world-wide currently suffering with epilepsy are resistant to antiepileptic drugs (AEDs). As an alternative to AEDs, novel therapies based on cell transplantation offer an opportunity for long-lasting modification of epileptic circuits. To develop such a treatment requires careful preclinical studies in a chronic epilepsy model featuring unprovoked seizures, hippocampal histopathology, and behavioral comorbidities.
Methods
Transplantation of progenitor cells from embryonic medial or caudal ganglionic eminence (MGE, CGE) were made in a well-characterized mouse model of status epilepticus-induced epilepsy (systemic pilocarpine). Behavioral testing (handling and open field), continuous video-electroencephalographic (vEEG) monitoring and slice electrophysiology outcomes were obtained up to 270 days after transplantation (DAT). Post hoc immunohistochemistry was used to confirm cell identity.
Results
MGE progenitors transplanted into the hippocampus of epileptic mice rescued handling and open field deficits starting at 60 DAT. In these same mice, an 84-88% reduction in seizure activity was observed between 180 and 210 DAT. Inhibitory postsynaptic current frequency, measured on pyramidal neurons in acute hippocampal slices at 270 DAT, was reduced in epileptic mice but restored to naïve levels in epileptic mice receiving MGE transplants. No reduction in seizure activity was observed in epileptic mice receiving intra-hippocampal CGE progenitors.
Interpretation
Our findings demonstrate that transplanted MGE progenitors enhance functional GABA-mediated inhibition, reduce spontaneous seizure frequency and rescue behavioral deficits in a chronic epileptic animal model more than six months after treatment. This article is protected by copyright. All rights reserved.
http://ift.tt/2wo92yD
Inhibiting persistent inward sodium currents prevents myotonia
Abstract
Objective: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes involuntary firing of muscle action potentials (myotonia), producing muscle stiffness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. Our goal was to identify currents that trigger spontaneous firing of muscle in the setting of reduced ClC-1 current.
Methods: In vitro intracellular current clamp and voltage clamp recordings were performed in muscle from a mouse model of myotonia congenita.
Results: Intracellular recordings revealed a slow after-depolarization (AfD) that triggers myotonic action potentials. The after depolarization is well-explained by a tetrododoxin-sensitive and voltage-dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, suggesting this may contribute to the end of myotonic runs. Highlighting the significance of this mechanism, we found that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC.
Interpretation: This work significantly changes our understanding of the mechanisms triggering myotonia. Our work suggests that the current focus of treating myotonia, blocking the transient Na+ current underlying action potentials, is an inefficient approach. We show that inhibiting NaPIC is paralleled by elimination of myotonia. We suggest the ideal myotonia therapy would selectively block NaPIC and spare the transient Na+ current. This article is protected by copyright. All rights reserved.
http://ift.tt/2uY6SSN
School staff perpetration of physical violence against students in Uganda: a multilevel analysis of risk factors
Objective
To conduct a multilevel analysis of risk factors for physical violence perpetration by school staff against Ugandan students.
DesignMultilevel logistic regression analysis of cross-sectional survey data from 499 staff and 828 caregivers of students at 38 primary schools, collected in 2012 and 2014 during the Good Schools Study.
SettingLuwero District, Uganda.
Main outcome measurePast-week use of physical violence by school staff against students was measured using the International Society for the Prevention of Child Abuse and Neglect 'Child Abuse Screening Tool- Child International' and the WHO Multi-Country Study on Women's Health and Domestic Violence against Women.
ResultsOf 499 staff, 215 (43%) reported perpetration of physical violence against students in the past week. Individual risk factors associated with physical violence perpetration included being a teacher versus another type of staff member (p<0.001), approving of physical discipline practices (p<0.001), having children (p<0.01), being age 30–39 years (p<0.05), using physical violence against non-students (p<0.05) and being a victim of intimate partner violence (IPV) (p<0.05). We observed weak evidence (p=0.06) that male staff members who had been a victim of IPV showed higher odds of violence perpetration compared with male staff who had not been a victim of IPV. No evidence was observed for school- or community-level risk factors.
ConclusionsPhysical violence perpetration from school staff is widespread, and interventions are needed to address this issue. Staff who have been victims of violence and who use violence against people other than students may benefit from additional interventions. Researchers should further investigate how school and community contexts influence staff's physical violence usage, given a lack of associations observed in this study.
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Clear cell sarcomas of kidney are characterized by BCOR gene abnormalities including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion
Abstract
Aims
Clear cell sarcoma of kidney (CCSK) is a rare paediatric renal malignant tumour. The majority of CCSKs have internal tandem duplications (ITD) of the BCOR gene while a minority has the YWHAE-NUTM2 gene fusion. A third 'double-negative' (DN) category comprises CCSKs with neither BCOR ITD nor YWHAE-NUTM2 fusion. The aim of this study was to characterize 11 histologically diagnosed CCSKs immunohistochemically (with CCND1, BCOR and CCNB3 stains), and genetically.
Methods and results
By next-generation sequencing, 10 cases (90.9%) had BCOR exon 15 ITD, with positive BCOR immunoreactivity in 4 (36%) or 8 (72%) cases depending on antibody clone. By RT-PCR, none had the YWHAE-NUTM2 fusion. The DN case had a BCOR-CCNB3 fusion and strong nuclear CCNB3 and BCOR immunoreactivity. Quantitative PCR showed markedly elevated BCOR gene expression in this case whereas BCOR ITD cases had lower elevations.
Conclusions
The majority of the CCSKs in our cohort have BCOR ITD, and none have the YWHAE-NUTM2 gene fusion. We verify the strong, diffuse cyclin D1 (CCND1) immunoreactivity in CCSKs described in recent reports. BCOR immunoreactivity is not consistently positive in all CCSKs with BCOR ITD and therefore cannot be used as a diagnostic immunohistochemical stain to identify BCOR ITD cases. The DN case is a BCOR-CCNB3 fusion sarcoma. Typically a primary bone sarcoma affecting male adolescents, this is the first report of a BCOR-CCNB3 sarcoma presenting in a kidney of a young child as a CCSK. The full spectrum of DN CCSKs awaits more comprehensive characterization.
This article is protected by copyright. All rights reserved.
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Morphologic Spectrum of Renal Cell Carcinoma, Unclassified: An Analysis of 136 Cases
Abstract
Aims
Renal cell carcinoma, unclassified (RCCU) is a category that includes a morphologically and biologically heterogeneous group of tumors that are unable to be diagnosed as other well-defined entities. We aim to describe the morphologic findings of tumors within this category and to determine the most frequent morphologic features leading to classification difficulty.
Methods and results
One hundred and thirty-six cases of RCCU were examined. Patients ranged in age from 23 to 87 years. Seventy-seven patients were men and 59 were women. International Society of Urological Pathology (ISUP) grade was most commonly 3 (n=66), followed by 2 (n=42) and 4 (n=28). Tumor size ranged from 0.6 cm to 24.9 cm. The AJCC pathologic T categories included pT1a (n=50), pT1b (n=14), pT2a (n=7), pT2b (n=4), pT3a (n=50), and pT4 (n=9). Forty-four cases included lymph node(s), of which 41% (n=18) had metastases. Tumors were assessed for a variety of histologic features and assigned to the following morphologic groups: predominantly oncocytoma/chromophobe RCC-like; clear cell RCC-like; papillary RCC-like; collecting duct-like; and pure sarcomatoid differentiation. The majority of the oncocytoma/chromophobe and clear cell RCC-like phenotypes were low stage (pT1 or pT2). The papillary RCC-like, collecting duct-like, and pure sarcomatoid phenotypes were mostly high stage (pT3 or pT4).
Conclusions
RCCU is a term that encompasses tumors with a variety of morphologic features and a wide biologic spectrum. The most common source of diagnostic difficulty was tumors composed of predominantly eosinophilic cells.
This article is protected by copyright. All rights reserved.
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High molecular weight caldesmon expression in ovarian adult granulosa cell tumor and fibrothecoma
Abstract
High molecular weight caldesmon (H-caldesmon) is the protein that binds to actin and tropomyosin regulating smooth muscle contraction function.1 It is mainly expressed in smooth muscle cells and the research data showed the specificity of smooth muscle is higher than that of desmin and actin.2 In clinical diagnosis, H-caldesmon can be used to identify myofibroblastic tumors from true leiomyoma and to differentiate uterine smooth muscle tumors from endometrial stromal sarcoma combined with CD10. Resently, we encountered a case of ovarian adult granulosa cell tumor.
This article is protected by copyright. All rights reserved.
http://ift.tt/2vPRbi1
H3K27me3 immunostaining for sex determination in the context of presumed tissue misidentification
Abstract
We have read with great interest the correspondence by Dr Crotty1 and colleagues on the use of XIST chromogenic in situ hybridization for sex determination in the context of presumed tissue misidentification.
The authors refer to H3K27me3 immunostaining which has been reported to label the inactivated X chromosome2 and therefore may serve the same purpose as XIST ISH, i.e. an in situ analysis of sex. The mentioned study by Dr Schaefer and colleagues beautifully describes the morphological phenomenon and discusses the underlying biology, but does not formally assess the applicability of H3K27me3 immunostaining for sex determination in a routine setting.
This article is protected by copyright. All rights reserved.
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A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma
BACKGROUND
ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1.
METHODS
A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m2 weekly (cohort 1) or at 36 mg/m2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine.
RESULTS
Eighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/m2 weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3-11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached).
CONCLUSIONS
ADI-PEG 20 was well tolerated in combination with gemcitabine and nab-paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1-deficient and -proficient tumors. Cancer 2017. © 2017 American Cancer Society.
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Results of a prospective phase 2 study of pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma
BACKGROUND
This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma.
METHODS
Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12).
RESULTS
Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy.
CONCLUSIONS
The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017. © 2017 American Cancer Society.
http://ift.tt/2w9mxlW
Semi-quantitative metabolic values on FDG PET/CT including extracardiac sites of disease as a predictor of treatment course in patients with cardiac sarcoidosis
Abstract
Background
Cardiac sarcoidosis is associated with major adverse cardiac events including cardiac arrest, for which anti-inflammatory treatment is indicated. Oral corticosteroid is the mainstay among treatment options; however, adverse effects are a major concern with long-term use. It would be beneficial for providers to predict treatment response and prognosis for proper management strategy of sarcoidosis, though it remains challenging. Fluorine (F)-18 fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography(CT) has an advantage over anatomical imaging in providing semi-quantitative functional parameters such as standard uptake value (SUV), metabolic volume, and total lesion glycolysis (TLG), which are well-established biomarkers in oncology. However, the relationship between these parameters and treatment response has not been fully investigated in cardiac sarcoidosis. Also, the prognostic value of extracardiac active inflammation noted on FDG-PET/CT in the setting of cardiac sarcoidosis is unclear. The aim of this retrospective study was to investigate the prognostic value of semi-quantitative values of both cardiac and extracardiac disease sites derived from FDG-PET/CT in predicting treatment course in cardiac sarcoidosis.
Methods
Sixteen consecutive patients with suspected cardiac sarcoidosis, who demonstrated abnormal myocardial activity on cardiac-inflammation FDG-PET/CT encompassing the entire chest/upper abdomen and subsequently underwent corticosteroid therapy for diagnosis of active cardiac sarcoidosis, were included. Semi-quantitative values of hypermetabolic lesions were derived from all visualized organ system and were compared to daily corticosteroid dose at 6 months.
Results
Of the 16 patients, 81.3% (13/16) of the patients showed extracardiac involvement. The lesion with the greatest SUV was identified in the heart in 11 patients (68.7%), in the liver in 1 patient (6.3%), and in lymph nodes in 4 patients (25%). The maximum SUV across all visualized organ systems including the heart were 8.8 ± 3.1 for the patients with corticosteroid dose ≤ 10 mg and 12.5 ± 3.3 for those with > 10 mg (P = 0.04). Metabolic volume and TLG across all visualized organ systems or any values in the heart alone showed no significant statistical difference between the two groups.
Conclusions
Maximum SUV across all involved organ-systems of the chest and upper abdomen, not that of the heart alone, could be a predictor of treatment course of steroid therapy at 6 months in patients with active cardiac sarcoidosis.
http://ift.tt/2woe5PH
Revisiting the Logan plot to account for non-negligible blood volume in brain tissue
Abstract
Background
Reference tissue-based quantification of brain PET data does not typically include correction for signal originating from blood vessels, which is known to result in biased outcome measures. The bias extent depends on the amount of radioactivity in the blood vessels. In this study, we seek to revisit the well-established Logan plot and derive alternative formulations that provide estimation of distribution volume ratios (DVRs) that are corrected for the signal originating from the vasculature.
Results
New expressions for the Logan plot based on arterial input function and reference tissue were derived, which included explicit terms for whole blood radioactivity. The new methods were evaluated using PET data acquired using [11C]raclopride and [18F]MNI-659. The two-tissue compartment model (2TCM), with which signal originating from blood can be explicitly modeled, was used as a gold standard.
DVR values obtained for [11C]raclopride using the either blood-based or reference tissue-based Logan plot were systematically underestimated compared to 2TCM, and for [18F]MNI-659, a proportionality bias was observed, i.e., the bias varied across regions. The biases disappeared when optimal blood-signal correction was used for respective tracer, although for the case of [18F]MNI-659 a small but systematic overestimation of DVR was still observed.
Conclusions
The new method appears to remove the bias introduced due to absence of correction for blood volume in regular graphical analysis and can be considered in clinical studies. Further studies are however required to derive a generic mapping between plasma and whole-blood radioactivity levels.
http://ift.tt/2uY9HDx
Expression Profiling of the MAP Kinase Phosphatase Family Reveals a Role for DUSP1 in the Glioblastoma Stem Cell Niche
Abstract
The dual specificity phosphatases (DUSPs) constitute a family of stress-induced enzymes that provide feedback inhibition on mitogen-activated protein kinases (MAPKs) critical in key aspects of oncogenic signaling. While described in other tumor types, the landscape of DUSP mRNA expression in glioblastoma (GB) remains largely unexplored. Interrogation of the REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT) revealed induction (DUSP4, DUSP6), repression (DUSP2, DUSP7–9), or mixed (DUSP1, DUSP5, DUSP10, DUSP15) DUSP transcription of select DUSPs in bulk tumor specimens. To resolve features specific to the tumor microenvironment, we searched the Ivy Glioblastoma Atlas Project (Ivy GAP) repository, which highlight DUSP1, DUSP5, and DUSP6 as the predominant family members induced within pseudopalisading and perinecrotic regions. The inducibility of DUSP1 in response to hypoxia, dexamethasone, or the chemotherapeutic agent camptothecin was confirmed in GB cell lines and tumor-derived stem cells (TSCs). Moreover, we show that loss of DUSP1 expression is a characteristic of TSCs and correlates with expression of tumor stem cell markers in situ (ABCG2, PROM1, L1CAM, NANOG, SOX2). This work reveals a dynamic pattern of DUSP expression within the tumor microenvironment that reflects the cumulative effects of factors including regional ischemia, chemotherapeutic exposure among others. Moreover, our observation regarding DUSP1 dysregulation within the stem cell niche argue for its importance in the survival and proliferation of this therapeutically resistant population.
http://ift.tt/2vPYeqW
Rank acquisition in rhesus macaque yearlings following permanent maternal separation: The importance of the social and physical environment
Abstract
Rank acquisition is a developmental milestone for young primates, but the processes by which primate yearlings attain social rank in the absence of the mother remain unclear. We studied 18 maternally reared yearling rhesus macaques (Macaca mulatta) that differed in their social and physical rearing environments. We found that early social experience and maternal rank, but not individual traits (weight, sex, age), predicted dominance acquisition in the new peer-only social group. Yearlings also used coalitions to reinforce the hierarchy, and social affiliation (play and grooming) was likely a product, rather than a determinant, of rank acquisition. Following relocation to a familiar environment, significant rank changes occurred indicating that familiarity with a physical environment was salient in rank acquisition. Our results add to the growing body of literature emphasizing the role of the social and physical environment on behavioral development, namely social asymmetries among peers.
http://ift.tt/2xbdkXv
New Research From Clinical Psychological Science
Read about the latest research published in Clinical Psychological Science:
Daniel E. Gustavson, Alta du Pont, Alexander S. Hatoum, Soo Hyun Rhee, William S. Kremen, John K. Hewitt, and Naomi P. Friedman
Procrastination has been linked to personality factors that are predictive of psychopathology. Despite this, the association between procrastination and internalizing and externalizing psychopathology is not well understood. Same-sex twin pairs who were part of the Colorado Longitudinal Twin Study completed assessments of neuroticism at ages 12 and 17, and assessments of procrastination, fear of failure, impulsivity, and internalizing and externalizing disorders at age 23. Procrastination was found to be associated with internalizing and externalizing factors. Fear of failure and neuroticism accounted for the relationship between procrastination and internalizing psychopathology, whereas impulsiveness accounted for the relationship between procrastination and externalizing psychopathology. These associations were due primarily to genetic influences.
Matteo Malgaroli, Isaac R. Galatzer-Levy, and George A. Bonanno
Although divorce is thought to be a highly distressing event, there are differences in the trajectories of people whose marriages dissolve. To better understand these diverse trajectories, the researchers analyzed data from the Health and Retirement Study, a U.S.-based study that has been collecting data every 2 years since 1992. The researchers identified participants who had reported a divorce between waves of data collection. Information on depression, chronic health conditions, and mortality were assessed from the two data collection points, before and after the divorce. The researchers identified four trajectories: resilient (67% maintained relatively stable health after the stressor), chronic depression (12% reported consistently elevated depressive symptoms), decreasing depression (11% reported an improvement in depressive symptoms after divorce), and emergent depression (10% became more depressed after the divorce). The risk of mortality was found to be greater for those in the emergent-depression trajectory.
Alazne Aizpitarte, Olivia E. Atherton, and Richard W. Robins
There is some debate as to whether relational aggression is developmentally normative or an indication of mental-health problems. To examine this, the researchers analyzed data from 674 youth of Mexican origin and their parents who were part of the California Families Project. Participants were assessed at ages 10, 12, 14, and 16 for externalizing symptoms and for relational aggression that had occurred in the previous 3 months. The generational status of each adolescent was also recorded. The researchers found bidirectional pathways between psychiatric disorders (oppositional-defiant disorder and conduct disorder) and relational aggression. These associations were found for both boys and girls and for both those born in Mexico and those born in the United States. The data indicated that there were individual differences in who was at risk, which suggest that relational aggression is developmentally normative for some but is a precursor to later mental-health problems for others.
http://ift.tt/2w7LRsK
Comparison of transforaminal lumbar interbody fusion outcomes in patients receiving rhBMP-2 versus autograft
Publication date: Available online 18 August 2017
Source:The Spine Journal
Author(s): Taleef R. Khan, Kalin R. Pearce, Steven J. McAnany, Colleen M. Peters, Munish C. Gupta, Lukas P. Zebala
Background ContextRecombinant human bone morphogenetic protein 2 (rhBMP-2) plays a pivotal role in complex spine surgery. Despite its limited approval, the off-label use of rhBMP-2 is prevalent, particularly in transforaminal lumbar interbody fusions (TLIF)PurposeTo determine the effectiveness and safety of rhBMP-2 use in TLIF procedures versus autograft.Study DesignRetrospective Cohort StudyPatient SamplePatients older than 18 years undergoing spine surgery for lumbar degenerative spine disease at a single academic institution.Outcome MeasuresClinical outcome was determined according to: patient records. Radiographic outcome was determined according to: plain x-rays and computed tomography (CT).MethodsA retrospective study from 1997-2014 was conducted on 191 adults undergoing anterior-posterior instrumented spinal fusion with TLIF at a single academic institution. Patient data was gathered from operative notes, follow up clinic notes and imaging studies to determine complications and fusion rates. One hundred eight-seven patients fit criteria, which included patients with a minimum of one TLIF, and had a minimum 2-year radiographic and clinical follow-up. Patients were further classified into a BMP group (n=83) or non-BMP group (n=104). Three logistic regression models were run using rhBMP-2 exposure as the independent variable. The respective outcome variables were TLIF-related complications (radiculitis, seroma, osteolysis, and ectopic bone), surgical complications, and all complications.ResultsBMP (n=83) and non-BMP (n=104) groups had similar baseline demographics (sex, diabetes, pre-existing cancer). On average, the BMP and non-BMP groups were similarly aged (51.9 vs. 47.9 years, p>0.05), but the BMP group had a shorter follow-up time (3.03 vs. 4.06 years; p<0.001) and fewer smokers (8 vs. 21 patients; p<0.048). The fusion rate for the BMP and non-BMP groups was 92.7% and 92.3%, respectively. The pseudoarthrosis rate was 7.5% (14/187 patients). Radiculitis was observed in 7 patients in the BMP group (8.4%) and 2 patients in the non-BMP group (1.9%) in the non-BMP group. Seroma was observed in 2 patients in the BMP group (2.4%) and none in the non-BMP group. No deep infections were observed in the BMP group and 1 patient in the non-BMP group (0.96%). While patients exposed to BMP were at a significantly greater risk of developing radiculitis and seroma (OR=4.53, CI=1.42 – 14.5), BMP exposure was not a significant predictor of surgical complications (OR=0.32, CI=0.10 – 1.00) or overall complications (OR=1.11, CI=0.53 – 2.34). The outcome of TLIF-related complications was too rare and the confidence interval too wide for practical significance of the first model.ConclusionEvidence supports the hypothesis that off-label use of rhBMP-2 in TLIF procedures is relatively effective for achieving bone fusion at rates similar to patients receiving autograft. Patients exhibited similar complication rates between the two groups, with the BMP group exhibiting slightly higher rates of radiculitis and seroma.
http://ift.tt/2uY1MGc
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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