Medicine by Alexandros G.Sfakianakis: 09/20/17

Τετάρτη 20 Σεπτεμβρίου 2017

Coordination-Accelerated “Iron Extraction” Enables Fast Biodegradation of Mesoporous Silica-Based Hollow Nanoparticles

Biodegradation behavior of inorganic silica-based nanoplatforms is of critical importance in their clinical translations, but still remains a great challenge in achieving this goal by composition regulation of biocompatible silica framework. In the present work, a chemical coordination-accelerated biodegradation strategy to endow hollow mesoporous silica nanoparticles (HMSNs) with unique coordination-responsive biodegradability, on-demand coordination-responsive drug releasing behavior, and significantly enhanced chemotherapeutic efficacy by directly doping iron (Fe) ions into the framework of mesoporous silica is reported. A simple but versatile dissolution-regrowth strategy has been developed to enable the framework Fe doping via chemical bonding. The deferiprone-mediated biodegradation of Fe-doped HMSNs (Fe-HMSNs) has been comprehensively evaluated both in simulated body fluid and intracellular level, which have exhibited a specific coordination-accelerated biodegradation behavior. In addition to high biocompatibility of Fe-HMSNs, the anticancer drug doxorubicin (DOX)-loaded Fe-HMSNs show enhanced tumor-suppressing effect on 4T1 mammary cancer xenograft. This work paves a new way for tuning the biodegradation performance of mesoporous silica-based nanoplatforms simply by biocompatible Fe-ion doping into silica framework based on the specific coordination property between introduced metal Fe ions with Fe-coordination proteins.

Coordination-accelerated biodegradation strategy: A chemical coordination-accelerated biodegradation strategy is illustrated to endow hollow mesoporous silica nanoparticles with proteinous coordination-responsive biodegradability (via "iron extraction"), on-demand coordination-responsive drug releasing behavior, and significantly enhanced chemotherapeutic efficacy by directly doping iron (Fe) ions into the framework of mesoporous silica.

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Biodegradable Shape Memory Polymers in Medicine

Shape memory materials have emerged as an important class of materials in medicine due to their ability to change shape in response to a specific stimulus, enabling the simplification of medical procedures, use of minimally invasive techniques, and access to new treatment modalities. Shape memory polymers, in particular, are well suited for such applications given their excellent shape memory performance, tunable materials properties, minimal toxicity, and potential for biodegradation and resorption. This review provides an overview of biodegradable shape memory polymers that have been used in medical applications. The majority of biodegradable shape memory polymers are based on thermally responsive polyesters or polymers that contain hydrolyzable ester linkages. These materials have been targeted for use in applications pertaining to embolization, drug delivery, stents, tissue engineering, and wound closure. The development of biodegradable shape memory polymers with unique properties or responsiveness to novel stimuli has the potential to facilitate the optimization and development of new medical applications.

Biodegradable shape memory polymers represent an important class of materials in medicine. The ability of materials to change shape in response to specific stimuli enables the simplification of medical procedures, use of minimally invasive techniques, and access to new treatment modalities. This Review provides an overview of available biodegradable shape memory polymers and their use in medical applications.

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Induction of reactive oxygen species: an emerging approach for cancer therapy

Abstract

Reactive oxygen species (ROS), a group of ions and molecules, include hydroxyl radicals (·OH), alkoxyl radicals, superoxide anion (O₂·−), singlet oxygen (¹O₂) and hydrogen peroxide (H₂O₂). Hydroxyl radicals and alkoxyl radicals are extremely and highly reactive species respectively. Endogenous ROS are mainly formed in mitochondrial respiratory chain. Low levels of ROS play important roles in regulating biological functions in mammalian cells. However, excess production of ROS can induce cell death by oxidative damaging effects to intracellular biomacromolecules. Cancer cell death types induced by ROS include apoptotic, autophagic, ferroptotic and necrotic cell death. Since abnormal metabolism in cancer cells, they have higher ROS content compared to normal cells. The higher endogenous ROS levels in cancer cells endow them more susceptible to the ROS-induction treatment. Indeed, some anticancer drugs currently used in clinic, such as molecular targeted drugs and chemotherapeutic agents, effectively kill cancer cells by inducing ROS generation. In addition, photodynamic therapy (PDT) is mainly based on induction of ROS burst to kill cancer cells. The mechanism of cell death induced by radiotherapy using ionizing radiation also refers to ROS production. Moreover, ROS play an important role in tumor immune therapy. Altogether, combining above traditional treatments with ROS-induced agents will be considered as a promising strategy in cancer therapy. In this review, we focus on our current understanding of the anticancer effects of ROS.

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Treatment Opportunities in Patients With Metabolic Myopathies

Abstract

Metabolic myopathies are disorders affecting utilization of carbohydrates or fat in the skeletal muscle. Adult patients with metabolic myopathies typically present with exercise-induced pain, contractures or stiffness, fatigue, and myoglobinuria. Symptoms are related to energy failure.

Purpose of review In this review, the current treatment options, including exercise therapy, dietary treatment, pharmacological supplementation, gene transcription, and enzyme replacement therapy, are described.

Recent findings Recognition of the metabolic block in the metabolic myopathies has started the development of new therapeutic options. Enzyme replacement therapy with rGAA has revolutionized treatment of early onset Pompe disease. Supplements of riboflavin, carnitine, and sucrose show promise in patients with respectively riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, primary carnitine deficiency, and McArdle disease. Treatment with citric acid cycle intermediates supply by triheptanoin seems promising in patients with glucogenoses, and studies are ongoing in patients with McArdle disease.

Summary Treatment of metabolic myopathies primarily relies on avoiding precipitating factors and dietary supplements that bypass the metabolic block. Only a few of the used supplements are validated, and further studies are needed to define efficacious treatments. Further potential treatment targets are molecular therapies aimed at enzyme correction, such as chaperone therapy, gene therapy, gene expression therapy, and enzyme replacement therapies.

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Effects of household washing on bacterial load and removal of Escherichia coli from lettuce and “ready-to-eat” salads

Abstract

Customer demands for fresh salads are increasing, but leafy green vegetables have also been linked to food-borne illness due to pathogens such as Escherichia coli O157:H7. As a safety measure, consumers often wash leafy vegetables in water before consumption. In this study, we analyzed the efficiency of household washing to reduce the bacterial content. Romaine lettuce and ready-to-eat mixed salad were washed several times in flowing water at different rates and by immersing the leaves in water. Lettuce was also inoculated with E. coli before washing. Only washing in a high flow rate (8 L/min) resulted in statistically significant reductions (p < .05), "Total aerobic count" was reduced by 80%, and Enterobacteriaceae count was reduced by 68% after the first rinse. The number of contaminating E. coli was not significantly reduced. The dominating part of the culturable microbiota of the washed lettuce was identified by rRNA 16S sequencing of randomly picked colonies. The majority belonged to Pseudomonadaceae, but isolates from Enterobacteriaceae and Staphylococcaceaceae were also frequently found. This study shows the inefficiency of tap water washing methods available for the consumer when it comes to removal of bacteria from lettuce. Even after washing, the lettuce contained high levels of bacteria that in a high dose and under certain circumstances may constitute a health risk.

Leafy green vegetables are often linked to food-borne illness, and consumers often wash these products at home as a safety measure. The efficiency of household washing to reduce the bacterial content was analyzed with and without E. coli inoculation, and only washing in a high flow rate (8 L/min) without E. coli resulted in statistically significant reductions. This study shows the inefficiency of tap water washing methods available for the consumer, and even after washing, the products contained high levels of bacteria that in a high dose and under certain circumstances may cause illness.

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Sentinel lymph node biopsy in periocular merkel cell carcinoma: a case report

The National Comprehensive Cancer Network guidelines for Merkel cell carcinoma recommend performance of the sentinel lymph node biopsy in all patients with clinically negative nodal disease for staging and tre...

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Magnitude of the Cytomegalovirus infection among pregnant women attending antenatal clinics in the city of Mwanza, Tanzania

Despite, Cytomegalovirus (CMV) infection being associated with a potential risk to the fetus, there is limited data from Tanzania and many other developing countries regarding the epidemiology and the impact o...

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Acute HIV infection presenting as hemophagocytic lymphohistiocytosis: case report and review of the literature

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon systemic inflammatory condition that can result from infections, autoimmune diseases and malignancies. It is a rarely reported life threatening complicat...

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Who’s holding the baby? A prospective diary study of the contact patterns of mothers with an infant

Models of infectious disease are increasingly utilising empirical contact data to quantify the number of potentially infectious contacts between age groups. While a growing body of data is being collected on c...

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Melanoma Drugs Effective as Adjuvants [News in Brief]

Targeted and immune therapies delay recurrence after surgery.

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Gemtuzumab Ozogamicin Makes a Comeback [News in Brief]

CD33-targeting agent reapproved at a lower dose for AML after studies show benefit outweighs risk.

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Anesthesia and Perioperative Care for Organ Transplantation.

No abstract available

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Acute Lung Injury and Repair: Scientific Fundamentals and Methods.

No abstract available

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Factors Influencing the Choice of Anesthesia as a Career by Undergraduates of the University of Rwanda.

No abstract available

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Administration of Hypertonic Solutions for Hemorrhagic Shock: A Systematic Review and Meta-analysis of Clinical Trials.

BACKGROUND: Several clinical trials on hypertonic fluid administration have been completed, but the results have been inconclusive. The objective of this study is to summarize current evidence for treating hypovolemic patients with hypertonic solutions by performing a systematic review and meta-analysis. METHODS: Major electronic databases were searched from inception through June 2014. We included only randomized controlled trials involving hemorrhagic shock patients treated with hypertonic solutions. After screening 570 trials, 12 were eligible for the final analysis. Pooled effect estimates were calculated with a random effect model. RESULTS: The 12 studies included 6 trials comparing 7.5% hypertonic saline (HS) with 0.9% saline or Ringer's lactate solution and 11 trials comparing 7.5% hypertonic saline with dextran (HSD) with isotonic saline or Ringer's lactate. Overall, there were no statistically significant survival benefits for patients treated with HS (relative risk [RR], 0.96; 95% confidence interval [CI], 0.82-1.12) or HSD (RR, 0.92; 95% CI, 0.80-1.06). Treatment with hypertonic solutions was also not associated with increased complications (RR, 1.03; 95% CI, 0.78-1.36). Subgroup analysis on trauma patients in the prehospital or emergency department settings did not change these conclusions. There was no evidence of significant publication bias. Metaregression analysis did not find any significant sources of heterogeneity. CONCLUSIONS: Current evidence does not reveal increased mortality when the administration of isotonic solutions is compared to HS or HSD in trauma patients with hemorrhagic shock. HS or HSD may be a viable alternative resuscitation fluid in the prehospital setting. Further studies are needed to determine the optimum volume and regimen of intravenous fluids for the treatment of trauma patients. (C) 2017 International Anesthesia Research Society

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The Little ICU Book, 2nd ed.

No abstract available

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Preventing Mistransfusions: An Evaluation of Institutional Knowledge and a Response.

BACKGROUND: Blood product mistransfusions occur when a process error causes transfusion of incompatible blood products. These events are known sources of negative patient outcomes. One such event demonstrated an institutional knowledge gap and an opportunity to reduce this source of transfusion errors. The focus of this study was to evaluate the application of point of care cognitive aids to bridge potentially lethal knowledge gaps in blood product to patient compatibility. METHODS: A patient-donor ABO antigen compatibility grid for red blood cells (RBC) and fresh frozen plasma (FFP) was developed for creation of a cognitive aid and a blood product safety quiz. Participants included 117 registered nurses and postgraduate medical interns who were given 2 minutes to complete the quiz for establishing institutional controls. A separate group of 111 registered nurses and interns were given the same timed quiz twice, without and then with a blood product compatibility cognitive aid. An analysis of covariance was used to evaluate without cognitive aid versus with cognitive aid quiz results while taking the specialty (nurse versus interns) and baseline score into consideration. The blood bank adopted the grid as a forcing function to be completed before release of blood products. RESULTS: The correct RBC answer percentage increased from 84.7% to 98.3% without and with cognitive aid (average improvement 13.6%, standard deviation [SD] = 18.3%, 95% confidence interval, 10.1%-17.1%, P

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The Relationship Between Women's Intention to Request a Labor Epidural Analgesia, Actually Delivering With Labor Epidural Analgesia, and Postpartum Depression at 6 Weeks: A Prospective Observational Study.

BACKGROUND: Postpartum depression (PPD) is associated with pain during and after delivery, with studies showing reduced rates among women delivering with labor epidural analgesia (LEA). We hypothesized that women who intend to deliver with LEA but do not receive it are at higher risk for PPD at 6 weeks due to the combined experience of untreated labor pain and unmatched expectations during labor, and evaluated the interaction between labor plans related to LEA, satisfaction with pain control when actually delivering with LEA, and PPD at 6 weeks after delivery. METHODS: A total of 1497 women with a vaginal delivery were enrolled into this prospective longitudinal study. Women's initial intention to deliver with or without LEA, how they subsequently delivered, and satisfaction with pain relief were recorded on postpartum day 1. Primary aim was selected as PPD at 6 weeks among women intending to deliver with but subsequently delivering without LEA compared with the rest of the cohort. Primary outcome was PPD at 6 weeks using the Edinburgh Postnatal Depression Scale; PPD was defined with a score >=10 (scale from 0 to 30). Demographic and obstetric data were recorded. Fisher exact test was used for comparisons between groups. The interaction between intention and actual delivery with regard to LEA and PPD was tested. RESULTS: Overall, 87 of 1326 women completing the study at 6 weeks had PPD (6.6%). For the primary aim, 439 (29.3%) delivered without LEA, of which 193 (12.9%) had intended to deliver with LEA; the PPD rate among these women was 8.1%, which was not statistically different from the rest of the cohort (6.3%; odds ratio [OR], 1.30; 95% confidence interval [CI], 0.72-2.38; P = .41). A total of 1058 women (70.7%) delivered with LEA and 439 (29.3%) delivered without; therefore, 1169 (78.1%) delivered as intended and 328 (21.9%) did not (unmatched expectations). Evaluating the interaction between effects, there was a strong negative additive interaction between intending to deliver without LEA and actually delivering with LEA (risk difference = -8.6%, 95% CI, 16.2%-1.6%; P = .014) suggesting that unmatched intention effect is significantly associated with negative outcome. In multiple regression analysis, while intending to deliver with LEA (OR, 1.06; 95% CI, 1.01-1.11; P = .029) and actually delivering with LEA (OR, 1.07; 95% CI, 1.01-1.13; P = .018) both increased the odds for PPD, the multiplicative interaction was protective (OR, 0.92; 95% CI, 0.86-0.99; P = .022), after adjusting for cofactors. CONCLUSIONS: Our study results did not demonstrate a significant increase in the odds for PPD at 6 weeks among women who intended to deliver with LEA but subsequently delivered without. However, we identified a protective interaction between intended LEA use and actual use on the incidence of PPD. Our data suggest an increased risk when women do not deliver as intended, particularly when not initially intending to deliver with LEA. The relationship between unplanned LEA and PPD may be mediated by a physically difficult delivery rather than or in addition to negative emotions related to unmet expectations or a sense of personal failure; therefore, counseling women after delivery to address any negative perceptions may be useful. (C) 2017 International Anesthesia Research Society

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Other Specialties Might Have a GPS.

No abstract available

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Rhino 7, Papa Zen, Fifty Shades, and Grande X Dietary Supplements by Gadget Island: Recall - Undeclared Drug Ingredients

Audience: Consumers [Posted 09/20/2017] ISSUE: Newark, CA, Gadget Island, Inc. is voluntarily recalling to the consumer level. The products have been found to contain undeclared Active Pharmaceutical Ingredients sildenafil, desmethyl carbodenafil...

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KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD)

Chronic kidney disease–mineral and bone disorder (CKD-MBD) encompasses laboratory and bone abnormalities and vascular calcification and has deleterious effects on clinical outcomes. KDOQI (Kidney Disease Outcomes Quality Initiative), an initiative of the National Kidney Foundation, addressed this issue with the publication of a clinical practice guideline for bone metabolism and disease in CKD in 2003, and 2 years later, a new definition and classification scheme for CKD-MBD was developed following a KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference.

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Oral Anticoagulants to Prevent Stroke in Nonvalvular Atrial Fibrillation in Patients With CKD Stage 5D: An NKF-KDOQI Controversies Report

Stroke risk may be more than 3-fold higher among patients with chronic kidney disease stage 5D (CKD-5D) compared to the general population, with the highest stroke rates noted among those 85 years and older. Atrial fibrillation (AF), a strong risk factor for stroke, is the most common arrhythmia and affects >7% of the population with CKD-5D. Warfarin use is widely acknowledged as an important intervention for stroke prevention with nonvalvular AF in the general population. However, use of oral anticoagulants for stroke prevention in patients with CKD-5D and nonvalvular AF continues to be debated by the nephrology community.

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Effects of Androgen Deprivation Therapy on Pain Perception, Quality-of-Life and Depression in Men with Prostate Cancer

Previous animal and human research suggests that testosterone has anti-nociceptive properties. Castration in male rodents increases pain perception which is reversed by testosterone replacement. Pain perception also improves in hypogonadal men with testosterone therapy. However, it remains unclear whether androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with an increase in pain perception.

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Unmet palliative care needs among patients with end-stage kidney disease: a national registry study about the last week of life

End-stage kidney disease (ESKD) is characterized by high physical and psychological burden and therefore, more knowledge about the palliative care provided close to death is needed.

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Rhino 7, Papa Zen, Fifty Shades, and Grande X Dietary Supplements by Gadget Island: Recall - Undeclared Drug Ingredients

Concurrent Chemoradiotherapy in Curatively Resected Gallbladder Carcinoma: A propensity score-matched analysis

The efficacy and safety of concurrent chemoradiotherapy (CCRT) in patients with advanced gallbladder carcinoma (GBC) after radical resection (S) remains unclear . The primary aim was to compare overall survival (OS) between patients receiving radical resection followed by CCRT (S+CCRT) and patients receiving radical resection only for advanced resectable GBC.

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Comparing the Effectiveness of Combined External Beam Radiation and Hyperthermia versus External Beam Radiation Alone in Treating Patients with Painful Bony Metastases: a Phase III Prospective Randomized Control Trial

Clinical experience of combined radiofrequency-based deep hyperthermia (HT) and external beam radiotherapy (RT) with bony metastases is limited. We aimed to compare the response, duration of pain relief and time to achieve complete pain relief after RT with or without HT.

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Deep inspiration breath hold radiotherapy in breast cancer: a word of caution on the dose to the axillary lymph node levels

Deep inspiration breath-hold (DIBH) radiotherapy gains more popularity for breast cancer therapy. The purpose of this study was to assess the differences of not intended regional nodal irradiation between free breathing (FB) and DIBH.

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Preparation of Liquid Crystal Networks for Macroscopic Oscillatory Motion Induced by Light

The goal of the protocol is to create liquid crystalline polymer films that can mechanically oscillate under continuous light irradiation. We describe in great detail the conception of free-standing films, from the liquid crystal alignment method to the photo-actuation. The experimental protocol applied to prepare this material is broadly applicable.

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Opioid Addiction Medications in Patients Taking Benzodiazepines or CNS Depressants: Drug Safety Communication - Careful Medication Management Can Reduce Risks

Audience: Health Professional, Pain Management [Posted 09/20/2017] ISSUE: Based on additional review, FDA is advising that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or...

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Corrigendum to “Niemann-Pick Disease Type C Presenting as a Developmental Coordination Disorder with Bullying by Peers in a School-Age Child”

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So What Did You Hear This Summer?

The lawn is starting to slow down. The kids are back in school. The leaves are threatening to turn. And the white slacks are put away. Summer must be behind us. Talk around the water cooler or around the block while walking pets is soon going to turn to speculation about the winter. Is it going to be a bad one? Is it going to be another one of those late winters?

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Solubility of Hydrophobic Compounds in Aqueous Solution Using Combinations of Self-assembling Peptide and Amino Acid

This protocol describes a clinically-applicable means of dissolving hydrophobic compounds in an aqueous environment using combinations of self-assembling peptide and amino acid solutions. Our method resolves a major limitation of hydrophobic therapeutics, which lack safe, efficient means of solubility and delivery methods into clinical settings.

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Overcoming the Challenges of Metastatic Cancer: An Interview with Dr. Rosandra Kaplan

NCI's Dr. Rosandra Kaplan discusses important trends in metastatic cancer research and new ideas for treating and preventing metastatic cancer.

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Opioid Addiction Medications in Patients Taking Benzodiazepines or CNS Depressants: Drug Safety Communication - Careful Medication Management Can Reduce Risks

UPF1 Governs Synaptic Plasticity through Association with a STAU2 RNA Granule

Neuronal mRNAs can be packaged in reversibly stalled polysome granules before their transport to distant synaptic locales. Stimulation of synaptic metabotropic glutamate receptors (mGluRs) reactivates translation of these particular mRNAs to produce plasticity-related protein; a phenomenon exhibited during mGluR-mediated LTD. This form of plasticity is deregulated in Fragile X Syndrome, a monogenic form of autism in humans, and understanding the stalling and reactivation mechanism could reveal new approaches to therapies. Here, we demonstrate that UPF1, known to stall peptide release during nonsense-mediated RNA decay, is critical for assembly of stalled polysomes in rat hippocampal neurons derived from embryos of either sex. Moreover, UPF1 and its interaction with the RNA binding protein STAU2 are necessary for proper transport and local translation from a prototypical RNA granule substrate and for mGluR-LTD in hippocampal neurons. These data highlight a new, neuronal role for UPF1, distinct from its RNA decay functions, in regulating transport and/or translation of mRNAs that are critical for synaptic plasticity.

SIGNIFICANCE STATEMENT The elongation and/or termination steps of mRNA translation are emerging as important control points in mGluR-LTD, a form of synaptic plasticity that is compromised in a severe monogenic form of autism, Fragile X Syndrome. Deciphering the molecular mechanisms controlling this type of plasticity may thus open new therapeutic opportunities. Here, we describe a new role for the ATP-dependent helicase UPF1 and its interaction with the RNA localization protein STAU2 in mediating mGluR-LTD through the regulation of mRNA translation complexes stalled at the level of elongation and/or termination.

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The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism

The neurotransmitter dopamine (DA) regulates multiple behaviors across phylogeny, with disrupted DA signaling in humans associated with addiction, attention-deficit/ hyperactivity disorder, schizophrenia, and Parkinson's disease. The DA transporter (DAT) imposes spatial and temporal limits on DA action, and provides for presynaptic DA recycling to replenish neurotransmitter pools. Molecular mechanisms that regulate DAT expression, trafficking, and function, particularly in vivo, remain poorly understood, though recent studies have implicated rho-linked pathways in psychostimulant action. To identify genes that dictate the ability of DAT to sustain normal levels of DA clearance, we pursued a forward genetic screen in Caenorhabditis elegans based on the phenotype swimming-induced paralysis (Swip), a paralytic behavior observed in hermaphrodite worms with loss-of-function dat-1 mutations. Here, we report the identity of swip-13, which encodes a highly conserved ortholog of the human atypical MAP kinase ERK8. We present evidence that SWIP-13 acts presynaptically to insure adequate levels of surface DAT expression and DA clearance. Moreover, we provide in vitro and in vivo evidence supporting a conserved pathway involving SWIP-13/ERK8 activation of Rho GTPases that dictates DAT surface expression and function.

SIGNIFICANCE STATEMENT Signaling by the neurotransmitter dopamine (DA) is tightly regulated by the DA transporter (DAT), insuring efficient DA clearance after release. Molecular networks that regulate DAT are poorly understood, particularly in vivo. Using a forward genetic screen in the nematode Caenorhabditis elegans, we implicate the atypical mitogen activated protein kinase, SWIP-13, in DAT regulation. Moreover, we provide in vitro and in vivo evidence that SWIP-13, as well as its human counterpart ERK8, regulate DAT surface availability via the activation of Rho proteins. Our findings implicate a novel pathway that regulates DA synaptic availability and that may contribute to risk for disorders linked to perturbed DA signaling. Targeting this pathway may be of value in the development of therapeutics in such disorders.

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Use of Immunolabeling to Analyze Stable, Dynamic, and Nascent Microtubules in the Zebrafish Embryo

Immunolabeling methods to analyze distinct populations of microtubules in the developing zebrafish brain are described here, which are broadly applicable to other tissues. The first protocol outlines an optimized method for immunolabeling stable and dynamic microtubules. The second protocol provides a method to image and quantify nascent microtubules specifically.

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Genome-wide Analysis of HDAC Inhibitor-mediated Modulation of microRNAs and mRNAs in B Cells Induced to Undergo Class-switch DNA Recombination and Plasma Cell Differentiation

Epigenetic factors can interact with genetic programs to modulate gene expression and regulate B cell function. By combining in vitro B-cell stimulation, qRT-PCR, and high-throughput microRNA-sequence and mRNA-sequence approaches, we can analyze the epigenetic modulation of miRNA and gene expression in B cells.

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In Reply

Abstract

We appreciate the comments and concerns raised by members of SAEM's Academy of Diversity and Inclusion in Emergency Medicine¹ regarding the findings of our article, "A Systematic Review of the Impact of Physician Implicit Racial Bias on Clinical Decision Making."² We agree with Samuels et al.¹ that there are notable methodological limitations of earlier studies examining the influence of physician implicit bias on clinical decision making that must be considered when interpreting the findings of our systematic review.

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Dedicated Hippocampal Inhibitory Networks for Locomotion and Immobility

Network activity is strongly tied to animal movement; however, hippocampal circuits selectively engaged during locomotion or immobility remain poorly characterized. Here we examined whether distinct locomotor states are encoded differentially in genetically defined classes of hippocampal interneurons. To characterize the relationship between interneuron activity and movement, we used in vivo, two-photon calcium imaging in CA1 of male and female mice, as animals performed a virtual-reality (VR) track running task. We found that activity in most somatostatin-expressing and parvalbumin-expressing interneurons positively correlated with locomotion. Surprisingly, nearly one in five somatostatin or one in seven parvalbumin interneurons were inhibited during locomotion and activated during periods of immobility. Anatomically, the somata of somatostatin immobility-activated neurons were smaller than those of movement-activated neurons. Furthermore, immobility-activated interneurons were distributed across cell layers, with somatostatin-expressing cells predominantly in stratum oriens and parvalbumin-expressing cells mostly in stratum pyramidale. Importantly, each cell's correlation between activity and movement was stable both over time and across VR environments. Our findings suggest that hippocampal interneuronal microcircuits are preferentially active during either movement or immobility periods. These inhibitory networks may regulate information flow in "labeled lines" within the hippocampus to process information during distinct behavioral states.

SIGNIFICANCE STATEMENT The hippocampus is required for learning and memory. Movement controls network activity in the hippocampus but it's unclear how hippocampal neurons encode movement state. We investigated neural circuits active during locomotion and immobility and found interneurons were selectively active during movement or stopped periods, but not both. Each cell's response to locomotion was consistent across time and environments, suggesting there are separate dedicated circuits for processing information during locomotion and immobility. Understanding how the hippocampus switches between different network configurations may lead to therapeutic approaches to hippocampal-dependent dysfunctions, such as Alzheimer's disease or cognitive decline.

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Imaging Voltage in Genetically Defined Neuronal Subpopulations with a Cre Recombinase-Targeted Hybrid Voltage Sensor

Genetically encoded voltage indicators create an opportunity to monitor electrical activity in defined sets of neurons as they participate in the complex patterns of coordinated electrical activity that underlie nervous system function. Taking full advantage of genetically encoded voltage indicators requires a generalized strategy for targeting the probe to genetically defined populations of cells. To this end, we have generated a mouse line with an optimized hybrid voltage sensor (hVOS) probe within a locus designed for efficient Cre recombinase-dependent expression. Crossing this mouse with Cre drivers generated double transgenics expressing hVOS probe in GABAergic, parvalbumin, and calretinin interneurons, as well as hilar mossy cells, new adult-born neurons, and recently active neurons. In each case, imaging in brain slices from male or female animals revealed electrically evoked optical signals from multiple individual neurons in single trials. These imaging experiments revealed action potentials, dynamic aspects of dendritic integration, and trial-to-trial fluctuations in response latency. The rapid time response of hVOS imaging revealed action potentials with high temporal fidelity, and enabled accurate measurements of spike half-widths characteristic of each cell type. Simultaneous recording of rapid voltage changes in multiple neurons with a common genetic signature offers a powerful approach to the study of neural circuit function and the investigation of how neural networks encode, process, and store information.

SIGNIFICANCE STATEMENT Genetically encoded voltage indicators hold great promise in the study of neural circuitry, but realizing their full potential depends on targeting the sensor to distinct cell types. Here we present a new mouse line that expresses a hybrid optical voltage sensor under the control of Cre recombinase. Crossing this line with Cre drivers generated double-transgenic mice, which express this sensor in targeted cell types. In brain slices from these animals, single-trial hybrid optical voltage sensor recordings revealed voltage changes with submillisecond resolution in multiple neurons simultaneously. This imaging tool will allow for the study of the emergent properties of neural circuits and permit experimental tests of the roles of specific types of neurons in complex circuit activity.

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Feedback Signal from Motoneurons Influences a Rhythmic Pattern Generator

Motoneurons are not mere output units of neuronal circuits that control motor behavior but participate in pattern generation. Research on the circuit that controls the crawling motor behavior in leeches indicated that motoneurons participate as modulators of this rhythmic motor pattern. Crawling results from successive bouts of elongation and contraction of the whole leech body. In the isolated segmental ganglia, dopamine can induce a rhythmic antiphasic activity of the motoneurons that control contraction (DE-3 motoneurons) and elongation (CV motoneurons). The study was performed in isolated ganglia where manipulation of the activity of specific motoneurons was performed in the course of fictive crawling (crawling). In this study, the membrane potential of CV was manipulated while crawling was monitored through the rhythmic activity of DE-3. Matching behavioral observations that show that elongation dominates the rhythmic pattern, the electrophysiological activity of CV motoneurons dominates the cycle. Brief excitation of CV motoneurons during crawling episodes resets the rhythmic activity of DE-3, indicating that CV feeds back to the rhythmic pattern generator. CV hyperpolarization accelerated the rhythm to an extent that depended on the magnitude of the cycle period, suggesting that CV exerted a positive feedback on the unit(s) of the pattern generator that controls the elongation phase. A simple computational model was implemented to test the consequences of such feedback. The simulations indicate that the duty cycle of CV depended on the strength of the positive feedback between CV and the pattern generator circuit.

SIGNIFICANCE STATEMENT Rhythmic movements of animals are controlled by neuronal networks that have been conceived as hierarchical structures. At the basis of this hierarchy, we find the motoneurons, few neurons at the top control global aspects of the behavior (e.g., onset, duration); and within these two ends, specific neuronal circuits control the actual rhythmic pattern of movements. We have investigated whether motoneurons are limited to function as output units. Analysis of the network that controls crawling behavior in the leech has clearly indicated that motoneurons, in addition to controlling muscle activity, send signals to the pattern generator. Physiological and modeling studies on the role of specific motoneurons suggest that these feedback signals modulate the phase relationship of the rhythmic activity.

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Synaptic Excitation in Spinal Motoneurons Alternates with Synaptic Inhibition and Is Balanced by Outward Rectification during Rhythmic Motor Network Activity

Regular firing in spinal motoneurons of red-eared turtles (Trachemys scripta elegans, either sex) evoked by steady depolarization at rest is replaced by irregular firing during functional network activity. The transition caused by increased input conductance and synaptic fluctuations in membrane potential was suggested to originate from intense concurrent inhibition and excitation. We show that the conductance increase in motoneurons during functional network activity is mainly caused by intrinsic outward rectification near threshold for action potentials by activation of voltage and Ca²⁺ gated K channels. Intrinsic outward rectification facilitates spiking by focusing synaptic depolarization near threshold for action potentials. By direct recording of synaptic currents, we also show that motoneurons are activated by out-of-phase peaks in excitation and inhibition during network activity, whereas continuous low-level concurrent inhibition and excitation may contribute to irregular firing.

SIGNIFICANCE STATEMENT Neurons embedded in active neural networks can enter a high-conductance state. High-conductance states were observed in spinal motoneurons during rhythmic motor behavior. Assuming no change in intrinsic conductance, it was suggested that the high-conductance state in motoneurons originated from balanced inhibition and excitation. In this study, we demonstrate that intrinsic outward rectification significantly contributes to the high-conductance state. Outward rectification balances synaptic excitation and maintains membrane potential near spike threshold. In addition, direct synaptic current recordings show out-of-phase excitation and inhibition in motoneurons during rhythmic network activity.

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Location of the Mesopontine Neurons Responsible for Maintenance of Anesthetic Loss of Consciousness

The transition from wakefulness to general anesthesia is widely attributed to suppressive actions of anesthetic molecules distributed by the systemic circulation to the cerebral cortex (for amnesia and loss of consciousness) and to the spinal cord (for atonia and antinociception). An alternative hypothesis proposes that anesthetics act on one or more brainstem or diencephalic nuclei, with suppression of cortex and spinal cord mediated by dedicated axonal pathways. Previously, we documented induction of an anesthesia-like state in rats by microinjection of small amounts of GABA_A-receptor agonists into an upper brainstem region named the mesopontine tegmental anesthesia area (MPTA). Correspondingly, lesioning this area rendered animals resistant to systemically delivered anesthetics. Here, using rats of both sexes, we applied a modified microinjection method that permitted localization of the anesthetic-sensitive neurons with much improved spatial resolution. Microinjected at the MPTA hotspot identified, exposure of 1900 or fewer neurons to muscimol was sufficient to sustain whole-body general anesthesia; microinjection as little as 0.5 mm off-target did not. The GABAergic anesthetics pentobarbital and propofol were also effective. The GABA-sensitive cell cluster is centered on a tegmental (reticular) field traversed by fibers of the superior cerebellar peduncle. It has no specific nuclear designation and has not previously been implicated in brain-state transitions.

SIGNIFICANCE STATEMENT General anesthesia permits pain-free surgery. Furthermore, because anesthetic agents have the unique ability to reversibly switch the brain from wakefulness to a state of unconsciousness, knowing how and where they work is a potential route to unraveling the neural mechanisms that underlie awareness itself. Using a novel method, we have located a small, and apparently one of a kind, cluster of neurons in the mesopontine tegmentum that are capable of effecting brain-state switching when exposed to GABA_A-receptor agonists. This action appears to be mediated by a network of dedicated axonal pathways that project directly and/or indirectly to nearby arousal nuclei of the brainstem and to more distant targets in the forebrain and spinal cord.

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Role of Somatostatin-Positive Cortical Interneurons in the Generation of Sleep Slow Waves

During non-rapid eye-movement (NREM) sleep, cortical and thalamic neurons oscillate every second or so between ON periods, characterized by membrane depolarization and wake-like tonic firing, and OFF periods, characterized by membrane hyperpolarization and neuronal silence. Cortical slow waves, the hallmark of NREM sleep, reflect near-synchronous OFF periods in cortical neurons. However, the mechanisms triggering such OFF periods are unclear, as there is little evidence for somatic inhibition. We studied cortical inhibitory interneurons that express somatostatin (SOM), because ~70% of them are Martinotti cells that target diffusely layer I and can block excitatory transmission presynaptically, at glutamatergic terminals, and postsynaptically, at apical dendrites, without inhibiting the soma. In freely moving male mice, we show that SOM+ cells can fire immediately before slow waves and their optogenetic stimulation during ON periods of NREM sleep triggers long OFF periods. Next, we show that chemogenetic activation of SOM+ cells increases slow-wave activity (SWA), slope of individual slow waves, and NREM sleep duration; whereas their chemogenetic inhibition decreases SWA and slow-wave incidence without changing time spent in NREM sleep. By contrast, activation of parvalbumin+ (PV+) cells, the most numerous population of cortical inhibitory neurons, greatly decreases SWA and cortical firing, triggers short OFF periods in NREM sleep, and increases NREM sleep duration. Thus SOM+ cells, but not PV+ cells, are involved in the generation of sleep slow waves. Whether Martinotti cells are solely responsible for this effect, or are complemented by other classes of inhibitory neurons, remains to be investigated.

SIGNIFICANCE STATEMENT Cortical slow waves are a defining feature of non-rapid eye-movement (NREM) sleep and are thought to be important for many of its restorative benefits. Yet, the mechanism by which cortical neurons abruptly and synchronously cease firing, the neuronal basis of the slow wave, remains unknown. Using chemogenetic and optogenetic approaches, we provide the first evidence that links a specific class of inhibitory interneurons—somatostatin-positive cells—to the generation of slow waves during NREM sleep in freely moving mice.

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Cell free nucleic acids as diagnostic and prognostic marker in leukemia

Summary

Nucleic acids in circulation, called cell free DNA (cfDNA) and cell free RNA (cfRNA), have recently been analyzed as suitable diagnostic and prognostic markers in cancer. There have also been several reports about the role of this type of marker in leukemia. The relevant literature was identified by a PubMed search (2000–2017) of English-language literature using the terms "cell free DNA", "Leukemia" and Micro-RNA. Many quantitative and qualitative cfDNA biomarkers including copy number alteration, mutation, LOH and micro-RNA deregulated expression have been investigated in different studies, indicating promising results to distinguish patients from healthy individuals. The findings of this study indicate that nucleic acids in circulation have a high diagnostic and prognostic value in leukemic patients and, thus, have the potential to be used alongside the usual methods in the management of this disease.

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Coagulase gene polymorphism, enterotoxigenecity, biofilm production, and antibiotic resistance in Staphylococcus aureus isolated from bovine raw milk in North West India

Staphylococcus aureus is the predominant bacterium responsible for various diseases in animals and humans. Preventive strategies could be better implemented by understanding the preval...

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Editorial Board [Masthead]

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Comment on “Ebola Virus Infection among Western Healthcare Workers Unable to Recall the Transmission Route”

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Corrigendum to “Nicotine Enhances Interspecies Relationship between Streptococcus mutans and Candida albicans”

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Use of Telemedicine to Deliver Global Medical Care

By Nathan Douthit

Telemedicine is an important developing field for global health. Its use has been endorsed by the World Health Organization (WHO), Medecins Sans Frontieres and multiple other national health services and Non-Governmental Organizations (NGOs). Telemedicine has multiple definitions, but the one endorsed by the WHO is:

"The delivery of health care services, where distance is a critical factor, by all health care profes- sionals using information and communication technologies for the exchange of valid information for diagnosis, treatment and prevention of disease and injuries, research and evaluation, and for the continuing education of health care providers, all in the interests of advancing the health of individuals and their communities". ¹

One of the earliest recorded instances of telemedicine was the transmission of an electrocardiograph in 1906. However, recent applications include sharing of data for specialist assistance in diagnosis and management, education of healthcare professionals and patients, research on difficult to reach populations and even screening services for health monitoring and maintenance. Telemedicine certainly has applications in the developed world and in urban centres. However, the effective delivery of telemedicine can make an unprecedented impact in developing countries and rural areas.

In the case report, "Remote care of a patient with stroke in rural Trinidad: use of telemedicine to optimize global neurological care," Reyes and Ramcharan describe "The use of… [telemedicine] for low-income countries to provide support for high-risk patients." Their case specifically focuses on the application of teleneurology, or remote access to specialists in neurology. The patient described was seen in hospital by a neurologist, but on discharge home it was noted that the "patient's home was located in a low income village 60 km away from the GP[general practitioner's] office." In order to continue monitoring the patient for improvement, the patient's 24 hour caregiver

"[W]as initially trained by the GP to collect, process and transmit the patient's data by the use of a smart phone and a laptop with internet access. The GP and the neurologist also used similar technology."

This allowed medical care to be provided to the patient in a timely fashion. The caregiver was educated to recognize seizures, falls, neurogenic bladder, and dysphasia.

"Once the event was recognised, the caregiver called on the GP assistance over a phone call and/or via email. The GP instructed the caregiver on first aid actions for the… event in order to prevent further complication… [and, if necessary, arranged] transportation of the patient to the nearest health facility available. Concurrently, the GP called on the senior neurologist for remote assistance…. The GP coordinated initial management of the complicated patient with the caregiver, paramedics and other doctors remotely…. The GP saw the patient directly to verify all instructions were carried out correctly, but there was no need for the neurologist to examine the patient for those reasons."

The authors conclude that this treatment model, "[S]uggest[s] that improved access to primary, secondary and tertiary levels of neurological care in remote and underserved regions of the world is a feasible way forward." They also correctly remind us that, "This is a global issue that requires urgent consensus and actions by stakeholders."

In light of this, BMJ Case Reports invites authors to publish cases regarding the trials and successes of telemedicine in delivering medicine in difficult to reach areas. Global health case reports can emphasize:

-successful models of management, such as the one above

-difficulties in implementing telemedicine due to cultural, geographical or technical constraints

-innovative uses of telemedicine

-the use of telemedicine across linguistic, cultural, ethnic and geopolitical barriers

Manuscripts may be submitted by students, physicians, nurses or other medical professionals to BMJ Case Reports. For more information, review the blog on how to write a global health case report.

Corrigendum to “Ferulic Acid Induces Th1 Responses by Modulating the Function of Dendritic Cells and Ameliorates Th2-Mediated Allergic Airway Inflammation in Mice”

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Primary Hepatic Angiosarcoma: A Case Report with 10-Year Patient Medical Data

In the current study, we report a case of a 46-year-old man who presented with sudden abdominal pain and was diagnosed with rupture of hepatic angiosarcoma (HAS). He underwent surgery, but died 13 days after the onset of the abdominal pain. Chronic exposure to carcinogens, such as thorium dioxide, arsenic, vinyl chloride, and radium, is associated with HAS. However, our patient had not been exposed to such carcinogens. He had submitted himself for annual medical checkups since he was employed. His liver was cirrhotic, and medical history data showed that he had had fatty liver for at least 10 years before HAS onset. Although liver cirrhosis may play a role in the occurrence of HAS, the connection of chronic fatty liver in the tumorigenesis remains unclear. Case reports regarding HAS with fatty liver are few. To the best of our knowledge, this is the first case of HAS occurring in a cirrhotic liver that advanced from persistent fatty stage. Given that HAS is a rare tumor, data collection is important for investigating its pathophysiology. Case presentations considering health conditions before HAS onset are limited; therefore, we present a case of HAS with annual health checkup data before disease onset.
Case Rep Oncol 2017;10:851–856

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Burned-Out Testicular Cancer: Really a Different History?

Two or more histological types characterize more than 60% of testicular germ cell tumors (GCTs). Burned-out testicular tumor refers to partial or complete histological regression of the primary testicular lesions. The most frequent GCT type involved in this kind of histological regression is choriocarcinoma, followed by embryonal carcinoma. To our knowledge, there are no cases of the burned-out phenomenon in teratoma. We report a case of a 19-year-old man presenting to our institute with a right testicular lesion, evidence of mediastinal and abdominal lymph node metastasis, and high levels of GCT serum biomarkers. After orchiectomy, the histopathological examination showed a mixed GCT: mature teratoma, immature teratoma, and histological features of testicular cancer regression (burned-out phenomenon). The patient underwent first-line chemotherapy (BEP regimen) which resulted in a complete instrumental and biochemical response after 4 cycles. Teratoma is considered a less aggressive type of GCT. In this particular case, metastatic disease seems to result from non-germ cell components which underwent early spontaneous regression.
Case Rep Oncol 2017;10:846–850

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Treatment of Leptomeningeal Metastases in a Patient with Non-Small Cell Lung Cancer Harboring EGFR T790M Mutation

Background: Leptomeningeal metastasis (LM) is an uncommon complication in patients with solid tumors, associated with poor survival. However, LM appears to be more frequent in lung cancer patients with EGFR mutations, posing a unique clinical challenge to treating physicians. Case Presentation: We report the case of a 68-year-old Asian man with metastatic lung adenocarcinoma harboring an EGFR L858R mutation, which was initially treated with gefitinib. He developed disease progression 1 year later. Re-biopsy of the right lower lobe primary lesion revealed only an EGFR L858R mutation in the absence of a T790M mutation. The patient also experienced persistent confusion and generalized fatigue, and magnetic resonance imaging (MRI) of the brain demonstrated extensive LM. At this time, a liquid biopsy revealed an EGFR T790M mutation. Following initiation of treatment with osimertinib, the patient exhibited a rapid response with MRI of the brain showing substantial improvement of the LM after 6 months. Unfortunately, the LM recurred after 1 year at which time the patient declined further systemic chemotherapy. Conclusion: To our knowledge, this is the second reported case of LM in a patient with lung cancer harboring an EGFR T790M mutation that was successfully treated with osimertinib.
Case Rep Oncol 2017;10:840–845

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Double-blind randomized clinical trial of percutaneous endoscopic gastrostomy versus radiologically inserted gastrostomy in children

Background

The aim of this RCT was to determine whether radiologically inserted gastrostomy (RIG) in children is associated with more complications than percutaneous endoscopic gastrostomy (PEG).

Methods

Children at a single tertiary children's hospital requiring a primary gastrostomy were randomized to PEG or RIG. Patients were followed by assessors blinded to the insertion method. Complications were recorded, assigned a severity score, and analysed by zero-inflated Poisson regression analysis on an intention-to-treat basis, adjusting for length of follow-up.

Results

Over a 3-year period, 214 children were randomized (PEG, 107; RIG, 107), of whom 100 received PEG and 96 RIG. There was no significant difference in the number of complications between PEG and RIG groups (P = 0·875), or in the complication score: patients undergoing RIG had a 1·04 (95 per cent c.i. 0·89 to 1·21) times higher complication score than those who underwent PEG (P = 0·597). Only age had an independent significant effect on complication score, with older patients having a 0·97 (0·95 to 1·00) times lower complication score per year.

Conclusion

PEG and RIG are both safe methods of gastrostomy insertion with a low rate of major complications. Registration number: NCT01920438 ( http://ift.tt/PmpYKN).

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Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): Implications for the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC)

BACKGROUND

The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) mostly in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories. In this multi-institutional, retrospective study, the authors investigated variations in the impact of an NIFTP diagnosis on the associated ROM for each TBSRTC category with an emphasis on the influence of pathologist and institutional diagnostic thresholds on the ROM.

METHODS

Baseline data on cytology and histology diagnostic categories were collected over a 3-year period at 3 academic center hospitals (institutions A, B, and C). Histology slides for all cases diagnosed as follicular variant of papillary thyroid carcinoma (FVPTC) were re-reviewed at each institution, and those that qualifying as NIFTP were separated from other PTCs.

RESULTS

The collective case cohort from the 3 institutions included 15,973 thyroid fine-needle aspiration cytology (FNAC) specimens and 5090 thyroid surgical resection specimens. Significant differences in baseline cytology and histology data were noted among the 3 institutions. The number of cases classified as NIFTP compared with FVPTC was highly variable (institution A, 14%; institution B, 39%; and institution C, 12%). For 3250 resected thyroid nodules with a previous FNAC diagnosis, the average decrease in ROM after the exclusion of NIFTP for all TBSRTC categories was as follows: institution A, 9.8%; institution B, 3.9%; and institution C, 1.3%.

CONCLUSIONS

The institutional frequency of NIFTP histopathology diagnosis and cytology baseline data will impact the ROM associated with specific FNAC diagnoses, especially among the indeterminate TBSRTC categories. The range of ROM for each TBSRTC diagnostic category is reflective of the inherent diagnostic thresholds and interobserver and interinstitutional variability in the diagnosis of thyroid lesions. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Preparing our next generation of pathologists: The criticality of critical reading

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[ 18 F]Fluoromisonidazole PET in rectal cancer

Abstract

Background

There is an increasing interest in developing predictive biomarkers of tissue hypoxia using functional imaging for personalised radiotherapy in patients with rectal cancer that are considered for neoadjuvant chemoradiotherapy (CRT). The study explores [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) positron emission tomography (PET) scans for predicting clinical response in rectal cancer patients receiving neoadjuvant CRT.

Methods

Patients with biopsy-proven rectal adenocarcinoma were imaged at 0–45 min, 2 and 4 h, at baseline and after 8–10 fractions of CRT (week 2). The first 6 patients did not receive an enema (the non-enema group) and the last 4 patients received an enema before PET-CT scan (the enema group). [¹⁸F]FMISO production failed on 2 occasions. Static PET images at 4 h were analysed using tumour-to-muscle (T:M) SUVmax and tumour-to-blood (T:B) SUVmax. The 0–45 min dynamic PET scans were analysed using Casciari model to report hypoxia and perfusion. Akaike information criteria (AIC) were used to compare data fittings for different pharmacokinetic models. Pathological tumour regression grade was scored using American Joint Committee on Cancer (AJCC) 7.0. Shapiro-Wilk test was used to evaluate the normality of the data.

Results

Five out of eleven (5/11) patients were classed as good responders (AJCC 0/1 or good clinical response) and 6/11 as poor responders (AJCC 2/3 or poor clinical response). The median T:M SUVmax was 2.14 (IQR 0.58) at baseline and 1.30 (IQR 0.19) at week 2, and the corresponding median tumour hypoxia volume was 1.08 (IQR 1.31) cm³ and 0 (IQR 0.15) cm³, respectively. The median T:B SUVmax was 2.46 (IQR 1.50) at baseline and 1.61 (IQR 0.14) at week 2, and the corresponding median tumour hypoxia volume was 5.68 (IQR 5.86) cm³ and 0.76 (IQR 0.78) cm³, respectively. For 0–45 min tumour modelling, the median hypoxia was 0.92 (IQR 0.41) min⁻¹ at baseline and 0.70 (IQR 0.10) min⁻¹ at week 2. The median perfusion was 4.10 (IQR 1.71) ml g⁻¹ min⁻¹ at baseline and 2.48 (IQR 3.62) ml g⁻¹ min⁻¹ at week 2. In 9/11 patients with both PET scans, tumour perfusion decreased in non-responders and increased in responders except in one patient. None of the changes in other PET parameters showed any clear trend with clinical outcome.

Conclusions

This pilot study with small number of datasets revealed significant challenges in delivery and interpretation of [¹⁸F]FMISO PET scans of rectal cancer. There are two principal problems namely spill-in from non-tumour tracer activity from rectal and bladder contents. Emphasis should be made on reducing spill-in effects from the bladder to improve data quality. This preliminary study has shown fundamental difficulties in the interpretation of [¹⁸F]FMISO PET scans for rectal cancer, limiting its clinical applicability.

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Evaluating a preoperative protocol that includes magnetic resonance imaging for lymph node metastasis in the Cholangiocarcinoma Screening and Care Program (CASCAP) in Thailand

Abstract

Background

Treatment planning especially liver resection in cholangiocarcinoma (CCA) depends on the extension of tumor and lymph node metastasis which is included as a key criterion for operability. Magnetic resonance imaging (MRI) offers a rapid and powerful tool for the detection of lymph node metastasis (LNM) and in the current manuscript is assessed as a critical tool in the preoperative protocol for liver resection for treatment of CCA. However, the accuracy of MRI to detect LNM from CCA had yet to be comprehensively evaluated.

Methods

The accuracy of MRI to detect LNM was assessed in a cohort of individuals with CCA from the Cholangiocarcinoma Screening and Care Program (CASCAP), a screening program designed to reduce CCA in Northeastern Thailand by community-based ultrasound (US) for CCA. CCA-positive individuals are referred to one of the nine tertiary centers in the study to undergo a preoperative protocol that included enhanced imaging by MRI. Additionally, these individuals also underwent lymph node biopsies for histological confirmation of LNM (the "gold standard") to determine the accuracy of the MRI results.

Results

MRI accurately detected the presence or absence of LNM in only 29 out of the 51 CCA cases (56.9%, 95% CI 42.2–70.7), resulting in a sensitivity of 57.1% (95% CI 34.0–78.2) and specificity of 56.7% (95% CI 37.4–74.5), with positive and negative predictive values of 48.0% (95% CI 27.8–68.7) and 65.4% (95% CI 44.3–82.8), respectively. The positive likelihood ratio was 1.32 (95% CI 0.76–2.29), and the negative likelihood ratio was 0.76 (95% CI 0.42–1.36).

Conclusions

MRI showed limited sensitivity and a poor positive predictive value for the diagnosis of LNM for CCA, which is of particular concern in this resource-limited setting, where simpler detection methods could be utilized that are more cost-effective in this region of Thailand. Therefore, the inclusion of MRI, a costly imaging method, should be reconsidered as part of protocol for treatment planning of CCA, given the number of false positives, especially as it is critical in determining the operability for CCA subjects.

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Erratum to: Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

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Randomized trial of Tibetan yoga in patients with breast cancer undergoing chemotherapy

BACKGROUND

The current randomized trial examined the effects of a Tibetan yoga program (TYP) versus a stretching program (STP) and usual care (UC) on sleep and fatigue in women with breast cancer who were undergoing chemotherapy.

METHODS

Women with stage (American Joint Committee on Cancer (AJCC) TNM) I to III breast cancer who were undergoing chemotherapy were randomized to TYP (74 women), STP (68 women), or UC (85 women). Participants in the TYP and STP groups participated in 4 sessions during chemotherapy, followed by 3 booster sessions over the subsequent 6 months, and were encouraged to practice at home. Self-report measures of sleep disturbances (Pittsburgh Sleep Quality Index), fatigue (Brief Fatigue Inventory), and actigraphy were collected at baseline; 1 week after treatment; and at 3, 6, and 12 months.

RESULTS

There were no group differences noted in total sleep disturbances or fatigue levels over time. However, patients in the TYP group reported fewer daily disturbances 1 week after treatment compared with those in the STP (difference, -0.43; 95% confidence interval [95% CI], -0.82 to -0.04 [P = .03]) and UC (difference, -0.41; 95% CI, -0.77 to -0.05 [P = .02]) groups. Group differences at the other time points were maintained for TYP versus STP. Actigraphy data revealed greater minutes awake after sleep onset for patients in the STP group 1 week after treatment versus those in the TYP (difference, 15.36; 95% CI, 7.25-23.48 [P = .0003]) and UC (difference, 14.48; 95% CI, 7.09-21.87 [P = .0002]) groups. Patients in the TYP group who practiced at least 2 times a week during follow-up reported better Pittsburgh Sleep Quality Index and actigraphy outcomes at 3 months and 6 months after treatment compared with those who did not and better outcomes compared with those in the UC group.

CONCLUSIONS

Participating in TYP during chemotherapy resulted in modest short-term benefits in sleep quality, with long-term benefits emerging over time for those who practiced TYP at least 2 times a week. Cancer 2017. © 2017 American Cancer Society.

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Probability of cancer in high-risk patients predicted by the protein-based lung cancer biomarker panel in China: LCBP study

BACKGROUND

The authors built a model for lung cancer diagnosis previously based on the blood biomarkers progastrin-releasing peptide (ProGRP), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and cytokeratin 19 fragment (CYFRA21-1). In the current study, they examined whether modification of the model to include relevant clinical information, risk factors, and low-dose chest computed tomography screening would improve the performance of the biomarker panel in large cohorts of Chinese adults.

METHODS

The current study was a large-scale multicenter study (ClinicalTrials.gov identifier NCT01928836) performed in a Chinese population. A total of 715 participants were enrolled from 5 regional centers in Beijing, Henan, Nanjing, Shanghai, and Chongqing between October 2012 and February 2014. Serum biomarkers ProGRP, CEA, SCC, and CYFRA21-1 were analyzed on the ARCHITECT i2000SR. Relevant clinical information was collected and used to develop a patient risk model and a nodule risk model.

RESULTS

The resulting patient risk model had an area under the receiver operating characteristic (ROC) curve of 0.7037 in the training data set and 0.7190 in the validation data set. The resulting nodule risk model had an area under the ROC curve of 0.9151 in the training data set and 0.5836 in the validation data set. Moreover, the nodule risk model had a relatively higher area under the ROC curve (0.9151 vs 0.8360; P = 0.001) compared with the American College of Chest Physician model in patients with lung nodules.

CONCLUSIONS

Both the patient risk model and the nodule risk model, developed for the early diagnosis of lung cancer, demonstrated excellent discrimination, allowing for the stratification of patients with different levels of lung cancer risk. These new models are applicable in high-risk Chinese populations. Cancer 2017. © 2017 American Cancer Society.

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EUS and related technologies for the diagnosis and treatment of pancreatic disease: research gaps and opportunities—Summary of a National Institute of Diabetes and Digestive and Kidney Diseases workshop

A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to address the research gaps and opportunities in pancreatic EUS. The event occurred on July 26, 2017 in 4 sessions: (1) benign pancreatic diseases, (2) high-risk pancreatic diseases, (3) diagnostic and therapeutics, and (4) new technologies. The current state of knowledge was reviewed, with identification of numerous gaps in knowledge and research needs. Common themes included the need for large multicenter consortia of various pancreatic diseases to facilitate meaningful research of these entities; to standardize EUS features of different pancreatic disorders, the technique of sampling pancreatic lesions, and the performance of various therapeutic EUS procedures; and to identify high-risk disease early at the cellular level before macroscopic disease develops.

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Editorial Board

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How to Be an Advocate for Your Profession and Your Practice

Our profession continues to be in the midst of significant transformation, which began with the passage of the Affordable Care Act (ACA) in 2010, and the Medicare Access and Childrens Health Insurance Program Reauthorization Act (MACRA) in 2015, and continues with the current attempts to repeal and replace the ACA. Passed with strong bipartisan support, MACRA introduced a new system of rules and regulations for Center for Medicare and Medicaid Services (CMS) reimbursement, and with it an expanding lexicon of acronyms (ie, MACRA, electronic health records [EHR], value-based modifier [VBP], meaningful use [MU], Quality Payment Program [QPP], Sustainable Growth Rate [SGR] formula, Advancing Care Information [ACI], certified EHR technology [CEHRT]).

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Cover

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Elsewhere in The AGA Journals

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Information for Authors and Readers

Clinical Gastroenterology and Hepatology is the go-to resource on a broad spectrum of themes in clinical gastroenterology and hepatology. The official clinical practice journal of the AGA Institute brings you the best original research in the field with a unique combination of reviews, editorials, podcasts, video abstracts, and outcomes research—all supporting clinical practice. Articles on education, policy, and practice management highlight issues pertinent to clinicians.

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Cancers, Vol. 9, Pages 127: Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

Cancers, Vol. 9, Pages 127: Liver Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

Cancers doi: 10.3390/cancers9090127

Authors: Germana Castelli Elvira Pelosi Ugo Testa

Liver cancer is the second most common cause of cancer-related death. The major forms of primary liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Both these tumors develop against a background of cirrhotic liver, non-alcoholic fatty liver disease, chronic liver damage and fibrosis. HCC is a heterogeneous disease which usually develops within liver cirrhosis related to various etiologies: hepatitis B virus (HBV) infection (frequent in Asia and Africa), hepatitis C virus (HCV), chronic alcohol abuse, or metabolic syndrome (frequent in Western countries). In cirrhosis, hepatocarcinogenesis is a multi-step process where pre-cancerous dysplastic macronodules transform progressively into HCC. The patterns of genomic alterations observed in these tumors were recently identified and were instrumental for the identification of potential targeted therapies that could improve patient care. Liver cancer stem cells are a small subset of undifferentiated liver tumor cells, responsible for cancer initiation, metastasis, relapse and chemoresistance, enriched and isolated according to immunophenotypic and functional properties: cell surface proteins (CD133, CD90, CD44, EpCAM, OV-6, CD13, CD24, DLK1, α2δ1, ICAM-1 and CD47); the functional markers corresponding to side population, high aldehyde dehydrogenase (ALDH) activity and autofluorescence. The identification and definition of liver cancer stem cells requires both immunophenotypic and functional properties.

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Roles of Nitric Oxide and Prostaglandins in the Sustained Antihypertensive Effects of Acanthospermum hispidum DC. on Ovariectomized Rats with Renovascular Hypertension

Although Acanthospermum hispidum is used in Brazilian folk medicine as an antihypertensive, no study evaluated its effects on a renovascular hypertension and ovariectomy model. So, this study investigated the mechanisms involved in the antihypertensive effects of an ethanol-soluble fraction obtained from A. hispidum (ESAH) using two-kidney-one-clip hypertension in ovariectomized rats (2K1C plus OVT). ESAH was orally administered at doses of 30, 100, and 300 mg/kg, daily, for 28 days, after 5 weeks of surgery. Enalapril (15 mg/kg) and hydrochlorothiazide (25 mg/kg) were used as standard drugs. Diuretic activity was evaluated on days 1, 7, 14, 21, and 28. Systolic, diastolic, and mean blood pressure and heart rate were recorded. Serum creatinine, urea, thiobarbituric acid reactive substances, nitrosamine, nitrite, aldosterone, vasopressin levels, and ACE activity were measured. The vascular reactivity and the role of nitric oxide (NO) and prostaglandins (PG) in the vasodilator response of ESAH on the mesenteric vascular bed (MVB) were also investigated. ESAH treatment induced an important saluretic and antihypertensive response, therefore recovering vascular reactivity in 2K1C plus OVT-rats. This effect was associated with a reduction of oxidative and nitrosative stress with a possible increase in the NO bioavailability. Additionally, a NO and PG-dependent vasodilator effect was observed on the MEV.

http://ift.tt/2xmmbrX

Electroacupuncture Improves Gastric Emptying in Critically Ill Neurosurgical Patients: A Pilot Study

Objective. To compare the efficacy of combined electroacupuncture and metoclopramide treatment with that of metoclopramide only in improving gastric emptying in critically ill neurosurgical patients. Methods. In this prospective case-control pilot study, a total of 16 adult critically ill mechanically ventilated patients who were treated in the surgical intensive care unit were enrolled. Electrical stimulation was applied to 4 pairs of points (maximum intensity

http://ift.tt/2wFSCyg

Comparison of the Feasibility and Safety of First- versus Second-Generation AMPLATZER™ Occluders for Left Atrial Appendage Closure

Introduction. Left atrial appendage closure (LAAC) is considered an alternative to oral anticoagulation therapy in patients with atrial fibrillation (AF). The aim of this study was to compare the safety and efficacy of the first- and second-generation AMPLATZER Devices for LAAC, AMPLATZER Cardiac Plug (ACP) versus AMPLATZER Amulet™. Methods. Procedural data, such as fluoroscopy time, radiation dose, and contrast-dye, as well as VARC criteria and major adverse events (MAEs) were assessed for both devices. The rate of peridevice leaks was analyzed at echocardiographic follow-up. Results. A total of 196 patients with AF underwent LAAC with the ACP () or Amulet device (). The use of Amulet was associated with significantly lower fluoroscopy time (14.8 ± 7.4 min versus 10.6 ± 4.1 min; ), lower radiation dose (4833 ± 3360 cGycm2 versus 3206 ± 2169 cGycm2; ), and reduced amount of contrast-dye (150.2 ± 83.9 ml versus 128.8 ± 46.0 ml; ). Furthermore, LAAC with Amulet devices resulted in lower device-resizing rates (3 versus 16 cases; ). Peridevice leaks were less frequent in the Amulet group (12 versus 4; ). MAE occurred in 6 ACP and 4 Amulet patients (). Conclusions. The Amulet device is associated with shorter fluoroscopy times and radiation dosages, reduced use of contrast-dye, lower recapture rates, and less peridevice leaks as compared to the ACP.

http://ift.tt/2wGkAK4

Molecular genotyping of noninvasive encapsulated follicular variant of papillary thyroid carcinoma

Summary

Aim

Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) has been managed as low-risk malignancy. Recently, a proposal was made to reclassify this tumor type as a premalignant lesion and rename it noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). However, a comprehensive study on molecular genotype-phenotype correlations of encapsulated FVPTC is lacking.

Methods and results

This study consisted of 177 consecutive FVPTCs from January 2014 to April 2016. These were classified into noninvasive (n=74), invasive (n=51) encapsulated FVPTC, and infiltrative FVPTC (n=52) according to standard criteria by two independent pathologists. Genetic alterations and other clinicopathologic information were compared. A BRAF^V^600E mutation was found in 12.2% (noninvasive) and 11.8% (invasive) of encapsulated FVPTCs and 34.6% of infiltrative FVPTCs (P=0.001). Mutation in encapsulated FVPTCs was limited to cases with rare or abortive papillae. RET/PTC1 and RET/PTC3 rearrangements were present (11.5%) only in infiltrative FVPTC. In contrast, N-, H-, and KRAS mutations were observed predominantly in encapsulated FVPTCs (48.6% in noninvasive and 66.7% in invasive) compared to infiltrative FVPTCs (15.4%) (P<0.001). Preoperative cytologic examination was indistinguishable between noninvasive and invasive encapsulated FVPTCs, while infiltrative FVPTC was more likely to be Bethesda class V/VI than the encapsulated type (60.4% vs. 38.1%; P=0.01).

Conclusion

There were no differences in clinicopathologic or molecular profiles between noninvasive and invasive encapsulated FVPTCs except in vascular and capsular invasion. Therefore, the diagnosis of NIFTP, like follicular adenoma, may require surgical resection and exclusion of those tumors with any papillae.

http://ift.tt/2xwrOob

MMP-Inhibitory Effects of Flavonoid Glycosides from Edible Medicinal Halophyte Limonium tetragonum

Limonium tetragonum has been well-known for its antioxidative properties as a halophyte. This study investigated the antimetastasis effect of solvent-partitioned L. tetragonum extracts (LTEs) and isolated compounds on HT1080 mouse melanoma cell model with a focus on matrix metalloproteinase (MMP) activity and TIMP and MAPK pathways. Upregulation and stimulation of MMPs result in elevated degradation of extracellular matrix which is part of several complications such as metastasis, cirrhosis, and arthritis. The anti-MMP capacity of LTEs was confirmed by their MMP-inhibitory effects, regulation of MMP and TIMP expression, and suppression of MAPK pathway. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be most active fractions which later yielded two known flavonoid glycosides, myricetin 3-galactoside and quercetin 3-o-beta-galactopyranoside. Anti-MMP potential of the compounds was confirmed by their ability to regulate MMP expression through inhibited MAPK pathway activation. These results suggested that L. tetragonum might serve as a potential source of bioactive substances with effective anti-MMP properties.

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Outcome after restorative proctocolectomy and ileal pouch–anal anastomosis in children and adults

Background

Studies comparing the outcome of ileal pouch–anal anastomosis (IPAA) in children and adults are scarce. This complicates decision-making in young patients. The aim of this study was to compare adverse events and pouch function between children and adults who underwent IPAA.

Methods

This cross-sectional cohort study included all consecutive children (aged less than 18 years) and adults with a diagnosis of inflammatory bowel disease or familial adenomatous polyposis who underwent IPAA in a tertiary referral centre between 2000 and 2015. Adverse events were assessed by chart review, and pouch function by interview using a pouch function score (PFS).

Results

In total, 445 patients underwent IPAA: 41 children (median age 15 years) and 404 adults (median age 39 years), with a median follow-up of 22 (i.q.r. 8–68) months. Being overweight (P = 0·001), previous abdominal surgery (P = 0·018), open procedures (P < 0·001) and defunctioning ileostomy (P = 0·014) were less common among children than adult patients. The occurrence of anastomotic leakage, surgical fistulas, chronic pouchitis and Crohn's of the pouch was not associated with paediatric age at surgery, nor was pouch failure. The development of anastomotic strictures was associated with having IPAA surgery during childhood (odds ratio 4·22, 95 per cent c.i. 1·13 to 15·77; P = 0·032). Pouch function at last follow-up was similar in the children and adult groups (median PFS 5·0 versus 6·0 respectively; P = 0·194).

Conclusion

Long-term pouch failure rates and pouch function were similar in children and adults. There is no need for a more cautious attitude to use of IPAA in children based on concerns about poor outcome.

http://ift.tt/2xn394Z

Paramedical staffs knowledge and attitudes towards antimicrobial resistance in Dire Dawa, Ethiopia: a cross sectional study

The continuing emergence, development and spread of pathogenic organisms that are resistant to antimicrobials are a cause of increasing concern. The control of antimicrobial resistance requires knowledge of fa...

http://ift.tt/2wvSmq7

Extended spectrum beta-lactamase and metallo beta-lactamase production among Escherichia coli and Klebsiella pneumoniae isolated from different clinical samples in a tertiary care hospital in Kathmandu, Nepal

Extended spectrum beta-lactamase (ESBL) and metallo beta-lactamase (MBL) production in Klebsiella pneumoniae and Escherichia coli are the commonest modes of drug resistance among these commonly isolated bacteria ...

http://ift.tt/2yoW6Y2

Vancomycin heteroresistance in coagulase negative Staphylococcus blood stream infections from patients of intensive care units in Mansoura University Hospitals, Egypt

Vancomycin heteroresistance in coagulase negative Staphylococci (CoNS) is a recent health concern especially in serious infections like bloodstream infections as it may lead to failure of therapy. Little informat...

http://ift.tt/2wvOO7v

Effectiveness of Therapeutic Exercise in Fibromyalgia Syndrome: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Objective. The aim of this study was to summarize evidence on the effectiveness of therapeutic exercise in Fibromyalgia Syndrome. Design. Studies retrieved from the Cochrane Plus, PEDro, and Pubmed databases were systematically reviewed. Randomized controlled trials and meta-analyses involving adults with fibromyalgia were included. The primary outcomes considered in this systematic review were pain, global well-being, symptoms of depression, and health-related quality of life. Results. Effects were summarized using standardized mean differences with 95% confidence intervals using a random effects model. This study provides strong evidence that physical exercise reduces pain (−1.11 [95% CI] −1.52; −0.71; overall effect ), global well-being (−0.67 [95% CI] −0.89, −0.45; ), and symptoms of depression (−0.40 [95% CI] −0.55, −0.24; ) and that it improves both components of health-related quality of life (physical: 0.77 [95% CI] 0.47; 1.08; ; mental: 0.49 [95% CI] 0.27; 0.71; ). Conclusions. This study concludes that aerobic and muscle strengthening exercises are the most effective way of reducing pain and improving global well-being in people with fibromyalgia and that stretching and aerobic exercises increase health-related quality of life. In addition, combined exercise produces the biggest beneficial effect on symptoms of depression.

http://ift.tt/2fzfeKO

Novel and classical human astroviruses in stool and cerebrospinal fluid: comprehensive screening in a tertiary care hospital, Switzerland

Novel and classical human astroviruses in stool and cerebrospinal fluid: comprehensive screening in a tertiary care hospital, Switzerland

Emerging Microbes & Infections 6, e84 (September 2017). doi:10.1038/emi.2017.71

Authors: Samuel Cordey, Diem-Lan Vu, Marie-Celine Zanella, Lara Turin, Aline Mamin & Laurent Kaiser

http://ift.tt/2wFA8xS

Cultivation of Anaplasma ovis in the HL-60 human promyelocytic leukemia cell line

Cultivation of Anaplasma ovis in the HL-60 human promyelocytic leukemia cell line

Emerging Microbes & Infections 6, e83 (September 2017). doi:10.1038/emi.2017.70

Authors: Ran Wei, Hong-Bo Liu, Frans Jongejan, Bao-Gui Jiang, Qiao-Cheng Chang, Xue Fu, Jia-Fu Jiang, Na Jia & Wu-Chun Cao

http://ift.tt/2wFEjd4

Tick-borne encephalitis in Japan, Republic of Korea and China

Tick-borne encephalitis in Japan, Republic of Korea and China

Emerging Microbes & Infections 6, e82 (September 2017). doi:10.1038/emi.2017.69

Authors: Kentaro Yoshii, Joon Young Song, Seong-Beom Park, Junfeng Yang & Heinz-Josef Schmitt

http://ift.tt/2wGh4zp

Zika virus infection confers protection against West Nile virus challenge in mice

Zika virus infection confers protection against West Nile virus challenge in mice

Emerging Microbes & Infections 6, e81 (September 2017). doi:10.1038/emi.2017.68

Authors: Ángela Vázquez-Calvo, Ana-Belén Blázquez, Estela Escribano-Romero, Teresa Merino-Ramos, Juan-Carlos Saiz, Miguel A Martín-Acebes & Nereida Jiménez de Oya

http://ift.tt/2wFYWWu

The Proangiogenic Capabilities of Malignant Ascites Generated by Aggressive Ovarian Tumors

Here we examined whether malignant ascites may determine ovarian tumor angiogenesis, and if so whether ascites generated by highly aggressive serous and undifferentiated cancers are more proangiogenic than those from less aggressive clear cell and endometrioid tumors. Angiogenesis was analyzed according to expression of CD31, CD34, and connexin 43. Proliferation and migration of endothelial cells were tested using fluorescence-based methods. The quantification of angiogenic agents and hypoxia-inducible factor 1α (HIF-1α) was performed using specific immunoassays. Results showed that the expression of CD31 and CD34 in serous and undifferentiated tumors was greater, whereas endothelial expression of connexin 43 was lower than in clear cell and endometrioid lesions. Serous cancers that formed in the presence of ascites displayed increased expression of connexin 43 in vascular smooth muscles as compared with tumors developed in the fluid's absence. Endothelial cells exposed to ascites from serous and undifferentiated tumors proliferated and migrated more vigorously than cells subjected to ascites from clear cell and endometrioid cancers. They also exhibited an increased level of HIF-1α and produced increased amounts of multiple proangiogenic agents. Our results indicate that high vascularization of aggressive ovarian tumors may be associated with profound angiogenic capabilities of ascites generated by these tumors.

http://ift.tt/2xR8W4h

Improving Prediction Accuracy of “Central Line-Associated Blood Stream Infections” Using Data Mining Models

Prediction of nosocomial infections among patients is an important part of clinical surveillance programs to enable the related personnel to take preventive actions in advance. Designing a clinical surveillance program with capability of predicting nosocomial infections is a challenging task due to several reasons, including high dimensionality of medical data, heterogenous data representation, and special knowledge required to extract patterns for prediction. In this paper, we present details of six data mining methods implemented using cross industry standard process for data mining to predict central line-associated blood stream infections. For our study, we selected datasets of healthcare-associated infections from US National Healthcare Safety Network and consumer survey data from Hospital Consumer Assessment of Healthcare Providers and Systems. Our experiments show that central line-associated blood stream infections (CLABSIs) can be successfully predicted using AdaBoost method with an accuracy up to 89.7%. This will help in implementing effective clinical surveillance programs for infection control, as well as improving the accuracy detection of CLABSIs. Also, this reduces patients' hospital stay cost and maintains patients' safety.

http://ift.tt/2fAwwr2

Transient Ischemic Attack and Ischemic Stroke in Danon Disease with Formation of Left Ventricular Apical Thrombus despite Normal Systolic Function

Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder presenting with hypertrophic cardiomyopathy, Wolf-Parkinson-White syndrome, skeletal myopathy, and mild intellectual disability. Early morbidity and mortality due to heart failure or sudden death are known in Danon disease, more in males than in females. Here, we present a 17-year-old female adolescent with Danon disease and severe concentric hypertrophy with normal left ventricular (LV) systolic function, who has been complaining of intermittent headache and weakness for about 3 years, initially diagnosed with hemiplegic migraine. Subsequently, her neurological manifestation progressed to transient ischemic attack (TIA) and eventually to ischemic stroke confirmed by CT scan with 1-day history of expressive aphasia followed by persistent left side weakness and numbness. Detailed echocardiogram for the first time revealed a small LV apical thrombus with unchanged severe biventricular hypertrophy and normal systolic function. This unexpected LV apical thrombus may be associated with a wide spectrum of neurological deficits ranging from TIA to ischemic stroke in Danon disease. Possibility of cerebral ischemic events should be suspected in Danon disease when presenting with neurological deficits even with normal systolic function. Careful assessment for LV apical thrombus is warranted in such cases.

http://ift.tt/2wGntdY

Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency

Abstract

Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. For patients with complete DPD deficiency, fluoropyrimidine-treatment has generally been discouraged. During routine pretreatment screening, we identified a 59-year old patient with a sigmoid adenocarcinoma who proved to have a complete DPD deficiency. Genetic analyses showed that this complete absence of DPD activity was likely to be caused by a novel DPYD genotype, consisting of a combination of amplification of exon 17 and 18 of DPYD and heterozygosity for DPYD*2A. Despite absence of DPD activity, the patient was treated with capecitabine-based chemotherapy, but capecitabine dose was drastically reduced to 150 mg once every five days (0.8% of original dose). Pharmacokinetic analyses showed that the area under the concentration-time curve (AUC) and half-life of 5-fluorouracil were respectively ten-fold and four-fold higher compared to control values of patients receiving capecitabine 850 mg/m². When extrapolating from the dosing schedule of once every five days to twice daily, the AUC of 5-fluorouracil was comparable to controls. Treatment was tolerated well for eight cycles by the patient without occurrence of capecitabine-related toxicity. This case report demonstrates that a more comprehensive genotyping and phenotyping approach, combined with pharmacokinetically-guided dose administration, enables save fluoropyrimidine-treatment with adequate drug exposure in completely DPD deficient patients. This article is protected by copyright. All rights reserved.

http://ift.tt/2fyUcfw

Histological subtypes of ovarian cancer associated with parity and breastfeeding in the prospective Million Women Study

Abstract

Ovarian cancer risk is known to be reduced amongst women who have had children, but reported associations with breastfeeding are varied. Few studies have had sufficient power to explore reliably these associations by tumour histotype.

In a prospective study of 1.1 million UK women, 8719 developed ovarian cancer during follow-up. Cox regression yielded adjusted relative risks (RRs) overall and by tumour histotype amongst women with different childbearing patterns.

Nulliparous women had a 24% greater ovarian cancer risk than women with one child, with significant heterogeneity by histotype (p=0.01). There was no significant increase in serous tumours, a modest increase in mucinous tumours, but a substantial increase in endometrioid (RR=1.49, 95% CI: 1.18-1.89) and clear-cell tumours (RR=1.68, 1.29-2.20).

Among parous women, each additional birth was associated with an overall 6% reduction in ovarian cancer risk; this association also varied by histotype (p=0.0006), with the largest reduction in risk for clear-cell tumours (RR per birth=0.75, 0.65-0.85, p<0.001) and weak, if any, effect for endometrioid, high-grade serous, or mucinous tumours. We found little association with age at first or last birth. There was about a 10% risk reduction per 12-months breastfeeding (RR=0.89, 0.84-0.94, p<0.001), with no significant heterogeneity by histotype, but statistical power was limited.

In this large prospective study, ovarian cancer risk associated with parity varied substantially by tumour histotype. Nulliparity was associated with a substantially greater overall risk than expected from the effect of a single birth, especially for clear cell and endometrioid tumours, perhaps suggesting that infertility is associated with these histotypes. This article is protected by copyright. All rights reserved.

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CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis

Abstract

Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of Corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism.

CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis; suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7^high SW620-CRHR2+ and miR-7^low HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing.

CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli. This article is protected by copyright. All rights reserved.

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Post-marketing research and its outcome for novel anticancer agents approved by both the FDA and EMA between 2005 and 2010: A cross-sectional study

Abstract

Post-marketing research in oncology has rarely been described. We aimed to characterize post-marketing trials for a consistent set of anticancer agents over a long period. We performed a cross-sectional analysis of post-marketing trials registered at ClinicalTrials.gov through September 2014 for novel anticancer agents approved by both the US Food and Drug Administration and the European Medicines Agency between 2005 and 2010. All relevant post-marketing trials were classified according to indication, primary outcome, starting date, sponsors, and planned enrollment. Supplemental indications were retrieved from regulatory documents and publication rate was assessed by two different methods. Ten novel anticancer agents were eligible: five were indicated for hematologic malignancies and the remaining five for solid cancers (three for kidney cancer). We identified 2345 post-marketing trials; 1362 (58.1%) targeted an indication other than the originally approved one. We observed extreme variations among drugs in both number of post-marketing trials [range 8–530] and overall population to be enrolled per trial [1–8381]. Post-marketing trials assessed almost all types of cancers, the three most frequently studied cancers being leukemia, kidney cancer and myeloma. In all, 6.6% of post-marketing trials had a clinical endpoint as a primary outcome, and 35.9% and 54.1% had a safety or surrogate endpoint, respectively, as a primary outcome. Nine drugs obtained approval for supplemental indications. The publication rate at 10 years was 12.3% to 26.1% depending on the analysis method. In conclusion, we found that post-marketing research in oncology is highly heterogeneous and the publication rate of launched trials is low. This article is protected by copyright. All rights reserved.

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Potent antitumor effect of tumor microenvironment-targeted oncolytic adenovirus against desmoplastic pancreatic cancer

Abstract

Pancreatic cancer is a leading cause of cancer-related death. Desmoplastic pancreatic tumors exhibit excessive extracellular matrix (ECM) and are thus highly resistant to anticancer therapeutics, since the ECM restricts drug penetration and dispersion. Here, we designed and generated two hypoxia-responsive and cancer-specific hybrid promoters, H(mT)E and H(E)mT. Transgene expression driven by each hybrid promoter was markedly higher under hypoxic conditions than normoxic conditions. Moreover, H(E)mT-driven transgene expression was highly cancer-specific and was superior to that of H(mT)E-driven expression. A decorin-expressing oncolytic adenovirus (Ad; oH(E)mT-DCN) replicating under the control of the H(E)mT promoter induced more potent and highly cancer-specific cell death compared with its cognate control oncolytic Ad, which harbored the endogenous Ad E1A promoter. Moreover, oH(E)mT-DCN exhibited enhanced antitumor efficacy compared with both the clinically approved oncolytic Ad ONYX-015 and its cognate control oncolytic Ad lacking DCN. oH(E)mT-DCN treatment also attenuated the expression of major ECM components, such as collagen I/III, elastin, and fibronectin, and induced tumor cell apoptosis, leading to extensive viral dispersion within orthotopic pancreatic tumors and pancreatic cancer patient-derived tumor spheroids. Collectively, these findings demonstrate that oH(E)mT-DCN exhibits potent antitumor efficacy by degrading the ECM and inducing apoptosis in a multifunctional process. This process facilitates the dispersion and replication of oncolytic Ad, making it an attractive candidate for the treatment of aggressive and desmoplastic pancreatic cancer. This article is protected by copyright. All rights reserved.

http://ift.tt/2fAtZNy

Migraine and invasive epithelial ovarian cancer risk in the Nurses' Health Study II and the Women's Health Study

Abstract

Migraine is a common primary headache disorder, which predominantly impacts women. Recently, migraine has been hypothesized to be associated with hormonally related cancers; however the potential association between migraine and ovarian cancer has not been studied.

Therefore, we evaluated the association between migraine and invasive epithelial ovarian cancer risk in two prospective cohorts, the Nurses' Health Study II (NHSII) and the Women's Health Study (WHS). Our prospective analysis included 113,124 NHSII participants aged 25-42 at study baseline as well as 33,490 participants in the WHS who were 45 years or older at study entry. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for the association between migraine and ovarian cancer risk in each cohort. In secondary analyses, we stratified by age and menopausal status. After adjusting for potential covariates, there was no statistically significant association between migraine and ovarian cancer risk in either the NHSII (HR=1.29, 95%CI: 0.96, 1.74) or the WHS (HR=0.60, 95%CI: 0.34, 1.06). In stratified analysis in the NHSII, there was a statistically significant positive association between migraine and ovarian cancer risk among women < 45 years of age (HR=1.76, 95%CI: 1.01, 3.07). We did not observe a clear association between migraine and ovarian cancer risk in two large prospective cohort studies. This article is protected by copyright. All rights reserved.

http://ift.tt/2xdHME3

Αρχειοθήκη ιστολογίου

Αναζήτηση αυτού του ιστολογίου

Τετάρτη 20 Σεπτεμβρίου 2017

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