A dramatic, objective antiandrogen withdrawal response: case report and review of the literature

PubMed Central

Lau, Yiu-Keung; Chadha, Manpreet K; Litwin, Alan; Trump, Donald L

2008-01-01

Antiandrogen withdrawal response is an increasingly recognized entity in patients with metastatic prostate cancer. To our knowledge, there have been no reports describing a durable radiologic improvement along with prostate-specific antigen (PSA) with discontinuation of the antiandrogen agent bicalutamide. We report a case in which a dramatic decline of serum PSA levels associated with a dramatic improvement in radiologic disease was achieved with bicalutamide discontinuation. PMID:18986533

Action, Not Rhetoric, Needed to Reverse the Opioid Overdose Epidemic.

PubMed

Davis, Corey; Green, Traci; Beletsky, Leo

2017-03-01

Despite shifts in rhetoric and some positive movement, Americans with the disease of addiction are still often stigmatized, criminalized, and denied access to evidencebased care. Dramatically reducing the number of lives unnecessarily lost to overdose requires an evidence-based, equity-focused, well-funded, and coordinated response. We present in this brief article evidence-based and promising practices for improving and refocusing the response to this simmering public health crisis. Topics covered include improving clinical decision-making, improving access to non-judgmental evidence-based treatment, investing in comprehensive public health approaches to problematic drug use, and changing the way law enforcement actors interact with people who use drugs.

Acute onset polyarthritis in older people: Is it RS3PE syndrome?

PubMed

Salam, Abdul; Henry, Rafik; Sheeran, Tom

2008-08-29

Remitting Seronegative Symmetrical Synovitis with Pitting oedema syndrome, a rare inflammatory arthritis, commonly affects people in the older age group. It can present as an acute onset polyarthritis with associated pitting oedema of the extremities. Patients show excellent response to low dose steroids with complete and sustained remissions. It can also be a paraneoplastic manifestation of an underlying occult malignancy, hence thorough clinical evaluation is warranted.We discuss a case of Remitting Seronegative Symmetrical Synovitis with pitting oedema syndrome where the patient presented with acute onset polyarthritis and pitting oedema of the extremities without an underlying systemic cause. Patient showed dramatic response to low dose steroids.

The place of targeted therapies in the management of non-small cell bronchial carcinoma. Molecular markers as predictors of tumor response and survival in lung cancer.

PubMed

Rosell, R; Moran, T; Fernanda Salazar, M; Mendez, P; De Aguirre, I; Ramirez, J-L; Isla, D; Cobo, M; Camps, C; Lopez-Vivanco, G; Alberola, V; Taron, M

2006-11-01

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. The main core of recent research has centered on epidermal growth factor receptor (EGFR) mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine-kinase inhibitors. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine-kinase inhibitors plus aromatase inhibitors. Understanding the relevance of these findings can help to change the clinical practice in oncology towards customizing chemotherapy and targeted therapies, leading to improvement both in survival and in cost-effectiveness.

Minor Viral and Host Genetic Polymorphisms Can Dramatically Impact the Biologic Outcome of an Epitope-Specific CD8 T-Cell Response

DTIC Science & Technology

2009-08-20

be associated with impaired antigen process - ing.45,46 Indeed, extra-epitopic mutations were observed in B81 subjects infected with subtype C in whom...Medical Research Council (United Kingdom) Senior Clinical Fellow. Sample collection was supported by the European Commission, DG XII, INCO -DC (grant...Gall S, Pfafferott KJ, et al. Im- mune selection for altered antigen processing leads to cytotoxic T lymphocyte escape in chronic HIV-1 infection. J Exp

Clinical Information Systems - From Yesterday to Tomorrow.

PubMed

Gardner, R M

2016-06-30

To review the history of clinical information systems over the past twenty-five years and project anticipated changes to those systems over the next twenty-five years. Over 250 Medline references about clinical information systems, quality of patient care, and patient safety were reviewed. Books, Web resources, and the author's personal experience with developing the HELP system were also used. There have been dramatic improvements in the use and acceptance of clinical computing systems and Electronic Health Records (EHRs), especially in the United States. Although there are still challenges with the implementation of such systems, the rate of progress has been remarkable. Over the next twenty-five years, there will remain many important opportunities and challenges. These opportunities include understanding complex clinical computing issues that must be studied, understood and optimized. Dramatic improvements in quality of care and patient safety must be anticipated as a result of the use of clinical information systems. These improvements will result from a closer involvement of clinical informaticians in the optimization of patient care processes. Clinical information systems and computerized clinical decision support have made contributions to medicine in the past. Therefore, by using better medical knowledge, optimized clinical information systems, and computerized clinical decision, we will enable dramatic improvements in both the quality and safety of patient care in the next twenty-five years.

Multiscale modelling and nonlinear simulation of vascular tumour growth

PubMed Central

Macklin, Paul; Anderson, Alexander R. A.; Chaplain, Mark A. J.; Cristini, Vittorio

2011-01-01

In this article, we present a new multiscale mathematical model for solid tumour growth which couples an improved model of tumour invasion with a model of tumour-induced angiogenesis. We perform nonlinear simulations of the multi-scale model that demonstrate the importance of the coupling between the development and remodeling of the vascular network, the blood flow through the network and the tumour progression. Consistent with clinical observations, the hydrostatic stress generated by tumour cell proliferation shuts down large portions of the vascular network dramatically affecting the flow, the subsequent network remodeling, the delivery of nutrients to the tumour and the subsequent tumour progression. In addition, extracellular matrix degradation by tumour cells is seen to have a dramatic affect on both the development of the vascular network and the growth response of the tumour. In particular, the newly developing vessels tend to encapsulate, rather than penetrate, the tumour and are thus less effective in delivering nutrients. PMID:18781303

Video Taping and Abnormal Psychology: Dramatized Clinical Interviews.

ERIC Educational Resources Information Center

Lyons, Michael J.; And Others

1984-01-01

Students in an abnormal psychology course worked in teams to produce dramatizations of diagnostic interviews and then presented them in class. Positive and negative aspects of the activity are discussed. (RM)

A Novel Model of Asymptomatic Plasmodium Parasitemia That Recapitulates Elements of the Human Immune Response to Chronic Infection

PubMed Central

Baccarella, Alyssa; Craft, Joshua F.; Boyle, Michelle J.; McIntyre, Tara I.; Wood, Matthew D.; Thorn, Kurt S.; Anidi, Chioma; Bayat, Aqieda; Chung, Me Ree; Hamburger, Rebecca; Kim, Chris Y.; Pearman, Emily; Pham, Jennifer; Tang, Jia J.; Boon, Louis; Kamya, Moses R.; Dorsey, Grant; Feeney, Margaret E.; Kim, Charles C.

2016-01-01

In humans, immunity to Plasmodium sp. generally takes the form of protection from symptomatic malaria (i.e., 'clinical immunity') rather than infection ('sterilizing immunity'). In contrast, mice infected with Plasmodium develop sterilizing immunity, hindering progress in understanding the mechanistic basis of clinical immunity. Here we present a novel model in which mice persistently infected with P. chabaudi exhibit limited clinical symptoms despite sustaining patent parasite burdens for many months. Characterization of immune responses in persistently infected mice revealed development of CD4+ T cell exhaustion, increased production of IL-10, and expansion of B cells with an atypical surface phenotype. Additionally, persistently infected mice displayed a dramatic increase in circulating nonclassical monocytes, a phenomenon that we also observed in humans with both chronic Plasmodium exposure and asymptomatic infection. Following pharmacological clearance of infection, previously persistently infected mice could not control a secondary challenge, indicating that persistent infection disrupts the sterilizing immunity that typically develops in mouse models of acute infection. This study establishes an animal model of asymptomatic, persistent Plasmodium infection that recapitulates several central aspects of the immune response in chronically exposed humans. As such, it provides a novel tool for dissection of immune responses that may prevent development of sterilizing immunity and limit pathology during infection. PMID:27583554

Acute onset polyarthritis in older people: Is it RS3PE syndrome?

PubMed Central

Salam, Abdul; Henry, Rafik; Sheeran, Tom

2008-01-01

Remitting Seronegative Symmetrical Synovitis with Pitting oedema syndrome, a rare inflammatory arthritis, commonly affects people in the older age group. It can present as an acute onset polyarthritis with associated pitting oedema of the extremities. Patients show excellent response to low dose steroids with complete and sustained remissions. It can also be a paraneoplastic manifestation of an underlying occult malignancy, hence thorough clinical evaluation is warranted. We discuss a case of Remitting Seronegative Symmetrical Synovitis with pitting oedema syndrome where the patient presented with acute onset polyarthritis and pitting oedema of the extremities without an underlying systemic cause. Patient showed dramatic response to low dose steroids. PMID:18759976

The Confluence of Stereotactic Ablative Radiotherapy and Tumor Immunology

PubMed Central

Finkelstein, Steven Eric; Timmerman, Robert; McBride, William H.; Schaue, Dörthe; Hoffe, Sarah E.; Mantz, Constantine A.; Wilson, George D.

2011-01-01

Stereotactic radiation approaches are gaining more popularity for the treatment of intracranial as well as extracranial tumors in organs such as the liver and lung. Technology, rather than biology, is driving the rapid adoption of stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), in the clinic due to advances in precise positioning and targeting. Dramatic improvements in tumor control have been demonstrated; however, our knowledge of normal tissue biology response mechanisms to large fraction sizes is lacking. Herein, we will discuss how SABR can induce cellular expression of MHC I, adhesion molecules, costimulatory molecules, heat shock proteins, inflammatory mediators, immunomodulatory cytokines, and death receptors to enhance antitumor immune responses. PMID:22162711

Clinical Information Systems – From Yesterday to Tomorrow

PubMed Central

2016-01-01

Summary Objectives To review the history of clinical information systems over the past twenty-five years and project anticipated changes to those systems over the next twenty-five years. Methods Over 250 Medline references about clinical information systems, quality of patient care, and patient safety were reviewed. Books, Web resources, and the author’s personal experience with developing the HELP system were also used. Results There have been dramatic improvements in the use and acceptance of clinical computing systems and Electronic Health Records (EHRs), especially in the United States. Although there are still challenges with the implementation of such systems, the rate of progress has been remarkable. Over the next twenty-five years, there will remain many important opportunities and challenges. These opportunities include understanding complex clinical computing issues that must be studied, understood and optimized. Dramatic improvements in quality of care and patient safety must be anticipated as a result of the use of clinical information systems. These improvements will result from a closer involvement of clinical informaticians in the optimization of patient care processes. Conclusions Clinical information systems and computerized clinical decision support have made contributions to medicine in the past. Therefore, by using better medical knowledge, optimized clinical information systems, and computerized clinical decision, we will enable dramatic improvements in both the quality and safety of patient care in the next twenty-five years. PMID:27362589

Highlights of the 2012 Research Workshop: Using nutrigenomics and metabolomics in clinical nutrition research.

PubMed

Zeisel, Steven H; Waterland, Robert A; Ordovás, José M; Muoio, Deborah M; Jia, Wei; Fodor, Anthony

2013-03-01

The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Research Workshop, "Using Nutrigenomics and Metabolomics in Clinical Nutrition Research," was held on January 21, 2012, in Orlando, Florida. The conference brought together experts in human nutrition who use nutrigenomic and metabolomic methods to better understand metabolic individuality and nutrition effects on health. We are beginning to understand how genetic variation and epigenetic events alter requirements for and responses to foods in our diet (the field of nutrigenetics/nutrigenomics and epigenetics). At the same time, methods for profiling almost all of the products of metabolism in plasma, urine, and tissues (metabolomics) are being refined. The relationships between diet and nutrigenomic-metabolomic profiles, as well as between these profiles and health, are being elucidated, and this will dramatically alter clinical practice in nutrition.

Pharmacogenetics and target identification in diabetes.

PubMed

Pearson, Ewan R

2018-02-24

In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11. Beyond monogenic diabetes, pharmacogenetic variants have yet to impact on clinical practice, yet the effect sizes (e.g. for metformin intolerance and OCT1 variants; or for metformin action and SLC2A2 variants) are potentially of clinical utility, especially if the genotype is already known at the point of prescribing. Over the next few years, increasing cohort sizes and linkage at scale to electronic medical records will provide considerable potential for stratification and novel target identification in diabetes. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pre-Operative Diet Impacts the Adipose Tissue Response to Surgical Trauma

PubMed Central

Nguyen, Binh; Tao, Ming; Yu, Peng; Mauro, Christine; Seidman, Michael A.; Wang, Yaoyu E.; Mitchell, James; Ozaki, C. Keith

2012-01-01

Background Short-term changes in pre-operative nutrition can have profound effects on surgery related outcomes such as ischemia reperfusions injury in pre-clinical models. Dietary interventions that lend protection against stress in animal models (e.g. fasting, dietary restriction [DR]) impact adipose tissue quality/quantity. Adipose tissue holds high surgical relevance due to its anatomic location and high tissue volume, and it is ubiquitously traumatized during surgery. Yet the response of adipose tissue to trauma under clinically relevant circumstances including dietary status remains poorly defined. We hypothesized that pre-operative diet alters the adipose tissue response to surgical trauma. Methods A novel mouse model of adipose tissue surgical trauma was employed. Dietary conditions (diet induced obesity [DIO], pre-operative DR) were modulated prior to application of surgical adipose tissue trauma in the context of clinically common scenarios (different ages, simulated bacterial wound contamination). Local/distant adipose tissue phenotypic responses were measured as represented by gene expression of inflammatory, tissue remodeling/growth, and metabolic markers. Results Surgical trauma had a profound effect on adipose tissue phenotype at the site of trauma. Milder but significant distal effects on non-traumatized adipose tissue were also observed. DIO exacerbated the inflammatory aspects of this response, and pre-operative DR tended to reverse these changes. Age and LPS-simulated bacterial contamination also impacted the adipose tissue response to trauma, with young adult animals and LPS treatment exacerbating the proinflammatory response. Conclusions Surgical trauma dramatically impacts both local and distal adipose tissue biology. Short-term pre-operative DR may offer a strategy to attenuate this response. PMID:23274098

Trial Prospector: Matching Patients with Cancer Research Studies Using an Automated and Scalable Approach

PubMed Central

Sahoo, Satya S; Tao, Shiqiang; Parchman, Andrew; Luo, Zhihui; Cui, Licong; Mergler, Patrick; Lanese, Robert; Barnholtz-Sloan, Jill S; Meropol, Neal J; Zhang, Guo-Qiang

2014-01-01

Cancer is responsible for approximately 7.6 million deaths per year worldwide. A 2012 survey in the United Kingdom found dramatic improvement in survival rates for childhood cancer because of increased participation in clinical trials. Unfortunately, overall patient participation in cancer clinical studies is low. A key logistical barrier to patient and physician participation is the time required for identification of appropriate clinical trials for individual patients. We introduce the Trial Prospector tool that supports end-to-end management of cancer clinical trial recruitment workflow with (a) structured entry of trial eligibility criteria, (b) automated extraction of patient data from multiple sources, (c) a scalable matching algorithm, and (d) interactive user interface (UI) for physicians with both matching results and a detailed explanation of causes for ineligibility of available trials. We report the results from deployment of Trial Prospector at the National Cancer Institute (NCI)-designated Case Comprehensive Cancer Center (Case CCC) with 1,367 clinical trial eligibility evaluations performed with 100% accuracy. PMID:25506198

Impact of Depleting Therapeutic Monoclonal Antibodies on the Host Adaptive Immunity: A Bonus or a Malus?

PubMed Central

Deligne, Claire; Milcent, Benoît; Josseaume, Nathalie; Teillaud, Jean-Luc; Sibéril, Sophie

2017-01-01

Clinical responses to anti-tumor monoclonal antibody (mAb) treatment have been regarded for many years only as a consequence of the ability of mAbs to destroy tumor cells by innate immune effector mechanisms. More recently, it has also been shown that anti-tumor antibodies can induce a long-lasting anti-tumor adaptive immunity, likely responsible for durable clinical responses, a phenomenon that has been termed the vaccinal effect of antibodies. However, some of these anti-tumor antibodies are directed against molecules expressed both by tumor cells and normal immune cells, in particular lymphocytes, and, hence, can also strongly affect the host adaptive immunity. In addition to a delayed recovery of target cells, lymphocyte depleting-mAb treatments can have dramatic consequences on the adaptive immune cell network, its rebound, and its functional capacities. Thus, in this review, we will not only discuss the mAb-induced vaccinal effect that has emerged from experimental preclinical studies and clinical trials but also the multifaceted impact of lymphocytes-depleting therapeutic antibodies on the host adaptive immunity. We will also discuss some of the molecular and cellular mechanisms of action whereby therapeutic mAbs induce a long-term protective anti-tumor effect and the relationship between the mAb-induced vaccinal effect and the immune response against self-antigens. PMID:28855903

The Role of Nonphysician Clinicians in the Rapid Expansion of HIV Care in Mozambique

PubMed Central

Sherr, Kenneth; Pfeiffer, James; Mussa, Antonio; Vio, Ferruccio; Gimbel, Sarah; Micek, Mark; Gloyd, Stephen

2017-01-01

The shortage of health workers impedes universal coverage of quality HIV services, especially in those countries hardest hit by the epidemic. The dramatic increase in international aid to scale-up HIV services, including antiretroviral therapy (ART), has highlighted workforce deficiencies and provided an opportunity to strengthen health systems capacity. In Mozambique, a country with a high HIV burden and a staggering workforce deficit, the Ministry of Health looked to past experience in workforce expansion to rapidly build ART delivery capacity, including reliance on existing non-physician clinicians (NPC) to prescribe ART and dramatically increasing the output of NPC training. As a result of responsible task shifting, the number of facilities providing ART tripled during a 6-month period, and patients from disadvantaged areas have access to quality ART services. Because the NPC-driven ART approach is integrated into primary health care, the addition of new clinical staff also promises to improve general health services. PMID:19858931

Pellagra-like condition is xeroderma pigmentosum/Cockayne syndrome complex and niacin confers clinical benefit.

PubMed

Hijazi, H; Salih, M A; Hamad, M H A; Hassan, H H; Salih, S B M; Mohamed, K A; Mukhtar, M M; Karrar, Z A; Ansari, S; Ibrahim, N; Alkuraya, F S

2015-01-01

An extremely rare pellagra-like condition has been described, which was partially responsive to niacin and associated with a multisystem involvement. The condition was proposed to represent a novel autosomal recessive entity but the underlying mutation remained unknown for almost three decades. The objective of this study was to identify the causal mutation in the pellagra-like condition and investigate the mechanism by which niacin confers clinical benefit. Autozygosity mapping and exome sequencing were used to identify the causal mutation, and comet assay on patient fibroblasts before and after niacin treatment to assess its effect on DNA damage. We identified a single disease locus that harbors a novel mutation in ERCC5, thus confirming that the condition is in fact xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. Importantly, we also show that the previously described dermatological response to niacin is consistent with a dramatic protective effect against ultraviolet-induced DNA damage in patient fibroblasts conferred by niacin treatment. Our findings show the power of exome sequencing in reassigning previously described novel clinical entities, and suggest a mechanism for the dermatological response to niacin in patients with XP/CS complex. This raises interesting possibilities about the potential therapeutic use of niacin in XP. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The cardiovascular and cardiac actions of ecstasy and its metabolites.

PubMed

Shenouda, S K; Carvalho, F; Varner, K J

2010-08-01

The recreational use of 3, 4 methylenedioxymethamphetamine (ecstasy or MDMA) has increased dramatically over the past thirty years due to its ability to increase stamina and produce feelings of emotional closeness and wellbeing. In spite of the popular perception that MDMA is a safe drug, there is a large literature documenting that the drug can produce significant neurotoxicity, especially in serotonergic and catecholaminergic systems. There are also experimental and clinical data which document that MDMA can alter cardiovascular function and produce cardiac toxicity, including rhythm disturbances, infarction and sudden death. This manuscript will review the literature documenting the cardiovascular responses elicited by MDMA in humans and experimental animals and will examine the underlying mechanisms mediating these responses. We will also review the available clinical, autopsy and experimental data linking MDMA with cardiac toxicity. Most available data indicate that oxidative stress plays an important role in the cardiotoxic actions of MDMA. Moreover, new data indicates that redox active metabolites of MDMA may play especially important roles in MDMA induced toxicity.

Mycobacterium leprae–host-cell interactions and genetic determinants in leprosy: an overview

PubMed Central

Pinheiro, Roberta Olmo; de Souza Salles, Jorgenilce; Sarno, Euzenir Nunes; Sampaio, Elizabeth Pereira

2011-01-01

Leprosy, also known as Hansen’s disease, is a chronic infectious disease caused by Mycobacterium leprae in which susceptibility to the mycobacteria and its clinical manifestations are attributed to the host immune response. Even though leprosy prevalence has decreased dramatically, the high number of new cases indicates active transmission. Owing to its singular features, M. leprae infection is an attractive model for investigating the regulation of human immune responses to pathogen-induced disease. Leprosy is one of the most common causes of nontraumatic peripheral neuropathy worldwide. The proportion of patients with disabilities is affected by the type of leprosy and delay in diagnosis. This article briefly reviews the clinical features as well as the immunopathological mechanisms related to the establishment of the different polar forms of leprosy, the mechanisms related to M. leprae–host cell interactions and prophylaxis and diagnosis of this complex disease. Host genetic factors are summarized and the impact of the development of interventions that prevent, reverse or limit leprosy-related nerve impairments are discussed. PMID:21366421

Dramatic response to alectinib in inflammatory myofibroblastic tumor with anaplastic lymphoma kinase fusion gene.

PubMed

Saiki, Masafumi; Ohyanagi, Fumiyoshi; Ariyasu, Ryo; Koyama, Junji; Sonoda, Tomoaki; Nishikawa, Shingo; Kitazono, Satoru; Yanagitani, Noriko; Horiike, Atsushi; Ninomiya, Hironori; Ishikawa, Yuichi; Nishio, Makoto

2017-12-01

Inflammatory myofibroblastic tumor (IMT) is a neoplasm characterized by the proliferaton of myofibroblasts with the infiltration of inflammatory cells. There is no standard treatment for patients with recurrent or metastatic IMT. We describe here a patient with hyper-progressive IMT with an anaplastic lymphoma kinase (ALK) fusion gene that dramatically responded to alectinib without adverse events. His dramatic and enduring response supports the observation that alectinib may be considered a good treatment option for rare aggressive ALK-positive tumors. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Rapid Response to High-Dose, Pulsatile Erlotinib in Afatinib-Refractory Leptomeningeal Carcinomatosis from Adenocarcinoma of the Lung: A Case Report.

PubMed

Fan, Frank S

2016-01-01

Leptomeningeal carcinomatosis occurred in an old female patient who was on a standard dose of afatinib for the treatment of her non-small cell lung cancer harboring an epidermal growth factor receptor gene mutation sensitive to tyrosine kinase inhibitors when extracranial lesions were still under control. Shifting to high-dose, pulsatile erlotinib dramatically saved her from the devastating condition in a very short period of time. Inadequate afatinib concentration in cerebrospinal fluid is reasonably suspected, and there is a call for clinical trials testing high-dose afatinib in leptomeningeal carcinomatosis.

A rare case of Ibuprofen-induced eosinophilic meningitis in a 13-year-old girl.

PubMed

Bansal, Sharad; Gupta, Mukesh; Sharma, Deepak; Bansal, Shweta

2014-01-01

Eosinophilic meningoencephalitis is based on clinical manifestations and microscopic identification of eosinophils present in cerebrospinal fluid (CSF). It is caused by a variety of helminthic infections with most common being angiostrongyliasis, gnathostomiasis, toxocariasis, cysticercosis, schistosomiasis, baylisascariasis, and paragonimiasis. Many case reports are there in which parasites have been found responsible, but there are rare reports of CSF eosinophilia associated with the use of drugs. We report a case of drug-induced (ibuprofen) eosinophilic meningitis in a healthy female who presented to us with severe headache and improved dramatically after drug withdrawal.

Physician/Computer Interaction

PubMed Central

Dlugacz, Yosef D.; Siegel, Carole; Fischer, Susan

1981-01-01

Despite the fact that the physician's involvement with computer operations has dramatically increased with automation in the health care industry, few studies have focused on the physician's experiences with and reactions to computers. This paper reports on these dimensions for physicians and their medical supervisors who have begun to use a computerized drug review system. Their attitudes and opinions are assessed towards this system and more generally towards the use of computers in medicine. Clinicians' attitudes towards computers are related to their clinical role and feelings about the working milieu. This report presents preliminary data of the study in terms of the frequency distribution of responses.

Fetal hemoglobin regulation in β-thalassemia: heterogeneity, modifiers and therapeutic approaches.

PubMed

Sripichai, Orapan; Fucharoen, Suthat

2016-12-01

Stress erythropoiesis induces fetal hemoglobin (HbF) expression in β-thalassemias, however the level of expression is highly variable. The last decade has seen dramatic advances in our understanding of the molecular regulators of HbF production and the genetic factors associated with HbF levels, leading to the promise of new methods of the clinical induction of HbF. Areas covered: This article will review the heterogeneity and genetic modifiers of HbF and HbF induction therapy in β-thalassemia. Expert commentary: One promising curative β-thalassemia therapy is to induce HbF synthesis in β-thalassemic erythrocytes to therapeutic levels before clinical symptom occurs. Further understanding of HbF level variation and regulation is needed in order to predict the response from HbF-inducing approaches.

Clinical trials in pediatric neuro-oncology: what is missing and how we can improve.

PubMed

Byer, Lennox; Kline, Cassie; Mueller, Sabine

2016-10-01

Brain tumors are the most common solid tumor in childhood, yet outcomes vary dramatically. High-grade gliomas have dismal outcomes with poor survival. By contrast, low-grade gliomas, have high survival rates, but children suffer from morbidity of tumor burden and therapy-associated side effects. In this article, we discuss how current trial designs often miss the opportunity to include end points beyond tumor response and thus fail to offer complete assessments of therapeutic approaches. Quality of life, neurocognitive function and neurofunctional deficits need to be considered when assessing overall success of a therapy. Herein, we identify specific end points that should be included in the interpretation of clinical trial results and accordingly, offer a more comprehensive approach to treatment decision-making.

Infliximab to treat severe ulcerative colitis

PubMed Central

Cury, Dídia Bisamra; de Souza Cury, Marcelo; Elias, Geraldo Vinicius Hemerly; Mizsputen, Sender Jankiel

2009-01-01

A 48-year-old female with severe ulcerative colitis refractory to conventional therapy was referred to our facility for management. The patient showed extensive ulcerative colitis since the age of 20 years and had failed therapy with 5-aminosalicylic acid agents and azathioprine. The disease remained active despite treatment with steroids and cyclosporine. The clinical and endoscopic parameters were consistent with severe disease. Infectious precipitants were ruled out. Given the severity of the disease and in order to avoid a colectomy, we started the patient on infliximab therapy. A dramatic clinical and endoscopic response was observed and she remained in remission at the end of a 1-year follow-up period. We discuss findings in the literature regarding the use of infliximab therapy in patients with ulcerative colitis who have failed steroids and cyclosporine. PMID:19360923

Changes in Imaging and Cognition in Juvenile Rats After Whole-Brain Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Robert J.; Jun, Brandon J.; Advanced Imaging Laboratory, Department of Radiology, Children's Hospital Los Angeles, Los Angeles, California

Purpose: In pediatric cancer survivors treated with whole-brain irradiation (WBI), long-term cognitive deficits and morbidity develop that are poorly understood and for which there is no treatment. We describe similar cognitive defects in juvenile WBI rats and correlate them with alterations in diffusion tensor imaging and magnetic resonance spectroscopy (MRS) during brain development. Methods and Materials: Juvenile Fischer rats received clinically relevant fractionated doses of WBI or a high-dose exposure. Diffusion tensor imaging and MRS were performed at the time of WBI and during the subacute (3-month) and late (6-month) phases, before behavioral testing. Results: Fractional anisotropy in the spleniummore » of the corpus callosum increased steadily over the study period, reflecting brain development. WBI did not alter the subacute response, but thereafter there was no further increase in fractional anisotropy, especially in the high-dose group. Similarly, the ratios of various MRS metabolites to creatine increased over the study period, and in general, the most significant changes after WBI were during the late phase and with the higher dose. The most dramatic changes observed were in glutamine-creatine ratios that failed to increase normally between 3 and 6 months after either radiation dose. WBI did not affect the ambulatory response to novel open field testing in the subacute phase, but locomotor habituation was impaired and anxiety-like behaviors increased. As for cognitive measures, the most dramatic impairments were in novel object recognition late after either dose of WBI. Conclusions: The developing brains of juvenile rats given clinically relevant fractionated doses of WBI show few abnormalities in the subacute phase but marked late cognitive alterations that may be linked with perturbed MRS signals measured in the corpus callosum. This pathomimetic phenotype of clinically relevant cranial irradiation effects may be useful for modeling, mechanistic evaluations, and testing of mitigation approaches.« less

Biologics for the treatment of pyoderma gangrenosum in ulcerative colitis.

PubMed

Arivarasan, K; Bhardwaj, Vaishali; Sud, Sukrit; Sachdeva, Sanjeev; Puri, Amarender Singh

2016-10-01

Pyoderma gangrenosum (PG) is an uncommon extra-intestinal manifestation of inflammatory bowel disease (IBD). Despite limited published literature, biologics have caused a paradigm shift in the management of this difficult-to-treat skin condition. The clinical data and outcomes of three patients with active ulcerative colitis and concurrent PG treated with biologics (infliximab two and adalimumab one) are reviewed in this report. Biologics were added because of the sub-optimal response of the colonic symptoms and skin lesions to parenteral hydrocortisone therapy. All three patients showed a dramatic response to the addition of the biologics. In view of the rapid healing of the skin lesions, superior response rate, and the additional benefit of improvement in the underlying colonic disease following treatment, anti-tumor necrosis factor blockers should be considered as a first line therapy in the management of PG with underlying IBD.

Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure

PubMed Central

Rothermel, Beverly A.; Berenji, Kambeez; Tannous, Paul; Kutschke, William; Dey, Asim; Nolan, Bridgid; Yoo, Ki-Dong; Demetroulis, Elaine; Gimbel, Michael; Cabuay, Barry; Karimi, Mohsen; Hill, Joseph A.

2014-01-01

Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease. PMID:16033866

Differential activation of stress-response signaling in load-induced cardiac hypertrophy and failure.

PubMed

Rothermel, Beverly A; Berenji, Kambeez; Tannous, Paul; Kutschke, William; Dey, Asim; Nolan, Bridgid; Yoo, Ki-Dong; Demetroulis, Elaine; Gimbel, Michael; Cabuay, Barry; Karimi, Mohsen; Hill, Joseph A

2005-09-21

Hypertrophic growth of the myocardium occurs in most forms of heart failure and may contribute to the pathogenesis of the failure state. Little is known about the regulatory mechanisms governing the often-coexisting phenotypes of hypertrophy, systolic failure, and diastolic stiffness that characterize clinical disease. We hypothesized that intracellular signaling pathways are differentially activated by graded degrees of hemodynamic stress. To test this, we developed models of graded pressure stress in mice and used them to directly compare compensated hypertrophy and pressure-overload heart failure. Surgical interventions were designed to be similar, on either side of a threshold separating compensated from decompensated responses. Our findings revealed two dramatically different hypertrophic phenotypes with only modest differences in the activation of relevant intracellular signaling pathways. Furthermore, we uncovered a functional requirement of calcineurin signaling in each model such that calcineurin suppression blunted hypertrophic growth. Remarkably, in each case, suppression of calcineurin signaling was not associated with clinical deterioration or increased mortality. Profiles of stress-response signaling and Ca2+ handling differ between the steady-state, maintenance phases of load-induced cardiac hypertrophy and failure. This information may be useful in identifying novel targets of therapy in chronic disease.

Dramatic effect of levetiracetam in early-onset epileptic encephalopathy due to STXBP1 mutation.

PubMed

Dilena, Robertino; Striano, Pasquale; Traverso, Monica; Viri, Maurizio; Cristofori, Gloria; Tadini, Laura; Barbieri, Sergio; Romeo, Antonino; Zara, Federico

2016-01-01

Syntaxin Binding Protein 1 (STXBP1) mutations determine a central neurotransmission dysfunction through impairment of the synaptic vesicle release, thus causing a spectrum of phenotypes varying from syndromic and non-syndromic epilepsy to intellectual disability of variable degree. Among the antiepileptic drugs, levetiracetam has a unique mechanism of action binding SV2A, a glycoprotein of the synaptic vesicle release machinery. We report a 1-month-old boy manifesting an epileptic encephalopathy with clonic seizures refractory to phenobarbital, pyridoxine and phenytoin that presented a dramatic response to levetiracetam with full epilepsy control and EEG normalization. Genetic analysis identified a novel de novo heterozygous mutation (c.[922A>T]p.[Lys308(∗)]) in the STXBP1 gene that severely affects the protein. The observation of a dramatic efficacy of levetiracetam in a case of STXBP1 epileptic encephalopathy refractory to other antiepileptic drugs and considerations regarding the specific mechanism of action of levetiracetam modulating the same system affected by STXBP1 mutations support the hypothesis that this drug may be able to reverse specifically the disease epileptogenic abnormalities. Further clinical observations and laboratory studies are needed to confirm this hypothesis and eventually lead to consider levetiracetam as the first choice treatment of patients with suspected or confirmed STXBP1-related epilepsies. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Biologics in the management of ulcerative colitis – comparative safety and efficacy of TNF-α antagonists

PubMed Central

Fausel, Rebecca; Afzali, Anita

2015-01-01

Ulcerative colitis can cause debilitating symptoms and complications such as colonic strictures, colonic dysplasia, colorectal cancer, and toxic megacolon or perforation. Goals of treatment in ulcerative colitis include resolution of gastrointestinal symptoms, healing of colonic mucosa, and prevention of disease complications. Our treatment armamentarium has expanded dramatically over the past 10 years, and we now have multiple biologic agents approved for the treatment of moderate-severe disease, in addition to conventional therapies such as 5-aminosalicylates, thiopurines, and corticosteroids. In this review, we will provide a detailed discussion of the three tumor necrosis factor-alpha (TNF-α) inhibitors currently approved for treatment of ulcerative colitis: infliximab, adalimumab, and golimumab. All three agents are effective for inducing and maintaining clinical response and remission in patients with ulcerative colitis, and they have comparable safety profiles. There are no head-to-head trials comparing their efficacy, and the choice of agent is most often based on insurance coverage, route of administration, and patient preference. Combination therapy with an immunomodulator is proven to be more effective than anti-TNF monotherapy, and patients who lose response to an anti-TNF agent should undergo dose intensification in order to regain clinical response. Despite therapeutic optimization, a significant percentage of patients will not achieve clinical remission with anti-TNF agents, and so newer therapies are on the horizon. PMID:25609972

Innate Immune Responses in ALV-J Infected Chicks and Chickens with Hemangioma In Vivo.

PubMed

Feng, Min; Dai, Manman; Xie, Tingting; Li, Zhenhui; Shi, Meiqing; Zhang, Xiquan

2016-01-01

Avian leukosis virus subgroup J (ALV-J) infection can cause tumors and immunosuppression. Since the precise mechanism of the innate immune response induced by ALV-J is unknown, we investigated the antiviral innate immune responses induced by ALV-J in chicks and chickens that had developed tumors. Spleen levels of interleukin-6 (IL-6), IL-10, IL-1β, and interferon-β (IFN-β) were not significantly different between the infected chick groups and the control groups from 1 day post hatch to 7 days post hatch. However, IL-6, IL-1β, and IFN-β protein levels in the three clinical samples with hemangiomas were dramatically increased compared to the healthy samples. In addition, the anti-inflammatory cytokine IL-10 increased sharply in two of three clinical samples. We also found a more than 20-fold up-regulation of ISG12-1 mRNA at 1 day post infection (d.p.i.) and a twofold up-regulation of ZC3HAV1 mRNA at 4 d.p.i. However, there were no statistical differences in ISG12-1 and ZC3HAV1 mRNA expression levels in the tumorigenesis phase. ALV-J infection induced a significant increase of Toll-like receptor 7 (TLR-7) at 1 d.p.i. and dramatically increased the mRNA levels of melanoma differentiation-associated gene 5 (MDA5) in the tumorigenesis phase. Moreover, the protein levels of interferon regulatory factor 1 (IRF-1) and signal transducer and activator of transcription 1 (STAT1) were decreased in chickens with tumors. These results suggest that ALV-J was primarily recognized by chicken TLR7 and MDA5 at early and late in vivo infection stages, respectively. ALV-J strain SCAU-HN06 did not induce any significant antiviral innate immune response in 1 week old chicks. However, interferon-stimulated genes were not induced normally during the late phase of ALV-J infection due to a reduction of IRF1 and STAT1 expression.

Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes.

PubMed

Stagno, Fabio; Stella, Stefania; Spitaleri, Antonio; Pennisi, Maria Stella; Di Raimondo, Francesco; Vigneri, Paolo

2016-01-01

The tyrosine kinase inhibitor Imatinib Mesylate has dramatically improved the clinical outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease, generating unprecedented rates of complete hematologic and cytogenetic responses and sustained reductions in BCR-ABL transcripts. Here, we present an overview on the efficacy and safety of Imatinib and describe the most important clinical studies employing this drug for the frontline treatment of chronic phase CML. We also discuss recent reports describing the long-term outcome of patients receiving Imatinib for their disease. The imminent availability of generic forms of Imatinib coupled with the approval of expensive second-generation tyrosine kinase inhibitors underlines an unmet need for early molecular parameters that may distinguish CML patients likely to benefit from the drug from those that should receive alternative forms of treatment.

Computational Model for Hyperfibrinolytic Onset of Acute Traumatic Coagulopathy.

PubMed

Wu, Tie Bo; Wu, Sheng; Buoni, Matthew; Orfeo, Thomas; Brummel-Ziedins, Kathleen; Cohen, Mitchell; Petzold, Linda

2018-04-19

The onset of acute traumatic coagulopathy in trauma patients exacerbates hemorrhaging and dramatically increases mortality. The disease is characterized by increased localized bleeding, and the mechanism for its onset is not yet known. We propose that the fibrinolytic response, specifically the release of tissue-plasminogen activator (t-PA), within vessels of different sizes leads to a variable susceptibility to local coagulopathy through hyperfibrinolysis which can explain many of the clinical observations in the early stages from severely injured coagulopathic patients. We use a partial differential equation model to examine the consequences of vessel geometry and extent of injury on fibrinolysis profiles. In addition, we simulate the efficacy of tranexamic acid treatment on coagulopathy initiated through endothelial t-PA release, and are able to reproduce the time-sensitive nature of the efficacy of this treatment as observed in clinical studies.

Age-associated Pro-inflammatory Remodeling and Functional Phenotype in the Heart and Large Arteries

PubMed Central

Wang, Mingyi; Shah, Ajay M

2015-01-01

The aging population is increasing dramatically. Aging–associated stress simultaneously drives proinflammatory remodeling, involving angiotensin II and other factors, in both the heart and large arteries. The structural remodeling and functional changes that occur with aging include cardiac and vascular wall stiffening, systolic hypertension and suboptimal ventricular-arterial coupling, features that are often clinically silent and thus termed a silent syndrome. These age-related effects are the result of responses initiated by cardiovascular proinflammatory cells. Local proinflammatory signals are coupled between the heart and arteries due to common mechanical and humoral messengers within a closed circulating system. Thus, targeting proinflammatory signaling molecules would be a promising approach to improve age-associated suboptimal ventricular-arterial coupling, a major predisposing factor for the pathogenesis of clinical cardiovascular events such as heart failure. PMID:25665458

Cryopyrin-associated periodic syndrome.

PubMed

Posch, Christian; Kaulfersch, Wilhelm; Rappersberger, Klemens

2014-01-01

Cryopyrin-associated periodic syndromes (CAPS) are characterized by apparently unprovoked attacks of fever, rashes, and musculoskeletal and sensorineural inflammation accompanied by high acute-phase reactants. Excessive interleukin-1 (IL-1) signaling appears to be a constant feature in the pathomechanism of the disease, driven by a gain-of-function mutation in the NLRP3 gene. Herein, we present the case of a 9-month-old boy with recurrent nonpruritic rashes and episodes of fever. The difficulties of early diagnosis due to initially mild clinical symptoms and the dramatic response to anti-IL-1 therapy after diagnosis emphasize the practical relevance of considering CAPS as a differential diagnosis in these patients. © 2012 Wiley Periodicals, Inc.

4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors

PubMed Central

Long, Adrienne H.; Haso, Waleed M.; Shern, Jack F.; Wanhainen, Kelsey M.; Murgai, Meera; Ingaramo, Maria; Smith, Jillian P.; Walker, Alec J.; Kohler, M. Eric; Venkateshwara, Vikas R.; Kaplan, Rosandra N.; Patterson, George H.; Fry, Terry J.; Orentas, Rimas J.; Mackall, Crystal L.

2015-01-01

Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic anti-tumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We discovered that tonic CAR CD3ζ phosphorylation, triggered by antigen-independent clustering of CAR scFvs, can induce early exhaustion of CAR T cells that limits anti-tumor efficacy. Such activation is present to varying degrees in all CARs studied, with the exception of the highly effective CD19 CAR. We further identify that CD28 costimulation augments, while 4-1BB costimulation ameliorates, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the dramatic anti-tumor effects of CD19 CARs and for the observations that CD19.BBz CAR T cells are more persistent than CD19.28z CAR T cells in clinical trials. PMID:25939063

Improving the in vivo therapeutic index of siRNA polymer conjugates through increasing pH responsiveness.

PubMed

Guidry, Erin N; Farand, Julie; Soheili, Arash; Parish, Craig A; Kevin, Nancy J; Pipik, Brenda; Calati, Kathleen B; Ikemoto, Nori; Waldman, Jacob H; Latham, Andrew H; Howell, Bonnie J; Leone, Anthony; Garbaccio, Robert M; Barrett, Stephanie E; Parmar, Rubina Giare; Truong, Quang T; Mao, Bing; Davies, Ian W; Colletti, Steven L; Sepp-Lorenzino, Laura

2014-02-19

Polymer based carriers that aid in endosomal escape have proven to be efficacious siRNA delivery agents in vitro and in vivo; however, most suffer from cytotoxicity due in part to a lack of selectivity for endosomal versus cell membrane lysis. For polymer based carriers to move beyond the laboratory and into the clinic, it is critical to find carriers that are not only efficacious, but also have margins that are clinically relevant. In this paper we report three distinct categories of polymer conjugates that improve the selectivity of endosomal membrane lysis by relying on the change in pH associated with endosomal trafficking, including incorporation of low pKa heterocycles, acid cleavable amino side chains, or carboxylic acid pH sensitive charge switches. Additionally, we determine the therapeutic index of our polymer conjugates in vivo and demonstrate that the incorporation of pH responsive elements dramatically expands the therapeutic index to 10-15, beyond that of the therapeutic index (less than 3), for polymer conjugates previously reported.

Creative Dramatics in the Elementary School.

ERIC Educational Resources Information Center

Texas Education Agency, Austin. Div. of Curriculum Development.

Creative dramatics is an art form which enables children under the guidance of an imaginative and responsive adult, to reinforce academic subjects, establish a positive self-image and develop the processes of concentration, analysis, evaluation, inference, and creativity. Designed to assist elementary teachers and administrators, this book does…

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group.

PubMed

Rodeghiero, Francesco; Stasi, Roberto; Gernsheimer, Terry; Michel, Marc; Provan, Drew; Arnold, Donald M; Bussel, James B; Cines, Douglas B; Chong, Beng H; Cooper, Nichola; Godeau, Bertrand; Lechner, Klaus; Mazzucconi, Maria Gabriella; McMillan, Robert; Sanz, Miguel A; Imbach, Paul; Blanchette, Victor; Kühne, Thomas; Ruggeri, Marco; George, James N

2009-03-12

Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.

Aspergillus vertebral osteomyelitis in a child with a primary monocyte killing defect: response to GM-CSF therapy.

PubMed

Abu Jawdeh, L; Haidar, R; Bitar, F; Mroueh, S; Akel, S; Nuwayri-Salti, N; Dbaibo, G S

2000-07-01

We report the first case of vertebral aspergillosis in a child with a primary defect in monocyte killing, an extremely rare immunodeficiency The diagnosis of defective monocyte killing was made by an in vitro assay that showed normal killing of Staphylococcus aureus by the patient's neutrophils but impaired killing by his monocytes. Importantly, the extensive granulomatous infection that involved the vertebral column, posterior mediastinum, pleura, and lung was not responsive to aggressive treatment with a combination of liposomal amphotericin B. intralesional amphotericin B. itraconazole, and granulocyte transfusions. Dramatic clinical and radiological improvement was only seen after the addition of granulocyte macrophage-colony stimulating factor (GM-CSF) to his treatment regimen. The use of GM-CSF in the treatment of invasive aspergillosis in immunocompromised patients requires further evaluation.

Analytical challenges translating mass spectrometry-based phosphoproteomics from discovery to clinical applications

PubMed Central

Iliuk, Anton B.; Arrington, Justine V.; Tao, Weiguo Andy

2014-01-01

Phosphoproteomics is the systematic study of one of the most common protein modifications in high throughput with the aim of providing detailed information of the control, response, and communication of biological systems in health and disease. Advances in analytical technologies and strategies, in particular the contributions of high-resolution mass spectrometers, efficient enrichments of phosphopeptides, and fast data acquisition and annotation, have catalyzed dramatic expansion of signaling landscapes in multiple systems during the past decade. While phosphoproteomics is an essential inquiry to map high-resolution signaling networks and to find relevant events among the apparently ubiquitous and widespread modifications of proteome, it presents tremendous challenges in separation sciences to translate it from discovery to clinical practice. In this mini-review, we summarize the analytical tools currently utilized for phosphoproteomic analysis (with focus on MS), progresses made on deciphering clinically relevant kinase-substrate networks, MS uses for biomarker discovery and validation, and the potential of phosphoproteomics for disease diagnostics and personalized medicine. PMID:24890697

CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results.

PubMed

Till, Brian G; Jensen, Michael C; Wang, Jinjuan; Qian, Xiaojun; Gopal, Ajay K; Maloney, David G; Lindgren, Catherine G; Lin, Yukang; Pagel, John M; Budde, Lihua E; Raubitschek, Andrew; Forman, Stephen J; Greenberg, Philip D; Riddell, Stanley R; Press, Oliver W

2012-04-26

Cellular immune responses have the potential to elicit dramatic and sustained clinical remissions in lymphoma patients. Recent clinical trial data demonstrate that modification of T cells with chimeric antigen receptors (CARs) is a promising strategy. T cells containing CARs with costimulatory domains exhibit improved activity against tumors. We conducted a pilot clinical trial testing a "third-generation" CD20-specific CAR with CD28 and 4-1BB costimulatory domains in patients with relapsed indolent B-cell and mantle cell lymphomas. Four patients were enrolled, and 3 received T-cell infusions after cyclophosphamide lymphodepletion. Treatment was well tolerated, although one patient developed transient infusional symptoms. Two patients without evaluable disease remained progression-free for 12 and 24 months. The third patient had an objective partial remission and relapsed at 12 months after infusions. Modified T cells were detected by quantitative PCR at tumor sites and up to 1 year in peripheral blood, albeit at low levels. No evidence of host immune responses against infused cells was detected. In conclusion, adoptive immunotherapy with CD20-specific T cells was well tolerated and was associated with antitumor activity. We will pursue alternative gene transfer technologies and culture conditions in future studies to improve CAR expression and cell production efficiency.

Sex-driven differences in immunological responses: challenges and opportunities for the immunotherapies of the third millennium.

PubMed

Mirandola, Leonardo; Wade, Raymond; Verma, Rashmi; Pena, Camilo; Hosiriluck, Nattamol; Figueroa, Jose A; Cobos, Everardo; Jenkins, Marjorie R; Chiriva-Internati, Maurizio

2015-03-01

Male-based studies, both at the biochemical and at the pre-clinical/clinical trial levels, still predominate in the scientific community. Many studies are based on the wrong assumption that both sexes are fundamentally identical in their response to treatments. As a result, findings obtained mainly in males are applied to females, resulting in negative consequences female patients. In cancer immunotherapy, there is still a scarce focus on this topic. Here we review the main differences in immune modulation and immune system biology between males and females with a particular focus on how these differences affect cancer immunotherapy and cancer vaccines. We reviewed articles published on PubMed from 1999 to 2014, using the keywords: sex hormones, immune response, estrogen, immunotherapy, testosterone, cancer vaccines, sex-based medicine. We also present new data wherein the expression of the cancer testis antigen, Ropporin-1, was determined in patients with multiple myeloma, showing that the expression of Ropporin-1 was influenced by sex. Male and female immune systems display radical differences mainly due to the immune regulatory effects of sex hormones. These differences might have a dramatic impact on the immunological treatment of cancer. Moreover, the expression of tumor antigens that can be targeted by anti-cancer vaccines is associated with sex. Future clinical trials focusing on cancer immunotherapy will need to take into account the differences in the immune response and in the frequency of target antigen expression between male and females, in order to optimize these anti-cancer immunotherapies of the third millennium.

Modeling attitude towards drug treament: the role of internal motivation, external pressure, and dramatic relief.

PubMed

Conner, Bradley T; Longshore, Douglas; Anglin, M Douglas

2009-04-01

Motivation for change has historically been viewed as the crucial element affecting responsiveness to drug treatment. Various external pressures, such as legal coercion, may engender motivation in an individual previously resistant to change. Dramatic relief may be the change process that is most salient as individuals internalize such external pressures. Results of structural equation modeling on data from 465 drug users (58.9% male; 21.3% Black, 34.2% Hispanic/Latino, and 35.1% White) entering drug treatment indicated that internal motivation and external pressure significantly and positively predicted dramatic relief and that dramatic relief significantly predicted attitudes towards drug treatment: chi (2) = 142.20, df = 100, p < 0.01; Robust Comparative Fit Index = 0.97, Root Mean Squared Error of Approximation = 0.03. These results indicate that when external pressure and internal motivation are high, dramatic relief is also likely to be high. When dramatic relief is high, attitudes towards drug treatment are likely to be positive. The findings indicate that interventions to get individuals into drug treatment should include processes that promote Dramatic Relief. Implications for addictions health services are discussed.

Sjögren's syndrome associated with protein losing gastroenteropathy manifested by intestinal lymphangiectasia successfully treated with prednisolone and hydroxychloroquine.

PubMed

Liao, C-Y; Chien, S-T; Wang, C-C; Chen, I-H; Chiu, H-W; Liu, M-Y; Lin, C-H; Ben, R-J; Tsai, M-K

2015-12-01

Protein-losing gastroenteropathy (PLGE), a rare manifestation of primary Sjögren's syndrome (SS), is characterized by profound edema and severe hypoalbuminemia secondary to excessive serum protein loss from the gastrointestinal tract and is clinically indistinguishable from nephrotic syndrome. We report a case of a 30-year-old Taiwanese woman with PLGE-associated SS. In addition to a positive Schirmer's test, she had eye-dryness, thirst, and high levels of anti-SSA antibodies, fulfilling SS criteria. PLGE diagnosis was highly appropriate given the clinical profile of hypoalbuminemia, hypercholesterolemia, pleural effusion, and ascites, with absent cardiac, hepatic, or renal disease. We were unable to perform technetium-99 m-labeled human serum albumin scintigraphy ((99m)Tc-HAS). However, the patient's edema and albumin level improved dramatically in response to a 3-month regime of oral prednisolone followed by oral hydroxychloroquine. © The Author(s) 2015.

Rapid amelioration of severe manic episodes with right unilateral ultrabrief pulse ECT: a case series of four patients.

PubMed

Sidorov, Alexey; Mayur, Prashanth

2017-02-01

The aim of this small case series is to describe four cases of severe mania, where ultrabrief pulse electroconvulsive therapy (ECT) was used as a primary mode of treatment. A retrospective file review was undertaken of four patients identified as having received ultrabrief pulse ECT for severe mania. The outcome measures for treatment efficacy were the Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI). All the patients showed significant clinical improvement. A comparison of pre- and post-treatment YMRS and CGI scores showed a dramatic decrease in all four cases. However, one patient was shifted to brief pulse ECT due to inadequate response. Ultrabrief pulse ECT may be an effective treatment in cases of severe mania. Due to the very small number of cases in the current case series, no specific conclusions regarding efficacy may be drawn; however, larger, controlled studies would be indicated.

Contributions of GABA to alcohol responsivity during adolescence: Insights from preclinical and clinical studies

PubMed Central

Silveri, Marisa M.

2015-01-01

There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the γ-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol abuse disorders. PMID:24631274

INTRAVENOUS VALPROATE: A NEW PERSPECTIVE IN THE TREATMENT OF MANIC SYMPTOMS

PubMed Central

Duggal, Harpreet S.; Jagadheesan, K.; Gupta, Subhash; Basu, Soumya; Akhtar, Sayeed; Nizamie, Haque S.

2002-01-01

Over the last few years, the use of valproate in psychiatry has increased considerably. With the advent of oral loading dose strategy, its role in rapid treatment of acute mania has been demonstrated. The intravenous formulation of valproate, while retaining the rapidity of action of oral loading, also avoids some of the adverse effects of the oral preparation. Moreover, reports are pouring in that intravenous valproate loading may be more efficacious than oral valproate loading in the treatment of acute mania. We report two patients whose manic symptoms showed a dramatic response to intravenous valproate without adverse effects. The pharmacology of intravenous valproate and its clinical relevance to psychiatry are discussed. PMID:21206565

First Report of Dramatic Tumor Responses with Ramucirumab and Paclitaxel After Progression on Pembrolizumab in Two Cases of Metastatic Gastroesophageal Adenocarcinoma.

PubMed

Chakrabarti, Sakti; Dong, Haidong; Paripati, Harshita R; Ross, Helen J; Yoon, Harry H

2018-04-19

Checkpoint inhibitors targeted at programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) can result in significant benefit to a small proportion of patients with cancer, including those with tumors of the stomach and gastroesophageal junction. These drugs are now approved for several solid tumors, including the recent accelerated approval of pembrolizumab for gastroesophageal adenocarcinomas in the third-line setting and beyond based on the KEYNOTE-059 phase II trial. Data are lacking on the efficacy of chemotherapy after progression on PD-1 blockade in metastatic gastroesophageal adenocarcinoma. This report describes the exceptional response of two patients who received ramucirumab plus paclitaxel after progressive disease on pembrolizumab. This early clinical observation suggests that the sequence of administration of PD-1 blockade and chemotherapy may be important in this disease. © AlphaMed Press 2018.

The Perceived Impact of the Patient Protection and Affordable Care Act on North Carolina's Free Clinics.

PubMed

Swan, Greg A; Foley, Kristie L

2016-01-01

The Patient Protection and Affordable Care Act of 2010 (ACA) may dramatically affect the demographics of the uninsured population and the funding prospects for free health clinics. We conducted a cross-sectional survey of 64 of 80 free clinics (80.0% response rate) in North Carolina to assess free clinic directors' knowledge of the ACA and their perceptions of how the ACA would affect clinic operations. Free clinic directors were knowledgeable about well publicized aspects of the ACA (eg, lack of Medicaid expansion in North Carolina), but they were less knowledgeable about provisions such as the Federal Tort Claims Act and high-risk pools, which may have direct and indirect effects on free clinics. Directors expressed concern over the unintended consequences of the ACA, such as reduced funding and reduced volunteerism. Anticipated clinic changes as a result of the ACA include initiation of electronic medical records and, to a lesser extent, a move to become "hybrid" clinics (federally qualified health center look-alikes). This study is focused on North Carolina free clinics that are members of the North Carolina Association of Free Clinics (NCAFC). Findings cannot be generalized to non-NCAFC free clinics or to free clinic networks outside the state. Despite its effort to expand health insurance coverage, the ACA may have unintended consequences to low-cost free clinics that serve uninsured populations. ©2016 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.

Comparison of air-charged and water-filled urodynamic pressure measurement catheters.

PubMed

Cooper, M A; Fletter, P C; Zaszczurynski, P J; Damaser, M S

2011-03-01

Catheter systems are utilized to measure pressure for diagnosis of voiding dysfunction. In a clinical setting, patient movement and urodynamic pumps introduce hydrostatic and motion artifacts into measurements. Therefore, complete characterization of a catheter system includes its response to artifacts as well its frequency response. The objective of this study was to compare the response of two disposable clinical catheter systems: water-filled and air-charged, to controlled pressure signals to assess their similarities and differences in pressure transduction. We characterized frequency response using a transient step test, which exposed the catheters to a sudden change in pressure; and a sinusoidal frequency sweep test, which exposed the catheters to a sinusoidal pressure wave from 1 to 30 Hz. The response of the catheters to motion artifacts was tested using a vortex and the response to hydrostatic pressure changes was tested by moving the catheter tips to calibrated heights. Water-filled catheters acted as an underdamped system, resonating at 10.13 ± 1.03 Hz and attenuating signals at frequencies higher than 19 Hz. They demonstrated significant motion and hydrostatic artifacts. Air-charged catheters acted as an overdamped system and attenuated signals at frequencies higher than 3.02 ± 0.13 Hz. They demonstrated significantly less motion and hydrostatic artifacts than water-filled catheters. The transient step and frequency sweep tests gave comparable results. Air-charged and water-filled catheters respond to pressure changes in dramatically different ways. Knowledge of the characteristics of the pressure-measuring system is essential to finding the best match for a specific application. Copyright © 2011 Wiley-Liss, Inc.

Modeling Attitude towards Drug Treament: The Role of Internal Motivation, External Pressure, and Dramatic Relief

PubMed Central

Longshore, Douglas; Anglin, M. Douglas

2009-01-01

Motivation for change has historically been viewed as the crucial element affecting responsiveness to drug treatment. Various external pressures, such as legal coercion, may engender motivation in an individual previously resistant to change. Dramatic relief may be the change process that is most salient as individuals internalize such external pressures. Results of structural equation modeling on data from 465 drug users (58.9% male; 21.3% Black, 34.2% Hispanic/Latino, and 35.1% White) entering drug treatment indicated that internal motivation and external pressure significantly and positively predicted dramatic relief and that dramatic relief significantly predicted attitudes towards drug treatment: χ2=142.20, df=100, p<0.01; Robust Comparative Fit Index=0.97, Root Mean Squared Error of Approximation=0.03. These results indicate that when external pressure and internal motivation are high, dramatic relief is also likely to be high. When dramatic relief is high, attitudes towards drug treatment are likely to be positive. The findings indicate that interventions to get individuals into drug treatment should include processes that promote Dramatic Relief. Implications for addictions health services are discussed. PMID:18535908

A Comprehensive Outline of Trastuzumab Resistance Biomarkers in HER2 Overexpressing Breast Cancer.

PubMed

Menyhárt, Otília; Santarpia, Libero; Győrffy, Balázs

2015-01-01

The introduction of trastuzumab for anti-HER2 therapy dramatically changed the clinical outcome for HER2 (ERBB2, neu) positive breast cancer patients. Today, patients eligible for trastuzumab are selected using HER2 expression/amplification status of the primary tumor. However, acquired and inherent resistance to anti-HER2 therapy in these patients poses a significant challenge, and better patient stratification will be needed to improve clinical response. Here, we provide a wide-ranging overview of potential biomarkers capable of stratifying patients regarding their response to trastuzumab. These include HER2 amplification, impaired access to the binding site (p95HER2, Δ16HER-2, MUC4), augmented signaling through other ERBB family receptors (HER1, HER3, HER4) and their ligands, activation of HER2 targets by alternate heterodimers (EphA2, IGF-1R, GDF15, MUC1*), signaling triggered by downstream members (PIK3CA, PTEN, SRC, mTOR), altered expression of cell cycle and apoptotic regulators (CDKs, p27(kip1), Bcl-2), hormone receptor status, resistance to antibody-dependent cellular cytotoxicity (FcγR), and altered miRNA expression signatures. Multigenic molecular profile analyses have revealed further genes not directly associated with classical oncogenic pathways. Although numerous biomarkers have shown promise in pre-clinical studies, many have delivered controversial results when evaluated in clinical trials. One of the keys for targeting ERBB2 will be to consider the entire ERBB family and downstream associated pathways responsible for the malignant transformation. The heterogeneity of the disease is likely to represent a significant obstacle to accurately predicting the course of resistance. The future most probably involves the incorporation of multiple biomarkers into a unified predictor enabling selection of patients for superior targeted drug administration.

Concurrent, but not sequential, PD-1 blockade with a DNA vaccine elicits anti-tumor responses in patients with metastatic, castration-resistant prostate cancer.

PubMed

McNeel, Douglas G; Eickhoff, Jens C; Wargowski, Ellen; Zahm, Christopher; Staab, Mary Jane; Straus, Jane; Liu, Glenn

2018-05-22

T-cell checkpoint inhibitors have demonstrated dramatic clinical activity against multiple cancer types, however little activity in patients with prostate cancer. Conversely, an anti-tumor vaccine was approved for the treatment of prostate cancer, having demonstrated an improvement in overall survival, despite few objective disease responses. In murine studies, we found that PD-1 expression on CD8+ T cells increased following anti-tumor vaccination, and that PD-1/PD-L1 blockade at the time of immunization elicited greater anti-tumor responses. Based on these data we initiated a pilot trial evaluating the immunological and clinical efficacy of a DNA encoding prostatic acid phosphatase (PAP) when delivered in combination with pembrolizumab. 26 patients were treated for 12 weeks with vaccine and received pembrolizumab either during this time or during the subsequent 12 weeks. Adverse events included grade 2 and 3 fatigue, diarrhea, thyroid dysfunction, and hepatitis. Median time to radiographic progression was not different between study arms. 8/13 (62%) of patients treated concurrently, and 1/12 (8%, p=0.01) of patients treated sequentially, experienced PSA declines from baseline. Of these, two were over 50% and one was a complete PSA response. No confirmed CR or PR were observed, however 4/5 patients treated concurrently had measurable decreases in tumor volume at 12 weeks. PSA declines were associated with the development of PAP-specific Th1-biased T cell immunity and CD8+ T cell infiltration in metastatic tumor biopsy specimens. These data are the first report of a clinical trial demonstrating that the efficacy of an anti-tumor vaccine can be augmented by concurrent PD-1 blockade.

A Rural School/Community: A Case Study of a Dramatic Turnaround & Its Implications for School Improvement.

ERIC Educational Resources Information Center

Carlson, Robert V.

This paper presents a case study of a rural community exhibiting a dramatic turnaround in community support for a new school bond issue. Demographic change was partly responsible for the change in community attitudes, with two waves of immigration altering the long-term conservative orientation of this community. After a series of failed…

The post-pulmonary infarction syndrome.

PubMed

Sklaroff, H J

1979-12-01

Following pulmonary infarction, three patients developed the classical signs and symptoms of the Dressler syndrome associated with persistent left pleural effusion. Each responded dramatically to corticosteroid therapy. While the pathogenesis of this "Post-Pulmonary Infarction syndrome," like the Dressler syndrome, is unclear, the response to corticosteroid therapy is both dramatic and diagnostic and may spare the patient prolonged discomfort and unnecessary diagnostic procedures.

Discovery and preclinical development of dasabuvir for the treatment of hepatitis C infection.

PubMed

El Kassas, Mohamed; Elbaz, Tamer; Hafez, Enas; Wifi, Mohamed Naguib; Esmat, Gamal

2017-06-01

Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality. Positively, the introduction of new directly-acting antivirals (DAAs) have led to dramatic improvements in response rates to antiviral therapy. Furthermore, newer generations of DAAs have demonstrated better safety profiles as well as efficacy than older generations. Current treatment recommendations are based on different combinations of DAAs. Current combination therapies rely on agents that target the different steps of viral replication by using different molecules from various DAAs families. Areas covered: In this review, the authors summarize data from of one of the recently developed NS5B polymerase inhibitors, dasabuvir, formerly known as ABT-333. Herein, the authors discuss the drug discovery data for dasabuvir including data from preclinical, toxicological resistance studies. The authors also review dasabuvir's clinical efficacy across various clinical challenges, in addition to its limitations in clinical practice. Expert opinion: Dasabuvir represents an important medical advance when used as a combination therapy for HCV. Unfortunately, it does present limitations like low genotypic coverage and further research is still required to address some of the lingering issues.

Acute clinical recovery from sport-related concussion.

PubMed

Nelson, Lindsay D; Janecek, Julie K; McCrea, Michael A

2013-12-01

Concussion is a highly prevalent injury in contact and collision sports that has historically been poorly understood. An influx of sport-concussion research in recent years has led to a dramatic improvement in our understanding of the injury's defining characteristics and natural history of recovery. In this review, we discuss the current state of knowledge regarding the characteristic features of concussion and typical acute course of recovery, with an emphasis on the aspects of functioning most commonly assessed by clinicians and researchers (e.g., symptoms, cognitive deficits, postural stability). While prototypical clinical recovery is becoming better understood, questions remain regarding what factors (e.g., injury severity, demographic variables, history of prior concussions, psychological factors) may explain individual variability in recovery. Although research concerning individual differences in response to concussion is relatively new, and in many cases limited methodologically, we discuss the evidence about several potential moderators of concussion recovery and point out areas for future research. Finally, we describe how increased knowledge about the negative effects of and recovery following concussion has been translated into clinical guidelines for managing concussed athletes.

Drug susceptibility and treatment response of common urinary tract infection pathogens in children.

PubMed

Chen, Pei-Chun; Chang, Luan-Yin; Lu, Chun-Yi; Shao, Pei-Lan; Tsai, I-Jung; Tsau, Yong-Kwei; Lee, Ping-Ing; Chen, Jong-Ming; Hsueh, Po-Ren; Huang, Li-Min

2014-12-01

To document the trends of sensitivity and to find whether it is necessary to change antibiotics in selected patients according to the sensitivity test results in our clinical practice. We collected urine culture results from 0-18-year-old patients in the National Taiwan University Hospital from January 1, 2003 to October 31, 2012. Their medical chart was reviewed to identify true pathogens responsible for their urinary tract infection (UTI). We checked the percentage of susceptibility of these pathogens to ampicillin, amoxicillin-clavulanate (AMC), cefazolin, cefmetazole, ceftriaxone, gentamicin, and trimethoprim-sulfamethoxazole (TMP-SMX) according to the Clinical and Laboratory Standards Institute (CLSI) guideline. The extended-spectrum-beta-lactamases (ESBLs) rate was also checked. In addition, we reviewed the treatment response of different antibiotics. Defervescence within 48 hours after initial antibiotics use was considered responsive. A total of 7758 urine cultures positive for Escherichia coli infection were collected during the 10-year period. The E. coli cefazolin susceptibility rate was 62-73% during 2003-2010, but it dropped to 23% in 2011 and 28% in 2012 after the new CLSI guideline (M100-S21) was released. However, other antibiotics did not show a significant difference. In UTI caused by E. coli, on average, the sensitivity rates for various antibiotics were as follows: cefmetazole, 90%; ceftriaxone, 85%; gentamicin, 77%; AMC, 61%; TMP-SMX, 47%; and ampicillin, 20%. The ESBL rate was also found to increase (2-11%; p < 0.01). The overall response rate of UTI caused by E. coli to first-line antibiotics such as first-generation cephalosporin and/or gentamicin was 78%. The susceptibility of common urinary tract pathogens to cefazolin has decreased dramatically since 2010. This trend may be due to the change in the CLSI guideline. Although the susceptibility rate to first-line empirical antibiotics shows a decreasing trend, we found that the clinical response was acceptable for our first-line empirical antibiotics. Copyright © 2013. Published by Elsevier B.V.

Vulval lichen planus-lichen sclerosus overlap.

PubMed

Howard, Matthew; Hall, Anthony

2018-01-01

Vulval lichen planus-lichen sclerosus overlap is an emerging observation. Few clinical reports exist with no reviews of literature. We present a focused update of this phenomenon and discuss a clinical case. We report a 63-year-old woman with a 20-year history of ulcerative vulvo-vaginitis, initially diagnosed as benign mucous membrane (cicatricial) pemphigoid. This led to prolonged treatment with oral corticosteroids with minimal improvement in symptoms. Subsequent complications of long-term use of systemic corticosteroid ensued. A clinico-pathological diagnosis of severe erosive lichen planus was made on clinical findings and on non-specific biopsy changes of ulceration and inflammation. Treatment with topical clobetasol propionate 0.05% ointment twice daily led to dramatic improvement of ulceration, easing of discomfort and marked improvement in quality of life. Clinical examination revealed Wickham's striae on the labia majora supporting the diagnosis. Six years after commencement of topical clobetasol, white plaques were noticed on the labia majora, perineum and peri-anal region consistent with lichen sclerosus, confirmed by repeat vulval skin biopsy and on vulvectomy. This case highlights the challenge of diagnosis of extensive vulvo-vaginal ulceration and the necessity to re-examine a previous diagnosis if there is poor response to treatment.

Listening to a patient: An exploratory experimental investigation into the effects of vocalization and therapist gender on interpreting clinical material.

PubMed

Dauphin, Barry; Halverson, Stacey; Pouliot, Sarah; Slowik, Linda

2018-01-01

Carefully listening to the patient is of paramount importance for psychoanalysis and psychoanalytic psychotherapy. The present study explored whether patient vocalization as well as the gender of the analyst play significant roles in clinical listening. Fifty-one psychoanalysts and psychoanalytic therapists were randomly assigned to listen to one of two dramatized psychoanalytic sessions. The content of the sessions was the same for both versions, but the sessions were dramatized differently. Some differences emerged between the versions, especially on ratings of reality testing, impulse control, pressured speech, patient was confusing, and awareness of imagery. Furthermore, differences emerged between male and female analysts in terms of ratings of intervention strategies and countertransference reactions to the patient material. Session version and gender affect different ratings. Implications of the findings are discussed as is the utility of using more ecologically valid material in conducting empirical research into clinical judgment.

Maximizing the clinical utility of antimüllerian hormone testing in women's health

PubMed Central

Leader, Benjamin; Baker, Valerie L.

2014-01-01

Purpose of review To provide an update on the latest clinical applications of serum antimüllerian hormone (AMH) testing with practical approaches to mitigate the impact of significant variability in AMH results. Recent findings Recent studies continue to demonstrate that AMH is the best single serum test for ovarian response management with, at most, a weak-to-moderate age-independent association with live-birth rate and time to conception. Data confirm serum AMH levels improve menopause prediction, monitoring of ovarian damage, and identification of women at risk for several ovary-related disorders such as polycystic ovary syndrome and premature or primary ovarian insufficiency. However, it is now recognized that serum AMH results can have dramatic variability due to common, biologic fluctuations within some individuals, use of hormonal contraceptives or other medications, certain surgical procedures, specimen treatment, assay changes, and laboratory calibration differences. Practical guidelines are provided to minimize the impact of variability in AMH results and maximize the accuracy of clinical decision-making. Summary AMH is an ovarian biomarker of central importance which improves the clinical management of women's health. However, with the simultaneous rapid expansion of AMH clinical applications and recognition of variability in AMH results, consensus regarding the clinical cutpoints is increasingly difficult. Therefore, a careful approach to AMH measurement and interpretation in clinical care is essential. PMID:24978853

Suppressive Effects on the Immune Response and Protective Immunity to a JEV DNA Vaccine by Co-administration of a GM-CSF-Expressing Plasmid in Mice

PubMed Central

Chen, Hui; Gao, Na; Fan, Dongying; Wu, Jiangman; Zhu, Junping; Li, Jieqiong; Wang, Juan; Chen, Yanlei; An, Jing

2012-01-01

As a potential cytokine adjuvant of DNA vaccines, granulocyte-macrophage colony–stimulating factor (GM-CSF) has received considerable attention due to its essential role in the recruitment of antigen-presenting cells, differentiation and maturation of dendritic cells. However, in our recent study of a Japanese encephalitis virus (JEV) DNA vaccine, co-inoculation of a GM-CSF plasmid dramatically suppressed the specific IgG response and resulted in decreased protection against JEV challenge. It is known that GM-CSF has been used in clinic to treat neutropenia for repopulating myeloid cells, and as an adjuvant in vaccine studies; it has shown various effects on the immune response. Therefore, in this study, we characterized the suppressive effects on the immune response to a JEV DNA vaccine by the co-administration of the GM-CSF-expressing plasmid and clarified the underlying mechanisms of the suppression in mice. Our results demonstrated that co-immunization with GM-CSF caused a substantial dampening of the vaccine-induced antibody responses. The suppressive effect was dose- and timing-dependent and likely related to the immunogenicity of the antigen. The suppression was associated with the induction of immature dendritic cells and the expansion of regulatory T cells but not myeloid-derived suppressor cells. Collectively, our findings not only provide valuable information for the application of GM-CSF in clinic and using as a vaccine adjuvant but also offer further insight into the understanding of the complex roles of GM-CSF. PMID:22493704

Smart surface coating of drug nanoparticles with cross-linkable polyethylene glycol for bio-responsive and highly efficient drug delivery

NASA Astrophysics Data System (ADS)

Wei, Weijia; Zhang, Xiujuan; Chen, Xianfeng; Zhou, Mengjiao; Xu, Ruirui; Zhang, Xiaohong

2016-04-01

Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability and minimal premature release of therapeutic molecules during circulation in the blood stream. To meet this requirement, herein, we develop GSH-responsive and crosslinkable amphiphilic polyethylene glycol (PEG) molecules to modify carrier-free drug NPs. These PEG molecules can be cross-linked on the surface of the NPs to endow them with greater stability and the cross-link is sensitive to intracellular environment for bio-responsive drug release. With this elegant design, our experimental results show that the liberation of DOX from DOX-cross-linked PEG NPs is dramatically slower than that from DOX-non-cross-linked PEG NPs, and the DOX release profile can be controlled by tuning the concentration of the reducing agent to break the cross-link between PEG molecules. More importantly, in vivo studies reveal that the DOX-cross-linked PEG NPs exhibit favorable blood circulation half-life (>4 h) and intense accumulation in tumor areas, enabling effective anti-cancer therapy. We expect this work will provide a powerful strategy for stabilizing carrier-free nanomedicines and pave the way to their successful clinical applications in the future.Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability and minimal premature release of therapeutic molecules during circulation in the blood stream. To meet this requirement, herein, we develop GSH-responsive and crosslinkable amphiphilic polyethylene glycol (PEG) molecules to modify carrier-free drug NPs. These PEG molecules can be cross-linked on the surface of the NPs to endow them with greater stability and the cross-link is sensitive to intracellular environment for bio-responsive drug release. With this elegant design, our experimental results show that the liberation of DOX from DOX-cross-linked PEG NPs is dramatically slower than that from DOX-non-cross-linked PEG NPs, and the DOX release profile can be controlled by tuning the concentration of the reducing agent to break the cross-link between PEG molecules. More importantly, in vivo studies reveal that the DOX-cross-linked PEG NPs exhibit favorable blood circulation half-life (>4 h) and intense accumulation in tumor areas, enabling effective anti-cancer therapy. We expect this work will provide a powerful strategy for stabilizing carrier-free nanomedicines and pave the way to their successful clinical applications in the future. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr09167e

Sex Differences in Device Therapy for Heart Failure: Utilization, Outcomes, and Adverse Events

PubMed Central

Herz, Naomi D.; Engeda, Joseph; Zusterzeel, Robbert; Sanders, William E.; O'Callaghan, Kathryn M.; Strauss, David G.; Jacobs, Samantha B.; Selzman, Kimberly A.; Piña, Ileana L.

2015-01-01

Abstract Background: Multiple studies of heart failure patients demonstrated significant improvement in exercise capacity, quality of life, cardiac left ventricular function, and survival from cardiac resynchronization therapy (CRT), but the underenrollment of women in these studies is notable. Etiological and pathophysiological differences may result in different outcomes in response to this treatment by sex. The observed disproportionate representation of women suggests that many women with heart failure either do not meet current clinical criteria to receive CRT in trials or are not properly recruited and maintained in these studies. Methods: We performed a systematic literature review through May 2014 of clinical trials and registries of CRT use that stratified outcomes by sex or reported percent women included. One-hundred eighty-three studies contained sex-specific information. Results: Ninety percent of the studies evaluated included ≤35% women. Fifty-six articles included effectiveness data that reported response with regard to specific outcome parameters. When compared with men, women exhibited more dramatic improvement in specific parameters. In the studies reporting hazard ratios for hospitalization or death, women generally had greater benefit from CRT. Conclusions: Our review confirms women are markedly underrepresented in CRT trials, and when a CRT device is implanted, women have a therapeutic response that is equivalent to or better than in men, while there is no difference in adverse events reported by sex. PMID:25793483

[Tumour lysis syndrome in small-cell lung cancer].

PubMed

Boshuizen, R C; Smit, A A J; Moons-Pasic, A; Bresser, P

2016-01-01

Small-cell lung cancer (SCLC) is a rapidly proliferating malignancy. Dramatic response to chemotherapy can therefore be expected. Unfortunately, tumour lysis prophylaxis is not mentioned in the current Dutch guidelines on SCLC treatment. A 64-year-old female was diagnosed with extensive SCLC and metastases. Shortly after diagnosis, chemotherapy was initiated. Based on Dutch guidelines, no tumour lysis prophylaxis was given. In addition to paraplegia, the patient also developed a clinical tumour lysis syndrome (TLS), and she passed away 5 days after start of treatment. Although tumour lysis prophylaxis is not mentioned in SCLC guidelines, tumour lysis in SCLC can occur as reported previously. Retrospectively, based on parameters applied to haematological malignancies, our patient was assessed as being at high risk of developing TLS.

Exacerbation of experimental autoimmune encephalomyelitis by passive transfer of IgG antibodies from a multiple sclerosis patient responsive to immunoadsorption.

PubMed

Pedotti, Rosetta; Musio, Silvia; Scabeni, Stefano; Farina, Cinthia; Poliani, Pietro Luigi; Colombo, Emanuela; Costanza, Massimo; Berzi, Angela; Castellucci, Fabrizio; Ciusani, Emilio; Confalonieri, Paolo; Hemmer, Bernhard; Mantegazza, Renato; Antozzi, Carlo

2013-09-15

The pathogenic role of antibodies in multiple sclerosis (MS) is still controversial. We transferred to mice with experimental autoimmune encephalomyelitis (EAE), animal model of MS, IgG antibodies purified from a MS patient presenting a dramatic clinical improvement during relapse after selective IgG removal with immunoadsorption. Passive transfer of patient's IgG exacerbated motor paralysis and increased mouse central nervous system (CNS) inflammation and demyelination. Binding of patient's IgG was demonstrated in mouse CNS, with a diffuse staining of white matter oligodendrocytes. These data support a growing body of evidence that antibodies can play an important role in the pathobiology of MS. Copyright © 2013 Elsevier B.V. All rights reserved.

The emotional impact of loss narratives: event severity and narrative perspectives.

PubMed

Habermas, Tilmann; Diel, Verena

2010-06-01

Out of the complex influences of event, narrative and listener characteristics on narrative emotions, this paper focuses on event severity, narrative perspectives, mood, and dispositions for emotion regulation and empathy. Event severity and perspective representation were systematically varied in sad autobiographical narratives to study their influence on quantity and quality of readers' emotional response. Each of three stories were manipulated to contain elaborated perspectives, only the past protagonists' perspective (dramatic narration), and very little perspectives at all (impersonal narration). We predicted that event severity influences the quantity of emotional response, while degree of perspective representation influences plausibility and whether emotional responses are sympathetic or interactional, that is, directed against the narrator. Hypotheses were confirmed except for plausibility, and perspective representation had an effect only on anger against and dislike of the narrator. In a second study, impersonal narration evoked anger at and negative evaluations of the narrator which were related to blaming the narrator for showing too little emotional involvement. The generalizability of findings across emotions and implications for sharing of emotions in everyday and clinical settings are discussed.

Yeast adapt to near-freezing temperatures by STRE/Msn2,4-dependent induction of trehalose synthesis and certain molecular chaperones.

PubMed

Kandror, Olga; Bretschneider, Nancy; Kreydin, Evgeniy; Cavalieri, Duccio; Goldberg, Alfred L

2004-03-26

Virtually nothing is known about the biochemical adaptations in eukaryotic cells that may enhance survival at low temperatures or upon freezing. Here we demonstrate an adaptive response in yeast that is activated below 10 degrees C and increases tolerance to low temperatures and freezing. This response involves a dramatic accumulation of the chemical chaperone trehalose and induction of trehalose-synthesizing enzymes (Tps1, Tps2) and certain heat shock proteins (Hsp104, Hsp42, Hsp12, Ssa4). mRNAs for these proteins increase dramatically below 10 degrees C and even at 0 degrees C. Their expression requires Msn2,4 transcription factors but also involves marked mRNA stabilization. Upon return to 30 degrees C, TPS1, TPS2, and HSP104 mRNAs, trehalose levels and tolerance to freezing fall dramatically within minutes. Mutants lacking trehalose or Msn2,4 die more rapidly at 0 degrees C and upon freezing. Thus, below 10 degrees C, yeast show an adaptive response that sustains viability at low or freezing temperatures, which are commonly encountered in natural environments and laboratory refrigerators.

[It starts as a Lumbovertebral syndrome and ends as an acute confusional state].

PubMed

Gianella, Pietro; Fusi, Tanja; Bernasconi, Enos

2013-12-31

Here we report the case of a 19-year-old somalian man who has been admitted to our emergency department because of an important lumbago without trauma. The physical examination on arrival showed a diffuse painful percussion of the left paraspinal muscles without neurological impairment. The laboratory exams displayed a significant elevation of the inflammatory response (CRP 154 mg/l, procalcitonin 0,05 µg/l), the blood cultures were negative and a thoracic and lumbar computed tomography (CT) was not conclusive. The unclear clinical picture led to a magnetic resonance imaging, showing the presence of an abscess in the left thoraco-lumbar paraspinal musculature with ongoing invasion of the epidural space. The clinical picture became dramatic as the patient suddenly developed a frank nuchal rigidity associated with an acute confusional state, caused by the rupture of the abscess in the meningeal space with secondary meningitis, confirmed by a lumbar puncture, where S. aureus was found.

Isolated brain stem lesion in children: is it acute disseminated encephalomyelitis or not?

PubMed

Alper, G; Sreedher, G; Zuccoli, G

2013-01-01

Isolated brain stem lesions presenting with acute neurologic findings create a major diagnostic dilemma in children. Although the brain stem is frequently involved in ADEM, solitary brain stem lesions are unusual. We performed a retrospective review in 6 children who presented with an inflammatory lesion confined to the brain stem. Two children were diagnosed with connective tissue disorder, CNS lupus, and localized scleroderma. The etiology could not be determined in 1, and clinical features suggested monophasic demyelination in 3. In these 3 children, initial lesions demonstrated vasogenic edema; all showed dramatic response to high-dose corticosteroids and made a full clinical recovery. Follow-up MRI showed complete resolution of lesions, and none had relapses at >2 years of follow-up. In retrospect, these cases are best regarded as a localized form of ADEM. We conclude that though ADEM is typically a disseminated disease with multifocal lesions, it rarely presents with monofocal demyelination confined to the brain stem.

How I manage ibrutinib-refractory chronic lymphocytic leukemia

PubMed Central

2017-01-01

The introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia (CLL). Although responses have been durable in the majority of patients, relapses do occur, especially in the high-risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes after ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population. Here, I discuss the diagnosis and management of ibrutinib-refractory CLL. The focus will be on common clinical scenarios that can be mistaken for relapse and how to accurately determine which patients are relapsing. Because there is no established standard of care, I discuss currently available options for standard therapy and existing clinical data. I also discuss new agents with the potential to be effective in patients refractory to ibrutinib. Finally, I discuss strategies for long-term disease control in this patient population. PMID:28096090

Revisiting Arieti's “Listening Attitude” and Hallucinated Voices

PubMed Central

Hoffman, Ralph E.

2010-01-01

Silvano Arieti proposed that auditory/verbal hallucinations (AVHs) are triggered by momentary states of heightened auditory attention that he identified as a “listening attitude.” Studies and clinical observations by our group support this view. Patients enrolled in our repetitive transcranial magnetic stimulation trials, if experiencing a significant curtailment of these hallucinations, often report an episodic sense that their voices are still occurring even if they no longer can be heard, suggesting episodic states of heightened auditory expectancy. Moreover, a functional magnetic resonance study reported by our group detected activation in the left insula prior to hallucination events. This finding is suggestive of activation in the same region detected in healthy subjects during “auditory search” in response to ambiguous sounds when anticipating meaningful speech. AVHs often are experienced with a deep emotional salience and may occur in the context of dramatic social isolation that together could reinforce heightened auditory expectancy. These findings and clinical observations suggest that Arieti's original formulation deserves further study. PMID:20363873

Progressive Primary Pulmonary Tuberculosis Presenting as the Sudden Unexpected Death in Infancy: A Case Report

PubMed Central

Dempers, Johan; Sens, Mary Ann; Wadee, Shabbir Ahmed; Kinney, Hannah C.; Odendaal, Hein J.; Wright, Colleen A.

2010-01-01

The classification of an unexpected infant death as the sudden infant death syndrome (SIDS) depends upon a complete autopsy and death scene investigation to exclude known causes of death. Here we report the death of a four-month-old infant in a tuberculosis endemic area that presented as a sudden unexpected death in infancy (SUDI) with no apparent explanation based on the death scene characteristics. The autopsy, however, revealed progressive primary pulmonary tuberculosis with intrathoracic adenopathy, compression of the tracheobronchial tree and miliary lesions in the liver. This case underscores the clinical difficulties in the diagnosis of infantile tuberculosis, as well as the possibility of sudden death as part of its protean manifestations. The pathology and clinical progression of tuberculosis in infants differs from older children and adults due to the immature immune response in infants. This case dramatically highlights the need for complete autopsies in all sudden and unexpected infant deaths, as well as the public health issues in a sentinel infant tuberculosis diagnosis. PMID:20705406

Neuroregression as an initial manifestation in a toddler with acquired pernicious anaemia

PubMed Central

Yoganathan, Sangeetha; Thomas, Maya Mary; Mathai, Sarah; Ghosh, Urmi

2015-01-01

The aetiology spectrum for neuroregression in infants and toddlers is diverse. Vitamin B12 deficiency-mediated neuroregression is less commonly considered as a differential. Prevalence of pernicious anaemia in the general population is 0.1% and is extremely rare in children. We describe a 35-month-old toddler with neuroregression, seizures, coarse tremors, bleating cry and neuropathy. His clinical symptomatology mimicked grey matter degenerative illness and infantile tremor syndrome, a nutritional deficiency-mediated movement disorder. His vitamin B12 level was low and serum homocysteine level was elevated. Haematological manifestations were not overt and anti-intrinsic factor antibody was positive. With parenteral vitamin B12 therapy, there was a dramatic response with clinical and laboratory translation. This report emphasises the need for a high index of suspicion and screening for markers of vitamin B12 deficiency in all children with unexplained acute or subacute neuroregression, seizures and movement disorders as it is potentially reversible. PMID:26678841

Neuroregression as an initial manifestation in a toddler with acquired pernicious anaemia.

PubMed

Yoganathan, Sangeetha; Thomas, Maya Mary; Mathai, Sarah; Ghosh, Urmi

2015-12-17

The aetiology spectrum for neuroregression in infants and toddlers is diverse. Vitamin B12 deficiency-mediated neuroregression is less commonly considered as a differential. Prevalence of pernicious anaemia in the general population is 0.1% and is extremely rare in children. We describe a 35-month-old toddler with neuroregression, seizures, coarse tremors, bleating cry and neuropathy. His clinical symptomatology mimicked grey matter degenerative illness and infantile tremor syndrome, a nutritional deficiency-mediated movement disorder. His vitamin B12 level was low and serum homocysteine level was elevated. Haematological manifestations were not overt and anti-intrinsic factor antibody was positive. With parenteral vitamin B12 therapy, there was a dramatic response with clinical and laboratory translation. This report emphasises the need for a high index of suspicion and screening for markers of vitamin B12 deficiency in all children with unexplained acute or subacute neuroregression, seizures and movement disorders as it is potentially reversible. 2015 BMJ Publishing Group Ltd.

Discrimination, developmental science, and the law: addressing dramatic shifts in civil rights jurisprudence.

PubMed

Levesque, Roger J R

2014-01-01

The civil rights movement fostered dramatic shifts in legal responses to discrimination based on race, gender, and a host of other group characteristics. The legal system now evinces yet another dramatic shift, as it moves from considering difference to focusing on neutrality, from efforts that seek to counter subjugation to those that adopt a "color-blind" approach. The shifting approach already has reached laws regulating responses to the group that spurred massive civil rights reform: minority youth. The shift requires a different body of empirical evidence to address it and a new look at equality jurisprudence. This article notes the need to turn to the current understanding of prejudice and discrimination for guidance, and uses, as illustration, developmental science to shed light on the development, manifestation, and alleviation of invidious discrimination. Using that understanding, the analysis details how the legal system can benefit from that research and better address discrimination in light of dramatic changes in law. The article articulates the need to address discrimination by recognizing and enlisting the law's inculcative powers through multiple sites of inculcation, ranging from families, schools, health and justice systems to religious and community groups. The discussion concludes with brief suggestions for reform benefiting from understandings of prejudice and its expression. (c) 2014 APA, all rights reserved.

Novel point estimation from a semiparametric ratio estimator (SPRE): long-term health outcomes from short-term linear data, with application to weight loss in obesity.

PubMed

Weissman-Miller, Deborah

2013-11-02

Point estimation is particularly important in predicting weight loss in individuals or small groups. In this analysis, a new health response function is based on a model of human response over time to estimate long-term health outcomes from a change point in short-term linear regression. This important estimation capability is addressed for small groups and single-subject designs in pilot studies for clinical trials, medical and therapeutic clinical practice. These estimations are based on a change point given by parameters derived from short-term participant data in ordinary least squares (OLS) regression. The development of the change point in initial OLS data and the point estimations are given in a new semiparametric ratio estimator (SPRE) model. The new response function is taken as a ratio of two-parameter Weibull distributions times a prior outcome value that steps estimated outcomes forward in time, where the shape and scale parameters are estimated at the change point. The Weibull distributions used in this ratio are derived from a Kelvin model in mechanics taken here to represent human beings. A distinct feature of the SPRE model in this article is that initial treatment response for a small group or a single subject is reflected in long-term response to treatment. This model is applied to weight loss in obesity in a secondary analysis of data from a classic weight loss study, which has been selected due to the dramatic increase in obesity in the United States over the past 20 years. A very small relative error of estimated to test data is shown for obesity treatment with the weight loss medication phentermine or placebo for the test dataset. An application of SPRE in clinical medicine or occupational therapy is to estimate long-term weight loss for a single subject or a small group near the beginning of treatment.

Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes.

PubMed

Rosenthal, E T; Bowles, K R; Pruss, D; van Kan, A; Vail, P J; McElroy, H; Wenstrup, R J

2015-12-01

Based on current consensus guidelines and standard practice, many genetic variants detected in clinical testing are classified as disease causing based on their predicted impact on the normal expression or function of the gene in the absence of additional data. However, our laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action. It is important to address these challenges now as the model for clinical testing moves toward the use of large multi-gene panels and whole exome/genome analysis, which will dramatically increase the number of genetic variants identified. © 2015 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Naturally-Occurring Canine Invasive Urothelial Carcinoma: A Model for Emerging Therapies

PubMed Central

Sommer, Breann C.; Dhawan, Deepika; Ratliff, Timothy L.; Knapp, Deborah W.

2018-01-01

The development of targeted therapies and the resurgence of immunotherapy offer enormous potential to dramatically improve the outlook for patients with invasive urothelial carcinoma (InvUC). Optimization of these therapies, however, is crucial as only a minority of patients achieve dramatic remission, and toxicities are common. With the complexities of the therapies, and the growing list of possible drug combinations to test, highly relevant animal models are needed to assess and select the most promising approaches to carry forward into human trials. The animal model(s) should possess key features that dictate success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). While it may not be possible to create these collective features in experimental models, these features are present in naturally-occurring InvUC in pet dogs. Naturally occurring canine InvUC closely mimics muscle-invasive bladder cancer in humans in regards to cellular and molecular features, molecular subtypes, biological behavior (sites and frequency of metastasis), and response to therapy. Clinical treatment trials in pet dogs with InvUC are considered a win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. This review will provide an overview of canine InvUC, the similarities to the human condition, and the potential for dogs with InvUC to serve as a model to predict the outcomes of targeted therapy and immunotherapy in humans. PMID:29732386

Naturally-Occurring Canine Invasive Urothelial Carcinoma: A Model for Emerging Therapies.

PubMed

Sommer, Breann C; Dhawan, Deepika; Ratliff, Timothy L; Knapp, Deborah W

2018-04-26

The development of targeted therapies and the resurgence of immunotherapy offer enormous potential to dramatically improve the outlook for patients with invasive urothelial carcinoma (InvUC). Optimization of these therapies, however, is crucial as only a minority of patients achieve dramatic remission, and toxicities are common. With the complexities of the therapies, and the growing list of possible drug combinations to test, highly relevant animal models are needed to assess and select the most promising approaches to carry forward into human trials. The animal model(s) should possess key features that dictate success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). While it may not be possible to create these collective features in experimental models, these features are present in naturally-occurring InvUC in pet dogs. Naturally occurring canine InvUC closely mimics muscle-invasive bladder cancer in humans in regards to cellular and molecular features, molecular subtypes, biological behavior (sites and frequency of metastasis), and response to therapy. Clinical treatment trials in pet dogs with InvUC are considered a win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. This review will provide an overview of canine InvUC, the similarities to the human condition, and the potential for dogs with InvUC to serve as a model to predict the outcomes of targeted therapy and immunotherapy in humans.

Promoting fundamental clinical skills: a competency-based college approach at the University of Washington.

PubMed

Goldstein, Erika A; Maclaren, Carol F; Smith, Sherilyn; Mengert, Terry J; Maestas, Ramoncita R; Foy, Hugh M; Wenrich, Marjorie D; Ramsey, Paul G

2005-05-01

The focus on fundamental clinical skills in undergraduate medical education has declined over the last several decades. Dramatic growth in the number of faculty involved in teaching and increasing clinical and research commitments have contributed to depersonalization and declining individual attention to students. In contrast to the close teaching and mentoring relationship between faculty and students 50 years ago, today's medical students may interact with hundreds of faculty members without the benefit of a focused program of teaching and evaluating clinical skills to form the core of their four-year curriculum. Bedside teaching has also declined, which may negatively affect clinical skills development. In response to these and other concerns, the University of Washington School of Medicine has created an integrated developmental curriculum that emphasizes bedside teaching and role modeling, focuses on enhancing fundamental clinical skills and professionalism, and implements these goals via a new administrative structure, the College system, which consists of a core of clinical teachers who spend substantial time teaching and mentoring medical students. Each medical student is assigned a faculty mentor within a College for the duration of his or her medical school career. Mentors continuously teach and reflect with students on clinical skills development and professionalism and, during the second year, work intensively with them at the bedside. They also provide an ongoing personal faculty contact. Competency domains and benchmarks define skill areas in which deepening, progressive attention is focused throughout medical school. This educational model places primary focus on the student.

Molecular and biological hallmarks of ageing.

PubMed

Aunan, J R; Watson, M M; Hagland, H R; Søreide, K

2016-01-01

Ageing is the inevitable time-dependent decline in physiological organ function that eventually leads to death. Age is a major risk factor for many of the most common medical conditions, such as cardiovascular disease, cancer, diabetes and Alzheimer's disease. This study reviews currently known hallmarks of ageing and their clinical implications. A literature search of PubMed/MEDLINE was conducted covering the last decade. Average life expectancy has increased dramatically over the past century and is estimated to increase even further. Maximum longevity, however, appears unchanged, suggesting a universal limitation to the human organism. Understanding the underlying molecular processes of ageing and health decline may suggest interventions that, if used at an early age, can prevent, delay, alleviate or even reverse age-related diseases. Hallmarks of ageing can be grouped into three main categories. The primary hallmarks cause damage to cellular functions: genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis. These are followed by antagonistic responses to such damage: deregulated nutrient sensing, altered mitochondrial function and cellular senescence. Finally, integrative hallmarks are possible culprits of the clinical phenotype (stem cell exhaustion and altered intercellular communication), which ultimately contribute to the clinical effects of ageing as seen in physiological loss of reserve, organ decline and reduced function. The sum of these molecular hallmarks produces the clinical picture of the elderly surgical patient: frailty, sarcopenia, anaemia, poor nutrition and a blunted immune response system. Improved understanding of the ageing processes may give rise to new biomarkers of risk or prognosis, novel treatment targets and translational approaches across disciplines that may improve outcomes. © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.

BRAF V600E mutations in papillary craniopharyngioma

PubMed Central

Brastianos, Priscilla K.; Santagata, Sandro

2016-01-01

Papillary craniopharyngioma is an intracranial tumor that results in high levels of morbidity. We recently demonstrated that the vast majority of these tumors harbor the oncogenic BRAF V600E mutation. The pathologic diagnosis of papillary craniopharyngioma can now be confirmed using mutation specific immunohistochemistry and targeted genetic testing. Treatment with targeted agents is now also a possibility in select situations. We recently reported a patient with a multiply recurrent papillary craniopharyngioma in whom targeting both BRAF and MEK resulted in a dramatic therapeutic response with a marked anti-tumor immune response. This work shows that activation of the MAPK pathway is the likely principal oncogenic driver of these tumors. We will now investigate the efficacy of this approach in a multicenter phase II clinical trial. Post-treatment resection samples will be monitored for the emergence of resistance mechanisms. Further advances in the non-invasive diagnosis of papillary craniopharyngioma by radiologic criteria and by cell-free DNA testing could someday allow neo-adjuvant therapy for this disease in select patient populations. PMID:26563980

Can infections prevent or cure allergy and autoimmunity?

PubMed

Kamradt, Thomas

2005-06-01

Extract: In western countries the prevalence and incidence of allergic and autoimmune diseases have been increasing dramatically over the last 50 years. In the last two decades, significant progress has been made towards understanding the genetic basis for susceptibility to autoimmunity or allergy. Genetic factors, however, cannot explain abrupt changes in disease incidence. It is therefore likely that environmental factors, specifically environmental factors that have changed over the last two generations, are critical for the increasing incidence of allergies and autoimmune diseases. Traditionally, autoimmune diseases such as multiple sclerosis (MS), type I diabetes, or rheumatoid arthritis (RA) are believed to have resulted from aberrant immune response to pathogens. In contrast, the "hygiene hypothesis," first postulated some 20 years ago, proposes that a lack of infections, especially during early childhood, predisposes one to the aberrant immune responses against harmless foreign antigens that cause allergic diseases such as rhinitis, atopic dermatitis, and allergic asthma. Several lines of epidemiological, clinical and experimental research point to more complex connections, either protective or pathogenic, between infection, allergy and autoimmunity.

Design considerations for liposomal vaccines: Influence of formulation parameters on antibody and cell-mediated immune responses to liposome associated antigens

PubMed Central

Watson, Douglas S.; Endsley, Aaron N.; Huang, Leaf

2012-01-01

Liposomes (phospholipid bilayer vesicles) are versatile and robust delivery systems for induction of antibody and T lymphocyte responses to associated subunit antigens. In the last 15 years, liposome vaccine technology has matured and now several vaccines containing liposome-based adjuvants have been approved for human use or have reached late stages of clinical evaluation. Given the intensifying interest in liposome-based vaccines, it is important to understand precisely how liposomes interact with the immune system and stimulate immunity. It has become clear that the physicochemical properties of liposomal vaccines – method of antigen attachment, lipid composition, bilayer fluidity, particle charge, and other properties – exert dramatic effects on the resulting immune response. Here, we present a comprehensive review of the physicochemical properties of liposomal vaccines and how they influence immune responses. A discussion of novel and emerging immunomodulators that are suitable for inclusion in liposomal vaccines is also presented. Through a comprehensive analysis of the body of liposomal vaccine literature, we enumerate a series of principles that can guide the rational design of liposomal vaccines to elicit immune responses of a desired magnitude and quality. We also identify major unanswered questions in the field, pointing the direction for future study. PMID:22306376

Exposure to toxic metals triggers unique responses from the rat gut microbiota.

PubMed

Richardson, Joshua B; Dancy, Blair C R; Horton, Cassandra L; Lee, Young S; Madejczyk, Michael S; Xu, Zhenjiang Zech; Ackermann, Gail; Humphrey, Gregory; Palacios, Gustavo; Knight, Rob; Lewis, John A

2018-04-26

Our understanding of the interaction between the gut microbiota and host health has recently improved dramatically. However, the effects of toxic metal exposure on the gut microbiota remain poorly characterized. As this microbiota creates a critical interface between the external environment and the host's cells, it may play an important role in host outcomes during exposure. We therefore used 16S ribosomal RNA (rRNA) gene sequencing to track changes in the gut microbiota composition of rats exposed to heavy metals. Rats were exposed daily for five days to arsenic, cadmium, cobalt, chromium, nickel, or a vehicle control. Significant changes to microbiota composition were observed in response to high doses of chromium and cobalt, and significant dose-dependent changes were observed in response to arsenic, cadmium and nickel. Many of these perturbations were not uniform across metals. However, bacteria with higher numbers of iron-importing gene orthologs were overly represented after exposure to arsenic and nickel, suggesting some possibility of a shared response. These findings support the utility of the microbiota as a pre-clinical tool for identifying exposures to specific heavy metals. It is also clear that characterizing changes to the functional capabilities of microbiota is critical to understanding responses to metal exposure.

A novel experimental method for measuring vergence and accommodation responses to the main near visual cues in typical and atypical groups.

PubMed

Horwood, Anna M; Riddell, Patricia M

2009-01-01

Binocular disparity, blur, and proximal cues drive convergence and accommodation. Disparity is considered to be the main vergence cue and blur the main accommodation cue. We have developed a remote haploscopic photorefractor to measure simultaneous vergence and accommodation objectively in a wide range of participants of all ages while fixating targets at between 0.3 and 2 m. By separating the three main near cues, we can explore their relative weighting in three-, two-, one-, and zero-cue conditions. Disparity can be manipulated by remote occlusion; blur cues manipulated by using either a Gabor patch or a detailed picture target; looming cues by either scaling or not scaling target size with distance. In normal orthophoric, emmetropic, symptom-free, naive visually mature participants, disparity was by far the most significant cue to both vergence and accommodation. Accommodation responses dropped dramatically if disparity was not available. Blur only had a clinically significant effect when disparity was absent. Proximity had very little effect. There was considerable interparticipant variation. We predict that relative weighting of near cue use is likely to vary between clinical groups and present some individual cases as examples. We are using this naturalistic tool to research strabismus, vergence and accommodation development, and emmetropization.

Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970

PubMed Central

Boucher, Diane M.; Eustace, Brenda; Gu, Yong; Hare, Brian; Johnson, Mac A.; Milton, Sean; Murphy, Cheryl E.; Takemoto, Darin; Tolman, Crystal; Wood, Mark; Charlton, Peter; Charrier, Jean-Damien; Furey, Brinley; Golec, Julian; Reaper, Philip M.; Pollard, John R.

2014-01-01

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients. PMID:25010037

Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970.

PubMed

Hall, Amy B; Newsome, Dave; Wang, Yuxin; Boucher, Diane M; Eustace, Brenda; Gu, Yong; Hare, Brian; Johnson, Mac A; Milton, Sean; Murphy, Cheryl E; Takemoto, Darin; Tolman, Crystal; Wood, Mark; Charlton, Peter; Charrier, Jean-Damien; Furey, Brinley; Golec, Julian; Reaper, Philip M; Pollard, John R

2014-07-30

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.

A Novel Experimental Method for Measuring Vergence and Accommodation Responses to the Main Near Visual Cues in Typical and Atypical Groups

PubMed Central

Horwood, Anna M; Riddell, Patricia M

2015-01-01

Binocular disparity, blur and proximal cues drive convergence and accommodation. Disparity is considered to be the main vergence cue and blur the main accommodation cue. We have developed a remote haploscopic photorefractor to measure simultaneous vergence and accommodation objectively in a wide range of participants of all ages while fixating targets at between 0.3m and 2m. By separating the three main near cues we can explore their relative weighting in three, two, one and zero cue conditions. Disparity can be manipulated by remote occlusion; blur cues manipulated by using either a Gabor patch or a detailed picture target; looming cues by either scaling or not scaling target size with distance. In normal orthophoric, emmetropic, symptom-free, naive visually mature participants, disparity was by far the most significant cue to both vergence and accommodation. Accommodation responses dropped dramatically if disparity was not available. Blur only had a clinically significant effect when disparity was absent. Proximity had very little effect. There was considerable inter-participant variation. We predict that relative weighting of near cue use is likely to vary between clinical groups and present some individual cases as examples. We are using this naturalistic tool to research strabismus, vergence and accommodation development and emmetropisation. PMID:19301186

Clinical supervision of allied health professionals in country South Australia: A mixed methods pilot study.

PubMed

Kumar, Saravana; Osborne, Kate; Lehmann, Tanya

2015-10-01

Recent times have witnessed dramatic changes in health care with overt recognition for quality and safety to underpin health care service delivery. In addition to systems-wide focus, the importance of supporting and mentoring people delivering the care has also been recognised. This can be achieved through quality clinical supervision. In 2010, Country Health South Australia Local Health Network developed a holistic allied health clinical governance structure, which was implemented in 2011. This research reports on emergent findings from the evaluation of the clinical governance structure, which included mandating clinical supervision for all allied health staff. A mixed method approach was chosen with evaluation of the impact of clinical supervision undertaken by a psychometrically sound instrument (Manchester Clinical Supervision Scale 26-item version), collected through an anonymous online survey and qualitative data collected through semistructured interviews and focus groups. Overall, 189 allied health professionals responded to the survey. Survey responses indicated allied health professionals recognised the importance of and valued receiving clinical supervision (normative domain), had levels of trust and rapport with, and were supported by supervisors (restorative domain) and positively affected their delivery of care and improvement in skills (formative domain). Qualitative data identified enablers such as profession specific gains, improved opportunities and consistency for clinical supervision and barriers such as persistent organisational issues, lack of clarity (delineation of roles) and communication issues. The findings from this research highlight that while clinical supervision has an important role to play, it is not a panacea for all the ills of the health care system. © 2015 National Rural Health Alliance Inc.

Dramatic response to nivolumab in xeroderma pigmentosum skin tumor.

PubMed

Chambon, Fanny; Osdoit, Sophie; Bagny, Kelly; Moro, Anne; Nguyen, Jacqueline; Réguerre, Yves

2018-02-01

We report the case of a 6-year-old female with xeroderma pigmentosum (XP) who developed a nonoperable scalp tumor, treated with anti-programmed cell death protein 1 (anti-PD-1) therapy (nivolumab). She presented with a sarcomatoid carcinoma of the scalp with bone lysis as well as vascular and meningeal contact. Nivolumab was initiated because it has emerged as a promising immunotherapy. We observed a dramatic tumor response with excellent tolerance. However, while on nivolumab therapy she developed two large skin melanomas and several squamous cell carcinomas, which have been resected. These results demonstrate that cancer immunotherapy in patients with XP can be impressive but complex and warrants further investigation. © 2017 Wiley Periodicals, Inc.

The foreign body response: at the interface of surgery and bioengineering.

PubMed

Major, Melanie R; Wong, Victor W; Nelson, Emily R; Longaker, Michael T; Gurtner, Geoffrey C

2015-05-01

The surgical implantation of materials and devices has dramatically increased over the past decade. This trend is expected to continue with the broadening application of biomaterials and rapid expansion of aging populations. One major factor that limits the potential of implantable materials and devices is the foreign body response, an immunologic reaction characterized by chronic inflammation, foreign body giant cell formation, and fibrotic capsule formation. The English literature on the foreign body response to implanted materials and devices is reviewed. Fibrotic encapsulation can cause device malfunction and dramatically limit the function of an implanted medical device or material. Basic science studies suggest a role for immune and inflammatory pathways at the implant-host interface that drive the foreign body response. Current strategies that aim to modulate the host response and improve construct biocompatibility appear promising. This review article summarizes recent basic science, preclinical, and clinicopathologic studies examining the mechanisms driving the foreign body response, with particular focus on breast implants and synthetic meshes. Understanding these molecular and cellular mechanisms will be critical for achieving the full potential of implanted biomaterials to restore human tissues and organs.

Making vaccines "on demand": a potential solution for emerging pathogens and biodefense?

PubMed

De Groot, Anne S; Einck, Leo; Moise, Leonard; Chambers, Michael; Ballantyne, John; Malone, Robert W; Ardito, Matthew; Martin, William

2013-09-01

The integrated US Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) has made great strides in strategic preparedness and response capabilities. There have been numerous advances in planning, biothreat countermeasure development, licensure, manufacturing, stockpiling and deployment. Increased biodefense surveillance capability has dramatically improved, while new tools and increased awareness have fostered rapid identification of new potential public health pathogens. Unfortunately, structural delays in vaccine design, development, manufacture, clinical testing and licensure processes remain significant obstacles to an effective national biodefense rapid response capability. This is particularly true for the very real threat of "novel pathogens" such as the avian-origin influenzas H7N9 and H5N1, and new coronaviruses such as hCoV-EMC. Conventional approaches to vaccine development, production, clinical testing and licensure are incompatible with the prompt deployment needed for an effective public health response. An alternative approach, proposed here, is to apply computational vaccine design tools and rapid production technologies that now make it possible to engineer vaccines for novel emerging pathogen and WMD biowarfare agent countermeasures in record time. These new tools have the potential to significantly reduce the time needed to design string-of-epitope vaccines for previously unknown pathogens. The design process-from genome to gene sequence, ready to insert in a DNA plasmid-can now be accomplished in less than 24 h. While these vaccines are by no means "standard," the need for innovation in the vaccine design and production process is great. Should such vaccines be developed, their 60-d start-to-finish timeline would represent a 2-fold faster response than the current standard.

Modeling Immunization To Infliximab in Children With Crohn's Disease Using Population Pharmacokinetics: A Pilot Study.

PubMed

Petitcollin, Antoine; Leuret, Oriane; Tron, Camille; Lemaitre, Florian; Verdier, Marie-Clémence; Paintaud, Gilles; Bouguen, Guillaume; Willot, Stéphanie; Bellissant, Eric; Ternant, David

2018-05-18

Antidrug antibodies (ADAs) dramatically increase infliximab clearance and are responsible for underexposure to the drug, leading to treatment failure. This pilot study aimed at developing a population pharmacokinetic model to detect and describe an early increase in infliximab clearance due to ADA. Twenty children with Crohn's disease (CD) were followed for 1 year or until treatment failure. Infliximab trough concentration, ADA, C-reactive protein (CRP), and Paediatric Crohn's Disease Activity Index (PCDAI) were recorded at each visit. A time-varying clearance population pharmacokinetic model was built to detect and describe an increase in infliximab clearance, independent from ADA testing. Factors associated with clearance variation and the relationships between infliximab concentrations, clearance variation, and clinical response were investigated. The model detected important increases in clearance in 4 patients. These patients had suboptimal early response, with higher mean PCDAI (P = 0.0086) and CRP (P = 0.028) compared with other patients. Two of them had detectable ADA. Clearance increase as described by the model and lower infliximab trough concentration at week 2 were associated with poorer outcomes in a multivariate Cox model (P = 0.001 and P = 0.0048, respectively). Being able to detect an increase in infliximab clearance, this model could allow the early detection of immunization to infliximab and therefore could help with dose adjustment in patients with CD. Moreover, the results suggest that clearance variations could be used as a predictive marker of clinical response. These findings need to be confirmed in a larger cohort, however, and predictive factors of clearance increase have to be investigated.

Making vaccines “on demand”

PubMed Central

De Groot, Anne S; Einck, Leo; Moise, Leonard; Chambers, Michael; Ballantyne, John; Malone, Robert W; Ardito, Matthew; Martin, William

2013-01-01

The integrated US Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) has made great strides in strategic preparedness and response capabilities. There have been numerous advances in planning, biothreat countermeasure development, licensure, manufacturing, stockpiling and deployment. Increased biodefense surveillance capability has dramatically improved, while new tools and increased awareness have fostered rapid identification of new potential public health pathogens. Unfortunately, structural delays in vaccine design, development, manufacture, clinical testing and licensure processes remain significant obstacles to an effective national biodefense rapid response capability. This is particularly true for the very real threat of “novel pathogens” such as the avian-origin influenzas H7N9 and H5N1, and new coronaviruses such as hCoV-EMC. Conventional approaches to vaccine development, production, clinical testing and licensure are incompatible with the prompt deployment needed for an effective public health response. An alternative approach, proposed here, is to apply computational vaccine design tools and rapid production technologies that now make it possible to engineer vaccines for novel emerging pathogen and WMD biowarfare agent countermeasures in record time. These new tools have the potential to significantly reduce the time needed to design string-of-epitope vaccines for previously unknown pathogens. The design process—from genome to gene sequence, ready to insert in a DNA plasmid—can now be accomplished in less than 24 h. While these vaccines are by no means “standard,” the need for innovation in the vaccine design and production process is great. Should such vaccines be developed, their 60-d start-to-finish timeline would represent a 2-fold faster response than the current standard. PMID:23877094

A review of dengue fever: a resurging tropical disease.

PubMed

Mangold, Karen A; Reynolds, Sally L

2013-05-01

Dengue is a resurging mosquito-borne disease that is often contracted in U.S. travelers to Latin America, Asia, and the Caribbean. The clinical symptoms range from a simple febrile illness to hemorrhagic fever or shock. The clinical course has a wide range of outcomes, and adequate supportive care can reduce mortality rates dramatically. Repeated exposures to the virus can lead to a more complicated clinical course.

Inadequate management of pregnancy-associated listeriosis: lessons from four case reports.

PubMed

Charlier, C; Goffinet, F; Azria, E; Leclercq, A; Lecuit, M

2014-03-01

Listeria monocytogenes infection during pregnancy can lead to dramatic fetal or neonatal outcomes. No clinical trial has evaluated treatment options, and retrospective studies of cases are therefore important to define optimal regimens. We report four cases of materno-neonatal listeriosis illustrating inadequate antimicrobial therapy management and discuss recommended treatment options. © 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

Developing business opportunities from concept to end point for craniofacial surgeons.

PubMed

Brown, Spencer A

2012-01-01

Craniofacial surgeons repair a wide variety of soft and hard tissues that produce the clinical expertise to recognize the need for an improved device or novel regenerative stem cell or use of molecules that may dramatically change the way clinical care for improved patient outcomes. The business pathway to bring a concept to clinical care requires knowledge, mentoring, and a team of experts in business and patent law.

Exhaustive Analysis of BH4 and Dopamine Biosynthesis Genes in Patients with Dopa-Responsive Dystonia

ERIC Educational Resources Information Center

Clot, Fabienne; Grabli, David; Cazeneuve, Cecile; Roze, Emmanuel; Castelnau, Pierre; Chabrol, Brigitte; Landrieu, Pierre; Nguyen, Karine; Ponsot, Gerard; Abada, Myriem; Doummar, Diane; Damier, Philippe; Gil, Roger; Thobois, Stephane; Ward, Alana J.; Hutchinson, Michael; Toutain, Annick; Picard, Fabienne; Camuzat, Agnes; Fedirko, Estelle; San, Chankannira; Bouteiller, Delphine; LeGuern, Eric; Durr, Alexandra; Vidailhet, Marie; Brice, Alexis

2009-01-01

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the "GCH1" gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the "TH" (tyrosine hydroxylase) or "SPR" (sepiapterin…

Management of community-acquired pneumonia in older adults

PubMed Central

Simonetti, Antonella F.; Viasus, Diego; Garcia-Vidal, Carolina

2014-01-01

Community-acquired pneumonia (CAP) is an increasing problem among the elderly. Multiple factors related to ageing, such as comorbidities, nutritional status and swallowing dysfunction have been implicated in the increased incidence of CAP in the older population. Moreover, mortality in patients with CAP rises dramatically with increasing age. Streptococcus pneumoniae is still the most common pathogen among the elderly, although CAP may also be caused by drug-resistant microorganisms and aspiration pneumonia. Furthermore, in the elderly CAP has a different clinical presentation, often lacking the typical acute symptoms observed in younger adults, due to the lower local and systemic inflammatory response. Several independent prognostic factors for mortality in the elderly have been identified, including factors related to pneumonia severity, inadequate response to infection, and low functional status. CAP scores and biomarkers have lower prognostic value in the elderly, and so there is a need to find new scales or to set new cut-off points for current scores in this population. Adherence to the current guidelines for CAP has a significant beneficial impact on clinical outcomes in elderly patients. Particular attention should also be paid to nutritional status, fluid administration, functional status, and comorbidity stabilizing therapy in this group of frail patients. This article presents an up-to-date review of the main aspects of CAP in elderly patients, including epidemiology, causative organisms, clinical features, and prognosis, and assesses key points for best practices for the management of the disease. PMID:25165554

Cost-benefit analysis of interferon alfa-2b in treatment of hairy cell leukemia.

PubMed

Ozer, H; Golomb, H M; Zimmerman, H; Spiegel, R J

1989-04-19

The clinical benefits as well as the cost benefits of use of recombinant interferon (IFN) alfa-2b instead of conventional chemotherapy (primarily chlorambucil) for progressive hairy cell leukemia were assessed retrospectively on the basis of 12 months of clinical data from 128 patients treated with IFN alfa-2b. Data from 71 matched historical control patients who had received conventional treatment were used for survival analysis. Hematologic response (reversal of cytopenias) was achieved by 18% of the control patients versus 73% of the IFN-treated patients. This response was associated with virtual elimination of the need for transfusions and splenectomy as well as dramatic decreases in the frequency of fatal infections (22.5% vs. 1.6%) and the 12-month mortality rate (28% vs. 3.1%). Direct costs per patient per year for medical care (transfusions, antibiotic treatment, splenectomy, and chemotherapy) of those receiving IFN alfa-2b were 2.8-fold lower than costs for medical care of control patients ($5,027 vs. $14,046). Indirect costs, which reflect the present value of future earnings lost due to premature death, were 13.3-fold lower for IFN-treated patients than for control patients ($4,771 vs. $63,507). Our analysis demonstrates that IFN alfa-2b offers substantial clinical and cost advantages to patients with hairy cell leukemia and that the introduction of this therapy using novel biotechnology furthers the health care community's commitment to cost containment.

Developments in neonatal care and nursing responses.

PubMed

Healy, Patricia; Fallon, Anne

This article reviews the origins and evolution of neonatology and considers the role of the neonatal nurse within this specialty. Neonatal nurses are a vital part of the neonatal team that provides care for sick babies. The nursing care required by sick babies and their families on a neonatal unit can be variable and complex. The past century has seen significant changes in the role of the neonatal nurse. This has come about through dramatic technological developments on neonatal units, an increased understanding of neonatal physiology and pathology, changes in the education of neonatal nurses, and active and ongoing clinical research within the specialty. The resulting significant advances in neonatal care, including that provided by neonatal nurses, have made a crucial and steadfast contribution to marked improvements in neonatal outcomes.

Longitudinal monitoring of EGFR mutations in plasma predicts outcomes of NSCLC patients treated with EGFR TKIs: Korean Lung Cancer Consortium (KLCC-12-02).

PubMed

Lee, Ji Yun; Qing, Xu; Xiumin, Wei; Yali, Bai; Chi, Sangah; Bak, So Hyeon; Lee, Ho Yun; Sun, Jong-Mu; Lee, Se-Hoon; Ahn, Jin Seok; Cho, Eun Kyung; Kim, Dong-Wan; Kim, Hye Ryun; Min, Young Joo; Jung, Sin-Ho; Park, Keunchil; Mao, Mao; Ahn, Myung-Ju

2016-02-09

We hypothesized that plasma-based EGFR mutation analysis for NSCLC may be feasible for monitoring treatment response to EGFR TKIs and also predict drug resistance.Clinically relevant mutations including exon 19 deletion (ex19del), L858R and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples (n = 367) from 81 NSCLC patients treated with EGFR TKI. Of a total 58 baseline cell-free DNA (cfDNA) samples available for ddPCR analysis, 43 (74.1%) had the same mutation in the matched tumors (clinical sensitivity: 70.8% [17/24] for L858R and 76.5% [26/34] for ex19del). The concordance rates of plasma with tissue-based results of EGFR mutations were 87.9% for L858R and 86.2% for ex19del. All 40 patients who were detected EGFR mutations at baseline showed a dramatic decrease of mutant copies (>50%) in plasma during the first two months after treatment. Median progression-free survival (PFS) was 10.1 months for patients with undetectable EGFR v 6.3 months for detectable EGFR mutations in blood after two-month treatment (HR 3.88, 95% CI 1.48-10.19, P = 0.006). We observed emerging resistance with early detection of T790M as a secondary mutation in 14 (28.6%) of 49 patients. Plasma-based EGFR mutation analysis using ddPCR can monitor treatment response to EGFR TKIs and can lead to early detection of EGFR TKIs resistance. Further studies confirming clinical implications of EGFR mutation in plasma are warranted to guide optimal therapeutic strategies upon knowledge of treatment response and resistance.

Two Novel Point Mutations in Clinical Staphylococcus aureus Reduce Linezolid Susceptibility and Switch on the Stringent Response to Promote Persistent Infection

PubMed Central

Gao, Wei; Chua, Kyra; Davies, John K.; Newton, Hayley J.; Seemann, Torsten; Harrison, Paul F.; Holmes, Natasha E.; Rhee, Hyun-Woo; Hong, Jong-In; Hartland, Elizabeth L.; Stinear, Timothy P.; Howden, Benjamin P.

2010-01-01

Staphylococcus aureus frequently invades the human bloodstream, leading to life threatening bacteremia and often secondary foci of infection. Failure of antibiotic therapy to eradicate infection is frequently described; in some cases associated with altered S. aureus antimicrobial resistance or the small colony variant (SCV) phenotype. Newer antimicrobials, such as linezolid, remain the last available therapy for some patients with multi-resistant S. aureus infections. Using comparative and functional genomics we investigated the molecular determinants of resistance and SCV formation in sequential S. aureus isolates from a patient who had a persistent and recurrent S. aureus infection, after failed therapy with multiple antimicrobials, including linezolid. Two point mutations in key staphylococcal genes dramatically affected clinical behaviour of the bacterium, altering virulence and antimicrobial resistance. Most strikingly, a single nucleotide substitution in relA (SACOL1689) reduced RelA hydrolase activity and caused accumulation of the intracellular signalling molecule guanosine 3′, 5′-bis(diphosphate) (ppGpp) and permanent activation of the stringent response, which has not previously been reported in S. aureus. Using the clinical isolate and a defined mutant with an identical relA mutation, we demonstrate for the first time the impact of an active stringent response in S. aureus, which was associated with reduced growth, and attenuated virulence in the Galleria mellonella model. In addition, a mutation in rlmN (SACOL1230), encoding a ribosomal methyltransferase that methylates 23S rRNA at position A2503, caused a reduction in linezolid susceptibility. These results reinforce the exquisite adaptability of S. aureus and show how subtle molecular changes cause major alterations in bacterial behaviour, as well as highlighting potential weaknesses of current antibiotic treatment regimens. PMID:20548948

A simplified immunoprecipitation method for quantitatively measuring antibody responses in clinical sera samples by using mammalian-produced Renilla luciferase-antigen fusion proteins.

PubMed

Burbelo, Peter D; Goldman, Radoslav; Mattson, Thomas L

2005-08-18

Assays detecting human antigen-specific antibodies are medically useful. However, the usefulness of existing simple immunoassay formats is limited by technical considerations such as sera antibodies to contaminants in insufficiently pure antigen, a problem likely exacerbated when antigen panels are screened to obtain clinically useful data. We developed a novel and simple immunoprecipitation technology for identifying clinical sera containing antigen-specific antibodies and for generating quantitative antibody response profiles. This method is based on fusing protein antigens to an enzyme reporter, Renilla luciferase (Ruc), and expressing these fusions in mammalian cells, where mammalian-specific post-translational modifications can be added. After mixing crude extracts, sera and protein A/G beads together and incubating, during which the Ruc-antigen fusion become immobilized on the A/G beads, antigen-specific antibody is quantitated by washing the beads and adding coelenterazine substrate and measuring light production. We have characterized this technology with sera from patients having three different types of cancers. We show that 20-85% of these sera contain significant titers of antibodies against at least one of five frequently mutated and/or overexpressed tumor-associated proteins. Five of six colon cancer sera tested gave responses that were statistically significantly greater than the average plus three standard deviations of 10 control sera. The results of competition experiments, preincubating positive sera with unmodified E. coli-produced antigens, varied dramatically. This technology has several advantages over current quantitative immunoassays including its relative simplicity, its avoidance of problems associated with E. coli-produced antigens and its use of antigens that can carry mammalian or disease-specific post-translational modifications. This assay should be generally useful for analyzing sera for antibodies recognizing any protein or its post-translational modifications.

A simplified immunoprecipitation method for quantitatively measuring antibody responses in clinical sera samples by using mammalian-produced Renilla luciferase-antigen fusion proteins

PubMed Central

Burbelo, Peter D; Goldman, Radoslav; Mattson, Thomas L

2005-01-01

Background Assays detecting human antigen-specific antibodies are medically useful. However, the usefulness of existing simple immunoassay formats is limited by technical considerations such as sera antibodies to contaminants in insufficiently pure antigen, a problem likely exacerbated when antigen panels are screened to obtain clinically useful data. Results We developed a novel and simple immunoprecipitation technology for identifying clinical sera containing antigen-specific antibodies and for generating quantitative antibody response profiles. This method is based on fusing protein antigens to an enzyme reporter, Renilla luciferase (Ruc), and expressing these fusions in mammalian cells, where mammalian-specific post-translational modifications can be added. After mixing crude extracts, sera and protein A/G beads together and incubating, during which the Ruc-antigen fusion become immobilized on the A/G beads, antigen-specific antibody is quantitated by washing the beads and adding coelenterazine substrate and measuring light production. We have characterized this technology with sera from patients having three different types of cancers. We show that 20–85% of these sera contain significant titers of antibodies against at least one of five frequently mutated and/or overexpressed tumor-associated proteins. Five of six colon cancer sera tested gave responses that were statistically significantly greater than the average plus three standard deviations of 10 control sera. The results of competition experiments, preincubating positive sera with unmodified E. coli-produced antigens, varied dramatically. Conclusion This technology has several advantages over current quantitative immunoassays including its relative simplicity, its avoidance of problems associated with E. coli-produced antigens and its use of antigens that can carry mammalian or disease-specific post-translational modifications. This assay should be generally useful for analyzing sera for antibodies recognizing any protein or its post-translational modifications. PMID:16109166

[The transsexualism syndrome: clinical aspects and therapeutic prospects].

PubMed

Gallarda, T; Amado, I; Coussinoux, S; Poirier, M F; Cordier, B; Olié, J P

1997-01-01

The prevalence rate of transsexualism varies from 1 to 50,000, to 1 to 100,000. Although it remains an infrequent affliction, transsexualism generates usually major suffering and may be responsible of many complications like suicide, self-mutilations, affective disorders and social disabilities. Since the first descriptions of Esquirol in the nineteenth, the medical community has always been questioned on medical, legal, social or ethical aspects of transsexualism. The aetiology of the trouble is still unknown. In the absence of biological marker, the syndrome of transsexualism can be defined only with clinical criteria. The main differential diagnosis are sexual ambiguities and psychotic disorders. For the specialists, satisfying the patients demand of a surgical and social reassignment still remains the only way to improve their clinical condition and avoid the onset of many dramatic complications. Without any treatment, the evolution of the trouble is chronic, without remission. Longitudinal studies of transsexual patients with a five year follow-up demonstrated subjective improvement in two thirds of the patients and don't find either higher rates of suicides nor psychotic decompensations after surgery and hormonotherapy. Clinical and neuropsychological studies of sexually differentiated cognitive abilities of transsexual patients, before and after hormonotherapy, could allow us in improving the understanding of sexual differences of the brain.

Protecting emergency responders, volume 3 : safety management in disaster and terrorism response.

DOT National Transportation Integrated Search

2004-01-01

When disaster strikes, the nation depends on the emergency response community. : No events demonstrated this truth as dramatically as the catastrophic terrorist attacks : of September 11, 2001. But the same holds true every time the nation faces a ma...

Recent advances in circulating tumor cells and cell-free DNA in metastatic prostate cancer: a review.

PubMed

Parimi, Sunil; Ko, Jenny J

2017-10-01

The treatment landscape of metastatic prostate cancer has changed dramatically over the past five years. As new discoveries are made and further novel therapies become available, there is a heightened urgency to develop biomarkers that can guide prognoses and predict therapy responses. Circulating tumor cells (CTCs) and cell-free circulating tumor DNA (ctDNA) in the blood have emerged as potential promising tumor avatars. Areas covered: In this review, we describe technological breakthroughs and clinical implementation of the CTCs and ctDNA. We also discuss the key challenges that must be overcome before circulating blood-based biomarkers can be universally adopted into the management of patients with metastatic prostate cancer. Expert commentary: Both CTCs and ctDNA have the potential to be incorporated into routine patient care, with increasing numbers of prospective trials incorporating them into clinical designs. CTCs and ctDNA will thus have an increasingly valuable role in augmenting our understanding of prostate cancer at a molecular level, aiding in prognostication of prostate cancer patients, acting as a surrogate for OS in clinical trials, and helping us prioritize our treatment selections by elucidating resistance mechanisms.

SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery

PubMed Central

2011-01-01

Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies. PMID:21929757

Recent progress in relapsed multiple myeloma therapy: implications for treatment decisions.

PubMed

Moreau, Philippe; de Wit, Edwin

2017-10-01

The availability of novel therapies for the treatment of multiple myeloma has had a dramatic impact on the depth of response that can be expected on initial treatment. Despite these advances, disease relapse remains inevitable in most patients and brings with it a different set of priorities for therapy. The most recent wave of novel agents may have a particular impact in the relapsed setting. In this review, we examine the evidence currently available from clinical trials for the use of novel agents, particularly in the formation of triplet therapy. We consider data supporting the addition of the proteasome inhibitors carfilzomib and ixazomib, or the monoclonal antibodies elotuzumab or daratumumab, to a treatment backbone of lenalidomide and dexamethasone. The clinical data set is less well developed for the addition of a third agent to the combination of bortezomib and dexamethasone; nonetheless, data are presented supporting the addition of the histone deacetylase inhibitor panobinostat, or elotuzumab or daratumumab. While acknowledging the lack of head-to-head data on which to base comparisons between the numerous regimens, we collate the latest data in order to provide a basis on which to make clinical decisions in this rapidly advancing field. © 2017 John Wiley & Sons Ltd.

HER2 mutated breast cancer responds to treatment with single agent neratinib, a second generation HER2/EGFR tyrosine kinase inhibitor

PubMed Central

Ben–Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M.; Ma, Cynthia X.; Ellis, Matthew J.

2015-01-01

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2 targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. In this case report, we describe a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second generation HER2/EGFR tyrosine kinase inhibitor, neratinib, resulted in partial response and dramatic improvement in the patient’s function status. This partial response lasted 11 months and when the patient’s cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2 amplified breast cancer after disease progression. This case is the first report, to our knowledge, of successful single agent treatment of HER2 mutated breast cancer. Two clinical trials of neratinib for HER2 mutated, metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancer, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2 mutated solid tumors is warranted. PMID:26358790

Smart surface coating of drug nanoparticles with cross-linkable polyethylene glycol for bio-responsive and highly efficient drug delivery.

PubMed

Wei, Weijia; Zhang, Xiujuan; Chen, Xianfeng; Zhou, Mengjiao; Xu, Ruirui; Zhang, Xiaohong

2016-04-21

Many drug molecules can be directly used as nanomedicine without the requirement of any inorganic or organic carriers such as silica and liposome nanostructures. This new type of carrier-free drug nanoparticles (NPs) has great potential in clinical treatment because of its ultra-high drug loading capacity and biodegradability. For practical applications, it is essential for such nanomedicine to possess robust stability and minimal premature release of therapeutic molecules during circulation in the blood stream. To meet this requirement, herein, we develop GSH-responsive and crosslinkable amphiphilic polyethylene glycol (PEG) molecules to modify carrier-free drug NPs. These PEG molecules can be cross-linked on the surface of the NPs to endow them with greater stability and the cross-link is sensitive to intracellular environment for bio-responsive drug release. With this elegant design, our experimental results show that the liberation of DOX from DOX-cross-linked PEG NPs is dramatically slower than that from DOX-non-cross-linked PEG NPs, and the DOX release profile can be controlled by tuning the concentration of the reducing agent to break the cross-link between PEG molecules. More importantly, in vivo studies reveal that the DOX-cross-linked PEG NPs exhibit favorable blood circulation half-life (>4 h) and intense accumulation in tumor areas, enabling effective anti-cancer therapy. We expect this work will provide a powerful strategy for stabilizing carrier-free nanomedicines and pave the way to their successful clinical applications in the future.

A Toy Clinic Shop: Innovation Management in a Shin-Tai Elementary School

ERIC Educational Resources Information Center

Hong, Jon-Chao; Hwang, Ming-Yueh; Liang, Hwey-Wen; Chang, Hsin-Wu

2008-01-01

In Taiwan there is a declining birth rate and a dramatic increase in the elderly population. There is also the trend of using school space that would otherwise be left unused. The experimental project "Toy Clinic Shop in Elementary School" offers an innovative management model for elementary schools to address these developments. The…

Initial Results of a New Clinical Practice Model: Impact on Learners at Risk

ERIC Educational Resources Information Center

Wasburn-Moses, Leah; Noltemeyer, Amity L.; Schmitz, Kristin J.

2015-01-01

The last several years have seen a dramatic increase in interest surrounding the role of clinical experiences in enhancing the learning of teacher candidates. Further, pressure has intensified to demonstrate the impact of teacher candidates on P-12 learners. With these goals in mind, a model alternative school/university partnership was created,…

Management Development in Health Care: Exploring the Experiences of Clinical Nurse Managers

ERIC Educational Resources Information Center

Purcell, Laura; Milner, Brigid

2005-01-01

Purpose--The purpose of this paper is to investigate the dramatic reforms in the health service in recent years. Design/methodology/approach--Examines management development in health care, and explores the experiences of clinical nurse managers. Findings--Duplication of agencies and multiplication of roles have led to tensions in terms of both…

Primary Healthcare Provider Knowledge, Beliefs and Clinic-Based Practices Regarding Alternative Tobacco Products and Marijuana: A Qualitative Study

ERIC Educational Resources Information Center

Bascombe, Ta Misha S.; Scott, Kimberly N.; Ballard, Denise; Smith, Samantha A.; Thompson, Winifred; Berg, Carla J.

2016-01-01

Use prevalence of alternative tobacco products and marijuana has increased dramatically. Unfortunately, clinical guidelines have focused on traditional cigarettes with limited attention regarding these emerging public health issues. Thus, it is critical to understand how healthcare professionals view this issue and are responding to it. This…

A dramatic increase in the positive blood culture rates of Helicobacter cinaedi: the evidence of differential detection abilities between the Bactec and BacT/Alert systems.

PubMed

Miyake, Noriko; Chong, Yong; Nishida, Ruriko; Nagasaki, Yoji; Kibe, Yasushi; Kiyosuke, Makiko; Shimomura, Takeshi; Shimono, Nobuyuki; Shimoda, Shinji; Akashi, Koichi

2015-11-01

In our hospital, positive blood culture rates of Helicobacter cinaedi dramatically increased after introducing the Bactec system. A simulated culture model of H. cinaedi bacteremia demonstrated no positive signals using the BacT/Alert system, despite efficient growth in bottles. Clinically suspected H. cinaedi bacteremia should be monitored more closely when using the BacT/Alert system, preferably with subcultivation after 7days of incubation. Copyright © 2015 Elsevier Inc. All rights reserved.

Standardized Guidance for the Establishment of a National Hydrographic Office in Developing Nations.

DTIC Science & Technology

1984-09-01

important as nations look to the sea for increasing supplies and new sources of food for burgeoning populations. 3. Military Considerations Military factors...Operations Franch The Survey Operations Branch will be responsible for all aspects of field operations 6 and will be organi7ed in five sections. (1...supplemental expendi- tures would be decreased dramatically. There would be a dramatic decline in travel expenditures, living expenses for food and lodging

[Role of the midbrain reticular formation in hormonal supply to the body in conditions of chronic emotional stress].

PubMed

Amiragova, M G; Arakhangel'skaia, M I

1983-08-01

Chronic animal experiments were made to study the endocrine and electroencephalographic responses of the cortico-subcortical structures to stress before and after coagulation of the midbrain reticular formation. The operation entailed dramatic changes in both the bioelectrical responses and thyroid and adrenal responses, which were found to be differentiated.

Evidence for factors modulating radiation-induced G2-delay: potential application as radioprotectors

NASA Technical Reports Server (NTRS)

Cheong, N.; Zeng, Z. C.; Wang, Y.; Iliakis, G.

2001-01-01

Manipulation of checkpoint response to DNA damage can be developed as a means for protecting astronauts from the adverse effects of unexpected, or background exposures to ionizing radiation. To achieve this goal reagents need to be developed that protect cells from radiation injury by prolonging checkpoint response, thus promoting repair. We present evidence for a low molecular weight substance excreted by cells that dramatically increases the duration of the G2-delay. This compound is termed G2-Arrest Modulating Activity (GAMA). A rat cell line (A1-5) generated by transforming rat embryo fibroblasts with a temperature sensitive form of p53 plus H-ras demonstrates a dramatic increase in radiation resistance after exposure to low LET radiation that is not associated with an increase in the efficiency of rejoining of DNA double strand breaks. Radioresistance in this cell line correlates with a dramatic increase in the duration of the G2 arrest that is modulated by a GAMA produced by actively growing cells. The properties of GAMA suggest that it is a low molecular weight heat-stable peptide. Further characterization of this substance and elucidation of its mechanism of action may allow the development of a biological response modifier with potential applications as a radioprotector. GAMA may be useful for protecting astronauts from radiation injury as preliminary evidence suggests that it is able to modulate the response of cells exposed to heavy ion radiation, similar to that encountered in outer space.

Requirement of the isocitrate lyase gene ICL1 for VPS41-mediated starvation response in Cryptococcus neoformans.

PubMed

Xu, Zhe; Zhi, Yafei; Dong, Jianzhang; Lin, Benfeng; Ye, Di; Liu, Xiaoguang

2016-07-01

Cryptococcus neoformans is a major cause of fungal meningitis in individuals with impaired immunity. Our previous studies have shown that the VPS41 gene plays a critical role in the survival of Cryptococcus neoformans under nitrogen starvation; however, the molecular mechanisms underlying VPS41-mediated starvation response remain to be elucidated. In the present study, we show that, under nitrogen starvation, VPS41 strongly enhanced ICL1 expression in C. neoformans and that overexpression of ICL1 in the vps41 mutant dramatically suppressed its defects in starvation response due to the loss of VPS41 function. Moreover, targeted deletion of ICL1 resulted in a dramatic decline in viability of C. neoformans cells under nitrogen deprivation. Taken together, our data suggest a model in which VPS41 up-regulates ICL1 expression, directly or indirectly, to promote survival of C. neoformans under nitrogen starvation.

Dramatically Promoted Swelling of a Hydrogel by Pillar[6]arene-Ferrocene Complexation with Multistimuli Responsiveness.

PubMed

Ni, Mengfei; Zhang, Ning; Xia, Wei; Wu, Xuan; Yao, Chenhao; Liu, Xin; Hu, Xiao-Yu; Lin, Chen; Wang, Leyong

2016-05-25

The swelling-shrinking transition of hydrogels is crucial for their wide applications such as actuators and drug delivery. We hereby fabricated a smart hydrogel with ferrocene groups on pendant of polymer networks. While it was immersed in the water-soluble pillar[6]arene (WP6) aqueous solution, the hydrogel was dramatically swollen, which was an approximately 11-fold promotion in weight compared with that in pure water, due to the formation of the inclusion complexes between WP6 and ferrocene groups in the hydrogel. In particular, the well-swollen hydrogel exhibited good responsiveness to multistimuli including temperature, pH, redox, and competitive guests by tuning the dissociation/formation of WP6-ferrocene inclusion complexes or the strength of their charges. Meanwhile, potential application of such a smart hydrogel in pH-responsive drug release was demonstrated as well.

Decorin in human oral cancer: A promising predictive biomarker of S-1 neoadjuvant chemosensitivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kasamatsu, Atsushi, E-mail: kasamatsua@faculty.chiba-u.jp; Department of Dentistry and Oral–Maxillofacial Surgery, Chiba University Hospital, Chiba 260-8670; Uzawa, Katsuhiro, E-mail: uzawak@faculty.chiba-u.jp

Highlights: • DCN is significantly up-regulated in chemoresistant cancer cell lines. • DCN is a key regulator for chemoresistant mechanisms in vitro and in vivo. • DCN predicts the clinical responses to S-1 NAC for patients with oral cancer. - Abstract: We reported previously that decorin (DCN) is significantly up-regulated in chemoresistant cancer cell lines. DCN is a small leucine-rich proteoglycan that exists and functions in stromal and epithelial cells. Accumulating evidence suggests that DCN affects the biology of several types of cancer by directly/indirectly targeting the signaling molecules involved in cell growth, survival, metastasis, and angiogenesis, however, the molecularmore » mechanisms of DCN in chemoresistance and its clinical relevance are still unknown. Here we assumed that DCN silencing cells increase chemosusceptibility to S-1, consisted of tegafur, prodrug of 5-fluorouracil. We first established DCN knockdown transfectants derived from oral cancer cells for following experiments including chemosusceptibility assay to S-1. In addition to the in vitro data, DCN knockdown zenografting tumors in nude mice demonstrate decreasing cell proliferation and increasing apoptosis with dephosphorylation of AKT after S-1 chemotherapy. We also investigated whether DCN expression predicts the clinical responses of neoadjuvant chemotherapy (NAC) using S-1 (S-1 NAC) for oral cancer patients. Immunohistochemistry data in the preoperative biopsy samples was analyzed to determine the cut-off point for status of DCN expression by receiver operating curve analysis. Interestingly, low DCN expression was observed in five (83%) of six cases with complete responses to S-1 NAC, and in one (10%) case of 10 cases with stable/progressive disease, indicating that S-1 chemosensitivity is dramatically effective in oral cancer patients with low DCN expression compared with high DCN expression. Our findings suggest that DCN is a key regulator for chemoresistant mechanisms, and is a predictive immunomarker of the response to S-1 NAC and patient prognosis.« less

MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts.

PubMed

Zhang, Xiaomeng; Wojtkowiak, Jonathan W; Martinez, Gary V; Cornnell, Heather H; Hart, Charles P; Baker, Amanda F; Gillies, Robert

2016-01-01

TH-302 is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. It is currently being evaluated in clinical trials, including two trials in Pancreatic Ductal Adenocarcinomas (PDAC). The current study was undertaken to evaluate imaging biomarkers for prediction and response monitoring of TH-302 efficacy in xenograft models of PDAC. Dynamic contrast-enhanced (DCE) and diffusion weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor vasculature and cellularity, respectively. Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC) maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans) within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Tumor cellularity, estimated from ADC, was significantly increased 24 and 48 hours after treatment in Hs766t, but was not observed in the Mia PaCa-2 and SU.86.86 groups. Notably, growth inhibition of Hs766t was observed immediately (day 3) following initiation of treatment, but was not observed in MiaPaCa-2 tumors until 8 days after initiation of treatment. Based on these preclinical findings, DCE-MRI measures of vascular perfusion dynamics and ADC measures of cell density are suggested as potential TH-302 response biomarkers in clinical trials.

DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21WAF1/CIP1.

PubMed

Xu, Shun; Huang, Haijiao; Chen, Yu-Ning; Deng, Yun-Ting; Zhang, Bing; Xiong, Xing-Dong; Yuan, Yuan; Zhu, Yanmei; Huang, Haiyong; Xie, Luoyijun; Liu, Xinguang

2016-11-01

Cisplatin is the most potent and widespread used chemotherapy drug for lung cancer treatment. However, the development of resistance to cisplatin is a major obstacle in clinical therapy. The principal mechanism of cisplatin is the induction of DNA damage, thus the capability of DNA damage response (DDR) is a key factor that influences the cisplatin sensitivity of cancer cells. Recent advances have demonstrated that miRNAs (microRNAs) exerted critical roles in DNA damage response; nonetheless, the association between DNA damage responsive miRNAs and cisplatin resistance and its underlying molecular mechanism still require further investigation. The present study has attempted to identify differentially expressed miRNAs in cisplatin induced DNA damage response in lung cancer cells, and probe into the effects of the misexpressed miRNAs on cisplatin sensitivity. Deep sequencing showed that miR-33b-3p was dramatically down-regulated in cisplatin-induced DNA damage response in A549 cells; and ectopic expression of miR-33b-3p endowed the lung cancer cells with enhanced survival and decreased γH2A.X expression level under cisplatin treatment. Consistently, silencing of miR-33b-3p in the cisplatin-resistant A549/DDP cells evidently sensitized the cells to cisplatin. Furthermore, we identified CDKN1A (p21) as a functional target of miR-33b-3p, a critical regulator of G1/S checkpoint, which potentially mediated the protection effects of miR-33b-3p against cisplatin. In aggregate, our results suggested that miR-33b-3p modulated the cisplatin sensitivity of cancer cells might probably through impairing the DNA damage response. And the knowledge of the drug resistance conferred by miR-33b-3p has great clinical implications for improving the efficacy of chemotherapies for treating lung cancers.

Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES).

PubMed

Illingworth, Marjorie A; Hanrahan, Donncha; Anderson, Claire E; O'Kane, Kathryn; Anderson, Jennifer; Casey, Maureen; de Sousa, Carlos; Cross, J Helen; Wright, Sukvhir; Dale, Russell C; Vincent, Angela; Kurian, Manju A

2011-11-01

Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and behavioural difficulties. We describe a case of FIRES in a 4-year-old boy that was associated with elevated voltage-gated potassium channel (VGKC) complex antibodies and a significant clinical and immunological response to immunomodulation. This case, therefore, potentially expands the clinical phenotype of VGKC antibody-associated disease to include that of FIRES. Prior to immunomodulation, neuropsychology assessment highlighted significant attention, memory, and word-finding difficulties. The UK version of the Wechsler Preschool and Primary Scale of Intelligence assessment indicated particular difficulties with verbal skills (9th centile). Immunomodulation was initially administered as intravenous methylprednisolone (followed by maintenance oral prednisolone) and later in the disease course as regular monthly intravenous immunoglobulin infusions and low-dose azathioprine. Now aged 6 years, the seizure burden in this child is much reduced, although increased seizure frequency is observed in the few days before his monthly immunoglobulin infusions. Formal IQ assessment has not been repeated but there is no clinical suggestion of further cognitive regression. VGKC complex antibodies have been reported in a range of central and peripheral neurological disorders (predominantly presenting in adulthood), and the identification of elevated VGKC complex antibodies, combined with the response to immunotherapies in this child, supports an autoimmune pathogenesis in FIRES with potential diagnostic and therapeutic implications. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

Gender Issues in Gifted Achievement: Are Girls Making Inroads While Boys Fall Behind?

ERIC Educational Resources Information Center

Rimm, Sylvia B.

2015-01-01

School and life achievement patterns for girls and women differ from those of boys and men. While girls have made dramatic progress in school, they need to be inspired to connect to lifelong achievement. Both research and clinical work at the Ohio-based Family Achievement Clinic find that more boys than girls underachieve in school. There is much…

A novel response to an outbreak of infectious syphilis in Christchurch, New Zealand.

PubMed

Coughlan, Edward; Young, Heather; Parkes, Catherine; Coshall, Maureen; Dickson, Nigel; Psutka, Rebecca; Saxton, Peter; Pink, Ramon; Adams, Katharine

2015-04-01

During 2012, Christchurch experienced a dramatic increase in cases of infectious syphilis among men who have sex with men. This was accompanied by some novel trends; notably, the acquisition of infection in a younger age group, with local sexual contacts, commonly via the use of social media. This study is a report on an approach to case identification and public health communication as a component of a multifaceted outbreak response. Enhanced syphilis surveillance data on public health responses to outbreaks of sexually transmissible infections was collated and reviewed, alongside clinical records and literature. Reported outbreak response methods were adapted for the Christchurch cohort. A Facebook page was created to raise awareness of infectious syphilis, the importance of screening and where to get tested. Twenty-six males were diagnosed with infectious syphilis in 2012, an increase from previous years, of which 22 reported only male sexual contact. High use of social media used to find potential sexual contacts was reported. Enhanced syphilis surveillance characterised in detail an infectious syphilis outbreak in Christchurch. Index cases were identified, contact tracing mapping was used to identify transmission networks and social media was also used to educate the risk group. There was a decrease in infectious syphilis presentations, with no cases in the last 3 months of 2012.

Syncope: what is the trigger?

PubMed

Hainsworth, R

2003-02-01

Although a syncopal attack is frequently preceded by prodromal symptoms, sometimes the onset can be so abrupt that there is no warning at all. The switch in autonomic responses responsible for such an attack is quite rapid and dramatic, but the trigger for this remains one of the unresolved mysteries in cardiovascular physiology.

Methods for transcriptomic analyses of the porcine host immune response: application to Salmonella infection using microarrays

USDA-ARS?s Scientific Manuscript database

Technological developments in both the collection and analysis of molecular genetic data over the past few years have provided new opportunities for an improved understanding of the global response to pathogen exposure. Such developments are particularly dramatic for scientists studying the pig, whe...

Electrical and Optical Activation of Mesoscale Neural Circuits with Implications for Coding.

PubMed

Millard, Daniel C; Whitmire, Clarissa J; Gollnick, Clare A; Rozell, Christopher J; Stanley, Garrett B

2015-11-25

Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery of circuit function and for engineered approaches to alleviate various disorders of the nervous system. However, evidence suggests that neural activity generated by artificial stimuli differs dramatically from normal circuit function, in terms of both the local neuronal population activity at the site of activation and the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. Here, we used voltage-sensitive dye imaging of primary somatosensory cortex in the anesthetized rat in response to deflections of the facial vibrissae and electrical or optogenetic stimulation of thalamic neurons that project directly to the somatosensory cortex. Although the different inputs produced responses that were similar in terms of the average cortical activation, the variability of the cortical response was strikingly different for artificial versus sensory inputs. Furthermore, electrical microstimulation resulted in highly unnatural spatial activation of cortex, whereas optical input resulted in spatial cortical activation that was similar to that induced by sensory inputs. A thalamocortical network model suggested that observed differences could be explained by differences in the way in which artificial and natural inputs modulate the magnitude and synchrony of population activity. Finally, the variability structure in the response for each case strongly influenced the optimal inputs for driving the pathway from the perspective of an ideal observer of cortical activation when considered in the context of information transmission. Artificial activation of neural circuitry through electrical microstimulation and optogenetic techniques is important for both scientific discovery and clinical translation. However, neural activity generated by these artificial means differs dramatically from normal circuit function, both locally and in the propagation to downstream brain structures. The precise nature of these differences and the implications for information processing remain unknown. The significance of this work is in quantifying the differences, elucidating likely mechanisms underlying the differences, and determining the implications for information processing. Copyright © 2015 the authors 0270-6474/15/3515702-14$15.00/0.

A case of idiopathic diabetes insipidus presented with bilateral hydroureteronephrosis and neurogenic bladder: A pediatric case report and literature review

PubMed Central

Yuksel, Ozgur Haki; Kivrak, Mithat; Sahin, Aytac; Akan, Serkan; Urkmez, Ahmet; Verit, Ayhan

2015-01-01

Diabetes insipidus (DI) is a condition with heterogeneous clinical symptoms characterized by polyuria (urine output >4 mL/kg/hr) and polydipsia (water intake >2 L/m 2/d). In children, acquired nephrogenic DI (NDI) is more common than central DI (CDI). Diagnosis is based on the presence of high plasma osmolality and low urinary osmolality with significant water diuresis. A water deprivation test with vasopressin challenge, though has limitations, is done to differentiate NDI from CDI and diagnose their incomplete forms. Neonates and young infants are better managed with hydration therapy alone. Older children with CDI are treated with desmopressin (1-deamino-8-D-arginine vasopressin, dDAVP). Its oral form is safe, highly effective and has dosing flexibility. We report a case of an 8-year-old male patient with CDI with severe bilateral non-obstructive hydronephrosis and megaureter. Dramatic clinical and radiological responses to dDAVP treatment were achieved and therapy reduced urine volume and led to marked radiological improvement in hydronephrosis. PMID:26600892

A case of idiopathic diabetes insipidus presented with bilateral hydroureteronephrosis and neurogenic bladder: A pediatric case report and literature review.

PubMed

Yuksel, Ozgur Haki; Kivrak, Mithat; Sahin, Aytac; Akan, Serkan; Urkmez, Ahmet; Verit, Ayhan

2015-01-01

Diabetes insipidus (DI) is a condition with heterogeneous clinical symptoms characterized by polyuria (urine output >4 mL/kg/hr) and polydipsia (water intake >2 L/m (2)/d). In children, acquired nephrogenic DI (NDI) is more common than central DI (CDI). Diagnosis is based on the presence of high plasma osmolality and low urinary osmolality with significant water diuresis. A water deprivation test with vasopressin challenge, though has limitations, is done to differentiate NDI from CDI and diagnose their incomplete forms. Neonates and young infants are better managed with hydration therapy alone. Older children with CDI are treated with desmopressin (1-deamino-8-D-arginine vasopressin, dDAVP). Its oral form is safe, highly effective and has dosing flexibility. We report a case of an 8-year-old male patient with CDI with severe bilateral non-obstructive hydronephrosis and megaureter. Dramatic clinical and radiological responses to dDAVP treatment were achieved and therapy reduced urine volume and led to marked radiological improvement in hydronephrosis.

Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research.

PubMed

Kavey, Rae-Ellen W; Allada, Vivek; Daniels, Stephen R; Hayman, Laura L; McCrindle, Brian W; Newburger, Jane W; Parekh, Rulan S; Steinberger, Julia

2007-01-01

Although for most children the process of atherosclerosis is subclinical, dramatically accelerated atherosclerosis occurs in some pediatric disease states, with clinical coronary events occurring in childhood and very early adult life. As with most scientific statements about children and the future risk for cardiovascular disease, there are no randomized trials documenting the effects of risk reduction on hard clinical outcomes. A growing body of literature, however, identifies the importance of premature cardiovascular disease in the course of certain pediatric diagnoses and addresses the response to risk factor reduction. For this scientific statement, a panel of experts reviewed what is known about very premature cardiovascular disease in 8 high-risk pediatric diagnoses and, from the science base, developed practical recommendations for management of cardiovascular risk.

Treatment of inflammatory facial acne vulgaris in Chinese patients with the 1450-nm diode laser: a pilot study

NASA Astrophysics Data System (ADS)

Liu, Huaxu; Dang, Yongyan; Wang, Zhan; Ma, Li; Ren, Qiushi

2007-02-01

The 1450-nm diode laser has been found to be effective for the treatment of inflammatory acne in USA, Europe and Japan. However, there is no report on its efficacy in Chinese acne vulgaris patients. We conduct this pilot study to evaluate the efficacy and safety of the 1450-nm diode laser in the treatment of inflammatory facial acne vulgaris in Chinese patients. Nineteen patients with inflammatory facial acne were treated with the 1450-nm diode laser at 4- to 6-week intervals. Clinical photographs and lesion counts were obtained at baseline and after each treatment. Subjective evaluation of response to treatment and pain was assessed using a questionnaire. In our study, clinical improvement was seen in all patients and was generally dramatic. Lesion counts decreased 34% after one treatment (p<0.01), 56% after two treatments (p<0.01), and 81% after three treatments (p<0.01). However, the treatment-related pain was comparatively hard to be tolerated in Chinese patitents, and the other main adverse effect was the hyper-pigmentation after treatments (36.84%, 7/19).

Clinical manifestations of scrub typhus.

PubMed

Rajapakse, Senaka; Weeratunga, Praveen; Sivayoganathan, Sriharan; Fernando, Sumadhya Deepika

2017-02-01

The mite-borne rickettsial zoonosis scrub typhus is widely prevalent in parts of Southeast and Far East Asia, and northern Australia. The disease is an acute febrile illness, associated with rash and often an eschar, which responds dramatically to treatment with antibiotics. In some cases it results in a serious illness leading to multiple organ involvement and death. The disease manifestations are thought to result from a systemic vasculitis, caused by both direct effects of the organisms as well as an exaggerated immune response, although little is understood about its pathogenesis. A wide spectrum of clinical manifestations, affecting nearly every organ system, have been described with scrub typhus. Some of these manifestations are serious and life threatening. In this systematic review, we summarise the typical and atypical manifestations of scrub typhus reported in the literature. Awareness of these unusual manifestations will hopefully guide clinicians towards diagnosing the condition early, and initiating early appropriate antibiotics and other supportive measures. © The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A quality management systems approach for CD4 testing in resource-poor settings.

PubMed

Westerman, Larry E; Kohatsu, Luciana; Ortiz, Astrid; McClain, Bernice; Kaplan, Jonathan; Spira, Thomas; Marston, Barbara; Jani, Ilesh V; Nkengasong, John; Parsons, Linda M

2010-10-01

Quality assurance (QA) is a systematic process to monitor and improve clinical laboratory practices. The fundamental components of a laboratory QA program include providing a functional and safe laboratory environment, trained and competent personnel, maintained equipment, adequate supplies and reagents, testing of appropriate specimens, internal monitoring of quality, accurate reporting, and external quality assessments. These components are necessary to provide accurate and precise CD4 T-cell counts, an essential test to evaluate start of and monitor effectiveness of antiretroviral therapy for HIV-infected patients. In recent years, CD4 testing has expanded dramatically in resource-limited settings. Information on a CD4 QA program as described in this article will provide guidelines not only for clinical laboratory staff but also for managers of programs responsible for supporting CD4 testing. All agencies involved in implementing CD4 testing must understand the needs of the laboratory and provide advocacy, guidance, and financial support to established CD4 testing sites and programs. This article describes and explains the procedures that must be put in place to provide reliable CD4 determinations in a variety of settings.

Pharmacogenetics in dermatology: a patient-centered update.

PubMed

Comfere, Nneka I; Ikediobi, Ogechi N; Peters, Margot S; el-Azhary, Rokea A; Gibson, Lawrence E

2013-08-01

The term pharmacogenetics is used to describe an evolving field that aims to understand the relationship between individual variations in genetic sequence and differences in the therapeutic and toxic response to medications. The promise of pharmacogenetics is empowerment of clinicians with information that will enable them to personalize drug therapy - to prescribe the right medication at the right dose for each patient, while minimizing adverse effects. Despite dramatic advances, wide application of pharmacogenetics to clinical practice has been slow for a number of reasons, including lack of evidence-based therapeutic guidelines as well as ethical concerns and cost. To illustrate applications to dermatology practice, we present three clinical scenarios that serve as a springboard for discussion of the principles of pharmacogenetics and how they can be used to guide treatment with azathioprine, 5-fluorouracil, and trastuzumab. The therapeutic and toxic effects of a given medication ultimately depend on its combined pharmacokinetic, pharmacodynamic, and pharmacogenetic properties in a given individual. Pharmacodynamic properties of individual medications must be correlated with single nucleotide polymorphisms. Test recommendations and standardization of therapy for specific disorders can then be established. © 2013 The International Society of Dermatology.

The history of COPD.

PubMed

Petty, Thomas L

2006-01-01

The evolution of knowledge concerning COPD and its components--emphysema, chronic bronchitis, and asthmatic bronchitis--covers 200 years. The stethoscope and spirometer became important early tools in diagnosis and assessment. Spirometry remains the most effective means of identification and assessment of the course of COPD and responses to therapy, and is grossly underused for this purpose. Knowledge of the pathogenesis, course and prognosis, and new approaches to therapy have dramatically improved our understanding of this important clinical entity. Smoking cessation improves the early course of disease. Long-term oxygen improves the length and quality of life in selected patients with hypoxemia. Surgery benefits a select few. Today, COPD is a steadily growing global healthcare problem, with increasing morbidity and mortality. Early identification and prevention, and treatment of emerging stages of disease through smoking cessation and a growing number of bronchoactive drugs promises to change the outcome.

Prolonged exclusive breast-feeding from vegan mother causing an acute onset of isolated methylmalonic aciduria due to a mild mutase deficiency.

PubMed

Ciani, F; Poggi, G M; Pasquini, E; Donati, M A; Zammarchi, E

2000-04-01

We describe a case of methylmalonic aciduria (MMA) occurred in a 22-month-old boy whose diet was exclusively based upon breast-feeding from a mother following a long-lasting strict vegetarian diet. Clinical picture showed a dramatic onset, with a profound drowsiness associated with a severe metabolic acidosis, hyperammonemia, macrocytic anemia, ketonuria, and massive methylmalonic aciduria without homocystinuria. Both symptoms and biochemical findings quickly improved thanks to prompt vitamin B(12)parenteral therapy. Biochemical and enzymatic findings allowed a diagnosis of mild mutase deficiency, which only and inadequate dietary B(12)contribution might have revealed. Our case highlights the risk of a prolonged strictly vegetarian diet of lactating mother for providing inadequate amounts of some nutrients to the breast-fed baby. Moreover, such a dietary behaviour could dramatically unmask otherwise clinically unapparent metabolic defects in the baby. Copyright 2000 Harcourt Publishers Ltd.

Mast cells contribute to the mucosal adjuvant effect of CTA1-DD after IgG-complex formation.

PubMed

Fang, Yu; Larsson, Lisa; Mattsson, Johan; Lycke, Nils; Xiang, Zou

2010-09-01

Mast cell activation is one of the most dramatic immune-mediated responses the body can encounter. In the worst scenario (i.e., anaphylaxis), this response is fatal. However, the importance of mast cells as initiators and effectors of both innate and adaptive immunity in healthy individuals has recently been appreciated. It was reported that mast cell activation can be used as an adjuvant to promote Ag-specific humoral immune responses upon vaccination. In this study, we have used a clinically relevant mucosal adjuvant, cholera toxin A1 subunit (CTA1)-DD, which is a fusion protein composed of CTA1, the ADP-ribosylating part of cholera toxin, and DD, two Ig-binding domains derived from Staphylococcus aureus protein A. CTA1-DD in combination with polyclonal IgG induced degranulation and production of TNF-alpha from mouse mast cells. Furthermore, CTA1-DD and polyclonal IgG complex induced mast cell degranulation in mouse skin tissue and nasal mucosa. We also found that intranasal immunization with hapten (4-hydroxy-3-nitrophenyl) acetyl (NP) coupled to chicken gammaglobulin admixed with CTA1-DD complexed with polyclonal IgG greatly enhanced serum IgG anti-NP Ab responses and stimulated higher numbers of NP-specific plasma cells in the bone marrow as compared with that observed in mice immunized with NP-chicken gammaglobulin with CTA1-DD alone. This CTA1-DD/IgG complex-mediated enhancement was mast cell dependent because it was absent in mast cell-deficient Kit(W-sh/W-sh) mice. In conclusion, our data suggest that a clinically relevant adjuvant, CTA1-DD, exerts additional augmenting effects through activation of mucosal mast cells, clearly demonstrating that mast cells could be further exploited for improving the efficacy of mucosal vaccines.

The influence of scapular depression on upper limb neurodynamic test responses

PubMed Central

Legakis, Allison; Boyd, Benjamin S

2012-01-01

Objectives Upper limb neurodynamic testing (ULNT) can be used clinically to assist in identifying neural tissue involvement in patients with upper quarter pain and dysfunction. Consideration for scapular positioning is a crucial component of ULNT standardization, as variations in positioning may dramatically impact sensory and motor responses. This study aimed to determine if there was a meaningful difference in test outcomes when the ULNT was performed in alternative scapular positions. Methods This cross-sectional study included 40 asymptomatic individuals. Repeated ULNT testing was performed on the dominant limb with the scapula blocked in neutral (ULNTb) and in scapular depression (ULNTd). Sensory responses, muscle activity, and range of motion outcomes were compared between the two test variations. Results Pre-positioning in scapular depression (ULNTd) led to reduced elbow extension range of motion, provoked greater upper trapezius muscle activity and an earlier onset and broader area of sensory responses compared to ULNTb. Discussion During ULNTb, the limbs were taken further into range and elicited reduced muscle activation and more localized sensory response providing a less vigorous version of the test. This study demonstrates that scapular positioning has a meaningful impact on ULNT test outcomes in healthy, asymptomatic individuals. The ULNTd can be considered a more vigorous version that may be appropriate when the cervical motions commonly utilized for structural differentiation are limited or contraindicated. PMID:23633886

A life-threatening case of TAFRO syndrome with dramatic response to tocilizumab, rituximab, and pulse steroids: The first case report in Latin America.

PubMed

José, Fabio Freire; Kerbauy, Lucila Nassif; Perini, Guilherme Fleury; Blumenschein, Danielle Isadora; Pasqualin, Denise da Cunha; Malheiros, Denise Maria Avancini Costa; Campos Neto, Guilherme de Carvalho; de Souza Santos, Fabio Pires; Piovesan, Ronaldo; Hamerschlak, Nelson

2017-03-01

This is the report of the first case of TAFRO syndrome (Thrombocytopenia, Anasarca, myelofibrosis, Renal dysfunction, Organomegaly) in Latin America. The patient was a 61-year-old white woman of Ashkenazi Jewish descent, who presented with a history of 8 days of nausea, vomiting, and fever; severe pitting edema in both legs, ascites, splenomegaly, and palpable axillary lymph nodes. Abdominal computed tomography (CT) showed bilateral pleural effusion and retroperitoneal lymph node enlargement. Anasarca and worsening of renal function led to admission to the intensive care unit (ICU) with multiple organ failure, requiring mechanical ventilation, vasopressor medications, and continuous renal replacement therapy (CRRT). Diagnosis of TAFRO syndrome was made on day 18 after admission, based on clinical findings and results of bone marrow and lymph node biopsies. She was treated with methylprednisolone, tocilizumab, and rituximab. One week after the first tocilizumab dose, she had dramatic improvements in respiratory and hemodynamic status, and was weaned from ventilator support and vasopressor medications. After 2 weeks of therapy, CRRT was switched to intermittent hemodialysis. On day 46, the patient was discharged from the ICU to the general ward, and 3 months after admission, she went home. Provided the interleukin-6 measurement is available, this approach is suggested in cases of TAFRO syndrome, in order to customize the treatment.

Rapidly Progressive Osteoarthritis: a Review of the Clinical and Radiologic Presentation.

PubMed

Flemming, Donald J; Gustas-French, Cristy N

2017-07-01

The purpose of this paper is to review the distinct clinical and radiographic features that may lead to prompt diagnosis of rapidly progressive osteoarthritis (RPOA) and thus obviate unnecessary and costly diagnostic workup. RPOA is uncommon but is more frequently seen in practice because of the aging population. RPOA is a destructive arthropathy that occurs most commonly in elderly women but can also be seen in patients that have sustained trauma. The dramatic radiologic manifestations of RPOA can lead to diagnostic confusion with other arthropathies, infection, and osteonecrosis. RPOA was originally described in the hip but may also involve the shoulder. The etiology of RPOA is not well understood, but subchondral fracture probably plays a role in the development of dramatic destruction of the joint that is seen in affected patients. Early diagnosis may reduce the complexity of surgical management. RPOA is an uncommon condition that occurs most frequently in elderly woman or in patients who have sustained trauma. Prompt recognition of the clinical and radiologic features of this arthropathy can reduce unnecessary diagnostic workup and complexity of surgical intervention.

Three-Dimensional Magnetic Resonance Spectroscopic Imaging of Brain and Prostate Cancer1

PubMed Central

Kurhanewicz, John; Vigneron, Daniel B; Nelson, Sarah J

2000-01-01

Abstract Clinical applications of magnetic resonance spectroscopic imaging (MRSI) for the study of brain and prostate cancer have expanded significantly over the past 10 years. Proton MRSI studies of the brain and prostate have demonstrated the feasibility of noninvasively assessing human cancers based on metabolite levels before and after therapy in a clinically reasonable amount of time. MRSI provides a unique biochemical “window” to study cellular metabolism noninvasively. MRSI studies have demonstrated dramatic spectral differences between normal brain tissue (low choline and high N-acetyl aspartate, NAA) and prostate (low choline and high citrate) compared to brain (low NAA, high choline) and prostate (low citrate, high choline) tumors. The presence of edema and necrosis in both the prostate and brain was reflected by a reduction of the intensity of all resonances due to reduced cell density. MRSI was able to discriminate necrosis (absence of all metabolites, except lipids and lactate) from viable normal tissue and cancer following therapy. The results of current MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy as well as the magnitude and time course of metabolic changes after therapy can improve our understanding of cancer aggressiveness and mechanisms of therapeutic response. Clinically, combined MRI/MRSI has already demonstrated the potential for improved diagnosis, staging and treatment planning of brain and prostate cancer. Additionally, studies are under way to determine the accuracy of anatomic and metabolic parameters in providing an objective quantitative basis for assessing disease progression and response to therapy. PMID:10933075

The treatment of severe premenstrual syndrome with goserelin with and without 'add-back' estrogen therapy: a placebo-controlled study.

PubMed

Leather, A T; Studd, J W; Watson, N R; Holland, E F

1999-02-01

The study aimed to determine if the addition of daily low-dose oral estrogen with a cyclical progestogen given to young women using a depot gonadotropin-releasing hormone (GnRH) analog implant for the treatment of their premenstrual syndrome (PMS) would affect the clinical outcome. In a double-blind placebo-controlled study in a specialist premenstrual syndrome clinic setting, 60 women aged between 20 and 45 years were randomized to one of three treatment groups: Group A (placebo implant four weekly + placebo tablets daily), Group B (goserelin 3.6 mg implant four weekly + estradiol valerate 2 mg daily with norethisterone 5 mg from days 21-28 of a 28-day cycle) or Group C (goserelin 3.6 mg implant four weekly + placebo tablets daily). Differences between PMS scores at 2, 4 and 6 months were compared with pretreatment values. There was a significant improvement in PMS scores in Group C (Zoladex + placebo) after 2, 4 and 6 months of treatment when compared to pretreatment values and Group A (placebo + placebo). The addition of a low-dose oral estrogen with a cyclical progestogen to GnRH analog treatment (Group B) resulted in a less dramatic response when compared to pretreatment values and no significant improvement when compared to Group A (placebo + placebo) at 2, 4 and 6 months of treatment. The addition of a low-dose oral estrogen with a cyclical progestogen to depot GnRH analog therapy in the treatment of PMS reduces the clinical response.

Programmed death 1-mediated T cell exhaustion during visceral leishmaniasis impairs phagocyte function.

PubMed

Esch, Kevin J; Juelsgaard, Rachel; Martinez, Pedro A; Jones, Douglas E; Petersen, Christine A

2013-12-01

Control of Leishmania infantum infection is dependent upon Th1 CD4(+) T cells to promote macrophage intracellular clearance of parasites. Deficient CD4(+) T cell effector responses during clinical visceral leishmaniasis (VL) are associated with elevated production of IL-10. In the primary domestic reservoir of VL, dogs, we define occurrence of both CD4(+) and CD8(+) T cell exhaustion as a significant stepwise loss of Ag-specific proliferation and IFN-γ production, corresponding to increasing VL symptoms. Exhaustion was associated with a 4-fold increase in the population of T cells with surface expression of programmed death 1 (PD-1) between control and symptomatic populations. Importantly, exhausted populations of CD8(+) T cells and to a lesser extent CD4(+) T cells were present prior to onset of clinical VL. VL-exhausted T cells did not undergo significant apoptosis ex vivo after Ag stimulation. Ab block of PD-1 ligand, B7.H1, promoted return of CD4(+) and CD8(+) T cell function and dramatically increased reactive oxygen species production in cocultured monocyte-derived phagocytes. As a result, these phagocytes had decreased parasite load. To our knowledge, we demonstrate for the first time that pan-T cell, PD-1-mediated, exhaustion during VL influenced macrophage-reactive oxygen intermediate production. Blockade of the PD-1 pathway improved the ability of phagocytes isolated from dogs presenting with clinical VL to clear intracellular parasites. T cell exhaustion during symptomatic canine leishmaniasis has implications for the response to vaccination and therapeutic strategies for control of Leishmania infantum in this important reservoir species.

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PubMed Central

Merchant, Melinda S.; Geller, James I.; Baird, Kristin; Chou, Alexander J.; Galli, Susana; Charles, Ava; Amaoko, Martha; Rhee, Eunice H.; Price, Anita; Wexler, Leonard H.; Meyers, Paul A.; Widemann, Brigitte C.; Tsokos, Maria; Mackall, Crystal L.

2012-01-01

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. PMID:23071222

Utilization of the cellular stress response to sensitize cancer cells to TRAIL-mediated apoptosis.

PubMed

Siegelin, Markus David

2012-08-01

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising death ligand who has received significant attention due to its specific anti-cancer activity. Recently, a number of clinical trials involving either recombinant soluble TRAIL or agonistic death receptor (DR) antibodies have even been initiated. One major caveat in TRAIL-based anti-cancer therapies is that a considerable number of cancer cells are notorious resistant to apoptosis induction by TRAIL. Overcoming this primary or secondary evolved resistance is an utmost important goal of present cancer research. The current literature suggests that TRAIL resistance is mediated by a number of endogenous factors. According to recent research, stress-related transcription factors have acquired a pivotal role in the sensitization of highly resistant cancer cells, for example, pancreatic cancer and glioblastoma cells, to TRAIL-mediated cell death. Out of this transcription factor family, C/EBP-homologous protein (CHOP) is linked to the control of DR-mediated apoptosis by modulation of several apoptotic and anti-apoptotic factors. Stress responses in certain organelles, such as endoplasmic reticulum (ER) and mitochondria, are potent inductors of CHOP expression. This report focuses on the influence of stress responses on endogenous or acquired resistance to extrinsic apoptosis in tumor cells and summarizes recent findings and results. The Medline and ClinicalTrials database with key words were used for this review. A potential novel treatment strategy for highly treatment-resistant tumors is the induction of a cellular stress response in cancer cells. The induction of an organelle-related stress response, such as nuclear, ER and mitochondrial stress, leads to a dramatic sensitization of a broad variety of cancer cells of different tumor entities to the apoptotic ligand, TRAIL. Importantly, non-neoplastic cells are not sensitized to TRAIL-mediated cell death through the unfolded protein response in most instances, suggesting that this treatment is not only of high efficacy, but even more less of unwanted toxicity in patients.

Contribution of engineered nanomaterials physicochemical properties to mast cell degranulation

NASA Astrophysics Data System (ADS)

Johnson, Monica M.; Mendoza, Ryan; Raghavendra, Achyut J.; Podila, Ramakrishna; Brown, Jared M.

2017-03-01

The rapid development of engineered nanomaterials (ENMs) has grown dramatically in the last decade, with increased use in consumer products, industrial materials, and nanomedicines. However, due to increased manufacturing, there is concern that human and environmental exposures may lead to adverse immune outcomes. Mast cells, central to the innate immune response, are one of the earliest sensors of environmental insult and have been shown to play a role in ENM-mediated immune responses. Our laboratory previously determined that mast cells are activated via a non-FcɛRI mediated response following silver nanoparticle (Ag NP) exposure, which was dependent upon key physicochemical properties. Using bone marrow-derived mast cells (BMMCs), we tested the hypothesis that ENM physicochemical properties influence mast cell degranulation. Exposure to 13 physicochemically distinct ENMs caused a range of mast degranulation responses, with smaller sized Ag NPs (5 nm and 20 nm) causing the most dramatic response. Mast cell responses were dependent on ENMs physicochemical properties such as size, apparent surface area, and zeta potential. Surprisingly, minimal ENM cellular association by mast cells was not correlated with mast cell degranulation. This study suggests that a subset of ENMs may elicit an allergic response and contribute to the exacerbation of allergic diseases.

The meteorology of cytokine storms, and the clinical usefulness of this knowledge.

PubMed

Clark, Ian A; Vissel, Bryce

2017-07-01

The term cytokine storm has become a popular descriptor of the dramatic harmful consequences of the rapid release of polypeptide mediators, or cytokines, that generate inflammatory responses. This occurs throughout the body in both non-infectious and infectious disease states, including the central nervous system. In infectious disease it has become a useful concept through which to appreciate that most infectious disease is not caused directly by a pathogen, but by an overexuberant innate immune response by the host to its presence. It is less widely known that in addition to these roles in disease pathogenesis these same cytokines are also the basis of innate immunity, and in lower concentrations have many essential physiological roles. Here we update this field, including what can be learned through the history of how these interlinking three aspects of biology and disease came to be appreciated. We argue that understanding cytokine storms in their various degrees of acuteness, severity and persistence is essential in order to grasp the pathophysiology of many diseases, and thus the basis of newer therapeutic approaches to treating them. This particularly applies to the neurodegenerative diseases.

Pazopanib efficacy in recurrent central nervous system hemangiopericytomas.

PubMed

Apra, Caroline; Alentorn, Agusti; Mokhtari, Karima; Kalamarides, Michel; Sanson, Marc

2018-04-26

There is currently no treatment for solitary fibrous tumors/hemangiopericytomas (SFT/H) of the central nervous system recurring after multiple surgeries and radiotherapies. The NAB2-STAT6 gene fusion is the hallmark of these tumors, and upregulates Early Growth Factor, activating several growth pathways. We treated two patients presenting pluri-recurrent meningeal SFT/H with Pazopanib, a broad-spectrum tyrosine kinase inhibitor. We analyzed the exome and RNA sequencing data of one of them and, in addition to another meningeal SFT/H, compared it to the transcriptomic profiling of 5 systemic SFT/H. A dramatic clinical and radiological response was observed in both cases, respectively 84 and 43% decrease after 3 months. As a comparison, Pazopanib has only a stabilizing effect in systemic SFT/H. Indeed, central nervous system SFT/H show overexpression of different tyrosine kinases targeted by Pazopanib. Two consecutive patients with untreatable central nervous system SFT/H showed a spectacular partial response to Pazopanib, an unprecedented result in SFT/H. This result could be explained by differences in expression profiles and calls for a confirmation in a larger cohort of patients.

Application of finite element analysis in pre-operative planning for deformity correction of abnormal hip joints--a case series.

PubMed

Rhyu, K H; Kim, Y H; Park, W M; Kim, K; Cho, T-J; Choi, I H

2011-09-01

In experimental and clinical research, it is difficult to directly measure responses in the human body, such as contact pressure and stress in a joint, but finite element analysis (FEA) enables the examination of in vivo responses by contact analysis. Hence, FEA is useful for pre-operative planning prior to orthopaedic surgeries, in order to gain insight into which surgical options will result in the best outcome. The present study develops a numerical simulation technique based on FEA to predict the surgical outcomes of osteotomy methods for the treatment of slipped capital femoral epiphyses. The correlation of biomechanical parameters including contact pressure and stress, for moderate and severe cases, is investigated. For severe slips, a base-of-neck osteotomy is thought to be the most reliable and effective surgical treatment, while any osteotomy may produce dramatic improvement for moderate slips. This technology of pre-operative planning using FEA can provide information regarding biomechanical parameters that might facilitate the selection of optimal osteotomy methods and corresponding surgical options.

Central nervous system and muscle involvement in an adolescent patient with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.

PubMed

Ishii, Kiyoko; Komaki, Hirofumi; Ohkuma, Aya; Nishino, Ichizo; Nonaka, Ikuya; Sasaki, Masayuki

2010-09-01

We report an adolescent case of late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by intermittent nausea and depressive state as early symptoms. At the age of 12 years and 11 months, the patient experienced intermittent nausea and vomiting, and depressive state. She was on medication for depression for 5 months but it was ineffective. Brain magnetic resonance imaging showed disseminated high-intensity areas in the periventricular white matter and in the splenium of the corpus callosum on T2-weighted images and fluid-attenuated inversion-recovery images. Progressive muscle weakness occurred and blood creatine kinase level was found to be elevated. The muscle biopsy revealed lipid storage myopathy. Urine organic acid analysis and mutation analysis of the ETFDH gene confirmed the diagnosis of MADD. With oral supplements of riboflavin and l-carnitine, in addition to a high-calorie and reduced-fat diet, her clinical symptoms improved dramatically. Early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD. Copyright 2009 Elsevier B.V. All rights reserved.

Regulation of Corticoid and Serotonin Receptor Brain System following Early Life Exposure of Glucocorticoids: Long Term Implications for the Neurobiology of Mood

PubMed Central

Vázquez, Delia M.; Neal, Charles R.; Patel, Paresh D.; Kaciroti, Niko; López, Juan F.

2011-01-01

Potent glucocorticoids (GC) administered early in life has improved premature infant survival dramatically. However, these agents may increase the risk for physical, neurological and behavior alterations. Anxiety, depression and attention difficulties are commonly described in adolescent and young adult survivors of prematurity. In the present study we administered vehicle, dexamethasone, or hydrocortisone to Sprague-Dawley rat pups on postnatal days 5 and 6, mimicking a short term clinical protocol commonly used in human infants. Two systems that are implicated in the regulation of stress and behavior were assessed: the limbic-hypothalamic-pituitary-adrenal axis [LHPA, glucocorticoid and mineralocorticoid receptors within] and the Serotonin (5-HT) system. We found that as adults, male Sprague-Dawley pups treated with GC showed agent specific altered growth, anxiety-related behavior, changes in corticoid response to novelty and gene expression changes within LHPA and 5-HT–related circuitry. The data suggest that prolonged GC-receptor stimulation during the early neonatal period can contribute to the development of individual differences in stress response and anxiety-related behavior later in life. PMID:21855221

Clinical roundtable monograph: Unmet needs in the management of chronic myelogenous leukemia.

PubMed

Jabbour, Elias J; Bixby, Dale; Akard, Luke P

2012-12-01

Approximately 5,000 cases of chronic myelogenous leukemia (CML) are diagnosed each year in the United States. The introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved survival time for many CML patients. Current first-line treatment options include imatinib and the second-generation agents nilotinib and dasatinib. Second- and third-line agents include nilotinib, dasatinib, bosutinib, and the new agent ponatinib. Despite the effectiveness of TKIs, some patients develop resistance or intolerance to these agents. A number of mutations of the BCR-ABL gene have been identified and are associated with TKI resistance. Patients may benefit from switching to a second-line TKI, undergoing hematopoietic stem cell transplant, or receiving newly emerging agents. Although early response is associated with improved patient outcome, clinicians lack tests that can determine which patients will benefit from which therapies. To ensure adequate response, patients should be monitored by both polymerase chain reaction and cytogenetic analysis of the bone marrow. This roundtable monograph reviews key unmet needs in patients with CML related to disease management and treatment options.

HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor.

PubMed

Ben-Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M; Ma, Cynthia X; Ellis, Matthew J

2015-09-01

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted. Copyright © 2015 by the National Comprehensive Cancer Network.

Affect regulation, brain development, and behavioral/emotional health in adolescence.

PubMed

Dahl, R E

2001-01-01

This paper addresses the importance of affect regulation (AR) in relation to a broad range of behavioral and emotional health problems that emerge during adolescence. AR is defined as the adaptive modulation of emotional experience to serve a goal or purpose. This conceptualization of AR emphasizes the use of cognitive skills to guide, inhibit, or modify emotion and behavior, including the expression of emotional responses, in learned, strategic ways-skills that ultimately underpin adult levels of social maturity and the ability to show "responsible" behavior across a range of emotional situations. Neurobehavioral systems that subserve these AR skills include areas of the inferior and orbital prefrontal cortex (PFC), with rich interconnections to several limbic structures and other cortical areas, including the dorsolateral PFC. Adolescence represents an important developmental period in the functional maturation of adult AR skills; it is also a critical time in the development of clinical disorders of AR (eg, rates of depression increase dramatically and gender differences in depression emerge). Maturational changes in AR that occur during adolescence-particularly with respect to the role of emotions influencing responsible decision making-are also relevant to understanding key aspects of the developmental pathways of some behavioral health problems, such as alcohol use and nicotine dependence. A strong case is made for developmental research in affective neuroscience aimed at this important maturational period, particularly the kind of transdisciplinary research leading toward mechanistic understanding of the development of adolescent-onset disorders. Improving understanding in these areas could ultimately lead to the development of early interventions in targeted high-risk populations, and has enormous clinical and social policy relevance.

Genetic Variation in the MAPK/ERK Pathway Affects Contact Hypersensitivity Responses.

PubMed

Legrand, Julien M D; Roy, Edwige; Baz, Batoul; Mukhopadhyay, Pamela; Wong, Ho Yi; Ram, Ramesh; Morahan, Grant; Walker, Graeme; Khosrotehrani, Kiarash

2018-05-10

Using a genetic resource that enables rapid mapping of genes for complex traits, we demonstrate dramatic diversity between murine strains in response to immune challenge. We identified several candidate genes that point to the MAPK/ERK pathway as a key modulator of this process. Copyright © 2018. Published by Elsevier Inc.

Medical humanitarianism, human rights and political advocacy: the case of the Israeli Open Clinic.

PubMed

Gottlieb, Nora; Filc, Dani; Davidovitch, Nadav

2012-03-01

In the context of neo-liberal retrenchments humanitarian NGOs have become alternative healthcare providers that partially fill the vacuum left by the welfare state's withdrawal from the provision of services to migrants and other marginalized populations. In many cases they thus help to build legitimacy for the state's retreat from social responsibilities. Human rights organizations play an important role in advocating for migrants' rights, but in many cases they represent a legalistic and individualized conceptualization of the right to health that limits their claims for social justice. This paper analyzes the interactions and tensions between the discourses of medical humanitarianism, human rights and political advocacy using the example of an "Open Clinic" run by an Israeli human rights organization as a case-study: In 2007 dramatically increasing patient numbers provoked an intense internal debate concerning the proposal to temporarily close the "Open Clinic" in order to press the government to take action. Based on protocols from internal meetings and parliamentary hearings and in-depth interviews, we have analyzed divergent contextualizations of the Clinic's closure. These reflect conflicting notions regarding the Clinic's variegated spectrum of roles--humanitarian, political, legitimizing, symbolic, empowering and organizational--and underlying conceptualizations of migrants' "deservingness". Our case-study thus helps to illuminate NGOs' role in the realm of migrant healthcare and points out options for a possible fruitful relationship between the divergent paradigms of medical humanitarianism, human rights and political advocacy. Copyright © 2011. Published by Elsevier Ltd.

Dramatic response to levetiracetam in post-ischaemic Holmes’ tremor

PubMed Central

Striano, P; Elefante, Andrea; Coppola, Antonietta; Tortora, Fabio; Zara, Federico; Minetti, Carlo

2009-01-01

Holmes’ tremor refers to an unusual combination of rest, postural and kinetic tremor of extremities. Common causes of Holmes’ tremor include stroke, trauma, vascular malformations and multiple sclerosis, with lesions involving the thalamus, brain stem or cerebellum. Although some drugs (eg, levodopa and dopaminergic drugs, clonazepam and propranolol) have been occasionally reported to give some benefit, medical treatment of Holmes’ tremor is unsatisfactory, and many patients require thalamic surgery to achieve satisfactory control. We report a patient in whom post-ischaemic Holmes’ tremor dramatically responded to levetiracetam treatment. PMID:21686707

Oil spill dispersants: boon or bane?

PubMed

Prince, Roger C

2015-06-02

Dispersants provide a reliable large-scale response to catastrophic oil spills that can be used when the preferable option of recapturing the oil cannot be achieved. By allowing even mild wave action to disperse floating oil into tiny droplets (<70 μm) in the water column, seabirds, reptiles, and mammals are protected from lethal oiling at the surface, and microbial biodegradation is dramatically increased. Recent work has clarified how dramatic this increase is likely to be: beached oil has an environmental residence of years, whereas dispersed oil has a half-life of weeks. Oil spill response operations endorse the concept of net environmental benefit, that any environmental costs imposed by a response technique must be outweighed by the likely benefits. This critical review discusses the potential environmental debits and credits from dispersant use and concludes that, in most cases, the potential environmental costs of adding these chemicals to a polluted area are likely outweighed by the much shorter residence time, and hence integrated environmental impact, of the spilled oil in the environment.

Optimal temperature for malaria transmission is dramatically lower than previously predicted

USGS Publications Warehouse

Mordecai, Erin A.; Paaijmans, Krijn P.; Johnson, Leah R.; Balzer, Christian; Ben-Horin, Tal; de Moor, Emily; McNally, Amy; Pawar, Samraat; Ryan, Sadie J.; Smith, Thomas C.; Lafferty, Kevin D.

2013-01-01

The ecology of mosquito vectors and malaria parasites affect the incidence, seasonal transmission and geographical range of malaria. Most malaria models to date assume constant or linear responses of mosquito and parasite life-history traits to temperature, predicting optimal transmission at 31 °C. These models are at odds with field observations of transmission dating back nearly a century. We build a model with more realistic ecological assumptions about the thermal physiology of insects. Our model, which includes empirically derived nonlinear thermal responses, predicts optimal malaria transmission at 25 °C (6 °C lower than previous models). Moreover, the model predicts that transmission decreases dramatically at temperatures > 28 °C, altering predictions about how climate change will affect malaria. A large data set on malaria transmission risk in Africa validates both the 25 °C optimum and the decline above 28 °C. Using these more accurate nonlinear thermal-response models will aid in understanding the effects of current and future temperature regimes on disease transmission.

Implementation and utilization of genetic testing in personalized medicine

PubMed Central

Abul-Husn, Noura S; Owusu Obeng, Aniwaa; Sanderson, Saskia C; Gottesman, Omri; Scott, Stuart A

2014-01-01

Clinical genetic testing began over 30 years ago with the availability of mutation detection for sickle cell disease diagnosis. Since then, the field has dramatically transformed to include gene sequencing, high-throughput targeted genotyping, prenatal mutation detection, preimplantation genetic diagnosis, population-based carrier screening, and now genome-wide analyses using microarrays and next-generation sequencing. Despite these significant advances in molecular technologies and testing capabilities, clinical genetics laboratories historically have been centered on mutation detection for Mendelian disorders. However, the ongoing identification of deoxyribonucleic acid (DNA) sequence variants associated with common diseases prompted the availability of testing for personal disease risk estimation, and created commercial opportunities for direct-to-consumer genetic testing companies that assay these variants. This germline genetic risk, in conjunction with other clinical, family, and demographic variables, are the key components of the personalized medicine paradigm, which aims to apply personal genomic and other relevant data into a patient’s clinical assessment to more precisely guide medical management. However, genetic testing for disease risk estimation is an ongoing topic of debate, largely due to inconsistencies in the results, concerns over clinical validity and utility, and the variable mode of delivery when returning genetic results to patients in the absence of traditional counseling. A related class of genetic testing with analogous issues of clinical utility and acceptance is pharmacogenetic testing, which interrogates sequence variants implicated in interindividual drug response variability. Although clinical pharmacogenetic testing has not previously been widely adopted, advances in rapid turnaround time genetic testing technology and the recent implementation of preemptive genotyping programs at selected medical centers suggest that personalized medicine through pharmacogenetics is now a reality. This review aims to summarize the current state of implementing genetic testing for personalized medicine, with an emphasis on clinical pharmacogenetic testing. PMID:25206309

Reducing Air Pollution from International Transportation

EPA Pesticide Factsheets

Because of their reliance on petroleum-based fuels and their dramatic growth rates in recent decades, air and sea transport are responsible for significant emissions of both traditional air pollutants and greenhouse gases.

Surge capacity for response to bioterrorism in hospital clinical microbiology laboratories.

PubMed

Shapiro, Daniel S

2003-12-01

Surge capacity is the ability to rapidly mobilize to meet an increased demand. While large amounts of federal funding have been allocated to public health laboratories, little federal funding has been allocated to hospital microbiology laboratories. There are concerns that hospital laboratories may have inadequate surge capacities to deal with a significant bioterrorism incident. A workflow analysis of a clinical microbiology laboratory that serves an urban medical center was performed to identify barriers to surge capacity in the setting of a bioterrorism event and to identify solutions to these problems. Barriers include a national shortage of trained medical technologists, the inability of clinical laboratories to deal with a dramatic increase in the number of blood cultures, a delay while manufacturers increase production of critical products and then transport and deliver these products to clinical laboratories, and a shortage of class II biological safety cabinets. Federal funding could remedy staffing shortages by making the salaries of medical technologists comparable to those of similarly educated health care professionals and by providing financial incentives for students to enroll in clinical laboratory science programs. Blood culture bottles, and possibly continuous-monitoring blood culture instruments, should be added to the national antibiotic stockpile. Federal support must ensure that companies that manufacture essential laboratory supplies are capable of rapidly scaling up production. Hospitals must provide increased numbers of biological safety cabinets and amounts of space dedicated to clinical microbiology laboratories. Laboratories should undertake limited cross-training of technologists, ensure that adequate packaging supplies are available, and be able to move to a 4-day blood culture protocol.

Familial dopa-responsive cervical dystonia.

PubMed

Schneider, S A; Mohire, M D; Trender-Gerhard, I; Asmus, F; Sweeney, M; Davis, M; Gasser, T; Wood, N W; Bhatia, K P

2006-02-28

The authors present four cases from two unrelated families with young-onset predominant cervical dystonia with a dramatic sustained response to levodopa. Onset age was 12 years (range 9 to 15). Additional symptoms included postural hand tremor and laryngeal dystonia. Genetic testing for GTP cyclohydrolase I, tyrosine hydroxylase, and sepiapterin reductase was negative. These cases may represent new forms of dopa-responsive dystonia. Levodopa is advisable in all patients with young-onset cervical dystonia.

Sexual phenotype drives variation in endocrine responses to social challenge in a quasi-clonal animal

PubMed Central

Huang, Shu-Ping; Garcia, Mark; Fuller, Adam

2018-01-01

In many species, males tend to behave more aggressively than females and female aggression often occurs during particular life stages such as maternal defence of offspring. Though many studies have revealed differences in aggression between the sexes, few studies have compared the sexes in terms of their neuroendocrine responses to contest experience. We investigated sex differences in the endocrine response to social challenge using mangrove rivulus fish, Kryptolebias marmoratus. In this species, sex is determined environmentally, allowing us to produce males and hermaphrodites with identical genotypes. We hypothesized that males would show elevated androgen levels (testosterone and 11-ketotestosterone) following social challenge but that hermaphrodite responses might be constrained by having to maintain both testicular and ovarian tissue. To test this hypothesis, we staged fights between males and between hermaphrodites, and then compared contest behaviour and hormone responses between the sexes. Hermaphrodites had significantly higher oestradiol but lower 11-ketotestosterone than males before contests. Males took longer to initiate contests but tended to fight more aggressively and sustain longer fights than hermaphrodites. Males showed a dramatic post-fight increase in 11-ketotestosterone but hermaphrodites did not. Thus, despite being genetically identical, males and hermaphrodites exhibit dramatically different fighting strategies and endocrine responses to contests. PMID:29765691

Automation in Clinical Microbiology

PubMed Central

Ledeboer, Nathan A.

2013-01-01

Historically, the trend toward automation in clinical pathology laboratories has largely bypassed the clinical microbiology laboratory. In this article, we review the historical impediments to automation in the microbiology laboratory and offer insight into the reasons why we believe that we are on the cusp of a dramatic change that will sweep a wave of automation into clinical microbiology laboratories. We review the currently available specimen-processing instruments as well as the total laboratory automation solutions. Lastly, we outline the types of studies that will need to be performed to fully assess the benefits of automation in microbiology laboratories. PMID:23515547

The Growth of Retail Clinics and the Medical Home: Two Trends in Conflict?

PubMed Central

Pollack, Craig Evan; Gidengil, Courtney; Mehrotra, Ateev

2012-01-01

There has been growing interest in the patient-centered medical home as a way to provide coordinated, high quality primary care. At the same time the number of retail clinics has increased dramatically. Many are concerned that retail clinics undermine the medical home by fragmenting care. In this piece we explore the juxtaposition of these trends, highlighting shared characteristics and sources of tension. We describe three types of relationships between retail clinics and primary care providers. With some relationships we argue that there is no conflict, while we describe areas of potential concern for other relationships. PMID:20439897

77 FR 55101 - National Wilderness Month, 2012

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-06

... centuries, America's dramatic landscapes have attracted people from around the world to begin new lives and... responsibility that falls to us all as Americans and as inhabitants of this small planet. During National...

State Guidance Documents for Young Children with Autism Spectrum Disorders: Content and Comparison

ERIC Educational Resources Information Center

Coakley, Tom

2010-01-01

The dramatic increase in the identification of young children with autism spectrum disorders (ASD) beginning in the 1980s presented many challenges to State Education Agencies responsible for Special Education for school aged children and State Part C Lead Agencies responsible for Early Intervention services for infants and toddlers under the…

Localized blastomycosis-like pyoderma with good response to cotrimoxazol and cryotherapy.

PubMed

Su, Ozlem; Demirkesen, Cuyan; Onsun, Nahide

2004-05-01

Blastomycosis-like pyoderma is an unusual, exaggerated, vegetative-tissue reaction to a prolonged primary or secondary bacterial infection. It is a rare disease, usually seen in immunocompromized patients. We report a case of localized blastomycosis-like pyoderma responding poorly to classic treatments, but that gave a dramatic response to a combination treatment of cotrimoxazol and cryotherapy.

The Learning Strategy of the Total Physical Response: A Review.

ERIC Educational Resources Information Center

Asher, James J.

1966-01-01

Described in this article are five pilot studies that explored the effects of the learning strategy of the total physical response under a variety of conditions using Japanese and Russian with adults and children. Some general conclusions suggest that dramatic facilitation in learning listening skills for a second language is related to acting out…

Defined contribution: a part of our future.

PubMed Central

Baugh, Reginald F.

2003-01-01

Rising employer health care costs and consumer backlash against managed care are trends fostering the development of defined contribution plans. Defined contribution plans limit employer responsibility to a fixed financial contribution rather than a benefit program and dramatically increase consumer responsibility for health care decision making. Possible outcomes of widespread adoption of defined contribution plans are presented. PMID:12934869

INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENTAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT.

EPA Science Inventory

INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT.

Genetically increasing the function of oncogenes or knocking out the function of a tumor supressor gene has dramatically increased the...

Acquired Resistance to Crizotinib from a Mutation in CD74–ROS1

PubMed Central

Awad, Mark M.; Katayama, Ryohei; McTigue, Michele; Liu, Wei; Deng, Ya-Li; Brooun, Alexei; Friboulet, Luc; Huang, Donghui; Falk, Matthew D.; Timofeevski, Sergei; Wilner, Keith D.; Lockerman, Elizabeth L.; Khan, Tahsin M.; Mahmood, Sidra; Gainor, Justin F.; Digumarthy, Subba R.; Stone, James R.; Mino-Kenudson, Mari; Christensen, James G.; Iafrate, A. John; Engelman, Jeffrey A.; Shaw, Alice T.

2013-01-01

Summary Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74–ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the meta-static sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.) PMID:23724914

Leucoencephalopathy following abuse of sniffed heroin.

PubMed

Lefaucheur, Romain; Lebas, Axel; Gérardin, Emmanuel; Grangeon, Lou; Ozkul-Wermester, Ozlem; Aubier-Girard, Carole; Martinaud, Olivier; Maltête, David

2017-01-01

A 29-year-old man was admitted for acute cognitive impairment. Three weeks earlier, he had been admitted for coma due to sniffed heroin abuse responsive to naloxone infusion. At admission, the patient presented with apraxia, severe memory impairment and anosognosia. Brain MRI revealed symmetric hyperintensities of supratentorial white matter, sparing brainstem and cerebellum, on FLAIR and B1000 sequences. Four months later, repeated neuropsychological assessment revealed dramatic improvement of global cognitive functions. Toxic leucoencephalopathy excluding the cerebellum and brainstem is a rare complication of heroin abuse, and seems to concern especially patients that use heroin by sniff or injection. In these patients, cognitive troubles are predominant, prognosis seems better and infratentorial brain structures can be spared. In conclusion, our observation emphasizes that heroin-induced encephalopathy can have a favourable outcome and that imaging and clinical patterns can indicate the mode of drug administration. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Case of Painful Hashimoto Thyroiditis that Mimicked Subacute Thyroiditis

PubMed Central

Seo, Hye Mi; Kim, Miyeon; Bae, Jaeseok; Kim, Jo-Heon; Lee, Jeong Won; Lee, Sang Ah; Koh, Gwanpyo

2012-01-01

Hashimoto thyroiditis (HT) is an autoimmune thyroid disorder that usually presents as a diffuse, nontender goiter, whereas subacute thyroiditis (SAT) is an uncommon disease that is characterized by tender thyroid enlargement, transient thyrotoxicosis, and an elevated erythrocyte sedimentation rate (ESR). Very rarely, patients with HT can present with painful, tender goiter or fever, a mimic of SAT. We report a case of painful HT in a 68-year-old woman who presented with pain and tenderness in a chronic goiter. Her ESR was definitely elevated and her thyroid laboratory tests suggested subclinical hypothyroidism of autoimmune origin. 99mTc pertechnetate uptake was markedly decreased. Fine needle aspiration biopsy revealed reactive and polymorphous lymphoid cells and occasional epithelial cells with Hürthle cell changes. Her clinical symptoms showed a dramatic response to glucocorticoid treatment. She became hypothyroid finally and is now on levothyroxine therapy. PMID:22570820

[Sinus histiocytosis (Destombes-Rosai-Dorfman disease) revealed by extranodal spinal involvement].

PubMed

Bernard, F; Sarran, N; Serre, I; Baldet, P; Callamand, P; Margueritte, G; Astruc, J

1999-02-01

Sinus histiocytosis with massive cervical lymphadenopathy (Rosai-Dorfman disease) is a non-neoplastic lymphoproliferative disorder. Extranodal involvement, especially of the nervous system, is unusual. We report a case revealed by neurological symptoms. A 10-year-old girl presented with paraparesis due to a dural extramedullary mass on magnetic resonance imaging. Massive cervical lymphadenopathy appeared secondarily. Radiological investigations showed mediastinal, paranasal sinus and lower eyelid involvement. The diagnosis of Rosai-Dorfman disease was established histologically and by immunohistochemical studies of nodal lesions by the demonstration of characteristic sinus histiocytosis with sheets of S-100 protein and CD-68 positive large histiocytes displaying lymphocyte phagocytosis. A dramatic response occurred with complete resolution of all clinical findings after treatment with corticosteroids and etoposide, although neurological lesions were unchanged on magnetic resonance imaging. Despite its rarity, this case underlines the unknown pathogenesis of this disease (immune dysfunction?) and the difficulties of treatment (choice of chemotherapeutic agents, duration).

Compulsive masturbation in infantile autism treated by mirtazapine.

PubMed

Albertini, Giorgio; Polito, Emilena; Sarà, Marco; Di Gennaro, Giancarlo; Onorati, Paolo

2006-05-01

This case report describes a child with a severe autistic syndrome worsened by hypersexual behavior consisting of compulsive masturbatory activity. Selective serotonin reuptake inhibitors have been reported to be beneficial in reducing hypersexual behaviors. A treatment with mirtazapine improved the entire clinical autistic picture with the disappearance of masturbation. This result suggests that selective serotonin reuptake inhibitors could be useful and promising tools in the treatment of hypersexual behaviors in children with autistic disorders. Moreover, the general, and in some ways unexpected, improvement of the social interaction, communication, and imagination, the dramatic reduction of aloof mannerisms, stereotypes, aggressiveness, and inappropriate emotional response to frustrations, as well as the first appearance of the pragmatic use of language and a strong impetus to emotional development disclosed a new spectrum of possible applications of these drugs, and mirtazapine in particular, suggesting the need for new and more extensive studies on the pharmacotherapy of autism.

Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP).

PubMed

Brennan, Tracy A; Lindborg, Carter M; Bergbauer, Christian R; Wang, Haitao; Kaplan, Frederick S; Pignolo, Robert J

2018-04-01

Episodic flare-ups of fibrodysplasia ossificans progressiva (FOP) are characterized clinically by severe, often posttraumatic, connective tissue swelling and intramuscular edema, followed histologically by an intense and highly angiogenic fibroproliferative reaction. This early inflammatory and angiogenic fibroproliferative response is accompanied by the presence of abundant mast cells far in excess of other reported myopathies. Using an injury-induced, constitutively-active transgenic mouse model of FOP we show that mast cell inhibition by cromolyn, but not aprepitant, results in a dramatic reduction of heterotopic ossification. Cromolyn, but not aprepitant, significantly decreases the total number of mast cells in FOP lesions. Furthermore, cromolyn specifically diminishes the number of degranulating and resting degranulated mast cells in pre-osseous lesions. This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition. Copyright © 2017 Elsevier Inc. All rights reserved.

Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma

PubMed Central

Zolkind, Paul; Przybylski, Dariusz; Marjanovic, Nemanja; Nguyen, Lan; Lin, Tianxiang; Johanns, Tanner; Alexandrov, Anton; Zhou, Liye; Allen, Clint T.; Miceli, Alexander P.; Schreiber, Robert D.; Artyomov, Maxim; Dunn, Gavin P.; Uppaluri, Ravindra

2018-01-01

Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1P315L (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics. PMID:29423108

Modelling Predictors of Molecular Response to Frontline Imatinib for Patients with Chronic Myeloid Leukaemia

PubMed Central

Brown, Fred; Adelson, David; White, Deborah; Hughes, Timothy; Chaudhri, Naeem

2017-01-01

Background Treatment of patients with chronic myeloid leukaemia (CML) has become increasingly difficult in recent years due to the variety of treatment options available and challenge deciding on the most appropriate treatment strategy for an individual patient. To facilitate the treatment strategy decision, disease assessment should involve molecular response to initial treatment for an individual patient. Patients predicted not to achieve major molecular response (MMR) at 24 months to frontline imatinib may be better treated with alternative frontline therapies, such as nilotinib or dasatinib. The aims of this study were to i) understand the clinical prediction ‘rules’ for predicting MMR at 24 months for CML patients treated with imatinib using clinical, molecular, and cell count observations (predictive factors collected at diagnosis and categorised based on available knowledge) and ii) develop a predictive model for CML treatment management. This predictive model was developed, based on CML patients undergoing imatinib therapy enrolled in the TIDEL II clinical trial with an experimentally identified achieving MMR group and non-achieving MMR group, by addressing the challenge as a machine learning problem. The recommended model was validated externally using an independent data set from King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Principle Findings The common prognostic scores yielded similar sensitivity performance in testing and validation datasets and are therefore good predictors of the positive group. The G-mean and F-score values in our models outperformed the common prognostic scores in testing and validation datasets and are therefore good predictors for both the positive and negative groups. Furthermore, a high PPV above 65% indicated that our models are appropriate for making decisions at diagnosis and pre-therapy. Study limitations include that prior knowledge may change based on varying expert opinions; hence, representing the category boundaries of each predictive factor could dramatically change performance of the models. PMID:28045960

Can the mild clinical course of crimean-congo hemorrhagic fever in children be explained by cytokine responses?

PubMed

Ozsurekci, Yasemin; Arasli, Mehmet; Karadag Oncel, Eda; Caglayik, Dilek Yagci; Kaya, Ali; Icagasioglu, Fusun Dilara; Engin, Aynur; Korukluoglu, Gulay; Elaldi, Nazif; Ceyhan, Mehmet

2013-11-01

Cytokines are possibly one of the factors responsible for death due to Crimean-Congo hemorrhagic fever (CCHF). This study aimed to determine the differences between the cytokine levels in children and adult patients with CCHF; the influence of cytokines; and the severity of the course of the disease, which seems to be milder in children. Thirty-four children and 36 adult patients diagnosed with CCHF between 2010 and 2011 were included in this study. Diagnosis was performed by serology or by the polymerase chain reaction for CCHF virus. Levels of IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 p70, IL-13, IL-17A, and IL-22 were measured in all serum samples. Although the disease had a fatal course in three adult patients, there were no deaths in children. Statistically significant differences were not observed between the cytokine concentrations in the adults and children. No differences were detected between the serum cytokine levels in the children with moderate and those with a severe clinical course of the disease. In the adult patients with fatal outcome, significantly higher serum levels of IL-2, IL-5, IL-9, IL-12 p70, and IL-13 were detected as compared to the cytokine levels in patients who survived the infection. No differences were detected between the serum levels of IFN-γ, IL-1β, IL-17A, IL-22, IL-10, IL-6, IL-4, and TNF-α in the patients who died and those who survived. Thus, the milder clinical course in children with CCHF cannot be explained by the cytokine network alone. The incomplete maturation of the immune system and timing and scale of immune responses could change the outcome dramatically. Copyright © 2013 Wiley Periodicals, Inc.

In Law We Trust? Trusted Computing and Legal Responsibility for Internet Security

NASA Astrophysics Data System (ADS)

Danidou, Yianna; Schafer, Burkhard

This paper analyses potential legal responses and consequences to the anticipated roll out of Trusted Computing (TC). It is argued that TC constitutes such a dramatic shift in power away from users to the software providers, that it is necessary for the legal system to respond. A possible response is to mirror the shift in power by a shift in legal responsibility, creating new legal liabilities and duties for software companies as the new guardians of internet security.

Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

PubMed Central

Mencacci, Niccolò E.; Isaias, Ioannis U.; Reich, Martin M.; Ganos, Christos; Plagnol, Vincent; Polke, James M.; Bras, Jose; Hersheson, Joshua; Stamelou, Maria; Pittman, Alan M.; Noyce, Alastair J.; Mok, Kin Y.; Opladen, Thomas; Kunstmann, Erdmute; Hodecker, Sybille; Münchau, Alexander; Volkmann, Jens; Samnick, Samuel; Sidle, Katie; Nanji, Tina; Sweeney, Mary G.; Houlden, Henry; Batla, Amit; Zecchinelli, Anna L.; Pezzoli, Gianni; Marotta, Giorgio; Lees, Andrew; Alegria, Paulo; Krack, Paul; Cormier-Dequaire, Florence; Lesage, Suzanne; Brice, Alexis; Heutink, Peter; Gasser, Thomas; Lubbe, Steven J.; Morris, Huw R.; Taba, Pille; Koks, Sulev; Majounie, Elisa; Raphael Gibbs, J.; Singleton, Andrew; Hardy, John; Klebe, Stephan

2014-01-01

GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson’s disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson’s disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson’s disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher’s exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4–25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson’s disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson’s disease. PMID:24993959

Misonidazole in patients receiving radical radiotherapy: pharmacokinetic effects of phenytoin tumor response and neurotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moore, J.L.; Biol, F.I.; Patterson, I.C.M.

1982-03-01

In 1978, a pilot study began of 29 patients with advanced tumors of the head and neck. The study showed an initial peripheral neuropathy rate of 55%, despite a dose limitation of 12 g/m/sup 2/ of misonidazole. Tumor response at 9 months was most encouraging. We are now able to examine tumor response and persistence of neuropathy in these patients 2 1/2 years after radical radiotherapy. The results are comparable with those obtained with hyperbaric oxygen in a clinical trial at this center during the 1970's. Neuropathy was a serious side effect but the drug phenytoin has been shown tomore » shorten the half-life of misonidazole. We have examined the effect of phenytoin on the pharmacokinetics of misonidazole in 13 patients who received radical radiotherapy for advanced head and neck tumors or oesophageal tumors. Misonidazole was given in multiple doses, i.e. daily or weekly as it would be used in conventional therapy. Phenytoin was given either daily throughout treatment, or it was withdrawn during treatment. There were dramatic changes in the half-life of misonidazole, but the concentration at the time of irradiation was little affected. The significant changes in the half-life of misonidazole and the increased concentration of the metabolite desmethylmisonidazole are discussed.« less

Intracranial Pressure Influences the Behavior of the Optic Nerve Head.

PubMed

Hua, Yi; Tong, Junfei; Ghate, Deepta; Kedar, Sachin; Gu, Linxia

2017-03-01

In this work, the biomechanical responses of the optic nerve head (ONH) to acute elevations in intracranial pressure (ICP) were systematically investigated through numerical modeling. An orthogonal experimental design was developed to quantify the influence of ten input factors that govern the anatomy and material properties of the ONH on the peak maximum principal strain (MPS) in the lamina cribrosa (LC) and postlaminar neural tissue (PLNT). Results showed that the sensitivity of ONH responses to various input factors was region-specific. In the LC, the peak MPS was most strongly dependent on the sclera thickness, LC modulus, and scleral canal size, whereas in the PLNT, the peak MPS was more sensitive to the scleral canal size, neural tissue modulus, and pia mater modulus. The enforcement of clinically relevant ICP in the retro-orbital subarachnoid space influenced the sensitivity analysis. It also induced much larger strains in the PLNT than in the LC. Moreover, acute elevation of ICP leads to dramatic strain distribution changes in the PLNT, but had minimal impact on the LC. This work could help to better understand patient-specific responses, to provide guidance on biomechanical factors resulting in optic nerve diseases, such as glaucoma, papilledema, and ischemic optic neuropathy, and to illuminate the possibilities for exploiting their potential to treat and prevent ONH diseases.

[Treatment of early-onset generalized dystonia by chronic bilateral stimulation of the internal globus pallidus. Apropos of a case].

PubMed

Coubes, P; Echenne, B; Roubertie, A; Vayssière, N; Tuffery, S; Humbertclaude, V; Cambonie, G; Claustres, M; Frerebeau, P

1999-05-01

Dystonia musculorum deformans is an inherited severe disease, with a wide clinical polymorphism. The most severe clinical forms with early onset carry a high risk of life-threatening complications. In the absence of any efficient medical treatment, bilateral pallidotomy has previously been reported to be of value in the management of this disease. We report the first clinical case of a severe early-onset generalized dystonia dramatically improved by a bilateral stimulation of the internal globus pallidus. In November 1996, we proposed this neurosurgical procedure for a 8-year-old girl, who had suffered since the age of 3 from severe generalized dystonia, and who progressively became totally dependent and bedridden. She had been under sedation and permanent controlled respiratory assistance for the last two months. The etiology of the disease remained unknown (the DYT1 mutation was absent). Under general anesthesia, we bilaterally implanted a four-contacts electrode in the internal globus pallidus, using the Leksell's stereotactic frame and a 1.5 tesla MRI control. A dramatic improvement was noted 6 weeks later and led us to connect the two electrodes to neurostimulators inserted under the abdominal skin.

Higher Order Language Competence and Adolescent Mental Health

ERIC Educational Resources Information Center

Cohen, Nancy J.; Farnia, Fataneh; Im-Bolter, Nancie

2013-01-01

Background: Clinic and community-based epidemiological studies have shown an association between child psychopathology and language impairment. The demands on language for social and academic adjustment shift dramatically during adolescence and the ability to understand the nonliteral meaning in language represented by higher order language…

Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis.

PubMed

Wang, Yini; Huang, Wenqiu; Hu, Liangding; Cen, Xinan; Li, Lihong; Wang, Jijun; Shen, Jianliang; Wei, Na; Wang, Zhao

2015-11-05

Hemophagocytic lymphohistiocytosis (HLH) is a refractory immune disorder with a significant risk of death. Although standard therapy has dramatically improved survival in HLH patients, approximately 30%, especially adults, show no response to current treatment strategies. This prospective study aimed to investigate the efficacy of liposomal doxorubicin treatment combined with etoposide and methylprednisolone (doxorubicin-etoposide-methylprednisolone; DEP) as a salvage therapy for adult refractory HLH. Adult patients who did not achieve at least partial response 2 weeks after initial standard HLH therapy were enrolled in this study between June 2013 and June 2014. Response to salvage therapy was assessed at 2 and 4 weeks after initiation of DEP therapy and patients were followed until death or until November 2014. Sixty-three refractory HLH patients were enrolled, including 29 cases of lymphoma-associated HLH, 22 cases of Epstein-Barr virus-associated HLH, and 4 cases of familial HLH. There were 8 cases with unknown underlying diseases. Seventeen cases (27.0%) achieved complete response and 31 cases (49.2%) achieved partial response. The overall response was 76.2% (48/63). Patients who showed no response to DEP died within 4 weeks after salvage therapy. Twenty-nine of the 48 patients who achieved partial or complete response survived to subsequent chemotherapy, allogenic hematopoietic stem cell transplantation, or splenectomy. Our study suggests that DEP regimen is an effective salvage regimen for adult refractory HLH, which can prolong patient survival as we continue to understand the responsible mechanisms and bridge the gap between HLH and its underlying diseases. This study was registered in the Chinese Clinical Trials Registry Platform (http://www.chictr.org.cn/) as ChiCTR-IPC-14005514. © 2015 by The American Society of Hematology.

Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease.

PubMed

Dionisi-Vici, Carlo; Diodato, Daria; Torre, Giuliano; Picca, Stefano; Pariante, Rosanna; Giuseppe Picardo, Sergio; Di Meo, Ivano; Rizzo, Cristiano; Tiranti, Valeria; Zeviani, Massimo; De Ville De Goyet, Jean

2016-04-01

Ethylmalonic encephalopathy is a fatal, rapidly progressive mitochondrial disorder caused by ETHE1 mutations, whose peculiar clinical and biochemical features are due to the toxic accumulation of hydrogen sulphide and of its metabolites, including thiosulphate. In mice with ethylmalonic encephalopathy, liver-targeted adeno-associated virus-mediated ETHE1 gene transfer dramatically improved both clinical course and metabolic abnormalities. Reasoning that the same achievement could be accomplished by liver transplantation, we performed living donor-liver transplantation in an infant with ethylmalonic encephalopathy. Unlike the invariably progressive deterioration of the disease, 8 months after liver transplantation, we observed striking neurological improvement with remarkable achievements in psychomotor development, along with dramatic reversion of biochemical abnormalities. These results clearly indicate that liver transplantation is a viable therapeutic option for ETHE1 disease. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Sialylated Fetuin-A as a candidate predictive biomarker for successful grass pollen allergen immunotherapy.

PubMed

Caillot, Noémie; Bouley, Julien; Jain, Karine; Mariano, Sandrine; Luce, Sonia; Horiot, Stéphane; Airouche, Sabi; Beuraud, Chloé; Beauvallet, Christian; Devillier, Philippe; Chollet-Martin, Sylvie; Kellenberger, Christine; Mascarell, Laurent; Chabre, Henri; Batard, Thierry; Nony, Emmanuel; Lombardi, Vincent; Baron-Bodo, Véronique; Moingeon, Philippe

2017-09-01

Eligibility to immunotherapy is based on the determination of IgE reactivity to a specific allergen by means of skin prick or in vitro testing. Biomarkers predicting the likelihood of clinical improvement during immunotherapy would significantly improve patient selection. Proteins were differentially assessed by using 2-dimensional differential gel electrophoresis and label-free mass spectrometry in pretreatment sera obtained from clinical responders and nonresponders within a cohort of 82 patients with grass pollen allergy receiving sublingual immunotherapy or placebo. Functional studies of Fetuin-A (FetA) were conducted by using gene silencing in a mouse asthma model, human dendritic cell in vitro stimulation assays, and surface plasmon resonance. Analysis by using quantitative proteomics of pretreatment sera from patients with grass pollen allergy reveals that high levels of O-glycosylated sialylated FetA isoforms are found in patients exhibiting a strong decrease in rhinoconjunctivitis symptoms after sublingual immunotherapy. Although FetA is involved in numerous inflammatory conditions, its potential role in allergy is unknown. In vivo silencing of the FETUA gene in BALB/c mice results in a dramatic upregulation of airway hyperresponsiveness, lung resistance, and T H 2 responses after allergic sensitization to ovalbumin. Both sialylated and nonsialytated FetA bind to LPS, but only the former synergizes with LPS and grass pollen or mite allergens to enhance the Toll-like receptor 4-mediated proallergic properties of human dendritic cells. As a reflection of the patient's inflammatory status, pretreatment levels of sialylated FetA in the blood are indicative of the likelihood of clinical responses during grass pollen immunotherapy. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Activity of intraarterial carboplatin as a single agent in the treatment of newly diagnosed extremity osteosarcoma.

PubMed

Petrilli, A S; Kechichian, R; Broniscer, A; Garcia, R J; Tanaka, C; Francisco, J; Lederman, H; Odone Filho, V; Camargo, O P; Bruniera, P; Pericles, P; Consentino, E; Ortega, J A

1999-08-01

Chemotherapy has dramatically improved the rates of cure and survival of patients with localized and metastatic osteosarcoma. Nonetheless, the number of chemotherapeutic agents active against osteosarcoma is limited to doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide. Carboplatin, a cisplatin analogue, has been tested as a single agent in patients with recurrent osteosarcoma or as part of multiagent chemotherapy in newly diagnosed patients. We tested the activity and toxicity of two cycles of intraarterial carboplatin as a "window therapy" (600 mg/m2 per cycle) in 33 consecutive patients with extremity osteosarcoma before the start of multiagent chemotherapy. Response was based on clinical (tumor diameter, local inflammatory signs, and range of motion) and radiological parameters (plain local films and arteriographic studies prior to drug administration). Patients' age ranged between 8 and 18 years (median age 13 years). Primary tumor originated from the femur (15 patients), tibia (10 patients), fibula (4 patients), humerus (3 patients), and calcaneus (1 patient). Only 7 patients (21%) had metastatic disease at diagnosis (5 in the lung and 2 in other bones). A favorable clinical and radiological response was documented in 81% and 73% of the patients, respectively. Clinical and radiological progression occurred in 12% and 9% of the patients, respectively. Seventeen of the patients remain alive and disease-free. Survival and event-free survival at 3 years for nonmetastatic patients are 71% (SE = 9%) and 65% (SE = 9%), respectively; for metastatic patients, the figures are 17% (SE = 15%) and 14% (SE = 13%), respectively. We conclude that carboplatin is an active agent in the treatment of newly diagnosed extremity osteosarcoma. Copyright 1999 Wiley-Liss, Inc.

Genes and plays: bringing ELSI issues to life.

PubMed

Rothenberg, Karen H; Bush, Lynn W

2012-02-01

Ethical complexities surround the promise of genomic technology and the power of genetic information as they alter conceptions of identity and dynamics within personal and professional relationships. Creative approaches such as dramatic vignettes offer a unique analytical stage for imagining the bioethical past and future. Dramatic narratives can bring to life images of differing perspectives and values when experiencing innovations in medicine. Although the scientific landscape shifts, concerns expressed in theatre from 50 years ago parallel many contemporary ELSI (ethical, legal, and social implications) issues, highlighting the ongoing struggle to appreciate the impact of emerging genetic technologies on relationships. To illuminate these enduring concerns, we explore how perceptions and relationships have influenced-and been influenced by-genetics as portrayed through dramatic vignettes. We build on the legacy of using case vignettes as a clinical teaching modality, and believe similar value exists within the research ethics domain. The selection of dialogue discussed encompasses abbreviated excerpts from two existing and one original vignette that we staged at the ELSI 2011 Congress and various academic and health institutions.

Perceived message sensation value (PMSV) and the dimensions and validation of a PMSV scale.

PubMed

Palmgreen, Philip; Stephenson, Michael T; Everett, Maureen W; Baseheart, John R; Francies, Regina

2002-01-01

Sensation seeking has been linked to drug abuse and risky behaviors, and is positively associated with preferences for messages high in sensation value (i.e., perceived to be highly novel, arousing, dramatic, or intense). This suggests the utility of valid and reliable measures of perceived message sensation value (PMSV) in research on information processing, persuasion, and reducing risk-related behaviors. Dimensions and construct validity of a 17-item PMSV scale were examined via 2 studies: 1 of 368 high school students' reactions to televised antimarijuana public service announcements (PSAs) and one of 444 college students' responses to televised anticocaine PSAs. Exploratory and confirmatory factor analyses indicated 3-dimensional solutions for the PMSV scale were nearly identical for high sensation seeking (HSS) and low sensation seeking (LSS) respondents in Study 1 and HSS respondents in Study 2. Total scale alphas were .87 for Study 1 and .93 for Study 2. The PMSV scale and its dimensions (Emotional Arousal, Dramatic Impact, Novelty) were positively correlated with affective response measures in both studies for HSS and LSS. Study 1 also examined cognitive, narrative, and sensory PSA processing, which were found to be positively associated with total PMSV and the Arousal and Dramatic Impact dimensions of PSMV for both HSS and LSS.

Inorganic phosphate-triggered release of anti-cancer arsenic trioxide from a self-delivery system: an in vitro and in vivo study

NASA Astrophysics Data System (ADS)

Chen, Fei-Yan; Yi, Jing-Wei; Gu, Zhe-Jia; Tang, Bin-Bing; Li, Jian-Qi; Li, Li; Kulkarni, Padmakar; Liu, Li; Mason, Ralph P.; Tang, Qun

2016-03-01

On-demand drug delivery is becoming feasible via the design of either exogenous or endogenous stimulus-responsive drug delivery systems. Herein we report the development of gadolinium arsenite nanoparticles as a self-delivery platform to store, deliver and release arsenic trioxide (ATO, Trisenox), a clinical anti-cancer drug. Specifically, unloading of the small molecule drug is triggered by an endogenous stimulus: inorganic phosphate (Pi) in the blood, fluid, and soft or hard tissue. Kinetics in vitro demonstrated that ATO is released with high ON/OFF specificity and no leakage was observed in the silent state. The nanoparticles induced tumor cell apoptosis, and reduced cancer cell migration and invasion. Plasma pharmacokinetics verified extended retention time, but no obvious disturbance of phosphate balance. Therapeutic efficacy on a liver cancer xenograft mouse model was dramatically potentiated with reduced toxicity compared to the free drug. These results suggest a new drug delivery strategy which might be applied for ATO therapy on solid tumors.On-demand drug delivery is becoming feasible via the design of either exogenous or endogenous stimulus-responsive drug delivery systems. Herein we report the development of gadolinium arsenite nanoparticles as a self-delivery platform to store, deliver and release arsenic trioxide (ATO, Trisenox), a clinical anti-cancer drug. Specifically, unloading of the small molecule drug is triggered by an endogenous stimulus: inorganic phosphate (Pi) in the blood, fluid, and soft or hard tissue. Kinetics in vitro demonstrated that ATO is released with high ON/OFF specificity and no leakage was observed in the silent state. The nanoparticles induced tumor cell apoptosis, and reduced cancer cell migration and invasion. Plasma pharmacokinetics verified extended retention time, but no obvious disturbance of phosphate balance. Therapeutic efficacy on a liver cancer xenograft mouse model was dramatically potentiated with reduced toxicity compared to the free drug. These results suggest a new drug delivery strategy which might be applied for ATO therapy on solid tumors. Electronic supplementary information (ESI) available: HRTEM image and electron diffraction pattern of individual GdAsOx NPs, cell viability measurements after 48 and 72 hours of incubation, body weight change curves, hematology curves, liver function curves, and renal function curves. See DOI: 10.1039/c6nr00536e

Therapeutic Advances in HCV Genotype 1 Infection: Insights from the Society of Infectious Diseases Pharmacists.

PubMed

Deming, Paulina; Martin, Michelle T; Chan, Juliana; Dilworth, Thomas J; El-Lababidi, Rania; Love, Bryan L; Mohammad, Rima A; Nguyen, Amy; Spooner, Linda M; Wortman, Suzanne B

2016-02-01

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States. The high morbidity and mortality due to untreated infection have prompted updated screening recommendations that now include one-time HCV screening for all patients born between 1945 and 1965, in addition to risk factor-based screening. Current guidelines recommend treatment for all patients with chronic HCV. Treatment for HCV genotype 1 has evolved dramatically since the approval of the direct-acting antivirals. The approval of ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir and dasabuvir, and simeprevir with sofosbuvir has dramatically altered the treatment landscape. High sustained virologic response (SVR) rates favor treatment, yet access to care poses a challenge for patients and providers. Current and emerging data with new therapies indicate high SVR rates in treatment-naïve and treatment-experienced patients, including patients with cirrhosis and in other special populations. Additional data suggest the addition of ribavirin can decrease treatment duration without compromising SVR rates. Resistance is an increasing area of interest in HCV, with baseline mutations identified and the potential for the development of resistance-associate variants in patients undergoing treatment. Due to the rapid evolution of HCV treatment, pharmacists should address challenges and play an integral role in agent selection, dosing, drug interaction screening, adverse effect monitoring, and the coordination of treatment. Clinical application of the latest information will reduce patient risk and improve outcomes. © 2016 Pharmacotherapy Publications, Inc.

A methodology for assessing departure of current plant communities from historical conditions over large landscapes

Treesearch

Brian M. Steele; Swarna K. Reddy; Robert E. Keane

2006-01-01

Fire frequency and severity, and vegetation composition and structure have been altered across much of North America during the past century because of fire exclusion and other land management practices. The cumulative results are now recognized to be partly responsible for dramatic increases in wildland fire severity and declines in ecosystem health. In response, the...

Convergent evolution and divergent selection: lizards at the White Sands ecotone.

PubMed

Rosenblum, Erica Bree

2006-01-01

Ecological transition zones, where organismal phenotypes result from a delicate balance between selection and migration, highlight the interplay of local adaptation and gene flow. Here, I study the response of an entire species assemblage to natural selection across a common ecotone. Three lizard species, distributed along a dramatic environmental gradient in substrate color, display convergent adaptation of blanched coloration on the gypsum dunes of White Sands National Monument. I investigate the role of gene flow in modulating phenotypic response to selection by quantifying color variation and genetic variation across the ecotone. I find species differences in degree of background matching and in genetic connectivity of populations across the ecotone. Differences among species in phenotypic response to selection scale precisely to levels of genetic isolation. Species with higher levels of gene flow across the ecotone exhibit less dramatic responses to selection. Results also reveal a strong signal of ecologically mediated divergence for White Sands lizards. For all species, phenotypic variation is better explained by habitat similarity than genetic similarity. Convergent evolution of blanched coloration at White Sands clearly reflects the action of strong divergent selection; however, adaptive response appears to be modulated by gene flow and demographic history and can be predicted by divergence-with-gene-flow models.

Botulinum Toxin in Aesthetic Medicine: Myths and Realities

PubMed Central

Monheit, Gary; Greener, Mark; Pickett, Andy

2018-01-01

BACKGROUND Several formulations of Botulinum toxin serotype A (BoNT-A) for aesthetic indications are available, with numbers likely to increase. Preparations are not interchangeable, based on dose unit comparisons. OBJECTIVE Numerous myths and misconceptions regarding the use of BoNT-A for aesthetic indications have arisen, which this review aims to lay to rest. MATERIALS AND METHODS This review assesses evidence for and against each of the most common myths regarding BoNT use in aesthetics. RESULTS BoNT-A neurotoxin/protein complexes are irrelevant to the toxin's therapeutic/aesthetic indications. BoNT-A neurotoxin/protein complexes do not influence movement from injection site or immunogenicity. Any relationship between neutralizing antibody formation and clinical response is complex and clinicians should consider other factors that may induce an apparent loss of clinical response. Diffusion appears predominately, perhaps exclusively, dose dependent. Careful placement and correct dosing optimizes likelihood of good outcomes. Manufacturers recommend reconstitution of products with sterile nonpreserved saline. However, compelling evidence suggests that reconstitution using preserved saline dramatically improves patient comfort without compromising efficacy. Several post-treatment instructions/restrictions are widely used despite the lack of evidence, but muscle activity after injection may be beneficial. Cooling the treatment area might hinder BoNT-A translocation and should probably be abandoned. CONCLUSION The existing evidence suggests that experienced users should achieve equivalent results regardless of BoNT-A formulation, but additional, well-designed, adequately powered, controlled randomized studies should be performed. PMID:29016535

Southeast Atmosphere Studies Workshop 2015

EPA Science Inventory

Concentrations of atmospheric trace species in the United States have changed dramatically over the past several decades in response to pollution control strategies, shifts in domestic energy policy, and economic development (and resulting emission changes) elsewhere in the world...

Personalized treatment of EGFR mutant and ALK-positive patients in NSCLC.

PubMed

Somasundaram, Aswin; Socinski, Mark A; Burns, Timothy F

2014-12-01

The epidermal growth factor receptor (EGFR) is mutated in 15% of adenocarcinomas of the lung. In addition, the anaplastic lymphoma kinase (ALK) is altered in 8% of adenocarcinomas of the lung. Treatment of EGFR mutant and ALK translocation-positive tumors in NSCLC with tyrosine kinase inhibitors (TKI) results in a dramatic therapeutic response and has revolutionized therapy. Unfortunately, resistance to TKIs invariably develops. Many promising new therapies are under investigation to overcome the resistance. We analyzed the current primary literature and recent national meetings to evaluate the clinical characteristics and therapeutic implications of relevant treatments for EGFR mutant and ALK-positive NSCLC in the first-line, acquired resistance, and adjuvant settings. Treatment with EGFR TKIs in the first-line setting of EGFR mutant NSCLC results in a significant clinical benefit. Several promising third generation EGFR TKIs are being evaluated in Phase II and III trials in the acquired resistance setting. Crizotinib is superior to chemotherapy in the first-line setting for ALK-positive NSCLC. Ceritinib is effective and approved for ALK-positive NSCLC in the acquired resistance setting. Continued investigation is needed to develop novel therapies to overcome acquired resistance to TKIs.

Synthetic and degradable patches: an emerging solution for rotator cuff repair

PubMed Central

Hakimi, Osnat; Mouthuy, Pierre-Alexis; Carr, Andrew

2013-01-01

The use of rotator cuff augmentation has increased dramatically over the last 10 years in response to the high rate of failure observed after non-augmented surgery. However, although augmentations have been shown to reduce shoulder pain, there is no consensus or clear guideline as to what is the safest or most efficacious material. Current augmentations, either available commercially or in development, can be classified into three categories: non-degradable structures, extra cellular matrix (ECM)-based patches and degradable synthetic scaffolds. Non-degradable structures have excellent mechanical properties, but can cause problems of infection and loss of integrity in the long-term. ECM-based patches usually demonstrate excellent biological properties in vitro, but studies have highlighted complications in vivo due to poor mechanical support and to infection or inflammation. Degradable synthetic scaffolds represent the new generation of implants. It is proposed that a combination of good mechanical properties, active promotion of biological healing, low infection risk and bio-absorption are the ideal characteristics of an augmentation material. Among the materials with these features, those processed by electrospinning have shown great promis. However, their clinical effectiveness has yet to be proven and well conducted clinical trials are urgently required. PMID:23837794

Clinical use of a ceramide-based moisturizer for treating dogs with atopic dermatitis

PubMed Central

Jung, Ji-young; Nam, Eui-hwa; Park, Seol-hee; Han, Seung-hee

2013-01-01

In humans, skin barrier dysfunction is thought to be responsible for enhanced penetration of allergens. Similar to conditions seen in humans, canine atopic dermatitis (CAD) is characterized by derangement of corneocytes and disorganization of intercellular lipids in the stratum corenum (SC) with decreased ceramide levels. This study was designed to evaluate the effects of a moisturizer containing ceramide on dogs with CAD. Dogs (n = 20, 3~8 years old) with mild to moderate clinical signs were recruited and applied a moisturizer containing ceramide for 4 weeks. Transepidermal water loss (TEWL), skin hydration, pruritus index for canine atopic dermatitis (PICAD) scores, and canine atopic dermatitis extent and severity index (CADESI) scores of all dogs were evaluated. Skin samples from five dogs were also examined with transmission electron microscopy (TEM) using ruthenium tetroxide. TEWL, PICAD, and CADESI values decreased (p < 0.05) and skin hydration increased dramatically over time (p < 0.05). Electron micrographs showed that the skin barrier of all five dogs was partially restored (p < 0.05). In conclusion, these results demonstrated that moisturizer containing ceramide was effective for treating skin barrier dysfunction and CAD symptoms. PMID:23814473

Management of Resistance to Crizotinib in Anaplastic Lymphoma Kinase-Positive Non-Small-cell Lung Cancer.

PubMed

Matikas, Alexios; Kentepozidis, Nikolaos; Georgoulias, Vassilis; Kotsakis, Athanasios

2016-11-01

During the past decade, the recognition of an ever-expanding list of driver oncogenic mutations in non-small-cell lung cancer has resulted in rapid therapeutic advances. Since the first description of the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement in 4% of cases of non-small-cell lung cancer in 2007, a highly potent and selective ALK inhibitor, crizotinib, was developed and approved in record time. However, it soon became apparent that although the responses can be dramatic and durable and primary intrinsic resistance to crizotinib is uncommon, the emergence of secondary resistance is inevitable. Efforts to elucidate the specific mechanisms that confer acquired resistance to crizotinib are underway. These have led to the recognition of the role of secondary resistance mutations, of ALK amplification, and of activation of bypass signaling, all of which contribute to resistance to crizotinib. Moreover, the rapid preclinical and clinical development of multiple second-generation ALK inhibitors that exhibit significant clinical activity against crizotinib-resistant disease has provided multiple options to treating physicians, with the ultimate goal the delivery of tailored medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

[Manpower requirements for medical doctors in psychiatric departments of community hospitals--bottom-up calculation for the psychiatric department of Donauspital in Vienna].

PubMed

Fischer, Peter; Hanak, Sören; Wally, Beate; Aigner, Martin

2016-03-01

Clinical psychiatry changed dramatically in the past 30 years. Clinical challenges are very different from those in old mental hospitals. Psychotherapy and sociotherapy are effective but very time-consuming parts of treatments of nearly every psychiatric disorder. Planning of staff resources based on the German "Psychiatrie Personalverordnung" does not match with modern quality requirements. As a result, the standards of evidence-based treatment cannot be offered to severely mentally ill inpatients. We carried out a buttom-up calculation of medical staffing for the concrete patients considering diagnosis, and length of stay of the psychiatric department of the Danube hospital in Vienna 2013 and 2014. This is an 80 bed unit responsible for an area of 250,000 inhabitants, providing about 1100 admissions each year. The calculated yearly sum of working hours for medical doctors in the particular department was 39,527. When considering a net working-time of 80%, the actual number of medical staff should be at least doubled to allow psychiatric treatment according to current guidelines. Severely ill psychiatric patients seem to be undertreated because of low staffing of psychiatric departments.

Hepatitis C virus resistance to the new direct-acting antivirals.

PubMed

Esposito, Isabella; Trinks, Julieta; Soriano, Vicente

2016-10-01

The treatment of hepatitis C virus (HCV) infection has dramatically improved in recent years with the widespread use of interferon-free combination regimens. Despite the high sustained virological response (SVR) rates (over 90%) obtained with direct-acting antivirals (DAAs), drug resistance has emerged as a potential challenge. The high replication rate of HCV and the low fidelity of its RNA polymerase result in a high degree of genetic variability in the HCV population, which ultimately explains the rapid selection of drug resistance associated variants (RAVs). Results from clinical trials and real-world experience have both provided important information on the rate and clinical significance of RAVs. They can be present in treatment-naive patients as natural polymorphisms although more frequently they are selected upon treatment failure. In patients engaged in high-risk behaviors, RAVs can be transmitted. Although DAA failures generally occur in less than 10% of treated chronic hepatitis C patients, selection of drug resistance is the rule in most cases. HCV re-treatment options are available, but first-line therapeutic strategies should be optimized to efficiently prevent DAA failure due to baseline HCV resistance. Considerable progress is being made and next-generation DAAs are coming with pangenotypic activity and higher resistance barrier.

Adoptive T-cell therapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors.

PubMed

Fujiwara, Hiroshi

2014-02-01

The functional properties of the adoptive immune response mediated by effector T lymphocytes are decisively regulated by their T-cell receptors (TCRs). Transfer of genes encoding target antigen-specific receptors enables polyclonal T cells to redirect toward cancer cells and virally infected cells expressing those defined antigens. Using this technology, a large population of redirected T cells displaying uniform therapeutic properties has been produced, powerfully advancing their clinical application as "cellular drugs" for adoptive immunotherapy against cancer. Clinically, anticancer adoptive immunotherapy using these genetically engineered T cells has an impressive and proven track record. Notable examples include the dramatic benefit of chimeric antigen receptor gene-modified T cells redirected towards B-cell lineage antigen CD19 in patients with chronic lymphocytic leukemia, and the impressive outcomes in the use of TCR gene-modified T cells redirected towards NY-ESO-1, a representative cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. In this review, we briefly overview the current status of this treatment option in the context of hematological malignancy, and discuss a number of challenges that still pose an obstacle to the full effectiveness of this strategy.

High-Throughput Flow Cytometry Identifies Small-Molecule Inhibitors for Drug Repurposing in T-ALL.

PubMed

Perez, Dominique R; Nickl, Christian K; Waller, Anna; Delgado-Martin, Cristina; Woods, Travis; Sharma, Nitesh D; Hermiston, Michelle L; Loh, Mignon L; Hunger, Stephen P; Winter, Stuart S; Chigaev, Alexandre; Edwards, Bruce; Sklar, Larry A; Matlawska-Wasowska, Ksenia

2018-05-01

Kinase inhibitors have dramatically increased patient survival in a multitude of cancers, including hematological malignancies. However, kinase inhibitors have not yet been integrated into current clinical trials for patients with T-cell-lineage acute lymphoblastic leukemia (T-ALL). In this study, we used a high-throughput flow cytometry (HTFC) approach to test a collection of small-molecule inhibitors, including 26 FDA-approved tyrosine kinase inhibitors in a panel of T-ALL cell lines and patient-derived xenografts. Because hypoxia is known to cause resistance to chemotherapy, we developed a synthetic niche that mimics the low oxygen levels found in leukemic bone marrow to evaluate the effects of hypoxia on the tested inhibitors. Drug sensitivity screening was performed using the Agilent BioCel automated liquid handling system integrated with the HyperCyt HT flow cytometry platform, and the uptake of propidium iodide was used as an indication of cell viability. The HTFC dose-response testing identified several compounds that were efficacious in both normal and hypoxic conditions. This study shows that some clinically approved kinase inhibitors target T-ALL in the hypoxic niche of the bone marrow.

Recent Advances in Nanotechnology for Diabetes Treatment

PubMed Central

DiSanto, Rocco Michael; Subramanian, Vinayak; Gu, Zhen

2015-01-01

Nanotechnology in diabetes research has facilitated the development of novel glucose measurement and insulin delivery modalities which hold the potential to dramatically improve quality of life for diabetics. Recent progress in the field of diabetes research at its interface with nanotechnology is our focus. In particular, we examine glucose sensors with nanoscale components including metal nanoparticles and carbon nanostructures. The addition of nanoscale components commonly increases glucose sensor sensitivity, temporal response, and can lead to sensors which facilitate continuous in vivo glucose monitoring. Additionally, we survey nanoscale approaches to “closed-loop” insulin delivery strategies which automatically release insulin in response to fluctuating blood glucose levels. “Closing the loop” between blood glucose level (BGL) measurements and insulin administration by removing the requirement of patient action holds the potential to dramatically improve the health and quality of life of diabetics. Advantages and limitations of current strategies, as well as future opportunities and challenges are also discussed. PMID:25641955

Functionalized graphene nanomaterials: new insight into direct exfoliation of graphite with supramolecular polymers

NASA Astrophysics Data System (ADS)

Cheng, Chih-Chia; Chang, Feng-Chih; Wang, Jui-Hsu; Chen, Jem-Kun; Yen, Ying-Chieh; Lee, Duu-Jong

2015-12-01

A novel urea-cytosine end-capped polypropylene glycol (UrCy-PPG) can self-assemble into a long-range ordered lamellar microstructure on the surface of graphene, due to the strong specific interactions between UrCy-PPG and graphene. In addition, the graphene composite produced exhibits a high conductivity (~1093 S m-1) with a dramatic thermo-responsive ON/OFF resistance-switching behavior (10 consecutive cycles).A novel urea-cytosine end-capped polypropylene glycol (UrCy-PPG) can self-assemble into a long-range ordered lamellar microstructure on the surface of graphene, due to the strong specific interactions between UrCy-PPG and graphene. In addition, the graphene composite produced exhibits a high conductivity (~1093 S m-1) with a dramatic thermo-responsive ON/OFF resistance-switching behavior (10 consecutive cycles). Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07076g

Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure.

PubMed

Guan, Yin; Zhao, Hong; Meng, Jing; Yan, Xiang; Jiao, ShunChang

2014-02-01

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Clinical Decision Support: a 25 Year Retrospective and a 25 Year Vision.

PubMed

Middleton, B; Sittig, D F; Wright, A

2016-08-02

The objective of this review is to summarize the state of the art of clinical decision support (CDS) circa 1990, review progress in the 25 year interval from that time, and provide a vision of what CDS might look like 25 years hence, or circa 2040. Informal review of the medical literature with iterative review and discussion among the authors to arrive at six axes (data, knowledge, inference, architecture and technology, implementation and integration, and users) to frame the review and discussion of selected barriers and facilitators to the effective use of CDS. In each of the six axes, significant progress has been made. Key advances in structuring and encoding standardized data with an increased availability of data, development of knowledge bases for CDS, and improvement of capabilities to share knowledge artifacts, explosion of methods analyzing and inferring from clinical data, evolution of information technologies and architectures to facilitate the broad application of CDS, improvement of methods to implement CDS and integrate CDS into the clinical workflow, and increasing sophistication of the end-user, all have played a role in improving the effective use of CDS in healthcare delivery. CDS has evolved dramatically over the past 25 years and will likely evolve just as dramatically or more so over the next 25 years. Increasingly, the clinical encounter between a clinician and a patient will be supported by a wide variety of cognitive aides to support diagnosis, treatment, care-coordination, surveillance and prevention, and health maintenance or wellness.

Implementation of a comprehensive pharmaceutical care program for an underserved population.

PubMed

Mascardo, Lisa A; Spading, Kimberly A; Abramowitz, Paul W

2012-07-15

The implementation of a prescription benefit program for low-income patients emphasizing clinical pharmacist services and strict formulary control is described, with a review of program expenditures and cost avoidance. In 2006, University of Iowa Hospitals and Clinics (UIHC) launched a program to provide a limited prescription benefit to indigent patients under the IowaCare Medicaid demonstration waiver. Sudden dramatic growth in IowaCare enrollment, combined with sharp budget cuts, forced UIHC pharmacy leaders to implement creative cost-control strategies: (1) the establishment of an ambulatory care clinic staffed by a clinical pharmacy specialist, (2) increased reliance on an almost exclusively generic formulary, (3) collaboration with social services staff to help secure medication assistance for patients requiring brand-name drugs, (4) optimized purchasing through the federal 340B Drug Pricing Program, and (5) the imposition of medication copayments and mailing fees for prescription refills. Now in its seventh year, the UIHC pharmacy program has expanded indigent patients' access to pharmaceutical care services while reducing their use of hospital and emergency room services and lowering program medication costs by an estimated 50% (from $2.6 million in fiscal year 2009 to $1.3 million in fiscal year 2010). The UIHC ambulatory care pharmacy implemented a prescription program in collaboration with social service workers to address the medication needs of the state's low-income and uninsured patients in a fiscally responsible manner by managing purchasing contracts, revising a generic formulary, implementing copayments and mailing fees, and reviewing medication profiles.

Treatment of acute otitis media - challenges in the era of antibiotic resistance.

PubMed

Dagan, R

2000-12-08

The last decade is characterized by the increase in antibiotic resistance among respiratory bacterial pathogens in the presence of only modest progress in the development of new antibacterial agents to overcome this resistance. A series of recent studies show clearly that the increased resistance among the main AOM pathogens (namely Streptococcus pneumoniae and Haemophilus influenzae) is associated with a dramatic decrease in bacteriologic response to antibiotic treatment, which in turn has an impact on clinical response. Thus, the individual patient is affected by the increasing antibiotic resistance. Moreover, the society as a whole is now also affected because the carriage and spread of antibiotic resistant AOM pathogens is remarkably impacted by antibiotic treatment. New studies show the remarkable ability of antibiotics to rapidly promote nasopharyngeal carriage and spread of antibiotic-resistant AOM pathogens. In these studies, the increase in carriage of antibiotic resistant S. pneumoniae is shown already after 3-4 days from initiation of antibiotic treatment and may last for weeks to months after treatment. Children carrying antibiotic-resistant organisms transmit those organisms to their family and to their day care centers and thus a vicious cycle is created in which increased antibiotic resistance with decreased response leads to increased antibiotic use, which in turn leads to further increase in resistance. New antibiotics are not likely to improve this situation. It is clear that the challenge in the next decade is to prevent AOM rather than to treat it. Efforts to prevent AOM include improved environmental factors, immunization with bacterial and viral vaccines and some creative measures such as prevention of colonization and attachment to epithelium of AOM pathogens. Whether these efforts will prove successful or, even if successful, will only modify the clinical and bacteriologic picture presenting new challenges, only time will tell.

Decorin in human oral cancer: a promising predictive biomarker of S-1 neoadjuvant chemosensitivity.

PubMed

Kasamatsu, Atsushi; Uzawa, Katsuhiro; Minakawa, Yasuyuki; Ishige, Shunsaku; Kasama, Hiroki; Endo-Sakamoto, Yosuke; Ogawara, Katsunori; Shiiba, Masashi; Takiguchi, Yuichi; Tanzawa, Hideki

2015-01-30

We reported previously that decorin (DCN) is significantly up-regulated in chemoresistant cancer cell lines. DCN is a small leucine-rich proteoglycan that exists and functions in stromal and epithelial cells. Accumulating evidence suggests that DCN affects the biology of several types of cancer by directly/indirectly targeting the signaling molecules involved in cell growth, survival, metastasis, and angiogenesis, however, the molecular mechanisms of DCN in chemoresistance and its clinical relevance are still unknown. Here we assumed that DCN silencing cells increase chemosusceptibility to S-1, consisted of tegafur, prodrug of 5-fluorouracil. We first established DCN knockdown transfectants derived from oral cancer cells for following experiments including chemosusceptibility assay to S-1. In addition to the in vitro data, DCN knockdown zenografting tumors in nude mice demonstrate decreasing cell proliferation and increasing apoptosis with dephosphorylation of AKT after S-1 chemotherapy. We also investigated whether DCN expression predicts the clinical responses of neoadjuvant chemotherapy (NAC) using S-1 (S-1 NAC) for oral cancer patients. Immunohistochemistry data in the preoperative biopsy samples was analyzed to determine the cut-off point for status of DCN expression by receiver operating curve analysis. Interestingly, low DCN expression was observed in five (83%) of six cases with complete responses to S-1 NAC, and in one (10%) case of 10 cases with stable/progressive disease, indicating that S-1 chemosensitivity is dramatically effective in oral cancer patients with low DCN expression compared with high DCN expression. Our findings suggest that DCN is a key regulator for chemoresistant mechanisms, and is a predictive immunomarker of the response to S-1 NAC and patient prognosis. Copyright © 2014 Elsevier Inc. All rights reserved.

Non-traumatic rhabdomyolysis: Background, laboratory features, and acute clinical management.

PubMed

Cervellin, Gianfranco; Comelli, Ivan; Benatti, Mario; Sanchis-Gomar, Fabian; Bassi, Antonella; Lippi, Giuseppe

2017-08-01

Rhabdomyolysis is a relatively rare condition, but its clinical consequences are frequently dramatic in terms of both morbidity and mortality. Although no consensus has been reached so far about the precise definition of this condition, the term rhabdomyolysis describes a rapid breakdown of striated, or skeletal, muscle. It is hence characterized by the rupture and necrosis of muscle fibers, resulting in release of cell degradation products and intracellular elements within the bloodstream and extracellular space. Notably, the percentage of patients with rhabdomyolysis who develop acute kidney injury, the most dramatic consequence, varies from 13% to over 50% according to both the cause and the clinical and organizational setting where they are diagnosed. Despite direct muscle injury (i.e., traumatic rhabdomyolysis) remains the most common cause, additional causes, frequently overlapping, include hypoxic, physical, chemical or biological factors. The conventional triad of symptoms includes muscle pain, weakness and dark urine. The laboratory diagnosis is essentially based on the measurement of biomarkers of muscle injury, being creatine kinase (CK) the biochemical "gold standard" for diagnosis, and myoglobin the "gold standard" for prognostication, especially in patients with non-traumatic rhabdomyolysis. The essential clinical management in the emergency department is based on a targeted intervention to manage the underlying cause, combined with infusion of fluids and eventually sodium bicarbonate. We will present and discuss in this article the pathophysiological and clinical features of non-traumatic rhabdomyolysis, focusing specifically on Emergency Department (ED) management. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS

PubMed Central

Thomas, Katja; Eisele, Judith; Rodriguez-Leal, Francisco Alejandro; Hainke, Undine

2016-01-01

Objective: Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cells. Beyond long-term immunologic and clinical data, little is known about acute changes in immunologic and routine laboratory parameters and their clinical relevance during the initial alemtuzumab infusion. Methods: Fifteen patients with highly active MS were recruited. In addition to parameters including heart rate, blood pressure, body temperature, and monitoring of adverse events, complete blood cell count, liver enzymes, kidney function, acute-phase proteins, serum cytokine profile, complement activation, peripheral immune cell distribution, and their potential of cytokine release were investigated prior to and after methylprednisolone and after alemtuzumab on each day of alemtuzumab infusion. Results: After the first alemtuzumab infusion, both the total leukocyte and granulocyte counts markedly increased, whereas lymphocyte counts dramatically decreased. In addition to lymphocyte depletion, cell subtypes important for innate immunity also decreased within the first week after alemtuzumab infusion. Although patients reported feeling well, C-reactive protein and procalcitonin peaked at serum levels consistent with septic conditions. Increases in liver enzymes were detected, although kidney function remained stable. Proinflammatory serum cytokine levels clearly rose after the first alemtuzumab infusion. Alemtuzumab led to impaired cytokine release ex vivo in nondepleted cells. Normal clinical parameters and mild adverse events were presented. Conclusions: Dramatic immunologic effects were observed. Standardized infusion procedure and pretreatment management attenuated infusion-related reactions. Alemtuzumab-mediated effects led to artificially altered parameters in standard blood testing. We recommend clinical decision-making based on primarily clinical symptoms within the first alemtuzumab treatment week. PMID:27213173

Clinical Interviewing with Older Adults

ERIC Educational Resources Information Center

Mohlman, Jan; Sirota, Karen Gainer; Papp, Laszlo A.; Staples, Alison M.; King, Arlene; Gorenstein, Ethan E.

2012-01-01

Over the next few decades the older adult population will increase dramatically, and prevalence rates of psychiatric disorders are also expected to increase in the elderly cohort. These demographic projections highlight the need for diagnostic instruments and methods that are specifically tailored to older adults. The current paper discusses the…

Dissecting the determinants of depressive disorders outcome: an in depth analysis of two clinical cases

PubMed Central

Serretti, Alessandro; Calati, Raffaella; Oasi, Osmano; De Ronchi, Diana; Colombo, Cristina

2007-01-01

Clinicians face everyday the complexity of depression. Available pharmacotherapies and psychotherapies improve patients suffering in a large part of subjects, however up to half of patients do not respond to treatment. Clinicians may forecast to a good extent if a given patient will respond or not, based on a number of data and sensations that emerge from face to face assessment. Conversely, clinical predictors of non response emerging from literature are largely unsatisfactory. Here we try to fill this gap, suggesting a comprehensive assessment of patients that may overcome the limitation of standardized assessments and detecting the factors that plausibly contribute to so marked differences in depressive disorders outcome. For this aim we present and discuss two clinical cases. Mr. A was an industrial manager who came to psychiatric evaluation with a severe depressive episode. His employment was demanding and the depressive episode undermined his capacity to manage it. Based on standardized assessment, Mr. A condition appeared severe and potentially dramatic. Mrs. B was a housewife who came to psychiatric evaluation with a moderate depressive episode. Literature predictors would suggest Mrs. B state as associated with a more favourable outcome. However the clinician impression was not converging with the standardized assessment and in fact the outcome will reverse the prediction based on the initial formal standard evaluation. Although the present report is based on two clinical cases and no generalizability is possible, a more detailed analysis of personality, temperament, defense mechanisms, self esteem, intelligence and social adjustment may allow to formalize the clinical impressions used by clinicians for biologic and pharmacologic studies. PMID:17286859

The ventricular intracardiac unipolar paced-evoked potential in an isolated animal heart.

PubMed

Economides, A P; Walton, C; Gergely, S

1988-02-01

The endocardial unipolar paced evoked response has excited a great deal of interest due to its possible use in the measurement of the metabolic state of the body and other pacer-related areas. Although rate-responsive pacing utilizing this signal has been clinically evaluated, little is known regarding the behavior of the components of this waveform under normal physiological conditions. We have developed an electronic circuit which allows the recording of the evoked response within a few milliseconds of a pacing stimulus of 5 V and 0.5 ms duration being applied using a single unipolar, smooth platinum electrode of 14 mm2 surface area. The paced evoked response was measured using a total of 20 isolated rabbit heart preparations. Five were run for 8 hours and the remaining fifteen were run for 5 hours. Our results indicate that the waveform components of the evoked response remain stable while the preparation is viable, but that two of the time-related measurements change with loss of viability. A significant lengthening of the stimulus-R interval was seen together with a dramatic shortening of the R-T period. The net result of these changes was an overall reduction of 17% in the complex duration. In addition, we found the R-T shortening to be a sensitive measure of myocardial integrity. We conclude that the combination of our interface charge elimination circuit and the isolated heart preparation has proved a useful system for the investigation of the paced evoked potential. Furthermore, the loss of myocardial viability has a complex action on this response.

Poster — Thur Eve — 27: Flattening Filter Free VMAT Quality Assurance: Dose Rate Considerations for Detector Response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Viel, Francis; Duzenli, Cheryl; British Columbia Cancer Agency, Department of Medical Physics, Vancouver Centre

2014-08-15

Introduction: Radiation detector responses can be affected by dose rate. Due to higher dose per pulse and wider range of mu rates in FFF beams, detector responses should be characterized prior to implementation of QA protocols for FFF beams. During VMAT delivery, the MU rate may also vary dramatically within a treatment fraction. This study looks at the dose per pulse variation throughout a 3D volume for typical VMAT plans and the response characteristics for a variety of detectors, and makes recommendations on the design of QA protocols for FFF VMAT QA. Materials and Methods: Linac log file data andmore » a simplified dose calculation algorithm are used to calculate dose per pulse for a variety of clinical VMAT plans, on a voxel by voxel basis, as a function of time in a cylindrical phantom. Diode and ion chamber array responses are characterized over the relevant range of dose per pulse and dose rate. Results: Dose per pulse ranges from <0.1 mGy/pulse to 1.5 mGy/pulse in a typical VMAT treatment delivery using the 10XFFF beam. Diode detector arrays demonstrate increased sensitivity to dose (+./− 3%) with increasing dose per pulse over this range. Ion chamber arrays demonstrate decreased sensitivity to dose (+/− 1%) with increasing dose rate over this range. Conclusions: QA protocols should be designed taking into consideration inherent changes in detector sensitivity with dose rate. Neglecting to account for changes in detector response with dose per pulse can lead to skewed QA results.« less

Potential functional applications of extracellular vesicles: a report by the NIH Common Fund Extracellular RNA Communication Consortium

PubMed Central

Quesenberry, Peter J.; Aliotta, Jason; Camussi, Giovanni; Abdel-Mageed, Asim B.; Wen, Sicheng; Goldberg, Laura; Zhang, Huang-Ge; Tetta, Ciro; Franklin, Jeffrey; Coffey, Robert J.; Danielson, Kirsty; Subramanya, Vinita; Ghiran, Ionita; Das, Saumya; Chen, Clark C.; Pusic, Kae M.; Pusic, Aya D.; Chatterjee, Devasis; Kraig, Richard P.; Balaj, Leonora; Dooner, Mark

2015-01-01

The NIH Extracellular RNA Communication Program's initiative on clinical utility of extracellular RNAs and therapeutic agents and developing scalable technologies is reviewed here. Background information and details of the projects are presented. The work has focused on modulation of target cell fate by extracellular vesicles (EVs) and RNA. Work on plant-derived vesicles is of intense interest, and non-mammalian sources of vesicles may represent a very promising source for different therapeutic approaches. Retro-viral-like particles are intriguing. Clearly, EVs share pathways with the assembly machinery of several other viruses, including human endogenous retrovirals (HERVs), and this convergence may explain the observation of viral-like particles containing viral proteins and nucleic acid in EVs. Dramatic effect on regeneration of damaged bone marrow, renal, pulmonary and cardiovascular tissue is demonstrated and discussed. These studies show restoration of injured cell function and the importance of heterogeneity of different vesicle populations. The potential for neural regeneration is explored, and the capacity to promote and reverse neoplasia by EV exposure is described. The tremendous clinical potential of EVs underlies many of these projects, and the importance of regulatory issues and the necessity of general manufacturing production (GMP) studies for eventual clinical trials are emphasized. Clinical trials are already being pursued and should expand dramatically in the near future. PMID:26320942

The rising level of medical student debt: potential risk for a national default.

PubMed

Ariyan, S

2000-04-01

At the turn of the 20th century, mostly as a result of the Flexner report, medical education changed dramatically by establishing a scientific basis for the study of medicine within the institutions of the major universities. There have been major and dramatic changes in medicine during the past 80 years that have improved medical education in the United States, but these changes have also placed major economic strains on students who have educational debts. If medicine is a social responsibility to the public, then the public should share the responsibility of identifying and supporting new approaches to funding and financially managing the teaching of future physicians. There is no universal solution because there are various approaches institutions may take to structure these financial responsibilities. This article describes trends in medical student educational debt, identifies the financial needs of medical students, and proposes ways of addressing those needs to avert a possible national financial crisis among medical students. We must invest in medical students because they will be the leaders we need to help care for our society and our own families in the next century.

Insight into k13-propeller gene polymorphism and ex vivo DHA-response profiles from Cameroonian isolates.

PubMed

Menard, Sandie; Tchoufack, Joëlle Njila; Maffo, Christelle Ngou; Nsango, Sandrine E; Iriart, Xavier; Abate, Luc; Tsapi, Majoline Tchioffo; Awono-Ambéné, Parfait H; Abega Mekongo, Francis A; Morlais, Isabelle; Berry, Antoine

2016-11-26

The spread of Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia is a major source of concern and the emergence of resistance in Africa would have dramatic consequences, by increasing malaria mortality and morbidity. It is therefore urgent to implement regular monitoring in sentinel sites in sub-Saharan Africa using robust and easy-to-implement tools. The prevalence of k13-propeller mutations and the phenotypic profiles are poorly known in sub-Saharan Africa. Here, the k13-propeller polymorphism was compared to both ex vivo susceptibility to DHA and early parasitological and clinical responses to artemisinin combination therapy (ACT). Plasmodium falciparum isolates were collected in 2015 in Yaoundé (Cameroon) from patients treated with dihydroartemisinin-piperaquine combination. Samples were analysed for their susceptibility to artemisinin using the k13-propeller sequencing, the ex vivo ring-stage survival assay, the in vivo parasite positive rate and the clinical statute at day 2. None of the collected isolates revealed the presence of resistance mutations in the k13-propeller sequence. The median ring-stage survival rate for all the 64 interpretable isolates after a 6-hour pulse of 700 nM dihydroartemisinin was low, 0.49% (IQR: 0-1.3). Total parasite clearance was observed for 87.5% of patients and the remaining parasitaemic isolates (12.5%) showed a high reduction of parasite load, ranging from 97.5 to 99.9%. Clinical symptoms disappeared in 92.8% of cases. This study demonstrated the absence of k13-resistant genotypes in P. falciparum isolates from Cameroon. Only synonymous mutations were found with a low prevalence (4.3%). A good association between k13 genotypes and the ex vivo ring-stage survival assay or parasitological and clinical data was obtained. These results give a baseline for the long-term monitoring of artemisinin derivative efficacy in Africa.

Comparative Transcriptomics Implicates Mechansims of Evolved Pollution Tolerance in a Killifish Population

EPA Science Inventory

Wild populations of the killifish Fundulus heteroclitus resident in heavily contaminated North American Atlantic coast estuaries have recently and independently evolved dramatic, heritable, and adaptive pollution tolerance. We compared physiological and transcriptome responses t...

L-shaped benzimidazole fluorophores: synthesis, characterization and optical response to bases, acids and anions.

PubMed

Lirag, Rio Carlo; Le, Ha T M; Miljanić, Ognjen Š

2013-05-14

Nine L-shaped benzimidazole fluorophores have been synthesized, computationally evaluated and spectroscopically characterized. These "half-cruciform" fluorophores respond to bases, acids and anions through changes in fluorescence that vary from moderate to dramatic.

Southeast Atmosphere Studies: learning from model-observation syntheses

EPA Science Inventory

Concentrations of atmospheric trace species in the United States have changed dramatically over the past several decades in response to pollution control strategies, shifts in domestic energy policy and economics, and economic development (and resulting emission changes) elsewher...

Clinical- and imaging-based prediction of stroke risk after transient ischemic attack: the CIP model.

PubMed

Ay, Hakan; Arsava, E Murat; Johnston, S Claiborne; Vangel, Mark; Schwamm, Lee H; Furie, Karen L; Koroshetz, Walter J; Sorensen, A Gregory

2009-01-01

Predictive instruments based on clinical features for early stroke risk after transient ischemic attack suffer from limited specificity. We sought to combine imaging and clinical features to improve predictions for 7-day stroke risk after transient ischemic attack. We studied 601 consecutive patients with transient ischemic attack who had MRI within 24 hours of symptom onset. A logistic regression model was developed using stroke within 7 days as the response criterion and diffusion-weighted imaging findings and dichotomized ABCD(2) score (ABCD(2) >/=4) as covariates. Subsequent stroke occurred in 25 patients (5.2%). Dichotomized ABCD(2) score and acute infarct on diffusion-weighted imaging were each independent predictors of stroke risk. The 7-day risk was 0.0% with no predictor, 2.0% with ABCD(2) score >/=4 alone, 4.9% with acute infarct on diffusion-weighted imaging alone, and 14.9% with both predictors (an automated calculator is available at http://cip.martinos.org). Adding imaging increased the area under the receiver operating characteristic curve from 0.66 (95% CI, 0.57 to 0.76) using the ABCD(2) score to 0.81 (95% CI, 0.74 to 0.88; P=0.003). The sensitivity of 80% on the receiver operating characteristic curve corresponded to a specificity of 73% for the CIP model and 47% for the ABCD(2) score. Combining acute imaging findings with clinical transient ischemic attack features causes a dramatic boost in the accuracy of predictions with clinical features alone for early risk of stroke after transient ischemic attack. If validated in relevant clinical settings, risk stratification by the CIP model may assist in early implementation of therapeutic measures and effective use of hospital resources.

Pain, Nicotine, and Smoking: Research Findings and Mechanistic Considerations

ERIC Educational Resources Information Center

Ditre, Joseph W.; Brandon, Thomas H.; Zale, Emily L.; Meagher, Mary M.

2011-01-01

Tobacco addiction and chronic pain represent 2 highly prevalent and comorbid conditions that engender substantial burdens upon individuals and systems. Interrelations between pain and smoking have been of clinical and empirical interest for decades, and research in this area has increased dramatically over the past 5 years. We conceptualize the…

Name Changes in Medically Important Fungi and Their Implications for Clinical Practice

PubMed Central

de Hoog, G. Sybren; Chaturvedi, Vishnu; Denning, David W.; Dyer, Paul S.; Frisvad, Jens Christian; Geiser, David; Gräser, Yvonne; Guarro, Josep; Haase, Gerhard; Kwon-Chung, Kyung-Joo; Meyer, Wieland; Pitt, John I.; Samson, Robert A.; Tintelnot, Kathrin; Vitale, Roxana G.; Walsh, Thomas J.

2014-01-01

Recent changes in the Fungal Code of Nomenclature and developments in molecular phylogeny are about to lead to dramatic changes in the naming of medically important molds and yeasts. In this article, we present a widely supported and simple proposal to prevent unnecessary nomenclatural instability. PMID:25297326

Treating Cancer with Amplitude-Modulated Electromagnetic Fields: A Potential Paradigm Shift, Again?

EPA Science Inventory

The Zimmerman et al. (2011) study published here, coupled with the group's two preceding papers (Barbault et al. (2009), Costa et al. (2011)), identify a potential modality for treating tumors at a dramatic reduction in trauma and cost. This set of clinical and explanatory labora...

Anger Control Bibliotherapy with a Convicted Murderer under Life Sentence: A Clinical Report.

ERIC Educational Resources Information Center

Daniel, Chris

1992-01-01

Used personalized bibliotherapy intervention approach to prevent build up of aggression in inmate with low tolerance to perceived provocation. Follow-up data over six-month period revealed dramatic decrease in discipline reports following therapy. Interview and questionnaire feedback from client indicated reduced incidence of feelings of…

Mobile Technology to Increase HIV/HCV Testing and Overdose Prevention/Response among People Who Inject Drugs

PubMed Central

Aronson, Ian David; Bennett, Alexander; Marsch, Lisa A.; Bania, Theodore C.

2017-01-01

The United States faces dramatically increasing rates of opioid overdose deaths, as well as persistent ongoing problems of undiagnosed HIV and HCV infection. These problems commonly occur together in substance using populations that have limited, if any, access to primary care and other routine health services. To collectively address all three issues, we developed the Mobile Intervention Kit (MIK), a tablet computer-based intervention designed to provide overdose prevention and response training and to facilitate HIV/HCV testing in community settings. Intervention content was produced in collaboration with experienced street outreach workers who appear onscreen in a series of educational videos. A preliminary pilot test of the MIK in a Bronx, NY street outreach syringe exchange program found the MIK is feasible and highly acceptable to a population of people who inject drugs. Participants accepted HIV and HCV testing post-intervention, as well as naloxone training to reverse overdose events. Pre-post tests also showed significant increases in knowledge of overdose prevention, HIV testing procedures, and asymptomatic HCV infection. Future iterations of the MIK can be optimized for use in community as well as clinical settings nationwide, and perhaps globally, with a focus on underserved urban populations. PMID:28879174

Regulation of corticoid and serotonin receptor brain system following early life exposure of glucocorticoids: long term implications for the neurobiology of mood.

PubMed

Vázquez, Delia M; Neal, Charles R; Patel, Paresh D; Kaciroti, Niko; López, Juan F

2012-03-01

Potent glucocorticoids (GC) administered early in life have improved premature infant survival dramatically. However, these agents may increase the risk for physical, neurological and behavior alterations. Anxiety, depression and attention difficulties are commonly described in adolescent and young adult survivors of prematurity. In the present study we administered vehicle, dexamethasone, or hydrocortisone to Sprague-Dawley rat pups on postnatal days 5 and 6, mimicking a short term clinical protocol commonly used in human infants. Two systems that are implicated in the regulation of stress and behavior were assessed: the limbic-hypothalamic-pituitary-adrenal axis [LHPA; glucocorticoid and mineralocorticoid receptors within] and the Serotonin (5-HT) system. We found that as adults, male Sprague-Dawley pups treated with GC showed agent specific altered growth, anxiety-related behavior, changes in corticoid response to novelty and gene expression changes within LHPA and 5-HT-related circuitry. The data suggest that prolonged GC-receptor stimulation during the early neonatal period can contribute to the development of individual differences in stress response and anxiety-related behavior later in life. Copyright © 2011 Elsevier Ltd. All rights reserved.

A novel mutation of the Keratin 12 gene responsible for a severe phenotype of Meesmann's corneal dystrophy

PubMed Central

Sullivan, Lori S.; Baylin, Eric B.; Font, Ramon; Daiger, Stephen P.; Pepose, Jay S.; Clinch, Thomas E.; Nakamura, Hisashi; Zhao, Xinping C.

2007-01-01

Purpose To determine if a mutation within the coding region of the keratin 12 gene (KRT12) is responsible for a severe form of Meesmann's corneal dystrophy. Methods A family with clinically identified Meesmann's corneal dystrophy was recruited and studied. Electron microscopy was performed on scrapings of corneal epithelial cells from the proband. Mutations in the KRT12 gene were sought using direct genomic sequencing of leukocyte DNA from two affected and two unaffected family members. Subsequently, the observed mutation was screened in all available family members using polymerase chain reaction and direct sequencing. Results A heterozygous missense mutation (Arg430Pro) was found in exon 6 of KRT12 in all 14 affected individuals studied. Unaffected family members and 100 normal controls were negative for this mutation. Conclusions We have identified a novel mutation in the KRT12 gene that is associated with a symptomatic phenotype of Meesmann's corneal dystrophy. This mutation results in a substitution of proline for arginine in the helix termination motif that may disrupt the normal helix, leading to a dramatic structural change of the keratin 12 protein. PMID:17653038

Recurrent abdominal pain as the presentation of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in an Asian girl: a case report and review of the literature.

PubMed

Chen, Yun-Ju; Yu, Hsin-Hui; Yang, Yao-Hsu; Lau, Yu-Lung; Lee, Wen-I; Chiang, Bor-Luen

2014-12-01

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is characterized by periodic fever, cutaneous rash, conjunctivitis, lymphadenopathy, abdominal pain, myalgia, and arthralgia. It is a rare autosomal dominant disease and strongly associated with heterozygous mutations in the tumor necrosis factor (TNF) receptor super family 1A (TNFRSF1A) gene. It is believed to be more common in Western countries than in Asian countries. Here, we present the case of a 14-year-old girl with periodic fever and abdominal pain with elevation of inflammatory markers for 2 years. After extensive work-up of infectious etiology with negative results, the diagnosis of TRAPS was made although no gene mutations were identified in the TNFRSF1A gene, MVK gene, and NALP3/CIAS1 gene. She had partial clinical response to corticosteroids and immunomodulatory agents. However, the treatment response to TNF-α inhibitor etanercept was dramatic. She has remained symptom free under regular weekly to biweekly etanercept treatment for 2 years. We also reviewed the related literature and summarized the data of 10 Asian cases of TRAPS. Copyright © 2012. Published by Elsevier B.V.

Immunogenicity and protective efficacy of a replication-defective infectious bronchitis virus vaccine using an adenovirus vector and administered in ovo.

PubMed

Zeshan, Basit; Zhang, Lili; Bai, Juan; Wang, Xinglong; Xu, Jiarong; Jiang, Ping

2010-06-01

In ovo vaccination remains an attractive option for a cost effective, uniform and mass application of vaccines for commercial poultry. However, the vaccines which can be delivered safely by this method are limited and there is no currently licensed embryo-safe vaccine against infectious bronchitis virus (IBV). In this study, a recombinant adenovirus expressing the S1 gene of nephropathogenic IBV (rAd-S1) was constructed and the immune responses and protective efficacy against homologous challenge were evaluated after in ovo vaccination. The results showed that the rAd-S1 led to dramatic augmentation of humoral and cellular responses in birds vaccinated in ovo followed by an intramuscular inoculation. Both IFN-gamma and IL-4 in chicken's lymphocytes were produced by this strategy. Following challenge with IBV, the chickens vaccinated with recombinant adenovirus showed fewer nephropathic lesions and less severe clinical signs as compared to those receiving wild-type adenovirus or PBS. The construction of non-replicating human adenovirus vector encoding S1 gene of IBV and its in ovo delivery demonstrated the potential of an alternative vaccination strategy against IBV. Copyright 2010 Elsevier B.V. All rights reserved.

Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies

PubMed Central

Ablain, Julien; Leiva, Magdalena; Peres, Laurent; Fonsart, Julien; Anthony, Elodie

2013-01-01

In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA- or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoid–treated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients. PMID:23509325

Mobile Technology to Increase HIV/HCV Testing and Overdose Prevention/Response among People Who Inject Drugs.

PubMed

Aronson, Ian David; Bennett, Alexander; Marsch, Lisa A; Bania, Theodore C

2017-01-01

The United States faces dramatically increasing rates of opioid overdose deaths, as well as persistent ongoing problems of undiagnosed HIV and HCV infection. These problems commonly occur together in substance using populations that have limited, if any, access to primary care and other routine health services. To collectively address all three issues, we developed the Mobile Intervention Kit (MIK), a tablet computer-based intervention designed to provide overdose prevention and response training and to facilitate HIV/HCV testing in community settings. Intervention content was produced in collaboration with experienced street outreach workers who appear onscreen in a series of educational videos. A preliminary pilot test of the MIK in a Bronx, NY street outreach syringe exchange program found the MIK is feasible and highly acceptable to a population of people who inject drugs. Participants accepted HIV and HCV testing post-intervention, as well as naloxone training to reverse overdose events. Pre-post tests also showed significant increases in knowledge of overdose prevention, HIV testing procedures, and asymptomatic HCV infection. Future iterations of the MIK can be optimized for use in community as well as clinical settings nationwide, and perhaps globally, with a focus on underserved urban populations.

Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies.

PubMed

Ablain, Julien; Leiva, Magdalena; Peres, Laurent; Fonsart, Julien; Anthony, Elodie; de Thé, Hugues

2013-04-08

In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA- or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoid-treated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients.

A Response to Professor Wu Zongjie's "Interpretation, Autonomy, and Transformation: Chinese Pedagogic Discourse in a Cross-Cultural Perspective"

ERIC Educational Resources Information Center

Curran, Thomas D.

2014-01-01

In response to an essay by Prof Wu Zongjie that was published in the "Journal of Curriculum Studies" [43(5), (2011), 569-590], I argue that, despite dramatic changes that have taken place in the language of Chinese academic discourse and pedagogy, evidence derived from the fields of psychology and the history of Chinese educational…

Incretin response to a standard test meal in a rat model of sleeve gastrectomy with diet-induced obesity.

PubMed

Al-Sabah, Suleiman; Alasfar, Fahad; Al-Khaledi, Ghanim; Dinesh, Reshma; Al-Saleh, Mervat; Abul, Habib

2014-01-01

Currently, the most effective treatment for obesity is bariatric surgery. Gastroduodenal bypass surgery produces sustained weight loss and improves glycemic control and insulin sensitivity. Previous studies have shown that sleeve gastrectomy (SG) produces similar results and implicate changes in incretin hormone release in these effects. Male Sprague-Dawley rats were divided into four groups; lean control (lean), diet-induced obesity (DIO), DIO animals that had undergone SG (SG), and DIO animals that had undergone a sham operation (sham). After a 2-week recovery period, the incretin response to a standard test meal was measured. Blood sampling was performed in free-moving rats at various time points using chronic vascular access to the right jugular vein. There was a significant increase in the bodyweight of DIO animals fed a high-fat/high-sugar diet compared with the lean animals, which was reversed by SG. DIO caused an impairment of the GLP-1 response to a standard test meal, but not the GIP response. SG resulted in a dramatic increase in the GLP-1 response to a standard test meal but had no effect on the GIP response. A rapid rise in blood sugar was observed in the SG group following a standard test meal that was followed by reactive hypoglycemia. SG dramatically increases the GLP-1 response to a standard test meal but has no effect on GIP in a rat model of DIO.

History of solid organ transplantation and organ donation.

PubMed

Linden, Peter K

2009-01-01

Solid organ transplantation is one of the most remarkable and dramatic therapeutic advances in medicine during the past 60 years. This field has progressed initially from what can accurately be termed a "clinical experiment" to routine and reliable practice, which has proven to be clinically effective, life-saving and cost-effective. This remarkable evolution stems from a serial confluence of: cultural acceptance; legal and political evolution to facilitate organ donation, procurement and allocation; technical and cognitive advances in organ preservation, surgery, immunology, immunosuppression; and management of infectious diseases. Some of the major milestones of this multidisciplinary clinical science are reviewed in this article.

Methicillin-resistant Staphylococcus aureus and skin infections among personnel at a pediatric clinic.

PubMed

Carpenter, L Rand; Kainer, Marion; Woron, Amy; Schaffner, William; Jones, Timothy F

2008-11-01

Ambulatory care visits for methicillin-resistant Staphylococcus aureus (MRSA) infections are increasing dramatically. We investigated a pediatric clinic worker's death caused by MRSA. Among 45 clinic personnel, 16 reported recent skin infections, and 4% were colonized with MRSA. Among 262 patients, 3.4% were colonized with MRSA. Standard precautions were inconsistently applied when treating skin infections. Eight (11%) of 71 environmental swipes contained S aureus. Health care workers in outpatient settings are increasingly exposed to substantial numbers of persons with MRSA, and infection control practices in the ambulatory care setting deserve reemphasis.

Autonomous system for launch vehicle range safety

NASA Astrophysics Data System (ADS)

Ferrell, Bob; Haley, Sam

2001-02-01

The Autonomous Flight Safety System (AFSS) is a launch vehicle subsystem whose ultimate goal is an autonomous capability to assure range safety (people and valuable resources), flight personnel safety, flight assets safety (recovery of valuable vehicles and cargo), and global coverage with a dramatic simplification of range infrastructure. The AFSS is capable of determining current vehicle position and predicting the impact point with respect to flight restriction zones. Additionally, it is able to discern whether or not the launch vehicle is an immediate threat to public safety, and initiate the appropriate range safety response. These features provide for a dramatic cost reduction in range operations and improved reliability of mission success. .

Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer

PubMed Central

Grisham, Rachel N.; Sylvester, Brooke E.; Won, Helen; McDermott, Gregory; DeLair, Deborah; Ramirez, Ricardo; Yao, Zhan; Shen, Ronglai; Dao, Fanny; Bogomolniy, Faina; Makker, Vicky; Sala, Evis; Soumerai, Tara E.; Hyman, David M.; Socci, Nicholas D.; Viale, Agnes; Gershenson, David M.; Farley, John; Levine, Douglas A.; Rosen, Neal; Berger, Michael F.; Spriggs, David R.; Aghajanian, Carol A.; Solit, David B.; Iyer, Gopa

2015-01-01

Purpose No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor. Patients and Methods Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed. Results Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor–based combination therapy. Conclusion Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease. PMID:26324360

Antiretroviral therapy: current drugs.

PubMed

Pau, Alice K; George, Jomy M

2014-09-01

The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus' replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date. Published by Elsevier Inc.

Acute hemorrhagic edema of infancy: report of three cases.

PubMed

Emerich, Paulo Sergio; Prebianchi, Patricia Almeida; Motta, Luciene Lage da; Lucas, Elton Almeida; Ferreira, Leonardo Mello

2011-01-01

Acute Hemorrhagic Edema of Infancy is an infrequent leukocytoclastic vasculitis which occurs almost exclusively in children between 4 months and 2 years of age. It is clinically characterized by the triad fever, purpuric lesions on the face, auricular pinna and extremities, and edema. Although the cutaneous findings are dramatic and of rapid onset, the prognosis is favorable, with spontaneous resolution within 1 to 3 weeks. Three cases are described in which clinical and histopathological findings are characteristic of acute hemorrhagic edema of infancy.

Achieving appropriate design for developing world heath care: the case of a low-cost autoclave for primary health clinics.

PubMed

Cho, Hallie S; Tao, Gregory D; Winter, Amos

2012-01-01

In developing world health clinics, incidence of surgical site infection is 2 to 10 times higher than in developed world hospitals. This paper identifies lack of availability of appropriately designed, low-cost autoclaves in developing world health clinics as a major contributing factor to the dramatic gap in surgical site infection rates. The paper describes the process of developing a low-cost autoclave that addresses the unique challenges faced by developing world primary health clinics and discusses how appropriateness of design was determined. The resulting pressure cooker-based autoclave design was fabricated and tested against the CDC specifications. Twelve partnering clinics in Nepal trialed these autoclaves from July until December 2012.

Human oocyte cryopreservation.

PubMed

Tao, Tao; Zhang, Wenling; Del Valle, Alfonso

2009-06-01

This review summarized the clinical breakthroughs in the human oocyte cryopreservation field in the past 2 years and gave special emphasis on the role of vitrification method. Human oocyte cryopreservation is an attractive strategy to preserve female fertility, as it offers more opportunities to the future destination of the female gametes and also raises fewer legal and ethical questions compared with embryo cryopreservation. It became promising in recent years because of dramatic improvement in cryopreservation technologies. Human oocyte cryopreservation would not become a clinical routine until the availability of reliable cryopreservation methods and long-term follow-up results of the babies born by this technique. Oocyte cryopreservation produced very exciting results with pregnancy and implantation rates comparable to embryo cryopreservation and in some cases comparable to fresh in-vitro fertilization cycles with both modified slow-freezing and vitrification methods. A cancer patient conceived and delivered her own babies by this technology after recovery from the disease. Oocyte cryopreservation became a new focus in assisted reproductive technology. We witnessed the advanced development of human oocyte cryopreservation in the past years because of increasing demand, medically, legally and ethically, and also because of the dramatic improvement of the freezing technique. There is still a long way to go to integrate it into a routine clinical procedure to benefit more patients and encourage clinicians to follow the standard protocols.

Hyperconnectivity is a fundamental response to neurological disruption.

PubMed

Hillary, Frank G; Roman, Cristina A; Venkatesan, Umesh; Rajtmajer, Sarah M; Bajo, Ricardo; Castellanos, Nazareth D

2015-01-01

In the cognitive and clinical neurosciences, the past decade has been marked by dramatic growth in a literature examining brain "connectivity" using noninvasive methods. We offer a critical review of the blood oxygen level dependent functional MRI (BOLD fMRI) literature examining neural connectivity changes in neurological disorders with focus on brain injury and dementia. The goal is to demonstrate that there are identifiable shifts in local and large-scale network connectivity that can be predicted by the degree of pathology. We anticipate that the most common network response to neurological insult is hyperconnectivity but that this response depends upon demand and resource availability. To examine this hypothesis, we initially reviewed the results from 1,426 studies examining functional brain connectivity in individuals diagnosed with multiple sclerosis, traumatic brain injury, mild cognitive impairment, and Alzheimer's disease. Based upon inclusionary criteria, 126 studies were included for detailed analysis. RESULTS from 126 studies examining local and whole brain connectivity demonstrated increased connectivity in traumatic brain injury and multiple sclerosis. This finding is juxtaposed with findings in mild cognitive impairment and Alzheimer's disease where there is a shift to diminished connectivity as degeneration progresses. This summary of the functional imaging literature using fMRI methods reveals that hyperconnectivity is a common response to neurological disruption and that it may be differentially observable across brain regions. We discuss the factors contributing to both hyper- and hypoconnectivity results after neurological disruption and the implications these findings have for network plasticity. PsycINFO Database Record (c) 2015 APA, all rights reserved.

Site-directed mutagenesis of the hinge peptide from the hemagglutinin protein: enhancement of the pH-responsive conformational change.

PubMed

Casali, Monica; Banta, Scott; Zambonelli, Carlo; Megeed, Zaki; Yarmush, Martin L

2008-06-01

Environmentally responsive proteins and peptides are increasingly finding utility in various engineered systems due to their ability to respond to the presentation of external stimuli. A classic example of this behavior is the influenza hemagglutinin (HA) fusion protein. At neutral pH, HA exists in a non-fusogenic state, but upon exposure to low pH, the conformation of the structure changes to expose a fusogenic peptide. During this structural change, massive rearrangements occur in a subunit of HA (HA2). Crystallography data has shown that a loop of 28 amino acids (residues 54-81) undergoes a dramatic transition from a random coil to an alpha-helix. This segment connects to two flanking helical regions (short and long) to form a long, continuous helix. Here, we report the results of site-directed mutagenesis study on LOOP-36 to further understand the mechanism of this important stimulus-responsive peptide. The conformational transition of a bacterially expressed LOOP-36 was found to be less dramatic than has been previously reported. The systematic mutation of glutamate and histidine residues in the peptide to glutamines (glutamine scanning) did not impact the conformational behavior of the peptide, but the substitution of the glycine residue at position 22 with alanine resulted in significant pH-responsive behavior. Therefore this mutant stimulus-responsive peptide may be more valuable for future protein engineering and bionanotechnology efforts.

Clinical Decision Support: a 25 Year Retrospective and a 25 Year Vision

PubMed Central

Sittig, D. F.; Wright, A.

2016-01-01

Summary Objective The objective of this review is to summarize the state of the art of clinical decision support (CDS) circa 1990, review progress in the 25 year interval from that time, and provide a vision of what CDS might look like 25 years hence, or circa 2040. Method Informal review of the medical literature with iterative review and discussion among the authors to arrive at six axes (data, knowledge, inference, architecture and technology, implementation and integration, and users) to frame the review and discussion of selected barriers and facilitators to the effective use of CDS. Result In each of the six axes, significant progress has been made. Key advances in structuring and encoding standardized data with an increased availability of data, development of knowledge bases for CDS, and improvement of capabilities to share knowledge artifacts, explosion of methods analyzing and inferring from clinical data, evolution of information technologies and architectures to facilitate the broad application of CDS, improvement of methods to implement CDS and integrate CDS into the clinical workflow, and increasing sophistication of the end-user, all have played a role in improving the effective use of CDS in healthcare delivery. Conclusion CDS has evolved dramatically over the past 25 years and will likely evolve just as dramatically or more so over the next 25 years. Increasingly, the clinical encounter between a clinician and a patient will be supported by a wide variety of cognitive aides to support diagnosis, treatment, care-coordination, surveillance and prevention, and health maintenance or wellness. PMID:27488402

Impact of voice- and knowledge-enabled clinical reporting--US example.

PubMed

Bushko, Renata G; Havlicek, Penny L; Deppert, Edward; Epner, Stephen

2002-01-01

This study shows qualitative and quantitative estimates of the national and the clinic level impact of utilizing voice and knowledge enabled clinical reporting systems. Using common sense estimation methodology, we show that the delivery of health care can experience a dramatic improvement in four areas as a result of the broad use of voice and knowledge enabled clinical reporting: (1) Process Quality as measured by cost savings, (2) Organizational Quality as measured by compliance, (3) Clinical Quality as measured by clinical outcomes and (4) Service Quality as measured by patient satisfaction. If only 15 percent of US physicians replaced transcription with modem clinical reporting voice-based methodology, about one half billion dollars could be saved. $6.7 Billion could be saved annually if all medical reporting currently transcribed was handled with voice-and knowledge-enabled dictation and reporting systems.

Fasting, but Not Aging, Dramatically Alters the Redox Status of Cysteine Residues on Proteins in Drosophila melanogaster

PubMed Central

Menger, Katja E.; James, Andrew M.; Cochemé, Helena M.; Harbour, Michael E.; Chouchani, Edward T.; Ding, Shujing; Fearnley, Ian M.; Partridge, Linda; Murphy, Michael P.

2015-01-01

Summary Altering the redox state of cysteine residues on protein surfaces is an important response to environmental challenges. Although aging and fasting alter many redox processes, the role of cysteine residues is uncertain. To address this, we used a redox proteomic technique, oxidative isotope-coded affinity tags (OxICAT), to assess cysteine-residue redox changes in Drosophila melanogaster during aging and fasting. This approach enabled us to simultaneously identify and quantify the redox state of several hundred cysteine residues in vivo. Cysteine residues within young flies had a bimodal distribution with peaks at ∼10% and ∼85% reversibly oxidized. Surprisingly, these cysteine residues did not become more oxidized with age. In contrast, 24 hr of fasting dramatically oxidized cysteine residues that were reduced under fed conditions while also reducing cysteine residues that were initially oxidized. We conclude that fasting, but not aging, dramatically alters cysteine-residue redox status in D. melanogaster. PMID:26095360

Brain Tissue Responses to Neural Implants Impact Signal Sensitivity and Intervention Strategies

PubMed Central

2015-01-01

Implantable biosensors are valuable scientific tools for basic neuroscience research and clinical applications. Neurotechnologies provide direct readouts of neurological signal and neurochemical processes. These tools are generally most valuable when performance capacities extend over months and years to facilitate the study of memory, plasticity, and behavior or to monitor patients’ conditions. These needs have generated a variety of device designs from microelectrodes for fast scan cyclic voltammetry (FSCV) and electrophysiology to microdialysis probes for sampling and detecting various neurochemicals. Regardless of the technology used, the breaching of the blood–brain barrier (BBB) to insert devices triggers a cascade of biochemical pathways resulting in complex molecular and cellular responses to implanted devices. Molecular and cellular changes in the microenvironment surrounding an implant include the introduction of mechanical strain, activation of glial cells, loss of perfusion, secondary metabolic injury, and neuronal degeneration. Changes to the tissue microenvironment surrounding the device can dramatically impact electrochemical and electrophysiological signal sensitivity and stability over time. This review summarizes the magnitude, variability, and time course of the dynamic molecular and cellular level neural tissue responses induced by state-of-the-art implantable devices. Studies show that insertion injuries and foreign body response can impact signal quality across all implanted central nervous system (CNS) sensors to varying degrees over both acute (seconds to minutes) and chronic periods (weeks to months). Understanding the underlying biological processes behind the brain tissue response to the devices at the cellular and molecular level leads to a variety of intervention strategies for improving signal sensitivity and longevity. PMID:25546652

Immunological thresholds in neurological gene therapy: highly efficient elimination of transduced cells might be related to the specific formation of immunological synapses between T cells and virus-infected brain cells

PubMed Central

Barcia, Carlos; Gerdes, Christian; Xiong, Wei-Dong; Thomas, Clare E.; Liu, Chunyan; Kroeger, Kurt M.; Castro, Maria G.; Lowenstein, Pedro R.

2007-01-01

First-generation adenovirus can be engineered with powerful promoters to drive expression of therapeutic transgenes. Numerous clinical trials for glioblastoma multiforme using first generation adenoviral vectors have either been performed or are ongoing, including an ongoing, Phase III, multicenter trial in Europe and Israel (Ark Therapeutics, Inc.). Although in the absence of anti-adenovirus immune responses expression in the brain lasts 6–18 months, systemic infection with adenovirus induces immune responses that inhibit dramatically therapeutic transgene expression from first generation adenoviral vectors, thus, potentially compromising therapeutic efficacy. Here, we show evidence of an immunization threshold for the dose that generates an immune response strong enough to eliminate transgene expression from the CNS. For the systemic immunization to eliminate transgene expression from the brain, ≥1 × 107 infectious units (iu) of adenovirus need to be used as immunogen. Furthermore, this immune response eliminates >90% of transgene expression from 1 × 107–1 × 10³ iu of vector injected into the striatum 60 days earlier. Importantly, elimination of transgene expression is independent of the nature of the promoter that drives transgene expression and is accompanied by brain infiltration of CD8+ T cells and macrophages. In conclusion, once the threshold for systemic immunization (i.e. 1 × 107 iu) is crossed, the immune response eliminates transgene expression by >90% even from brains that receive as little as 1000 iu of adenoviral vectors, independently of the type of promoter that drives expression. PMID:18084640

DEVELOPMENT OF A DNA ARCHIVE FOR GENETIC MONITORING OF FISH POPULATIONS

EPA Science Inventory

Analysis of intraspecific genetic diversity provides a potentially powerful tool to estimate the impacts of environmental stressors on populations. Genetic responses of populations to novel stressors include dramatic shifts in genotype frequencies at loci under selection (i.e. ad...

Evolution and devolution : a national perspective on the changing role of metropolitan planning organizations in areawide intermodal planning.

DOT National Transportation Integrated Search

1997-01-01

The Intermodal Surface Transportation Efficiency Act of 1991 (ISTEA) dramatically changed the metropolitan planning process by presenting new opportunities and responsibilities to the institutions in charge of metropolitan planning. The legislation f...

The high mobility group protein 1 enhances binding of the estrogen receptor DNA binding domain to the estrogen response element.

PubMed

Romine, L E; Wood, J R; Lamia, L A; Prendergast, P; Edwards, D P; Nardulli, A M

1998-05-01

We have examined the ability of the high-mobility group protein 1 (HMG1) to alter binding of the estrogen receptor DNA-binding domain (DBD) to the estrogen response element (ERE). HMG1 dramatically enhanced binding of purified, bacterially expressed DBD to the consensus vitellogenin A2 ERE in a dose-dependent manner. The ability of HMG1 to stabilize the DBD-ERE complex resulted in part from a decrease in the dissociation rate of the DBD from the ERE. Antibody supershift experiments demonstrated that HMG1 was also capable of forming a ternary complex with the ERE-bound DBD in the presence of HMG1-specific antibody. HMG1 did not substantially affect DBD-ERE contacts as assessed by methylation interference assays, nor did it alter the ability of the DBD to induce distortion in ERE-containing DNA fragments. Because HMG1 dramatically enhanced estrogen receptor DBD binding to the ERE, and the DBD is the most highly conserved region among the nuclear receptor superfamily members, HMG1 may function to enhance binding of other nuclear receptors to their respective response elements and act in concert with coactivator proteins to regulate expression of hormone-responsive genes.

Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada

USDA-ARS?s Scientific Manuscript database

In 2013, porcine epidemic diarrhea virus (PEDV) emerged in the United States as a rapidly spreading epidemic causing dramatic death losses in suckling piglets. Neonatal piglets are most vulnerable to clinical disease and their only protection is passive immunity from their dam. At the end of the thi...

Students as Resurrectionists--A Multimodal Humanities Project in Anatomy Putting Ethics and Professionalism in Historical Context

ERIC Educational Resources Information Center

Hammer, Rachel R.; Jones, Trahern W.; Hussain, Fareeda Taher Nazer; Bringe, Kariline; Harvey, Ronee E.; Person-Rennell, Nicole H.; Newman, James S.

2010-01-01

Because medical students have many different learning styles, the authors, medical students at Mayo Clinic, College of Medicine researched the history of anatomical specimen procurement, reviewing topic-related film, academic literature, and novels, to write, direct, and perform a dramatization based on Robert Louis Stevenson's "The…

A Review and Conceptual Framework for Integrating Leadership into Clinical Practice

ERIC Educational Resources Information Center

Kutz, Matthew R.

2012-01-01

Context: The purpose of this review is to assess leadership education and practice in athletic training. Leadership is a critical component of athletic training and health care. Leadership research in athletic training is dramatically behind other health care professions. Objective: To develop a model for integrating leadership behavior and…

Measurement of Attention and Related Functions in the Preschool Child

ERIC Educational Resources Information Center

Mahone, E. Mark

2005-01-01

The goal of this review of the clinical and research literature is to identify, describe, and critique published methods for assessment of attention and related functions in preschool children (ages 6 and younger). The need for valid assessment of preschool children has grown dramatically in the past two decades following the implementation of…

Elevated VGKC-Complex Antibodies in a Boy with Fever-Induced Refractory Epileptic Encephalopathy in School-Age Children (FIRES)

ERIC Educational Resources Information Center

Illingworth, Marjorie A.; Hanrahan, Donncha; Anderson, Claire E.; O'Kane, Kathryn; Anderson, Jennifer; Casey, Maureen; de Sousa, Carlos; Cross, J. Helen; Wright, Sukvhir; Dale, Russell C.; Vincent, Angela; Kurian, Manju A.

2011-01-01

Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and…

Sequencing, annotation, and characterization of the influenza ferret infectome.

PubMed

León, Alberto J; Banner, David; Xu, Luoling; Ran, Longsi; Peng, Zhiyu; Yi, Kang; Chen, Chao; Xu, Fengping; Huang, Jinrong; Zhao, Zhen; Lin, Zhen; Huang, Stephen H S; Fang, Yuan; Kelvin, Alyson A; Ross, Ted M; Farooqui, Amber; Kelvin, David J

2013-02-01

Ferrets have become an indispensable tool in the understanding of influenza virus virulence and pathogenesis. Furthermore, ferrets are the preferred preclinical model for influenza vaccine and therapeutic testing. Here we characterized the influenza infectome during the different stages of the infectious process in ferrets with and without prior specific immunity to influenza. RNA from lung tissue and lymph nodes from infected and naïve animals was subjected to next-generation sequencing, followed by de novo data assembly and annotation of the resulting sequences; this process generated a library comprising 13,202 ferret mRNAs. Gene expression profiles during pandemic H1N1 (pdmH1N1) influenza virus infection were analyzed by digital gene expression and solid support microarrays. As expected during primary infection, innate immune responses were triggered in the lung tissue; meanwhile, in the lymphoid tissue, genes encoding antigen presentation and maturation of effector cells of adaptive immunity increased dramatically. After 5 days postinfection, the innate immune gene expression was replaced by the adaptive immune response, which correlates with viral clearance. Reinfection with homologous pandemic influenza virus resulted in a diminished innate immune response, early adaptive immune gene regulation, and a reduction in clinical severity. The fully annotated ferret infectome will be a critical aid to the understanding of the molecular events that regulate disease severity and host-influenza virus interactions among seasonal, pandemic, and highly pathogenic avian influenzas.

New clinical and experimental insights into Old World and neotropical ocular toxoplasmosis.

PubMed

Pfaff, Alexander W; de-la-Torre, Alejandra; Rochet, Elise; Brunet, Julie; Sabou, Marcela; Sauer, Arnaud; Bourcier, Tristan; Gomez-Marin, Jorge E; Candolfi, Ermanno

2014-02-01

Retinal lesions or other ocular manifestations are serious consequences of infection with the protozoan parasite Toxoplasma gondii. Whilst classically considered a consequence of congenital transmission, recent screening studies estimated that 2% of T. gondii seropositive persons in Europe and North America have retinal lesions, most of them persisting unnoticed. The situation is more dramatic in South America, probably due to the predominance of virulent strains. Some of these strains seem to exhibit ocular or neuronal tropism and are responsible for severe ocular lesions. Despite the medical importance, the physiopathological mechanisms have only recently begun to be elucidated. The particular immune-privileged situation in the eye has to be considered. Studies on French patients showed low or undetectable ocular parasite loads, but a clear Th1/Th17 type immune reaction. Suitable mouse models have appeared in the last few years. Using such a model, IL-17A proved to impair parasite control and induce pathology. In contrast, in South American patients, the parasite seems to be much less efficiently controlled through a Th2 type or suppressive immune response that favors parasite replication. Finally, several host genetic markers controlling immune response factors have been associated with ocular involvement of T. gondii infection, mainly in South America. Copyright © 2013 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Hemorrhagic shock and encephalopathy syndrome in a quadriplegic child: an argument for the triggering role of impaired thermoregulatory response.

PubMed

Baugnon, Thomas; Duracher-Gout, Caroline; Blanot, Stéphane; Vecchione, Antonio; Guillou, Florence; Carli, Pierre A; Meyer, Philippe G

2010-07-01

A case presentation of hemorrhagic shock and encephalopathy syndrome (HSES). To describe an unusual complication of uncontrolled fever in a tetraplegic child and to discuss possible pathophysiological mechanisms in these circumstances. HSES is a rare and dramatic disorder of unknown origin occurring mainly in infants and young children. Clinical features of HSES associate hyperpyrexia, acute diarrhea, circulatory collapse, coma, convulsions, and multiple organ failure (MOF). Altered physiologic thermoregulatory response in infants exposed to abruptly increased core temperature or altered thermal environment, and links with heat stroke, have been mentioned in previous publications. We report a case of HSES occurring in a 6-year-old girl with post-traumatic C4 quadriplegia. She eventually experienced hyperpyrexia, deep shock, watery diarrhea, and severe MOF developed rapidly. Despite rapidly resolving MOF, severe brain lesions consistent with HSES were observed and resulted in permanent neurologic impairment. Negative bacterial and viral screening eliminated a septic origin. In this child, impaired thermoregulatory response to acute hyperpyrexia resulting from complete quadriplegia could be the necessary condition for the development of HSES in the presence of acute hyperpyrexia of unknown origin. Quadriplegic patients, especially young children, could be considered at increased risk of developing severe MOF and acute central nervous system impairment consistent with HSES, when exposed to heat stress and should be treated promptly.

The osteogenic capacity of biomimetic hierarchical micropore/nanorod-patterned Sr-HA coatings with different interrod spacings.

PubMed

Zhou, Jianhong; Li, Bo; Han, Yong; Zhao, Lingzhou

2016-07-01

Advanced titanium based bone implant with fast established, rigid and stable osseointegration is stringently needed in clinic. Here the hierarchical micropore/nanorod-patterned strontium doped hydroxyapatite (Ca9Sr1(PO4)6(OH)2, Sr1-HA) coatings (MNRs) with different interrod spacings varying from about 300 to 33nm were developed. MNRs showed dramatically differential biological performance closely related to the interrod spacing. Compared to micropore/nanogranule-patterned Sr1-HA coating (MNG), MNRs with an interrod spacing of larger than 137nm resulted in inhibited in vitro mesenchymal stem cell functions and in vivo osseointegration, while those of smaller than 96nm gave rise to dramatically enhanced the biological effect, especially those of mean 67nm displayed the best effect. The differential biological effect of MNRs was related to their modulation on the focal adhesion mediated mechanotransduction. These results suggest that MNRs with a mean interrod spacing of 67nm may give rise to an advanced implant of improved clinical performance. Copyright © 2016 Elsevier Inc. All rights reserved.

Third-generation Ah receptor-responsive luciferase reporter plasmids: amplification of dioxin-responsive elements dramatically increases CALUX bioassay sensitivity and responsiveness.

PubMed

He, Guochun; Tsutsumi, Tomoaki; Zhao, Bin; Baston, David S; Zhao, Jing; Heath-Pagliuso, Sharon; Denison, Michael S

2011-10-01

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related dioxin-like chemicals are widespread and persistent environmental contaminants that produce diverse toxic and biological effects through their ability to bind to and activate the Ah receptor (AhR) and AhR-dependent gene expression. The chemically activated luciferase expression (CALUX) system is an AhR-responsive recombinant luciferase reporter gene-based cell bioassay that has been used in combination with chemical extraction and cleanup methods for the relatively rapid and inexpensive detection and relative quantitation of dioxin and dioxin-like chemicals in a wide variety of sample matrices. Although the CALUX bioassay has been validated and used extensively for screening purposes, it has some limitations when screening samples with very low levels of dioxin-like chemicals or when there is only a small amount of sample matrix for analysis. Here, we describe the development of third-generation (G3) CALUX plasmids with increased numbers of dioxin-responsive elements, and stable transfection of these new plasmids into mouse hepatoma (Hepa1c1c7) cells has produced novel amplified G3 CALUX cell bioassays that respond to TCDD with a dramatically increased magnitude of luciferase induction and significantly lower minimal detection limit than existing CALUX-type cell lines. The new G3 CALUX cell lines provide a highly responsive and sensitive bioassay system for the detection and relative quantitation of very low levels of dioxin-like chemicals in sample extracts.

Precocious puberty and large multicystic ovaries in young girls with primary hypothyroidism.

PubMed

Sanjeevaiah, Aravind Raj; Sanjay, Subbarayappa; Deepak, Tejesweni; Sharada, Ardanareshwaran; Srikanta, Sri S

2007-10-01

To describe 2 cases of primary hypothyroidism, precocious puberty, large multicystic ovaries, possible diagnostic dilemma, unilateral oophorectomies, and subsequent response to levothyroxine replacement therapy. We present the clinical, biochemical, radiologic, and histopathologic findings in 2 patients with rare cases of Van Wyk-Grumbach syndrome and megaovaries, who underwent unilateral oophorectomy. Two patients, an 8-year-old girl and a 3-year-old girl (cases 1 and 2, respectively), were referred to our center. Both patients presented with precocious puberty and vaginal bleeding and had undergone unilateral oophorectomy before referral. In the first patient (case 1), the surgical intervention was a consequence of torsion of the left megaovary, necessitating emergency oophorectomy. Oophorectomy in the second patient (case 2) was a result of initial diagnostic confusion, inasmuch as a sexcord stromal tumor was suspected. A detailed history, physical examination, and laboratory results pointed toward primary hypothyroidism due to Hashimoto's thyroiditis and thyroid dysgenesis, respectively. Serial ultrasound studies of the abdomen and pelvis revealed large multicystic ovaries, with progressive enlargement (including regrowth from an apparent ovarian "postsurgical remnant"). Both patients responded dramatically after initiation of levothyroxine replacement therapy, with no further vaginal bleeding and reversal of megaovary to normal size (in case 1). In a highly selected minority of children with untreated primary hypothyroidism, there is development of precocious puberty and progressively enlarging multicystic ovaries. The precise endocrine, neuroanatomic, and neurophysiologic bases for this phenomenon are unclear. Nevertheless, the entire clinicopathologic picture, including giant ovaries, dramatically reverts to normal status with the restoration of a euthyroid state by means of simple levothyroxine replacement therapy.

Usefulness of predictive tests for cancer treatment.

PubMed

Rosell, R; Cuello, M; Cecere, F; Santarpia, M; Reguart, N; Felip, E; Taron, M

2006-08-01

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. At least six lines of research have recently emerged as potential contributors to changes in clinical practice. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. Secondly, single nucleotide polymorphisms in the ERCC1 gene influence survival and toxicity with cisplatin-based chemotherapy. The main core of recent research has centered on EGFR mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine kinase inhibitors. In contrast, K-ras mutations confer a negative effect in these patients. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine kinase inhibitors plus aromatase inhibitors. microRNAs control the expression of cognate target genes, and downregulation of Dicer has been shown to be a strong predictor of relapse in surgically resected non-small-cell lung cancer patients. Finally, overexpression of the Wingless-type (Wnt) genes and methylation of Wnt antagonists like WIF and secreted frizzled related proteins have been documented in non-small-cell lung cancer and are believed to be an important mechanism of cancer stem cell maintenance.

Temperament alters the metabolic response to glucose and insulin challenges and feed restriction in steers

USDA-ARS?s Scientific Manuscript database

Recently the dramatic metabolic differences between Temperamental and Calm cattle have been elucidated; Temperamental cattle maintain greater circulating concentrations of non-esterified fatty acids (NEFA) when compared to Calm cattle, which may influence other metabolic parameters including glucos...

Regional climate response collaboratives: Multi-institutional support for climate resilience

USDA-ARS?s Scientific Manuscript database

Federal investments by U.S. agencies to enhance climate resilience at regional scales have grown dramatically over the last five years. This leads to questions about how best to leverage existing agency-specific research, infrastructure, and capacity while avoiding redundancy. This article discusses...

Characterization of Thyroid Hormone Transporter Protein Expression during Tissue-specific Metamorphic Events in Xenopus tropicalis

EPA Science Inventory

Thyroid hormone (TH) induces the dramatic morphological and physiological changes that together comprise amphibian metamorphosis. TH-responsive tissues vary widely with developmental timing of TH-induced changes. How larval tadpole tissues are able to employ distinct metamorphi...

Alkaloids May Not be Responsible for Endophyte Associated Reductions in Tall Fescue Decomposition Rates

USDA-ARS?s Scientific Manuscript database

1. Fungal endophyte - grass symbioses can have dramatic ecological effects, altering individual plant physiology, plant and animal community structure and function, and ecosystem processes such as litter decomposition and nutrient cycling. 2. Within the tall fescue (Schedonorus arundinaceus) - funga...

Pollinator Research at EPA

EPA Science Inventory

Of great concern, honey bee populations have experienced dramatic declines in the US and in many other countries. In response to this issue, the White House instructed the EPA and USDA to lead a Federal Task Force to develop a National Strategy on Pollinator Health which called f...

The Charter School Experience: Autonomy in Practice

ERIC Educational Resources Information Center

McDonald, Tonya Senne

2013-01-01

While traditional public school and charter school systems continue to undergo dramatic reforms in response to the educational crisis, charter schools are praised as possessing the distinguishing characteristic of maintaining autonomy in exchange for increased accountability (Buckley & Schneider, 2009). The expectations for charter schools are…

Why Teach Drama?

ERIC Educational Resources Information Center

Bradley, David

1968-01-01

A strictly literary study of drama can be misleading, but plays brought alive through dramatic activities and productions may be the most profitable core of the secondary-school humanities program. The practical study of drama requires the student's active imagination, self-discipline, creative and positive responses to situations, improvisation,…

Runaway Children and Their Families: A Treatment Typology.

ERIC Educational Resources Information Center

Orten, James D.; Soll, Sharon Kelts

1980-01-01

Analyzes the development of the runaway problem and the dramatic increases in number of runaways. This typology classifies runaways by level of alienation with family and the degree to which the child internalizes running away as response to stress. Treatment is discussed. (Author/NRB)

Response of sunshine bass to ration at elevated culture temperature

USDA-ARS?s Scientific Manuscript database

Temperature and ammonia increase dramatically during summer production of sunshine bass. Global temperatures are projected to increase. A factorial experiment investigated the effects of three digestible protein (DP; 33, 40, 47%), two lipid (L; 10, 18 %) and two ration levels (satiation, restricted)...

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells.

PubMed

Armstrong, J L; Ruiz, M; Boddy, A V; Redfern, C P F; Pearson, A D J; Veal, G J

2005-02-28

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 microM) or R116010 (1 or 10 microM) in combination with either 10 microM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma.

Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

PubMed Central

Armstrong, J L; Ruiz, M; Boddy, A V; Redfern, C P F; Pearson, A D J; Veal, G J

2005-01-01

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 μM) or R116010 (1 or 10 μM) in combination with either 10 μM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma. PMID:15714209

[The molecular biology of epithelial ovarian cancer].

PubMed

Leary, Alexandra; Pautier, Patricia; Tazi, Youssef; Morice, Philippe; Duvillard, Pierre; Gouy, Sébastien; Uzan, Catherine; Gauthier, Hélène; Balleyguier, Corinne; Lhommé, Catherine

2012-12-01

Epithelial ovarian cancer frequently presents at an advanced stage where the cornerstone of management remains surgery and platinum-based chemotherapy. Unfortunately, despite sometimes dramatic initial responses, advanced ovarian cancer almost invariably relapses. Little progress has been made in the identification of effective targeted-therapies for ovarian cancer. The majority of clinical trials investigating novel agents have been negative and the only approved targeted-therapy is bevacizumab, for which reliable predictive biomarkers still elude us. Ovarian cancer is treated as a uniform disease. Yet, biological studies have highlighted the heterogeneity of this malignancy with marked differences in histology, oncogenesis, prognosis, chemo-responsiveness, and molecular profile. Recent high throughput molecular analyses have identified a huge number of genomic/phenotypic alterations. Broadly speaking, high grade serous carcinomas (type II) display significant genomic instability and numerous amplifications and losses; low grade (type I) tumors are genomically stable but display frequent mutations. Importantly, many of these genomic alterations relate to known oncogenes for which targeted-therapies are available or in development. There is today a real potential for personalized medicine in ovarian cancer. We will review the current literature regarding the molecular characterization of epithelial ovarian cancer and discuss the biological rationale for a number of targeted strategies. In order to translate these biological advances into meaningful clinical improvements for our patients, it is imperative to incorporate translational research in ovarian cancer trials, a number of strategies will be proposed such as the acquisition of quality tumor samples, including sequential pre- and post-treatment biopsies, the potential of liquid biopsies, and novel trial designs more adapted to the molecular era of ovarian cancer research.

Maintenance ECT as a therapeutic approach to medication-refractory epilepsy in an adult with mental retardation: case report and review of literature.

PubMed

Shah, Nilesh; Pande, Nikhil; Bhat, Tushar; Murke, Mukund; Andrade, Chittaranjan

2012-06-01

Electroconvulsive therapy (ECT) raises the seizure threshold. This physiological change may benefit patients with seizure disorders. Whereas ECT has recently been used to terminate medication-refractory status epilepticus, there is little current literature on its planned administration as a specific maintenance treatment for medication-refractory epilepsy. We used maintenance ECT to treat an 18-year-old man with a long-standing generalized tonic-clonic seizure disorder who had shown poor response to several antiepileptic drugs administered in combination with antiepileptic medication compliance confirmed through drug level monitoring. A total of 52 ECTs were administered across nearly 20 months at a mean frequency of once in nearly 12 days. From the very outset, ECT dramatically decreased the frequency of spontaneous seizures from approximately 6 to 24 per week at baseline to approximately 1 to 2 per week after ECT initiation. The efficacy of maintenance ECT in spontaneous seizure prophylaxis was greater when the ECT treatment interval was narrower. Improvement with ECT was associated with improved behavior and improved psychosocial functioning on clinical report. No cognitive or other adverse effects were reported or clinically ascertained. The ECT charge administered at the last 10 treatment sessions was 1434 millicoulombs. This is probably the highest electrical stimulus dose recorded in literature. Maintenance ECT may reduce the frequency of breakthrough seizures in patients with seizure disorder that is inadequately responsive to antiepileptic medication regimes. Very high ECT seizure thresholds may be observed when many antiepileptic drugs are concurrently administered in high doses.

Angiotensin-converting enzyme inhibitor use by older adults is associated with greater functional responses to exercise.

PubMed

Buford, Thomas W; Manini, Todd M; Hsu, Fang-Chi; Cesari, Matteo; Anton, Stephen D; Nayfield, Susan; Stafford, Randall S; Church, Timothy S; Pahor, Marco; Carter, Christy S

2012-07-01

To assess the association between angiotensin converting enzyme inhibitors (ACEis) and improvements in the physical function of older adults in response to chronic exercise training. Secondary analysis of the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study, a multisite randomized clinical trial to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability. Four academic research centers within the United States. Four hundred twenty-four individuals aged 70 to 89 with mild to moderate functional impairments categorized for this analysis as ACEi users, users of other antihypertensive drugs, or antihypertensive nonusers. A 12-month intervention of structured physical activity (PA) or health education promoting successful aging (SA). Change in walking speed during a 400-m test and performance on a battery of short-duration mobility tasks (Short Physical Performance Battery (SPPB)). Physical activity significantly improved the adjusted walking speed of ACEi users (P < .001) but did not of nonusers. PA improved the adjusted SPPB score of ACEi users (P < .001) and of persons who used other antihypertensive drugs (P = .005) but not of antihypertensive nonusers (P = .91).The percentage of ACEi users deriving clinically significant benefit from exercise training for walking speed (30%) and SPPB score (48%) was dramatically higher than for nonusers (14% and 12%, respectively). For older adults at risk for disability, exercise-derived improvements in physical function were greater for ACEi users than users of other antihypertensive drugs and antihypertensive nonusers. © 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.

Angiotensin-Converting Enzyme Inhibitor Use by Older Adults Is Associated with Greater Functional Responses to Exercise

PubMed Central

Buford, Thomas W.; Manini, Todd M.; Hsu, Fang-Chi; Cesari, Matteo; Anton, Stephen D.; Nayfield, Susan; Stafford, Randall S.; Church, Timothy S.; Pahor, Marco; Carter, Christy S.

2013-01-01

OBJECTIVES To assess the association between angiotensin converting enzyme inhibitors (ACEis) and improvements in the physical function of older adults in response to chronic exercise training. DESIGN Secondary analysis of the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study, a multisite randomized clinical trial to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability. SETTING Four academic research centers within the United States. PARTICIPANTS Four hundred twenty-four individuals aged 70 to 89 with mild to moderate functional impairments categorized for this analysis as ACEi users, users of other antihypertensive drugs, or antihypertensive nonusers. INTERVENTION A 12-month intervention of structured physical activity (PA) or health education promoting successful aging (SA). MEASUREMENTS Change in walking speed during a 400-m test and performance on a battery of short-duration mobility tasks (Short Physical Performance Battery (SPPB)). RESULTS Physical activity significantly improved the adjusted walking speed of ACEi users (P < .001) but did not of nonusers. PA improved the adjusted SPPB score of ACEi users (P < .001) and of persons who used other antihypertensive drugs (P = .005) but not of antihypertensive nonusers (P = .91). The percentage of ACEi users deriving clinically significant benefit from exercise training for walking speed (30%) and SPPB score (48%) was dramatically higher than for nonusers (14% and 12%, respectively). CONCLUSION For older adults at risk for disability, exercise-derived improvements in physical function were greater for ACEi users than users of other antihypertensive drugs and antihypertensive nonusers. PMID:22726232

Negative frequency-dependent selection maintains a dramatic flower color polymorphism in the rewardless orchid Dactylorhiza sambucina (L.) Soò

PubMed Central

Gigord, Luc D. B.; Macnair, Mark R.; Smithson, Ann

2001-01-01

The orchid Dactylorhiza sambucina shows a stable and dramatic flower-color polymorphism, with both yellow- and purple-flowered individuals present in natural populations throughout the range of the species in Europe. The evolutionary significance of flower-color polymorphisms found in many rewardless orchid species has been discussed at length, but the mechanisms responsible for their maintenance remain unclear. Laboratory experiments have suggested that behavioral responses by pollinators to lack of reward availability might result in a reproductive advantage for rare-color morphs. Consequently, we performed an experiment varying the relative frequency of the two color morphs of D. sambucina to test whether rare morph advantage acted in the natural habitat of the species. We show here clear evidence from this manipulative experiment that rare-color morphs have reproductive advantage through male and female components. This is the first demonstration, to our knowledge, that negative frequency-dependent selection through pollinator preference for rare morphs can cause the maintenance of a flower-color polymorphism. PMID:11353863

Dual response of BDNF to sublethal concentrations of beta-amyloid peptides in cultured cortical neurons.

PubMed

Aliaga, E; Silhol, M; Bonneau, N; Maurice, T; Arancibia, S; Tapia-Arancibia, L

2010-01-01

Beta-amyloid (Abeta) deposition is one important pathological hallmark in Alzheimer's disease (AD). However, low levels of Abeta may modify critical endogenous protection systems before neurodegeneration occurs. We examined the time-course effect of sublethal concentrations of Abeta on total BDNF (panBDNF), BDNF transcripts (I, II, IV and VI), trkB.FL, trkB.T1 and p75(NGFR) mRNA expression in cultured cortical neurons. We have shown that Abeta exhibited a dual response on BDNF mRNA, i.e. an increase at short times (3-5 h) and a dramatic decrease at longer times (24 or 48 h). The early increase in BDNF expression seems to be driven by increased expression of transcripts I and IV. The BDNF drop was specific since did not occur for other mRNAs examined. The BDNF protein content showed a similar profile but did not follow the dramatic reduction as its encoding mRNA. These observations may help to explain cognitive deficits observed at initial stages of AD.

Do film soundtracks contain nonlinear analogues to influence emotion?

PubMed Central

Blumstein, Daniel T.; Davitian, Richard; Kaye, Peter D.

2010-01-01

A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses. PMID:20504815

Do film soundtracks contain nonlinear analogues to influence emotion?

PubMed

Blumstein, Daniel T; Davitian, Richard; Kaye, Peter D

2010-12-23

A variety of vertebrates produce nonlinear vocalizations when they are under duress. By their very nature, vocalizations containing nonlinearities may sound harsh and are somewhat unpredictable; observations that are consistent with them being particularly evocative to those hearing them. We tested the hypothesis that humans capitalize on this seemingly widespread vertebrate response by creating nonlinear analogues in film soundtracks to evoke particular emotions. We used lists of highly regarded films to generate a set of highly ranked action/adventure, dramatic, horror and war films. We then scored the presence of a variety of nonlinear analogues in these film soundtracks. Dramatic films suppressed noise of all types, contained more abrupt frequency transitions and musical sidebands, and fewer noisy screams than expected. Horror films suppressed abrupt frequency transitions and musical sidebands, but had more non-musical sidebands, and noisy screams than expected. Adventure films had more male screams than expected. Together, our results suggest that film-makers manipulate sounds to create nonlinear analogues in order to manipulate our emotional responses.

Relativistic and Nuclear Medium Effects on the Coulomb Sum Rule.

PubMed

Cloët, Ian C; Bentz, Wolfgang; Thomas, Anthony W

2016-01-22

In light of the forthcoming high precision quasielastic electron scattering data from Jefferson Lab, it is timely for the various approaches to nuclear structure to make robust predictions for the associated response functions. With this in mind, we focus here on the longitudinal response function and the corresponding Coulomb sum rule for isospin-symmetric nuclear matter at various baryon densities. Using a quantum field-theoretic quark-level approach which preserves the symmetries of quantum chromodynamics, as well as exhibiting dynamical chiral symmetry breaking and quark confinement, we find a dramatic quenching of the Coulomb sum rule for momentum transfers |q|≳0.5  GeV. The main driver of this effect lies in changes to the proton Dirac form factor induced by the nuclear medium. Such a dramatic quenching of the Coulomb sum rule was not seen in a recent quantum Monte Carlo calculation for carbon, suggesting that the Jefferson Lab data may well shed new light on the explicit role of QCD in nuclei.

Surgical Management of the Thick-Skinned Nose.

PubMed

Davis, Richard E; Hrisomalos, Emily N

2018-02-01

When executed properly, open structure rhinoplasty can dramatically improve the consistency, durability, and quality of the cosmetic surgical outcome. Moreover, in expert hands, dramatic transformations in skeletal architecture can be accomplished with minimal risk and unparalleled control, all while preserving nasal airway function. While skeletal enhancements have become increasingly more controlled and precise, the outer skin-soft tissue envelope (SSTE) often presents a formidable obstacle to a satisfactory cosmetic result. In noses with unusually thick skin, excessive skin volume and characteristically hostile healing responses frequently combine to obscure or sometimes even negate cosmetic skeletal modifications and taint the surgical outcome. For this challenging patient subgroup, care must be taken to optimize the SSTE using a graduated treatment strategy directed at minimizing skin thickness and controlling unfavorable healing responses. When appropriate efforts are implemented to manage thick nasal skin, cosmetic outcomes are often substantially improved, sometimes even negating the ill-effects of thick skin altogether. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Increased co-first authorships in biomedical and clinical publications: a call for recognition.

PubMed

Conte, Marisa L; Maat, Stacy L; Omary, M Bishr

2013-10-01

There has been a dramatic increase in the number and percentage of publications in biomedical and clinical journals in which two or more coauthors claim first authorship, with a change in some journals from no joint first authorship in 1990 to co-first authorship of >30% of all research publications in 2012. As biomedical and clinical research become increasingly complex and team-driven, and given the importance attributed to first authorship by grant reviewers and promotion and tenure committees, the time is ripe for journals, bibliographic databases, and authors to highlight equal first author contributions of published original research.

Development trends for new cancer therapeutics and vaccines.

PubMed

Reichert, Janice M; Wenger, Julia B

2008-01-01

Global commercial development of cancer treatments has dramatically increased over the past 15 years. To assess trends in the process, we analyzed data for 1111 candidates that entered clinical study during 1990-2006. Our results show that although the average number of therapeutic candidates entering clinical study per year more than doubled, the US approval success rate was low (8%) during the period. The therapeutics took seven years on average to go through the clinical and US approval phases, but cancer vaccines have yet to gain any US approvals. These results indicate that improvement in the efficiency of the development process for innovative cancer treatments is needed.

Pre- and post-test genetic counseling for chromosomal and Mendelian disorders.

PubMed

Fonda Allen, Jill; Stoll, Katie; Bernhardt, Barbara A

2016-02-01

Genetic carrier screening, prenatal screening for aneuploidy, and prenatal diagnostic testing have expanded dramatically over the past 2 decades. Driven in part by powerful market forces, new complex testing modalities have become available after limited clinical research. The responsibility for offering these tests lies primarily on the obstetrical care provider and has become more burdensome as the number of testing options expands. Genetic testing in pregnancy is optional, and decisions about undergoing tests, as well as follow-up testing, should be informed and based on individual patients' values and needs. Careful pre- and post-test counseling is central to supporting informed decision-making. This article explores three areas of technical expansion in genetic testing: expanded carrier screening, non-invasive prenatal screening for fetal aneuploidies using cell-free DNA, and diagnostic testing using fetal chromosomal microarray testing, and provides insights aimed at enabling the obstetrical practitioner to better support patients considering these tests. Copyright © 2016 Elsevier Inc. All rights reserved.

Federal-state aquaculture drug registration partnership: A success story in the making

USGS Publications Warehouse

Schnick, R.A.; Gingerich, W.H.; Koltes, K.H.

1996-01-01

During the past 20 years, aquaculture has grown both as a vital tool for fisheries management and as a viable industry. But now a crisis has arisen from the Food and Drug Administration's (FDA) increased regulation of drug use in aquaculture in response to public concerns about human food safety, human health, and environmental effects. Lack of approved drugs and chemicals has dramatically reduced the effectiveness and increased the cost of fish production for natural resource management agencies. To make badly needed therapeutants available, the FDA is requiring an array of specialized laboratory research studies and clinical field trials. Pharmaceutical manufacturers are reluctant to undertake any major efforts to gain approval of aquaculture drugs because each (i.e., use on one species for one purpose) is estimated to cost a minimum of $3.5 million. Hence, the expenditure is not warranted by the apparent market potential. Only three therapeutants and one anesthetic are currently approved and available to hatchery managers.

'Smart' nanoparticles as drug delivery systems for applications in tumor therapy.

PubMed

Fang, Zhi; Wan, Lin-Yan; Chu, Liang-Yin; Zhang, Yan-Qiong; Wu, Jiang-Feng

2015-01-01

In the therapy of clinical diseases such as cancer, it is important to deliver drugs directly to tumor sites in order to maximize local drug concentration and reduce side effects. This objective may be realized by using 'smart' nanoparticles (NPs) as drug delivery systems, because they enable dramatic conformational changes in response to specific physical/chemical stimuli from the diseased cells for targeted and controlled drug release. In this review, we first briefly summarize the characteristics of 'smart' NPs as drug delivery systems in medical therapy, and then discuss their targeting transport, transmembrane and endosomal escape behaviors. Lastly, we focus on the applications of 'smart' NPs as drug delivery systems for tumor therapy. Biodegradable 'smart' NPs have the potential to achieve maximum efficacy and drug availability at the desired sites, and reduce the harmful side effects for healthy tissues in tumor therapy. It is necessary to select appropriate NPs and modify their characteristics according to treatment strategies of tumor therapy.

Current consensus and guidelines of contrast enhanced ultrasound for the characterization of focal liver lesions

PubMed Central

Jang, Jae Young; Kim, Moon Young; Jeong, Soung Won; Kim, Tae Yeob; Kim, Seung Up; Lee, Sae Hwan; Suk, Ki Tae; Park, Soo Young; Woo, Hyun Young; Kim, Sang Gyune; Heo, Jeong; Baik, Soon Koo; Kim, Hong Soo

2013-01-01

The application of ultrasound contrast agents (UCAs) is considered essential when evaluating focal liver lesions (FLLs) using ultrasonography (US). Microbubble UCAs are easy to use and robust; their use poses no risk of nephrotoxicity and requires no ionizing radiation. The unique features of contrast enhanced US (CEUS) are not only noninvasiveness but also real-time assessing of liver perfusion throughout the vascular phases. The later feature has led to dramatic improvement in the diagnostic accuracy of US for detection and characterization of FLLs as well as the guidance to therapeutic procedures and evaluation of response to treatment. This article describes the current consensus and guidelines for the use of UCAs for the FLLs that are commonly encountered in US. After a brief description of the bases of different CEUS techniques, contrast-enhancement patterns of different types of benign and malignant FLLs and other clinical applications are described and discussed on the basis of our experience and the literature data. PMID:23593604

Living donor kidney transplantation: "beauty and the beast"!

PubMed

Danovitch, Gabriel M

2013-01-01

The report by Terasaki and colleagues in 1995 that the outcomes of spousal and biologically unrelated transplants were essentially the same as for 1-haplotype matched living related transplants changed the course of clinical transplantation. This article, entitled metaphorically "Beauty and the Beast", describes the dramatic change in the practice of living donor transplantation that followed. In the ensuing two decades, biologically unrelated living donor transplantation became commonplace in the developed world and reached its apotheosis in cross-country living donor paired exchange programs that have made transplantation accessible to many whose donors were deemed "incompatible". Such exchanges can indeed be thought of as a "thing of beauty". Sadly, the same observation was abused to exploit vulnerable donors, and the "beast" in the form of transplant tourism became a feature of transplantation in the developing world. The responsibility of the transplant community to protect the welfare of living donors and their recipients and the key role of trust in the evaluation of living donors is discussed.

Henoch–Schönlein purpura: a clinical case with dramatic presentation

PubMed Central

Bento, João; Magalhães, Adriana; Moura, Conceição Souto; Hespanhol, Venceslau

2010-01-01

A case study involving a 55-year-old Caucasian male with end-stage glomerulosclerosis is presented here. Kidney biopsies showed no deposits on imunofluorescent microscopy. Relapsing massive haemoptysis and suspected bronchovascular malformation required lung lobectomy which revealed malformative and tortuous small blood vessels, with no vasculitis. Blood antinuclear antibodies, antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies were undetectable. Seric immunoglobulins and complement levels were normal. Three months later, arthralgia and joint oedema first appeared. Skin biopsy revealed vasculitis immune-reactive to immunoglobulin A. Systemic corticotherapy was then started. Two weeks later, the patient presented with abdominal pain melena and rectal bleeding (haematoquesia). Endoscopic study showed diffuse gastrointestinal haemorrhage. Angiographic study revealed diffuse lesions compatible with vasculitis and haemorrhage from multiple spots. Cyclophosphamide and then intravenous immunoglobulin were associated to treatment without response. Increasing blood loss occurred, with massive gastrointestinal haemorrhage and haemorrhagic ascitis. Death occurred due to uncontrolled diffuse bleeding. Necropsy findings showed generalised small vessels vasculitis compatible with Henoch–Schönlein purpura. PMID:22778211

Accelerating image reconstruction in dual-head PET system by GPU and symmetry properties.

PubMed

Chou, Cheng-Ying; Dong, Yun; Hung, Yukai; Kao, Yu-Jiun; Wang, Weichung; Kao, Chien-Min; Chen, Chin-Tu

2012-01-01

Positron emission tomography (PET) is an important imaging modality in both clinical usage and research studies. We have developed a compact high-sensitivity PET system that consisted of two large-area panel PET detector heads, which produce more than 224 million lines of response and thus request dramatic computational demands. In this work, we employed a state-of-the-art graphics processing unit (GPU), NVIDIA Tesla C2070, to yield an efficient reconstruction process. Our approaches ingeniously integrate the distinguished features of the symmetry properties of the imaging system and GPU architectures, including block/warp/thread assignments and effective memory usage, to accelerate the computations for ordered subset expectation maximization (OSEM) image reconstruction. The OSEM reconstruction algorithms were implemented employing both CPU-based and GPU-based codes, and their computational performance was quantitatively analyzed and compared. The results showed that the GPU-accelerated scheme can drastically reduce the reconstruction time and thus can largely expand the applicability of the dual-head PET system.

Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer.

PubMed

Nurwidya, Fariz; Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal

2016-09-01

Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer.

[What clinicians should know about human papilloma virus vaccines].

PubMed

Sanclemente, Gloria

2003-01-01

Human papillomaviruses (HPVs) are epitheliotropic viruses that infect the basal layer of mucosal and keratinizing epithelia. HPV viral genome is made up of an early transcription region (E) and a late region composed of genes L1, L2, and a long control region (LCR). Despite the benign character of most lesions, HPV oncogenicity has been demonstrated in anal cancer, epidermodysplasia verruciformis, and cervical cancer. Nearly 12% of worldwide cancer incidence is due to HPV infection and HPV-16 is the most prevalent genotype found. Therefore, efforts in vaccines against HPVs have been directed mainly toward this genotype to dramatically diminish worldwide anogenital cancer incidence. Therapeutic vaccines are based on induction of an immunologic response against infected cells that express modified viral antigens E6 and E7. Prophylactic vaccines are based on prevention of infection by means of induction of humoral immunity against capsid viral proteins L1 and L2. This article reviews basics of the design of HPV vaccines and the type of vaccines currently being evaluated in clinical studies.

Students as resurrectionists--A multimodal humanities project in anatomy putting ethics and professionalism in historical context.

PubMed

Hammer, Rachel R; Jones, Trahern W; Hussain, Fareeda Taher Nazer; Bringe, Kariline; Harvey, Ronee E; Person-Rennell, Nicole H; Newman, James S

2010-01-01

Because medical students have many different learning styles, the authors, medical students at Mayo Clinic, College of Medicine researched the history of anatomical specimen procurement, reviewing topic-related film, academic literature, and novels, to write, direct, and perform a dramatization based on Robert Louis Stevenson's The Body-Snatcher. Into this performance, they incorporated dance, painting, instrumental and vocal performance, and creative writing. In preparation for the performance, each actor researched an aspect of the history of anatomy. These micro-research projects were presented in a lecture before the play. Not intended to be a research study, this descriptive article discusses how student research and ethics discussions became a theatrical production. This addition to classroom and laboratory learning addresses the deep emotional response experienced by some students and provides an avenue to understand and express these feelings. This enhanced multimodal approach to"holistic learning" could be applied to any topic in the medical school curriculum, thoroughly adding to the didactics with history, humanities, and team dynamics.

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

PubMed Central

Nguyen, Chinh; Barker, Bridget Marie; Hoover, Susan; Nix, David E.; Ampel, Neil M.; Frelinger, Jeffrey A.; Orbach, Marc J.

2013-01-01

SUMMARY Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii. This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine. PMID:23824371

Human breast milk: A review on its composition and bioactivity.

PubMed

Andreas, Nicholas J; Kampmann, Beate; Mehring Le-Doare, Kirsty

2015-11-01

Breast milk is the perfect nutrition for infants, a result of millions of years of evolution, finely attuning it to the requirements of the infant. Breast milk contains many complex proteins, lipids and carbohydrates, the concentrations of which alter dramatically over a single feed, as well as over lactation, to reflect the infant's needs. In addition to providing a source of nutrition for infants, breast milk contains a myriad of biologically active components. These molecules possess diverse roles, both guiding the development of the infants immune system and intestinal microbiota. Orchestrating the development of the microbiota are the human milk oligosaccharides, the synthesis of which are determined by the maternal genotype. In this review, we discuss the composition of breast milk and the factors that affect it during the course of breast feeding. Understanding the components of breast milk and their functions will allow for the improvement of clinical practices, infant feeding and our understanding of immune responses to infection and vaccination in infants. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Workers safety in public psychiatric services: problems, laws and protections.

PubMed

Carabellese, F; Urbano, M; Coluccia, A; Gualtieri, G

2017-01-01

The dramatic case of murder of a psychiatrist during her service in her public office (Centro di Salute Mentale of Bari-Libertà) has led the authors to reflect on the safety of workplaces, in detail of public psychiatric services. It is in the light of current legislation, represented by the Legislative Decree of April 9th, 2008 no. 81, which states the implementing rules of Law 123/2007. In particular, the Authors analyzed the criticalities of the application of this Law, with the aim of safeguarding the health and safety of the workers in all psychiatric services (nursing departments, outpatient clinics, community centers, day care centers, etc.). The Authors suggest the need to set up an articulated specific organizational system of risk assessment of psychiatric services, that can prevent and protect the workers from identified risks, and finally to ensure their active participation in prevention and protection activities, in absence of which specific profiles of responsibility would be opened up to the employers.

Metastatic breast cancer: The Odyssey of personalization.

PubMed

Sonnenblick, A; Pondé, N; Piccart, M

2016-10-01

Metastatic breast cancer is the most frequent cause of cancer death for women worldwide. In the last 15 years, a large number of new agents have entered clinical use, a result of the dramatic increase in our understanding of the molecular underpinnings of metastatic breast cancer. However, while these agents have led to better outcomes, they are also at the root cause of increasing financial pressure on healthcare systems. Moreover, decision making in an era where every year new agents are added to the therapeutic armamentarium has also become a significant challenge for medical oncologists. In the present article, we will provide an ample review on the most recent developments in the field of treatment of the different subtypes of metastatic breast cancer with a critical discussion on the slow progress made in identifying response biomarkers. New hopes in the form of ctDNA monitoring and functional imaging will be presented. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor T790M mutation: A case report.

PubMed

Uemura, Takehiro; Oguri, Tetsuya; Okayama, Minami; Furuta, Hiromi; Kanemitsu, Yoshihiro; Takakuwa, Osamu; Ohkubo, Hirotsugu; Takemura, Masaya; Maeno, Ken; Ito, Yutaka; Niimi, Akio

2017-04-01

We herein report a case of dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor ( EGFR ) T790M mutation encoded in exon 20. The patient was a 59-year-old woman with EGFR exon 19 deletion-positive lung adenocarcinoma, who relapsed with multiple brain metastases. Computed tomography-guided biopsy of the left pleural tumor revealed adenocarcinoma harboring an EGFR exon 19 deletion and an EGFR T790M mutation encoded in exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor. Two days after treatment initiation, the patient displayed profound disturbance of consciousness, possibly due to carcinomatous meningitis, and treatment had to be discontinued due to difficulty in taking osimertinib. However, the patient gradually started to recover consciousness and, after 3 days, she was again able to take osimertinib. One month after the initiation of osimertinib treatment, magnetic resonance imaging revealed an apparent reduction in brain metastases. The patient is currently under continued treatment with osimertinib. At the last follow-up (February, 2017) she exhibited partial response to the treatment.

Advanced manufacturing: Technology and international competitiveness

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tesar, A.

1995-02-01

Dramatic changes in the competitiveness of German and Japanese manufacturing have been most evident since 1988. All three countries are now facing similar challenges, and these challenges are clearly observed in human capital issues. Our comparison of human capital issues in German, Japanese, and US manufacturing leads us to the following key judgments: Manufacturing workforces are undergoing significant changes due to advanced manufacturing technologies. As companies are forced to develop and apply these technologies, the constituency of the manufacturing workforce (especially educational requirements, contingent labor, job content, and continuing knowledge development) is being dramatically and irreversibly altered. The new workforcemore » requirements which result due to advanced manufacturing require a higher level of worker sophistication and responsibility.« less

BRCA2 Mutation as a Possible Cause of Poor Response to 177Lu-PSMA Therapy.

PubMed

Ahmadzadehfar, Hojjat; Gaertner, Florian; Lossin, Philipp S; Schwarz, Bettina; Essler, Markus

2018-05-14

We present the case of a 66-year-old man with castration-resistant prostate cancer, with an increasing prostate-specific antigen level, and a progressive disease during Lu-PSMA radionuclide therapy. Because the patient had a BRCA2 mutation, poly-ADP ribose polymerase inhibitor therapy was started. The patient showed a dramatic subjective and biological response to this therapy with a progression-free survival of 5 months.

Münchhausen by proxy syndrome in clinical child neuropsychology: a case presenting with neuropsychological symptoms.

PubMed

Heubrock, D

2001-12-01

Münchhausen by proxy syndrome (MBPS) is a rare but dramatic variant of child abuse. In MBPS adults, mostly the mother, invent, manipulate, or produce the child's illness, and as a consequence the child has to undergo numerous diagnostic or treatment procedures. Typically, valid information about the etiology of the child's illness is withheld by the parents, and reversible symptoms vanish, when the child and the responsible adults are separated. Although valid statistical data about the epidemiology of MBPS are not available, MBPS should be considered more often than normally recognized. Neurological and neuropsychological presentations including developmental delays and learning problems appear to be common among MBPS cases so that clinical child neuropsychologists should be aware of this problem and consider MBPS at least in some of the mysterious cases that come to their attention. The present study describes a case of MBPS in which neurological and neuropsychological symptoms predominate. It presents a MBPS variant that is characterized by developmental delays and learning problems induced by unnecessary isolation at home, hospitalization, and treatment procedures. In the present case MBPS was at first suspected following neuropsychological assessment, since some of the main features of non-authenticity of symptom presentation gave cause for suspecting deceptive behavior on the mother's (and possibly also on the maternal grandmother's) side.

Update on the core and developing cerebrospinal fluid biomarkers for Alzheimer disease

PubMed Central

Babić, Mirjana; Švob Štrac, Dubravka; Mück-Šeler, Dorotea; Pivac, Nela; Stanić, Gabrijela; Hof, Patrick R.; Šimić, Goran

2014-01-01

Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed. PMID:25165049

An osteoarthritis model of care should be a national priority for New Zealand.

PubMed

Baldwin, Jennifer; Briggs, Andrew; Bagg, Warwick; Larmer, Peter

2017-12-15

Osteoarthritis is highly prevalent, disabling and costly to the person and the community. The burden of this chronic condition is predicted to increase dramatically over the coming decades. Healthcare spending on osteoarthritis is unsustainable and action is needed to improve care delivery. At present, there is an over-emphasis on surgical and pharmacological interventions, despite evidence supporting conservative treatments such as exercise, weight loss and education. While clinical guidelines provide recommendations regarding best practice (ie, what to do), they fail to address how to operationalise these recommendations into clinical practice. Models of care (MoCs) can help bridge the evidence-practice gap by outlining evidence-informed interventions as well as how to implement them within a local system. However, New Zealand has no osteoarthritis MoC. The Mobility Action Programme, funded by the Ministry of Health, is delivering evidence-informed, multi-disciplinary care for osteoarthritis through local initiatives. Although the programme remains under evaluation it presents an opportunity to inform development of a national osteoarthritis MoC for New Zealand. A policy framework, such as a MoC, is needed to scale up successful programs and deliver best practice care nationwide. Ultimately, addressing the burden of osteoarthritis will require system-wide approaches involving public policy responses to target primary prevention.

How personality became treatable: The mutual constitution of clinical knowledge and mental health law

PubMed Central

2013-01-01

In recent years, personality disorders – psychiatric constructs understood as enduring dysfunctions of personality – have come into ever-greater focus for British policymakers, mental health professionals and service-users. Disputes have focussed largely on highly controversial attempts by the UK Department of Health to introduce mental health law and policy (now enshrined within the 2007 Mental Health Act of England and Wales). At the same time, clinical framings of personality disorder have dramatically shifted: once regarded as untreatable conditions, severe personality disorders are today thought of by many clinicians to be responsive to psychiatric and psychological intervention. In this article, I chart this transformation by means of a diachronic analysis of debates and institutional shifts pertaining to both attempts to change the law, and understandings of personality disorder. In so doing, I show how mental health policy and practice have mutually constituted one another, such that the aims of clinicians and policymakers have come to be closely aligned. I argue that it is precisely through these reciprocally constitutive processes that the profound reconfiguration of personality disorder from being an obdurate to a plastic condition has occurred; this demonstrates the significance of interactions between law and the health professions in shaping not only the State’s management of pathology, but also perceptions of its very nature.

Polarity-dependent effects of transcranial direct current stimulation in obsessive-compulsive disorder.

PubMed

D'Urso, Giordano; Brunoni, Andre Russowsky; Anastasia, Annalisa; Micillo, Marco; de Bartolomeis, Andrea; Mantovani, Antonio

2016-01-01

About one third of patients with obsessive-compulsive disorder (OCD) fail to experience significant clinical benefit from currently available treatments. Hyperactivity of the presupplementary motor area (pre-SMA) has been detected in OCD patients, but it is not clear whether it is the primary cause or a secondary compensatory mechanism in OCD pathophysiology. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique with polarity-dependent effects on motor cortical excitability. A 33-year-old woman with treatment-resistant OCD received 20 daily consecutive 2 mA/20 min tDCS sessions with the active electrode placed on the pre-SMA, according to the 10-20 EEG system, and the reference electrode on the right deltoid. The first 10 sessions were anodal, while the last 10 were cathodal. Symptoms severity was assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) severity score. In the end of anodal stimulation, OCD symptoms had worsened. Subsequent cathodal stimulation induced a dramatic clinical improvement, which led to an overall 30% reduction in baseline symptoms severity score on the Y-BOCS. Our study supports the hypothesis that pre-SMA hyperfunction might be responsible for OCD symptoms and shows that cathodal inhibitory tDCS over this area might be an option when dealing with treatment-resistant OCD.

Spice drugs are more than harmless herbal blends: a review of the pharmacology and toxicology of synthetic cannabinoids

PubMed Central

Seely, Kathryn A.; Lapoint, Jeff; Moran, Jeffery H.; Fattore, Liana

2014-01-01

“K2” and “Spice” drugs (collectively hereafter referred to as Spice) represent a relatively new class of designer drugs that have recently emerged as popular alternatives to marijuana, otherwise characterized as “legal highs”. These drugs are readily available on the Internet and sold in many head shops and convenience stores under the disguise of innocuous products like herbal blends, incense, or air fresheners. Although package labels indicate “not for human consumption”, the number of intoxicated people presenting to emergency departments is dramatically increasing. The lack of validated and standardized human testing procedures and an endless supply of potential drugs of abuse are primary reasons why researchers find it difficult to fully characterize clinical consequences associated with Spice. While the exact chemical composition and toxicology of Spice remains to be determined, there is mounting evidence identifying several synthetic cannabinoids as causative agents responsible for psychoactive and adverse physical effects. This review provides updates of the legal status of common synthetic cannabinoids detected in Spice and analytical procedures used to test Spice products and human specimens collected under a variety of clinical circumstances. The pharmacological and toxicological consequences of synthetic cannabinoid abuse are also reviewed to provide a future perspective on potential short- and long-term implications. PMID:22561602

Adoptive immunotherapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors.

PubMed

Fujiwara, Hiroshi

2014-12-15

Accumulating clinical evidence suggests that adoptive T-cell immunotherapy could be a promising option for control of cancer; evident examples include the graft-vs-leukemia effect mediated by donor lymphocyte infusion (DLI) and therapeutic infusion of ex vivo-expanded tumor-infiltrating lymphocytes (TIL) for melanoma. Currently, along with advances in synthetic immunology, gene-modified T cells retargeted to defined tumor antigens have been introduced as "cellular drugs". As the functional properties of the adoptive immune response mediated by T lymphocytes are decisively regulated by their T-cell receptors (TCRs), transfer of genes encoding target antigen-specific receptors should enable polyclonal T cells to be uniformly redirected toward cancer cells. Clinically, anticancer adoptive immunotherapy using genetically engineered T cells has an impressive track record. Notable examples include the dramatic benefit of chimeric antigen receptor (CAR) gene-modified T cells redirected towards CD19 in patients with B-cell malignancy, and the encouraging results obtained with TCR gene-modified T cells redirected towards NY-ESO-1, a cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. This article overviews the current status of this treatment option, and discusses challenging issues that still restrain the full effectiveness of this strategy, especially in the context of hematological malignancy.

Human melanoma cells resistant to MAPK inhibitors can be effectively targeted by inhibition of the p90 ribosomal S6 kinase

PubMed Central

Kosnopfel, Corinna; Sinnberg, Tobias; Sauer, Birgit; Niessner, Heike; Schmitt, Anja; Makino, Elena; Forschner, Andrea; Hailfinger, Stephan; Garbe, Claus; Schittek, Birgit

2017-01-01

The clinical availability of small molecule inhibitors specifically targeting mutated BRAF marked a significant breakthrough in melanoma therapy. Despite a dramatic anti-tumour activity and improved patient survival, rapidly emerging resistance, however, greatly limits the clinical benefit. The majority of the already described resistance mechanisms involve a reactivation of the MAPK signalling pathway. The p90 ribosomal S6 kinase (RSK), a downstream effector of the MAPK signalling cascade, has been reported to enhance survival of melanoma cells in response to chemotherapy. Here, we can show that RSK activity is significantly increased in human melanoma cells with acquired resistance to the BRAFV600E/K inhibitor vemurafenib. Interestingly, inhibition of RSK signalling markedly impairs the viability of vemurafenib resistant melanoma cells and is effective both in two-dimensional and in three-dimensional culture systems, especially in a chronic, long-term application. The effect of RSK inhibition can be partly replicated by downregulation of the well-known RSK target, Y-box binding protein 1 (YB-1). Intriguingly, RSK inhibition also retains its efficacy in melanoma cells with combined resistance to vemurafenib and the MEK inhibitor trametinib. These data suggest that active RSK signalling might be an attractive novel therapeutic target in melanoma with acquired resistance to MAPK pathway inhibitors. PMID:28415756

Increasing complexity of clinical research in gastroenterology: implications for the training of clinician-scientists.

PubMed

Scott, Frank I; McConnell, Ryan A; Lewis, Matthew E; Lewis, James D

2012-04-01

Significant advances have been made in clinical and epidemiologic research methods over the past 30 years. We sought to demonstrate the impact of these advances on published gastroenterology research from 1980 to 2010. Twenty original clinical articles were randomly selected from each of three journals from 1980, 1990, 2000, and 2010. Each article was assessed for topic, whether the outcome was clinical or physiologic, study design, sample size, number of authors and centers collaborating, reporting of various statistical methods, and external funding. From 1980 to 2010, there was a significant increase in analytic studies, clinical outcomes, number of authors per article, multicenter collaboration, sample size, and external funding. There was increased reporting of P values, confidence intervals, and power calculations, and increased use of large multicenter databases, multivariate analyses, and bioinformatics. The complexity of clinical gastroenterology and hepatology research has increased dramatically, highlighting the need for advanced training of clinical investigators.

A Domain Analysis Model for eIRB Systems: Addressing the Weak Link in Clinical Research Informatics

PubMed Central

He, Shan; Narus, Scott P.; Facelli, Julio C.; Lau, Lee Min; Botkin, Jefferey R.; Hurdle, John F.

2014-01-01

Institutional Review Boards (IRBs) are a critical component of clinical research and can become a significant bottleneck due to the dramatic increase, in both volume and complexity of clinical research. Despite the interest in developing clinical research informatics (CRI) systems and supporting data standards to increase clinical research efficiency and interoperability, informatics research in the IRB domain has not attracted much attention in the scientific community. The lack of standardized and structured application forms across different IRBs causes inefficient and inconsistent proposal reviews and cumbersome workflows. These issues are even more prominent in multi-institutional clinical research that is rapidly becoming the norm. This paper proposes and evaluates a domain analysis model for electronic IRB (eIRB) systems, paving the way for streamlined clinical research workflow via integration with other CRI systems and improved IRB application throughput via computer-assisted decision support. PMID:24929181

Psychotherapeutics and the problematic origins of clinical psychology in America.

PubMed

Taylor, E

2000-09-01

The problematic place of psychotherapy within the larger history of scientific psychology is reviewed, especially in the absence of any definitive history of clinical psychology yet written. Although standard histories of psychology imply that psychotherapy was somehow derived from the tradition of German laboratory science, modern historiography reveals a dramatically different story. Personality, abnormal, social, and clinical psychology have their roots in an international psychotherapeutic alliance related more to French neurophysiology, and this alliance flourished for several decades before psychoanalysis. Reconstruction of the American contribution to this alliance, the so-called Boston school of abnormal psychology, suggests an era of medical psychology in advance of today. Note is also made of the possible misattribution of Lightner Witmer as the father of clinical psychology.

Opportunities and Challenges for Women Engineers in Industry.

ERIC Educational Resources Information Center

O'Brien, J. Edwin

There are real opportunities for women in engineering, reflecting demands created by the dramatic rate of change in society. Increasingly complex technology, fast response time, the demands of production and managerial positions, increased levels of education and sophistication of employees, shifts in motivational needs, and new organizational…

Nation, Districts Step up Safety

ERIC Educational Resources Information Center

Shah, Nirvi

2013-01-01

President Barack Obama's announcement last week of a wide-ranging anti-violence plan in response to the Newtown, Connecticut, school shootings comes as many districts are adopting new and sometimes dramatic measures--including arming teachers and volunteers--intended to prevent similar tragedies in their own schools. School safety experts warn…

Online Resource Creation Catalyzes Collaboration

ERIC Educational Resources Information Center

Millichap, Nancy; Toler, Michael

2005-01-01

Some positive responses emerged from the tragic events of September 11, 2001, including recognition of the importance of international education, especially about non-Western cultural regions of the world. Colleges and universities in particular saw dramatically increased interest in teaching and learning about Islam and the Arab world. Many…

COMPARATIVE TOXICITY OF AIR POLLUTION PARTICLES COLLECTED FROM DIFFERENT GEOGRAPHICAL LOCATIONS

EPA Science Inventory

Air pollution particulate matter (PM) is responsible for more than 500,000 deaths worldwide each year. PM pollution is a complex mixture containing dozens of different compounds; the composition of PM can vary dramatically among different locations depending on the sources of pa...

A Psychoecological Model of Academic Performance among Hispanic Adolescents

ERIC Educational Resources Information Center

Chun, Heejung; Dickson, Ginger

2011-01-01

Although the number of students who complete high school continues to rise, dramatic differences in school success remain across racial/ethnic groups. The current study addressed Hispanic adolescents' academic performance by investigating the relationships of parental involvement, culturally responsive teaching, sense of school belonging, and…

Activin Modulates the Transcriptional Response of LβT2 Cells to Gonadotropin-Releasing Hormone and Alters Cellular Proliferation

PubMed Central

Zhang, Hao; Bailey, Janice S.; Coss, Djurdjica; Lin, Bo; Tsutsumi, Rie; Lawson, Mark A.; Mellon, Pamela L.; Webster, Nicholas J. G.

2009-01-01

Both GnRH and activin are crucial for the correct function of pituitary gonadotrope cells. GnRH regulates LH and FSH synthesis and secretion and gonadotrope proliferation, whereas activin is essential for expression of FSH. Little is known, however, about the interplay of signaling downstream of these two hormones. In this study, we undertook expression profiling to determine how activin pre-treatment alters the transcriptional response of LβT2 gonadotrope cells to GnRH stimulation. Activin treatment alone altered the transcriptional profile of 303 genes including inducing that of the 17β-hydroxysteroid dehydrogenase B1 gene that converts estrone to 17β-estradiol, altering the sensitivity of the cells to estrone. Furthermore, activin had a dramatic effect on the response of LβT2 cells to GnRH. Hierarchical clustering of 2453 GnRH-responsive genes identified groups of genes the response of which to GnRH was either enhanced or blunted after activin treatment. Mapping of these genes to gene ontology classifications or signaling pathways highlighted significant differences in the classes of altered genes. In the presence of activin, GnRH regulates genes in pathways controlling cell energetics, cytoskeletal rearrangements, organelle organization, and mitosis in the absence of activin, but genes controlling protein processing, cell differentiation, and secretion. Therefore, we demonstrated that activin enhanced GnRH induction of p38MAPK activity, caused GnRH-dependent phosphorylation of p53, and reduced the ability of GnRH to cause G1 arrest. Thus, although activin alone changes a modest number of transcripts, activin pretreatment dramatically alters the response to GnRH from an antiproliferative response to a more differentiated, synthetic response appropriate for a secretory cell. PMID:16772531

Immunotherapy for Ovarian Cancer: What's Next?

PubMed Central

Kandalaft, Lana E.; Powell, Daniel J.; Singh, Nathan; Coukos, George

2011-01-01

In the past decade, we have witnessed important gains in the treatment of ovarian cancer; however, additional advances are required to reduce mortality. With compelling evidence that ovarian cancers are immunogenic tumors, immunotherapy should be further pursued and optimized. The dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory antibodies, create new opportunities in ovarian cancer therapeutics. Herein, we review current progress and future prospects in vaccine and adoptive T-cell therapy development as well as immunomodulatory therapy tools available for immediate clinical testing. PMID:21079136

At the Bench: Chimeric antigen receptor (CAR) T cell therapy for the treatment of B cell malignancies.

PubMed

Daniyan, Anthony F O; Brentjens, Renier J

2016-12-01

The chimeric antigen receptor (CAR) represents the epitome of cellular engineering and is one of the best examples of rational biologic design of a synthetic molecule. The CAR is a single polypeptide with modular domains, consisting of an antibody-derived targeting moiety, fused in line with T cell-derived signaling domains, allowing for T cell activation upon ligand binding. T cells expressing a CAR are able to eradicate selectively antigen-expressing tumor cells in a MHC-independent fashion. CD19, a tumor-associated antigen (TAA) present on normal B cells, as well as most B cell-derived malignancies, was an early target of this technology. Through years of experimental refinement and preclinical optimization, autologously derived CD19-targeting CAR T cells have been successfully, clinically deployed, resulting in dramatic and durable antitumor responses but not without therapy-associated toxicity. As CD19-targeted CAR T cells continue to show clinical success, work at the bench continues to be undertaken to increase further the efficacy of this therapy, while simultaneously minimizing the risk for treatment-related morbidities. In this review, we cover the history and evolution of CAR technology and its adaptation to targeting CD19. Furthermore, we discuss the future of CAR T cell therapy and the need to ask, as well as answer, critical questions as this treatment modality is being translated to the clinic. © Society for Leukocyte Biology.

Developmental Therapeutics Consortium report on study design effects on trial outcomes in chronic myeloid leukaemia.

PubMed

Giles, Francis; Mahon, François-Xavier; Gjertsen, Bjorn; Swords, Ronan; Labar, Boris; Turkina, Anna; Rosti, Gianantonio

2012-09-01

Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukaemia (CML). Results from ongoing phase 3 trials with nilotinib [Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd)] and dasatinib [Dasatinib Versus Imatinib Study in Treatment-Naive CML-CP Patients (DASISION)] in newly diagnosed patients with CML in chronic phase have demonstrated that these TKIs resulted in significant improvements in responses vs. imatinib. The Developmental Therapeutics Consortium (DTC) systematically reviewed the published literature to provide a comparative analysis of the ENESTnd and DASISION trial designs and data reported on each study. The recent approval of nilotinib and dasatinib based on these two pivotal studies offers physicians the option to optimise frontline treatment based on a patient's comorbidities, risk factors and tolerability profiles. Although nilotinib and dasatinib provide effective therapeutic options for the frontline treatment of CML, the lack of an evidenced-based, side-by-side comparison makes it difficult to directly compare these agents. Despite potential bias from differences in patient populations and study design, indirect cross-trial comparisons to determine the relative effectiveness of these agents will be performed by physicians. This DTC report provides a comprehensive summary of the study designs, protocols and results of the ENESTnd and DASISION trials, which will assist physicians in making informed decisions on the best treatment approach for their patients. © 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.

Comparison of Detection Limits of 4th Generation Combination HIV Antigen/Antibody, p24 Antigen and Viral Load Assays on Diverse HIV Isolates.

PubMed

Stone, Mars; Bainbridge, John; Sanchez, Ana M; Keating, Sheila M; Pappas, Andrea; Rountree, Wes; Todd, Chris; Bakkour, Sonia; Manak, Mark; Peel, Sheila A; Coombs, Robert W; Ramos, Eric M; Shriver, M Kathleen; Contestable, Paul; Nair, Sangeetha Vijaysri; Wilson, David H; Stengelin, Martin; Murphy, Gary; Hewlett, Indira; Denny, Thomas N; Busch, Michael P

2018-05-23

Detection of acute HIV infection is critical for HIV public health and diagnostics. Clinical 4 th generation antigen-antibody (Ag/Ab) combination (combo) and p24 Ag immunoassays have enhanced detection of acute infection compared to Ab alone assays, but require ongoing evaluation with currently circulating diverse subtypes. Genetically and geographically diverse HIV clinical isolates were used to assess clinical HIV diagnostic, blood screening and next generation assays. Blinded 300 member panels of 20 serially diluted well-characterized antibody negative HIV isolates were distributed to manufacturers and end-user labs to assess relative analytic sensitivity of currently approved and pre-approved clinical HIV 4 th generation Ag/Ab combo or p24 Ag alone immunoassays across diverse subtypes. The limits of virus detection (LODs) were estimated for different subtypes relative to confirmed viral loads. Analysis of immunoassay sensitivity was benchmarked against confirmed viral load measurements on the blinded panel. Based on the proportion of positive results on 300 observations all Ag/Ab combo and standard sensitivity p24 Ag assays performed similarly and within half log LODs, illustrating similar breadth of reactivity and diagnostic utility. Ultrasensitive p24 Ag assays achieved dramatically increased sensitivities, while the rapid combo-assays performed poorly. Similar performance of the different commercially available 4 th gen assays on diverse subtypes supports their use in broad geographic settings with locally circulating HIV clades and recombinant strains. Next generation pre-clinical ultrasensitive p24 Ag assays achieved dramatically improved sensitivity, while p24 Ag detection by rapid 4 th gen assays performed poorly. Copyright © 2018 American Society for Microbiology.

The effect of juvenile hormone on Polistes wasp fertility varies with cooperative behavior.

PubMed

Tibbetts, Elizabeth A; Sheehan, Michael J

2012-04-01

Social insects provide good models for studying how and why the mechanisms that underlie reproduction vary, as there is dramatic reproductive plasticity within and between species. Here, we test how the effect of juvenile hormone (JH) on fertility covaries with cooperative behavior in workers and nest-founding queens in the primitively eusocial wasp Polistes metricus. P. metricus foundresses and workers appear morphologically similar and both are capable of reproduction, though there is variation in the extent of social cooperation and the probability of reproduction across castes. Do the endocrine mechanisms that mediate reproduction co-vary with cooperative behavior? We found dramatic differences in the effect of JH on fertility across castes. In non-cooperative nest-founding queens, all individuals responded to JH by increasing their fertility. However, in cooperative workers, the effect of JH on fertility varies with body weight; large workers increase their fertility in response to JH while small workers do not. The variation in JH response may be an adaptation to facilitate resource allocation based on the probability of independent reproduction. This work contrasts with previous studies in closely related Polistes dominulus paper wasps, in which both foundresses and workers form cooperative associations and both castes show similar, condition-dependent JH response. The variation in JH responsiveness within and between species suggests that endocrine responsiveness and the factors influencing caste differentiation are surprisingly evolutionarily labile. Copyright © 2012 Elsevier Inc. All rights reserved.

Fluid Mechanics of Wing Adaptation for Separation Control

NASA Technical Reports Server (NTRS)

Chandrasekhara, M. S.; Wilder, M. C.; Carr, L. W.; Davis, Sanford S. (Technical Monitor)

1997-01-01

The unsteady fluid mechanics associated with use of a dynamically deforming leading edge airfoil for achieving compressible flow separation control has been experimentally studied. Changing the leading edge curvature at rapid rates dramatically alters the flow vorticity dynamics which is responsible for the many effects observed in the flow.

Work/Family Conflicts: Policy Implications.

ERIC Educational Resources Information Center

Baker, Maureen

In the past 20 years, the percentage of married women in the Canadian labor force has risen dramatically. Despite women's increased participation in the labor force, child care and housework are still largely done by women. While the difficulty of combining work and family responsibilities can result in work/family conflicts, a variety of…

Tree response to experimental watershed acidification

Treesearch

N.K. Jensen; E.J. Holzmueller; P.J. Edwards; M. Thomas-Van Gundy; D.R. DeWalle; K.W.J. Williard

2014-01-01

Forest ecosystems in the Eastern USA are threatened by acid deposition rates that have increased dramatically since industrialization. We utilized two watersheds at the Fernow Experimental Forest in West Virginia to examine long-term effects of acidification on ecological processes. One watershed has been treated with ammonium sulfate (approximately twice the ambient...

NEWPATH: An Innovative Program to Nurture IT Entrepreneurs

ERIC Educational Resources Information Center

Soundarajan, Neelam; Camp, Stephen M.; Lee, David; Ramnath, Rajiv; Weide, Bruce W.

2016-01-01

The number of freshmen interested in entrepreneurship has grown dramatically in the last few years. In response, many universities have created entrepreneurship programs, including ones focused on engineering entrepreneurship. In this paper, we report on NEWPATH, an innovative NSF-supported program at Ohio State, designed to nurture students to…

Materials for Children about Nuclear War.

ERIC Educational Resources Information Center

Eiss, Harry

President Reagan's Fiscal Year 1987 budget was an attempt to increase dramatically spending on national defense, on nuclear weapons, while cutting back on social programs. The increases for almost all nuclear weapons indicate the Administration of the United States saw its major responsibility as one of providing a strong military, one centered on…

Learning From Pictures.

ERIC Educational Resources Information Center

Williams, Catharine M.

Well prepared, carefully chosen, two-dimensional visual aids are valuable in the learning process as a source of information and as a stimulator of student response. A student's visual perception and his degree of self-awareness can be evaluated by his reaction to pictures. At the instructional level, pictures can expand an experience, dramatize a…

An improved algorithm for evaluating trellis phase codes

NASA Technical Reports Server (NTRS)

Mulligan, M. G.; Wilson, S. G.

1982-01-01

A method is described for evaluating the minimum distance parameters of trellis phase codes, including CPFSK, partial response FM, and more importantly, coded CPM (continuous phase modulation) schemes. The algorithm provides dramatically faster execution times and lesser memory requirements than previous algorithms. Results of sample calculations and timing comparisons are included.

An improved algorithm for evaluating trellis phase codes

NASA Technical Reports Server (NTRS)

Mulligan, M. G.; Wilson, S. G.

1984-01-01

A method is described for evaluating the minimum distance parameters of trellis phase codes, including CPFSK, partial response FM, and more importantly, coded CPM (continuous phase modulation) schemes. The algorithm provides dramatically faster execution times and lesser memory requirements than previous algorithms. Results of sample calculations and timing comparisons are included.

Linking the cardiomyocyte circadian clock to myocardial metabolism

USDA-ARS?s Scientific Manuscript database

The energetic demands imposed upon the heart vary dramatically over the course of the day. In the face of equally commanding oscillations in the neurohumoral mileu, the heart must respond both rapidly and appropriately to its diurnal environment, for the survival of the organism. A major response of...

Reconciling Stable Asymmetry with Recovery of Function: An Adaptive Systems Perspective on Functional Plasticity.

ERIC Educational Resources Information Center

Bullock, Daniel; And Others

1987-01-01

This commentary, written in response to Witelson's work (1987), examines alternative ways of determining how the developmentally stable functional asymmetry (hemispheric specialization) observed in neurologically intact children can be reconciled with the dramatic recovery of function often displayed following unilateral brain damage. (PCB)

The Workers' College

ERIC Educational Resources Information Center

Harper, William A.

1977-01-01

The economy has dramatized for educators the need for educators to make teaching and learning more responsive to the world of work. The efforts of the AACJC are described with regard to education-work councils, occupational safety and health, women in occupational education, and a joint study with the American Vocational Association. (LBH)

Bridging the Learning/Assessment Gap: Showcase Teaching

ERIC Educational Resources Information Center

Jennings, Wayne; Caulfield, Joan

2005-01-01

Continuing dramatic developments in the ability of neuroscientists to peer inside the brain to discover its incredible intricacy places awesome responsibility on all educators to "do the right thing" for their students. Here, the authors offer readers powerful brain-compatible and research-based teaching and learning strategies based on how the…

Elevated enzyme activities in soils under the invasive nitrogen-fixing tree Falcataria moluccana

Treesearch

Steven D. Allison; Caroline Nielsen; R. Flint Hughes

2006-01-01

Like other N-fixing invasive species in Hawaii, Falcataria moluccana dramatically alters forest structure, litterfall quality and quantity, and nutrient dynamics. We hypothesized that these biogeochemical changes would also affect the soil microbial community and the extracellular enzymes responsible for carbon and nutrient mineralization. Across...

Quantifying soil respiration at landscape scales. Chapter 11

Treesearch

John B. Bradford; Michael G. Ryan

2008-01-01

Soil CO2, efflux, or soil respiration, represents a substantial component of carbon cycling in terrestrial ecosystems. Consequently, quantifying soil respiration over large areas and long time periods is an increasingly important goal. However, soil respiration rates vary dramatically in space and time in response to both environmental conditions...

Spruce beetle (Coleoptera: Scolytidae) response to traps baited with selected semiochemicals in Utah.

Treesearch

Darrell W. Ross; Gary E. Daterman; A. Steven Munson

2005-01-01

Spruce beetle, Dendroctonus rufipennis (Kirby), populations periodically reach outbreak densities throughout the range of spruce, Picea spp., in western North America. During outbreaks it may kill thousands to millions of trees over vast areas, dramatically altering forest structure, composition, and ecological processes, thus impacting a variety...

The response of ammonia-oxidizer activity and community structure to fertilizer amendment of orchard soils

USDA-ARS?s Scientific Manuscript database

Soil microorganisms have the potential to dramatically alter the nitrogen (N) availability in agricultural systems, and therefore affect the efficiency of fertilizer application. Data regarding the effects of cereal management systems on the soil microbiology functional to N cycling have yielded var...

Behavioral treatment of the traumatically brain-injured: a case study.

PubMed

Horton, A M; Howe, N R

1981-10-01

The present case illustrates the application of behavioral modification methodology with a traumatically brain-injured adult. Such a treatment regime utilizing a report-card system and a response-cost procedure was implemented to decrease behaviors of using foul language and biting staff members. Dramatic improvement was demonstrated.

Scarcity and Surplus: Shifting Regimes of Childhood in Nicaragua

ERIC Educational Resources Information Center

Tully, Sheila R.

2007-01-01

This article explores the multiple meanings of children and childhood in Nicaragua during periods of dramatic sociopolitical and economic transitions. The article compares the state's responsibilities to Nicaraguan children and their families during the decade of revolution and first year of the post-revolutionary period. It argues that each state…

Spatially explicit animal response to composition of habitat

Treesearch

Benjamin P. Pauli; Nicholas P. McCann; Patrick A. Zollner; Robert Cummings; Jonathan H. Gilbert; Eric J. Gustafson

2013-01-01

Complex decisions dramatically affect animal dispersal and space use. Dispersing individuals respond to a combination of fine-scale environmental stimuli and internal attributes. Individual-based modeling offers a valuable approach for the investigation of such interactions because it combines the heterogeneity of animal behaviors with spatial detail. Most individual-...

"The Guilt Thing": Balancing Domestic and Professional Roles

ERIC Educational Resources Information Center

Guendouzi, Jackie

2006-01-01

Women's representation in the workforce has increased dramatically over the past 30 years; yet, women "take a greater responsibility for the care of children" (Equal Opportunities Commission, 2006). Research has suggested working mothers may experience guilt resulting from the social constrictions of a traditional model of intensive mothering (B.…

DEVELOPMENT OF NITROGEN LOADING-RESPONSE RELATIONSHIPS FOR ESTUARINE WATERS USING AN EMPIRICAL COMPARATIVE SYSTEMS APPROACH

EPA Science Inventory

There is growing evidence that human activities have dramatically changed the amounts, distribution, and movement of major nutrient elements (nitrogen-N and phosphorus-P) in the landscape and have increased nutrient loading to receiving waters. Some of these changes affect use o...

48 CFR 227.7105-1 - General.

Code of Federal Regulations, 2010 CFR

2010-10-01

... recordings, and other audiovisual works in any medium; sound recordings in any medium; musical, dramatic, and... works, or perform or display the work publicly. When the Government is not responsible for the content... liabilities that may arise out of the content, performance, use, or disclosure of such data. (b) Follow the...

Enhanced Online Access Requires Redesigned Delivery Options and Cost Models

ERIC Educational Resources Information Center

Stern, David

2007-01-01

Rapidly developing online information technologies provide dramatically new capabilities and opportunities, and place new responsibilities on all involved to recreate networks for scholarly communication. Collaborations between all segments of the information network are made possible and necessary as we attempt to find a balanced and mutually…

Urban Adolescents' Postschool Aspirations and Awareness

ERIC Educational Resources Information Center

Scanlon, David; Saxon, Karyn; Cowell, Molly; Kenny, Maureen E.; Perez-Gualdron, Leyla; Jernigan, Maryam

2008-01-01

The young adult years (approximately the age when one leaves high school to age 23) are pivotal to adult life success. They are the years when adolescents typically assume dramatic increases in responsibility for self-direction in areas such as socialization, independent living, citizenship, employment, education, and mental and physical health.…

Nutritional impacts on gene expression in the surface mucosa of blue catfish (Ictalurus furcatus)

USDA-ARS?s Scientific Manuscript database

Short-term feed deprivation is a common occurrence in both wild and farmed fish species, due to reproductive processes, seasonal variations in temperature, or in response to a disease outbreak. Fasting can have dramatic physiological and biological onsequences for fish, including impacts on mucosal ...

Library Reorganization & Restructuring. SPEC Kit 215.

ERIC Educational Resources Information Center

Eustis, Joanne D., Comp.; Kenney, Donald J. Comp.

As the entity traditionally responsible for serving the information needs of the university, research libraries have little choice but to change dramatically in the next 25 years. This SPEC Survey on library reorganization seeks to understand how librarians have sought to meet this challenge through the redesigning of their organization.…

Program Transition Challenges in International Baccalaureate Schools

ERIC Educational Resources Information Center

Hallinger, Philip; Lee, Moosung; Walker, Allan

2011-01-01

International Baccalaureate (IB) schools have experienced dramatic growth worldwide over the past decade in response to burgeoning demand for high-quality education with an international orientation. One increasingly common trend has found international schools adopting two or more of the three programs offered by the IB: the Diploma, Middle Years…

Law of the Student Press. Second Edition.

ERIC Educational Resources Information Center

Student Press Law Center, Washington, DC.

Noting dramatic changes in First Amendment protections for high school students and new legal issues facing college newspaper editors, this book describes in detail the legal rights and responsibilities of both the high school and college press. While the book is extensively footnoted, it intentionally avoids "legal-ese" and "brings…

Primers As Socializing Agents in American and Finnish Schools.

ERIC Educational Resources Information Center

Hyona, Jukka; And Others

1995-01-01

Content analysis of 12 Finnish and 18 American primers for grades 3 through 6 published primarily during the 1980s examined story type, plot setting, protagonist's characteristics, dramatic tasks, portrayals of family structure and parental responsibility, and extrafamilial peer and adult relationships. Results suggest that a nation's cultural…

Changes in enterovirus serotype constituent ratios altered the clinical features of infected children in Guangdong Province, China, from 2010 to 2013.

PubMed

Zhou, Hong-Tao; Guo, Yong-Hui; Chen, Man-Jun; Pan, Yu-Xian; Xue, Lin; Wang, Bin; Tao, Shao-Hua; Yu, Nan

2016-08-09

Enterovirus (EV)-related hand, foot, and mouth disease/herpangina (HFMD/HA) has been prevalent in Guangdong Province, China, since 2010. Clinical data for EV-related HFMD/HA inpatients admitted to the Department of Paediatrics of Zhujiang Hospital from 2010 to 2013 were retrospectively reviewed. The corresponding EV serotypes were also determined by reverse transcription-polymerase chain reaction or BLAST analysis of the sequenced partial lengths of the viral protein1/5'-untranslated region. A total of 867 eligible inpatients admitted during 2010-2013 were included in the study. Of these, the serotype of the responsible EV was successfully identified in 824 cases. The incidence of enterovirus 71 (EV71) infection amongst pediatric HFMD/HA inpatients decreased dramatically from 55.5 % in 2010 to 8.1 % in 2013, with a similar decrease recorded for coxsackievirus A16 (CVA16). However, the incidence of non-EV71/CVA16 infection increased from 30.0 % in 2010 to 83.8 % in 2013. We noted that the types of infection caused by different EV serotypes varied: EV71 was responsible for 100 % of the paralysis cases (26/26), 84.6 % of the deaths (11/13), and 84.1 % of cases with severe central nervous system involvement (SCNSI) (74/88); echovirus contributed to 16.4 % of the deaths (2/13) and 4.4 % of the SCNSI cases; and coxsackievirus accounted for only 2.2 % of the SCNSI cases (2/90). The clinical features of HFMD/HA cases varied greatly during the time period examined, with drastic changes in the hospitalization rates (45.1, 63.7, 36.4, and 19.1 % for 2010, 2011, 2012, and 21013, respectively), mortality rates (2.3, 0.9, 2.5, and 0.0 %, respectively), paralysis (5.1, 1.2, 5.4, and 0.0 %, respectively), SCNSI (16.8, 7.1, 12.7, and 2.2 %, respectively), and acute respiratory infection (21.1, 22.0, 45.9, and 59.0 %, respectively). The incidences of infection caused by different EV serotypes, along with the clinical features of HFMD/HA cases, changed drastically in Guangdong Province, China, from 2010 to 2013, with the biggest changes observed in 2013. The changed constituent ratios of the different EV serotypes might therefore be responsible for the differences in the observed clinical features of HFMD/HA during this period.

Third-Generation Ah Receptor–Responsive Luciferase Reporter Plasmids: Amplification of Dioxin-Responsive Elements Dramatically Increases CALUX Bioassay Sensitivity and Responsiveness

PubMed Central

He, Guochun; Tsutsumi, Tomoaki; Zhao, Bin; Baston, David S.; Zhao, Jing; Heath-Pagliuso, Sharon; Denison, Michael S.

2011-01-01

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related dioxin-like chemicals are widespread and persistent environmental contaminants that produce diverse toxic and biological effects through their ability to bind to and activate the Ah receptor (AhR) and AhR-dependent gene expression. The chemically activated luciferase expression (CALUX) system is an AhR-responsive recombinant luciferase reporter gene–based cell bioassay that has been used in combination with chemical extraction and cleanup methods for the relatively rapid and inexpensive detection and relative quantitation of dioxin and dioxin-like chemicals in a wide variety of sample matrices. Although the CALUX bioassay has been validated and used extensively for screening purposes, it has some limitations when screening samples with very low levels of dioxin-like chemicals or when there is only a small amount of sample matrix for analysis. Here, we describe the development of third-generation (G3) CALUX plasmids with increased numbers of dioxin-responsive elements, and stable transfection of these new plasmids into mouse hepatoma (Hepa1c1c7) cells has produced novel amplified G3 CALUX cell bioassays that respond to TCDD with a dramatically increased magnitude of luciferase induction and significantly lower minimal detection limit than existing CALUX-type cell lines. The new G3 CALUX cell lines provide a highly responsive and sensitive bioassay system for the detection and relative quantitation of very low levels of dioxin-like chemicals in sample extracts. PMID:21775728

Atrial fibrillation was changed into sinus bradycardia in a ROS1-positive advanced lung adenocarcinoma patient who achieved durable response to Crizotinib: A case report and literature review.

PubMed

Liu, Lan; Wu, Jing; Zhao, Wei; Huang, Mei-Juan

2017-05-01

The c-ros oncogene 1 receptor tyrosine kinase (ROS1)-rearrangements represent a new and rare genetic subtype of non-small-cell lung cancer. In recent years, the use of crizotinib in ROS1-rearranged lung cancer exhibits significant clinical efficacy. Crizotinib is generally well tolerated and the most frequent adverse events include visual disorders, gastrointestinal disturbances, cardiac, and endocrine abnormalities. From a cardiac perspective, crizotinib is associated with 2 main cardiac effects, QT interval prolongation and bradycardia. We reported a case of a 67-year-old man with ROS1-rearranged advanced lung adenocarcinoma. Crizotinib was initiated as first-line treatment, combined with whole brain radiation therapy. Interestingly, after treatment of crizotinib, the patient suffered a transient QTc interval prolongation and his persistent atrial fibrillation was changed into sinus bradycardia. Only 22 days after crizotinib treatment, the patient's tumor achieved a partial response. So far the patient has taken crizotinib for >19 months with no evidence of disease progression. The present study demonstrates dramatic benefit of crizotinib for patients with ROS1 rearrangement. Besides, we should caution the cardiac effects caused by crizotinb and our case provides evidence that crizotinib may be safe for patients with atrial fibrillation under close monitoring.

The marriage of nutrigenomics with the microbiome: the case of infant-associated bifidobacteria and milk.

PubMed

Sela, David A; Mills, David A

2014-03-01

Broadly, nutrigenomics examines the association of exogenous nutrients and molecular responses to maintain homeostasis in an individual. Phenotypic expression profiling, often transcriptomics, has been applied to identify markers and metabolic consequences of suboptimal diet, lifestyle, or both. The decade after the Human Genome Project has been marked with advances in high-throughput analysis of biological polymers and metabolites, prompting a rapid increase in characterization of the profound nature by which our symbiotic microbiota influences human physiology. Although the technology is widely accessible to assess microbiome composition, genetic potential, and global function, nutrigenomics studies often exclude the microbial contribution to host responses to ingested nutritive molecules. Perhaps a hallmark of coevolution, milk provides a dramatic example of a diet that promotes a particular microbial community structure, because the lower infant gastrointestinal tract is often dominated by bifidobacteria that flourish on milk glycans. Systems-level approaches should continue to be applied to examine the microbial communities in the context of their host's dietary habits and metabolic status. In addition, studies of isolated microbiota species should be encouraged to inform clinical studies and interventions as well as community studies. Whereas nutrigenomics research is beginning to account for resident microbiota, the need remains to consistently consider our microscopic partners in the human holobiont.

Deformation and annealing response of TD-nickel chromium

NASA Technical Reports Server (NTRS)

Kane, R. D.; Ebert, L. J.

1975-01-01

The recrystallization and grain growth processes occurring in TD-NiCr were examined with respect to deformation severity, annealing time, and temperature. Results indicated that two different annealing responses of TD-NiCr are possible, depending on the initial state and processing history prior to annealing. As-received sheet showed a dramatic increase in grain size with decreasing annealing temperature, whereas sheet prior-annealed at 1316 C for 1 hr exhibited very little variation with subsequent annealing temperature.

Parameters: US Army War College Quarterly. Volume 21. Number 1. Spring 1991

DTIC Science & Technology

1991-01-01

continuing deterrence and immediate crisis response. Notwithstanding the dramatic growth in US trade in the Pacific Basin, with a corresponding increase ...warning time or, as I would prefer to call it, "available response time," is truly increasing with respect to any future conflict in Europe, that fact...posture, readiness levels, and other Cold War defense burdens. Increased warning time will be a curse, however, if it lulls us and our alliance partners

Rapid Vegetational Change in Coastal North America: The Response to Climate Since the LGM

NASA Technical Reports Server (NTRS)

Peteet, Dorothy; Kneller, Margaret

1999-01-01

The late-glacial interval provided rapid shifts in climate which are mirrored by dramatic vegetational changes in North America. Through a transect of lake and mire sites from Connecticut to Virginia on the east coast and Kodiak Island on the western coast, we trace the warming following the LGM with the response of forests and tundra. A brief cold reversal in Virginia is seen from 12,260 to 12,200. The subsequent longer and extreme Younger Dryas event is marked in the southern New England - New Jersey region by dramatic boreal and deciduous forest changes. In the southeastern US, forests also change rapidly, with hemlock forest expansion suggesting increased moisture. In Kodiak Island, the warm, moist tundra of the Bolling/Allerod is replaced by colder, windswept Empetrum-dominated tundra during the Younger Dryas. The Pleistocene/Holocene shift in vegetation is remarkably pronounced in eastern North America as well as the Alaskan coastline. Response time of vegetation to climate change appears to be on the order of decades throughout these coastal locations, probably because of the proximity of sites to important ecotonal boundaries, and the magnitude of the events. Even in Virginia's Holocene record, a cold reversal inferred from increases in spruce and fir is noted at 7500 C14 yr BP. This response of the forests to a short-lived cooling shows the sensitivity of the biosphere to a rapid climate shifts.

Predicting multi-wall structural response to hypervelocity impact using the hull code

NASA Technical Reports Server (NTRS)

Schonberg, William P.

1993-01-01

Previously, multi-wall structures have been analyzed extensively, primarily through experiment, as a means of increasing the meteoroid/space debris impact protection of spacecraft. As structural configurations become more varied, the number of tests required to characterize their response increases dramatically. As an alternative to experimental testing, numerical modeling of high-speed impact phenomena is often being used to predict the response of a variety of structural systems under different impact loading conditions. The results of comparing experimental tests to Hull Hydrodynamic Computer Code predictions are reported. Also, the results of a numerical parametric study of multi-wall structural response to hypervelocity cylindrical projectile impact are presented.

On the Pressure Response in the Brain due to Short Duration Blunt Impacts

PubMed Central

Pearce, Christopher W.; Young, Philippe G.

2014-01-01

When the head is subject to non-penetrating (blunt) impact, contusion-type injuries are commonly identified beneath the impact site (the coup) and, in some instances, at the opposite pole (the contre-coup). This pattern of injury has long eluded satisfactory explanation and blunt head injury mechanisms in general remain poorly understood. There are only a small number of studies in the open literature investigating the head's response to short duration impacts, which can occur in collisions with light projectiles. As such, the head impact literature to date has focussed almost exclusively on impact scenarios which lead to a quasi-static pressure response in the brain. In order to investigate the response of the head to a wide range of impact durations, parametric numerical studies were performed on a highly bio-fidelic finite element model of the human head created from in vivo magnetic resonance imaging (MRI) scan data with non-linear tissue material properties. We demonstrate that short duration head impacts can lead to potentially deleterious transients of positive and negative intra-cranial pressure over an order of magnitude larger than those observed in the quasi-static regime despite reduced impact force and energy. The onset of this phenomenon is shown to be effectively predicted by the ratio of impact duration to the period of oscillation of the first ovalling mode of the system. These findings point to dramatically different pressure distributions in the brain and hence different patterns of injury depending on projectile mass, and provide a potential explanation for dual coup/contre-coup injuries observed clinically. PMID:25478695

On the pressure response in the brain due to short duration blunt impacts.

PubMed

Pearce, Christopher W; Young, Philippe G

2014-01-01

When the head is subject to non-penetrating (blunt) impact, contusion-type injuries are commonly identified beneath the impact site (the coup) and, in some instances, at the opposite pole (the contre-coup). This pattern of injury has long eluded satisfactory explanation and blunt head injury mechanisms in general remain poorly understood. There are only a small number of studies in the open literature investigating the head's response to short duration impacts, which can occur in collisions with light projectiles. As such, the head impact literature to date has focussed almost exclusively on impact scenarios which lead to a quasi-static pressure response in the brain. In order to investigate the response of the head to a wide range of impact durations, parametric numerical studies were performed on a highly bio-fidelic finite element model of the human head created from in vivo magnetic resonance imaging (MRI) scan data with non-linear tissue material properties. We demonstrate that short duration head impacts can lead to potentially deleterious transients of positive and negative intra-cranial pressure over an order of magnitude larger than those observed in the quasi-static regime despite reduced impact force and energy. The onset of this phenomenon is shown to be effectively predicted by the ratio of impact duration to the period of oscillation of the first ovalling mode of the system. These findings point to dramatically different pressure distributions in the brain and hence different patterns of injury depending on projectile mass, and provide a potential explanation for dual coup/contre-coup injuries observed clinically.

Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes.

PubMed

Carrillo, Eddy H; Gordon, Laura E; Richardson, J David; Polk, Hiram C

2002-03-01

A systemic inflammatory response (SIR) is seen in approximately 75% of patients with complex blunt liver injuries treated nonoperatively. Many feel this response is caused by blood, bile, and necrotic tissue accumulation in the peritoneal cavity. Our current treatment for these patients is a delayed laparoscopic washout of the peritoneal cavity, resulting in a dramatic resolution of the SIR. Spectrophotometric analysis of the intraperitoneal fluid has confirmed the presence of high concentrations of free hemoglobin (Hb). We hypothesize that free Hb enhances the local peritoneal response by increasing tumor necrosis factor-alpha (TNF-alpha) production by monocytes, contributing to the local inflammatory response and SIR. Monocytes from five healthy volunteers were isolated and cultured in RPMI-1640 for 24 hours. Treatment groups included saline controls, lipopolysaccharide ([LPS], 10 ng/mL, from Escherichia coli), human Hb (25 microg/mL), and Hb + LPS. Supernatants were analyzed by enzyme-linked immunosorbent assay. Student's t test with Mann-Whitney posttest was used for statistical analysis with p < or = 0.05 considered significant. Free Hb significantly increased TNF-alpha production 915 +/- 223 pg/mL versus saline (p = 0.02). LPS and Hb + LPS further increased TNF-alpha production (2294 pg/mL and 2501 pg/mL, respectively, p < 0.001) compared with saline controls. These data confirm that free Hb is a proinflammatory mediator resulting in the production of significant amounts of TNF-alpha. These in vitro findings support our clinical data in which timely removal of intraperitoneal free hemoglobin helps prevent its deleterious local and systemic inflammatory effects in patients with complex liver injuries managed nonoperatively.

The 'Antiretrovirals, Sexual Transmission Risk and Attitudes' (ASTRA) study. Design, methods and participant characteristics.

PubMed

Speakman, Andrew; Rodger, Alison; Phillips, Andrew N; Gilson, Richard; Johnson, Margaret; Fisher, Martin; Ed Wilkins; Anderson, Jane; O'Connell, Rebecca; Lascar, Monica; Aderogba, Kazeem; Edwards, Simon; McDonnell, Jeffrey; Perry, Nicky; Sherr, Lorraine; Collins, Simon; Hart, Graham; Johnson, Anne M; Miners, Alec; Elford, Jonathan; Geretti, Anna-Maria; Burman, William J; Lampe, Fiona C

2013-01-01

Life expectancy for people diagnosed with HIV has improved dramatically however the number of new infections in the UK remains high. Understanding patterns of sexual behaviour among people living with diagnosed HIV, and the factors associated with having condom-less sex, is important for informing HIV prevention strategies and clinical care. In addition, in view of the current interest in a policy of early antiretroviral treatment (ART) for all people diagnosed with HIV in the UK, it is of particular importance to assess whether ART use is associated with increased levels of condom-less sex. In this context the ASTRA study was designed to investigate current sexual activity, and attitudes to HIV transmission risk, in a large unselected sample of HIV-infected patients under care in the UK. The study also gathered background information on demographic, socio-economic, lifestyle and disease-related characteristics, and physical and psychological symptoms, in order to identify other key factors impacting on HIV patients and the behaviours which underpin transmission. In this paper we describe the study rationale, design, methods, response rate and the demographic characteristics of the participants. People diagnosed with HIV infection attending 8 UK HIV out-patient clinics in 2011-2012 were invited to participate in the study. Those who agreed to participate completed a confidential, self-administered pen-and-paper questionnaire, and their latest CD4 count and viral load test results were recorded. During the study period, 5112 eligible patients were invited to take part in the study and 3258 completed questionnaires were obtained, representing a response rate of 64% of eligible patients. The study includes 2248 men who have sex with men (MSM), 373 heterosexual men and 637 women. Future results from ASTRA will be a key resource for understanding HIV transmission within the UK, targeting prevention efforts, and informing clinical care of individuals living with HIV.

High-intensity therapeutic ultrasound: metrological requirements versus clinical usage

NASA Astrophysics Data System (ADS)

Aubry, J.-F.

2012-10-01

High-intensity therapeutic ultrasound (HITU) is an appealing non-invasive, non-ionizing therapeutic modality with a wide range of tissue interactions ranging from transient permeabilization of cell membranes to thermal ablation. The ability to guide and monitor the treatment with an associated ultrasonic or magnetic resonance imaging device has resulted in a dramatic rise in the clinical use of therapeutic ultrasound in the past two decades. Nevertheless, the range of clinical applications and the number of patients treated has grown at a much higher pace than the definition of standards. In this paper the metrological requirements of the therapeutic beams are reviewed and are compared with the current clinical use of image-guided HITU mostly based on a practical approach. Liver therapy, a particularly challenging clinical application, is discussed to highlight the differences between some complex clinical situations and the experimental conditions of the metrological characterization of ultrasonic transducers.

[Spontaneous splenic rupture as complication of infective mononucleosis: a clinical case].

PubMed

Delle Monache, Guido; Orlando, Dante; Frassanito, Salvatore; Sciarra, Roberto; Rinaldi, Manlio Tullio

2003-01-01

Spontaneous splenic rupture is a very rare complication of infectious mononucleosis, already described by other authors. In this case report we show the findings occurring in a young man who presented with sudden left thoracic pain and dyspnea. The initial work-up was oriented towards a suspected diagnosis of left spontaneous pneumothorax. Initially, little attention was paid to the clinical history that was characterized by flu-like symptoms during the previous 2 weeks; this, along with a rushed physical examination, could have had dramatic consequences, due to the unavoidable diagnostic delay. A thorough clinical evaluation by Internists, coupled with the essential ultrasonographic diagnostic support, allowed an earlier diagnosis followed by definitive cure, i.e. splenectomy.

Clinical Factors Associated with PANDAS

PubMed Central

Murphy, Tanya K.; Storch, Eric A.; Lewin, Adam B.; Edge, Paula J.; Goodman, Wayne K.

2011-01-01

Objective To explore associated clinical factors in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS). Study design Children with tics and/or OCD (n = 109) were examined by personal and family history, diagnostic interview, physical examination, medical record review, and measurement of baseline levels of streptococcal antibodies. Results Significant group differences were found on several variables, such that those diagnosed with PANDAS (versus without PANDAS) were more likely to have had dramatic onset; definite remissions; remission of neuropsychiatric symptoms during antibiotic therapy; a history of tonsillectomies/adenoidectomies; evidence of GAS infection, and clumsiness. Conclusion The identification of clinical features associated with PANDAS should assist in delineating risks for this subtype of OCD/tics. PMID:21868033

Infrared imaging enhances retinal crystals in Bietti's crystalline dystrophy.

PubMed

Brar, Vikram S; Benson, William H

2015-01-01

Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti's crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time.

What Does It Mean to Be Autistic? Inter-State Variation in Special Education Criteria for Autism Services

ERIC Educational Resources Information Center

MacFarlane, Jaclyn R.; Kanaya, Tomoe

2009-01-01

The prevalence of Autism and other Autism Spectrum Disorders (ASDs) has increased dramatically in recent years. The criterion for a clinical diagnosis of Autism, however, is independent from the special education eligibility requirements for Autism services. While the DSM-IV-TR provides a nationally-accepted definition for Autism and ASD, under…

What Is Everyday Ethics? A Review and a Proposal for an Integrative Concept.

PubMed

Zizzo, Natalie; Bell, Emily; Racine, Eric

2016-01-01

"Everyday ethics" is a term that has been used in the clinical and ethics literature for decades to designate normatively important and pervasive issues in healthcare. In spite of its importance, the term has not been reviewed and analyzed carefully. We undertook a literature review to understand how the term has been employed and defined, finding that it is often contrasted to "dramatic ethics." We identified the core attributes most commonly associated with everyday ethics. We then propose an integrative model of everyday ethics that builds on the contribution of different ethical theories. This model proposes that the function of everyday ethics is to serve as an integrative concept that (1) helps to detect current blind spots in bioethics (that is, shifts the focus from dramatic ethics) and (2) mobilizes moral agents to address these shortcomings of ethical insight. This novel integrative model has theoretical, methodological, practical, and pedagogical implications, which we explore. Because of the pivotal role that moral experience plays in this integrative model, the model could help to bridge empirical ethics research with more conceptual and normative work. Copyright 2016 The Journal of Clinical Ethics. All rights reserved.

The history of MR imaging as seen through the pages of radiology.

PubMed

Edelman, Robert R

2014-11-01

The first reports in Radiology pertaining to magnetic resonance (MR) imaging were published in 1980, 7 years after Paul Lauterbur pioneered the first MR images and 9 years after the first human computed tomographic images were obtained. Historical advances in the research and clinical applications of MR imaging very much parallel the remarkable advances in MR imaging technology. These advances can be roughly classified into hardware (eg, magnets, gradients, radiofrequency [RF] coils, RF transmitter and receiver, MR imaging-compatible biopsy devices) and imaging techniques (eg, pulse sequences, parallel imaging, and so forth). Image quality has been dramatically improved with the introduction of high-field-strength superconducting magnets, digital RF systems, and phased-array coils. Hybrid systems, such as MR/positron emission tomography (PET), combine the superb anatomic and functional imaging capabilities of MR imaging with the unsurpassed capability of PET to demonstrate tissue metabolism. Supported by the improvements in hardware, advances in pulse sequence design and image reconstruction techniques have spurred dramatic improvements in imaging speed and the capability for studying tissue function. In this historical review, the history of MR imaging technology and developing research and clinical applications, as seen through the pages of Radiology, will be considered.

Time from HIV infection to virological suppression: dramatic fall from 2007 to 2016.

PubMed

Medland, Nicholas A; Nicholson, Suellen; Chow, Eric P F; Read, Timothy R H; Bradshaw, Catriona S; Denham, Ian; Fairley, Christopher K

2017-11-13

Time from HIV infection to virological suppression: dramatic fall from 2007 to 2016. We examined the time from HIV infection to virological suppression in MSM who were first diagnosed at Melbourne Sexual Health Centre between 2007 and 2016. Retrospective cohort. Date of infection was imputed from the testing history or serological evidence of recent infection (negative or indeterminate western blot) or baseline CD4 cell count. Date of virological suppression was determined using clinical viral load data. We analysed predictors of diagnosis with serological evidence of recent infection (logistic regression) and time from diagnosis to suppression and from infection to suppression (Cox regression) using demographic, clinical, and behavioral covariates. Between 2007 and 2016, the median time from HIV infection to diagnosis fell from 6.8 to 4.3 months (P = 0.001), from diagnosis to suppression fell from 22.7 to 3.2 months (P < 0.0001), and from infection to suppression fell from 49.0 to 9.6 months (P < 0.0001). Serological evidence of recent infection increased from 15.6 to 34.3% (P < 0.0001) of diagnoses. In the multivariate analyses, age, being recently arrived from a non-English speaking country, history of IDU, other sexually transmitted infections, and sexual risk were not associated with any of these measures. The duration of infectiousness in MSM diagnosed with HIV infection at Melbourne Sexual Health Centre in Victoria has fallen dramatically between 2007 and 2016 and the proportion diagnosed with serological evidence of recent infection has increased. This effect is observed across all population subgroups and marks a positive milestone for the treatment as prevention paradigm.

The generation and analyses of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic

PubMed Central

Gabitzsch, Elizabeth S.; Tsang, Kwong Yok; Palena, Claudia; David, Justin M.; Fantini, Massimo; Kwilas, Anna; Rice, Adrian E.; Latchman, Yvette; Hodge, James W.; Gulley, James L.; Madan, Ravi A.; Heery, Christopher R.; Balint, Joseph P.

2015-01-01

Phenotypic heterogeneity of human carcinoma lesions, including heterogeneity in expression of tumor-associated antigens (TAAs), is a well-established phenomenon. Carcinoembryonic antigen (CEA), MUC1, and brachyury are diverse TAAs, each of which is expressed on a wide range of human tumors. We have previously reported on a novel adenovirus serotype 5 (Ad5) vector gene delivery platform (Ad5 [E1-, E2b-]) in which regions of the early 1 (E1), early 2 (E2b), and early 3 (E3) genes have been deleted. The unique deletions in this platform result in a dramatic decrease in late gene expression, leading to a marked reduction in host immune response to the vector. Ad5 [E1-, E2b-]-CEA vaccine (ETBX-011) has been employed in clinical studies as an active vaccine to induce immune responses to CEA in metastatic colorectal cancer patients. We report here the development of novel recombinant Ad5 [E1-, E2b-]-brachyury and-MUC1 vaccine constructs, each capable of activating antigen-specific human T cells in vitro and inducing antigen-specific CD4+ and CD8+ T cells in vaccinated mice. We also describe the use of a combination of the three vaccines (designated Tri-Ad5) of Ad5 [E1-, E2b-]-CEA, Ad5 [E1-, E2b-]-brachyury and Ad5 [E1-, E2b-]-MUC1, and demonstrate that there is minimal to no “antigenic competition” in in vitro studies of human dendritic cells, or in murine vaccination studies. The studies reported herein support the rationale for the application of Tri-Ad5 as a therapeutic modality to induce immune responses to a diverse range of human TAAs for potential clinical studies. PMID:26374823

Mycolactone-mediated neurite degeneration and functional effects in cultured human and rat DRG neurons

PubMed Central

Sinisi, M; Fox, M; MacQuillan, A; Quick, T; Korchev, Y; Bountra, C; McCarthy, T; Anand, P

2016-01-01

Background Mycolactone is a polyketide toxin secreted by the mycobacterium Mycobacterium ulcerans, responsible for the extensive hypoalgesic skin lesions characteristic of patients with Buruli ulcer. A recent pre-clinical study proposed that mycolactone may produce analgesia via activation of the angiotensin II type 2 receptor (AT2R). In contrast, AT2R antagonist EMA401 has shown analgesic efficacy in animal models and clinical trials for neuropathic pain. We therefore investigated the morphological and functional effects of mycolactone in cultured human and rat dorsal root ganglia (DRG) neurons and the role of AT2R using EMA401. Primary sensory neurons were prepared from avulsed cervical human DRG and rat DRG; 24 h after plating, neurons were incubated for 24 to 96 h with synthetic mycolactone A/B, followed by immunostaining with antibodies to PGP9.5, Gap43, β tubulin, or Mitotracker dye staining. Acute functional effects were examined by measuring capsaicin responses with calcium imaging in DRG neuronal cultures treated with mycolactone. Results Morphological effects: Mycolactone-treated cultures showed dramatically reduced numbers of surviving neurons and non-neuronal cells, reduced Gap43 and β tubulin expression, degenerating neurites and reduced cell body diameter, compared with controls. Dose-related reduction of neurite length was observed in mycolactone-treated cultures. Mitochondria were distributed throughout the length of neurites and soma of control neurons, but clustered in the neurites and soma of mycolactone-treated neurons. Functional effects: Mycolactone-treated human and rat DRG neurons showed dose-related inhibition of capsaicin responses, which were reversed by calcineurin inhibitor cyclosporine and phosphodiesterase inhibitor 3-isobutyl-1-Methylxanthine, indicating involvement of cAMP/ATP reduction. The morphological and functional effects of mycolactone were not altered by Angiotensin II or AT2R antagonist EMA401. Conclusion Mycolactone induces toxic effects in DRG neurons, leading to impaired nociceptor function, neurite degeneration, and cell death, resembling the cutaneous hypoalgesia and nerve damage in individuals with M. Ulcerans infection. PMID:27325560

Selective elimination of breast cancer surgery in exceptional responders: historical perspective and current trials.

PubMed

van la Parra, Raquel F D; Kuerer, Henry M

2016-03-08

With improvements in chemotherapy regimens, targeted therapies, and our fundamental understanding of the relationship of tumor subtype and pathologic complete response (pCR), there has been dramatic improvement in pCR rates in the past decade, especially among triple-negative and human epidermal growth factor receptor 2-positive breast cancers. Rates of pCR in these groups of patients can be in the 60 % range and thus question the paradigm for the necessity of breast and nodal surgery in all cases, particularly when the patient will be receiving adjuvant local therapy with radiotherapy. Current practice for patients who respond well to neoadjuvant chemotherapy (NCT) is often to proceed with the same breast and axillary procedures as would have been offered women who had not received NCT, regardless of the apparent clinical response. Given these high response rates in defined subgroups among exceptional responders it is appropriate to question whether surgery is now a redundant procedure in their overall management. Further, definitive radiation without surgical resection with or without systemic therapy has been proven effective for several other malignant disease sites including some stages of esophageal, anal, laryngeal, prostate, cervical, and lung carcinoma. The main impediments for potential elimination of surgery have been the fact that prior and current standard and functional breast imaging methods are incapable of accurate prediction of residual disease and that integrating percutaneous biopsy of the breast primary and nodes following NCT may circumvent this issue. This article highlights historical attempts at omission of surgery following NCT in an earlier era, the current status of breast and nodal imaging to predict residual carcinoma, and ongoing and planned trials designed to identify appropriate patients who might be selected for clinical trials designed to test the safety of selected elimination of breast cancer surgery in percutaneous image-guided biopsy-proven exceptional responders to NCT.

Clinical implications of contemporary gender theory.

PubMed

Kulish, Nancy

2010-04-01

The current intellectual scene in psychoanalysis is marked by vigorous theoretical controversies about gender. The ideas being debated have important implications for clinical work, which have not been thoroughly explicated or integrated into common practice. These implications include the following: gender can accrue idiosyncratic meanings; gender identity is considered fluid and rigidity of gender identity deemed problematic; gender-related conflicts are typically described as divergent; analysis of superego conflicts related to gender becomes particularly important; and, finally, gender-related biases are seen as inevitable and must be taken into account in the clinical situation. A detailed clinical example illustrates the application of these ideas. While the more dramatic cases related to gender have been more frequent subjects of study, conflicts about gender are everyday occurrences for our patients and deserve further attention.

Surrogate endpoints in randomized cardiovascular clinical trials.

PubMed

Domanski, Michael; Pocock, Stuart; Bernaud, Corine; Borer, Jeffrey; Geller, Nancy; Revkin, James; Zannad, Faiez

2011-08-01

Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

The Invisible Army

PubMed Central

2017-01-01

ABSTRACT The “invisible army” of clinical microbiologists is facing major changes and challenges. The rate of change in both the science and technology is accelerating with no end in sight, putting pressure on our army to learn and adapt as never before. Health care funding in the United States is undergoing dramatic change which will require a new set of assumptions about how clinical microbiology is practiced here. A major challenge facing the discipline is the replacement of a generation of clinical microbiologists. In my opinion, it is incumbent on us in the invisible army to continue to work with the American Society for Microbiology (ASM) in meeting the future challenges faced by our discipline. In this commentary, I will first discuss some recent history of clinical microbiology within ASM and then some current challenges we face. PMID:28659316

[The Clinical Investigation Centers in France: Whatzat? What for? How does it work?].

PubMed

Montagne, O; Le Corvoisier, P

2008-01-01

For the last 15 years, French university-affiliated hospitals have dramatically modified how biomedical research is conducted in France. Multidisciplinary and technically complex research projects are increasingly difficult to conduct in clinical units. To ensure quality, good clinical practice, and security, platforms dedicated to clinical research with specific staff have been implanted. These units, called Clinical Investigation Centers (CICs), are open to academic and industrial investigators working in the medical fields involving patients and healthy volunteers. The CICs' activities are always closely related to the university hospital research programs and can also serve as a tool for locally implanted clinical and fundamental research teams (INSERM). Nowadays, clinical research requires specific tools and platforms. To enhance French university hospital research efficiency and provide a more open research environment, all investigators, on-site as well as from other institutions, are invited to use these cohesive research facilities and skills to conduct protocols that are fully adapted to their needs in optimal conditions of professional clinical research.

The Effect of Malnutrition on Norovirus Infection

PubMed Central

Hickman, Danielle; Jones, Melissa K.; Zhu, Shu; Kirkpatrick, Ericka; Ostrov, David A.; Wang, Xiaoyu; Ukhanova, Maria; Sun, Yijun; Mai, Volker; Salemi, Marco; Karst, Stephanie M.

2014-01-01

ABSTRACT Human noroviruses are the primary cause of severe childhood diarrhea in the United States, and they are of particular clinical importance in pediatric populations in the developing world. A major contributing factor to the general increased severity of infectious diseases in these regions is malnutrition—nutritional status shapes host immune responses and the composition of the host intestinal microbiota, both of which can influence the outcome of pathogenic infections. In terms of enteric norovirus infections, mucosal immunity and intestinal microbes are likely to contribute to the infection outcome in substantial ways. We probed these interactions using a murine model of malnutrition and murine norovirus infection. Our results reveal that malnutrition is associated with more severe norovirus infections as defined by weight loss, impaired control of norovirus infections, reduced antiviral antibody responses, loss of protective immunity, and enhanced viral evolution. Moreover, the microbiota is dramatically altered by malnutrition. Interestingly, murine norovirus infection also causes changes in the host microbial composition within the intestine but only in healthy mice. In fact, the infection-associated microbiota resembles the malnutrition-associated microbiota. Collectively, these findings represent an extensive characterization of a new malnutrition model of norovirus infection that will ultimately facilitate elucidation of the nutritionally regulated host parameters that predispose to more severe infections and impaired memory immune responses. In a broad sense, this model may provide insight into the reduced efficacy of oral vaccines in malnourished hosts and the potential for malnourished individuals to act as reservoirs of emergent virus strains. PMID:24595373

MYCN acts as a direct co-regulator of p53 in MYCN amplified neuroblastoma.

PubMed

Agarwal, Saurabh; Milazzo, Giorgio; Rajapakshe, Kimal; Bernardi, Ronald; Chen, Zaowen; Barberi, Eveline; Koster, Jan; Perini, Giovanni; Coarfa, Cristian; Shohet, Jason M

2018-04-17

The MYC oncogenes and p53 have opposing yet interrelated roles in normal development and tumorigenesis. How MYCN expression alters the biology and clinical responsiveness of pediatric neuroblastoma remains poorly defined. Neuroblastoma is p53 wild type at diagnosis and repression of p53 signaling is required for tumorigenesis. Here, we tested the hypothesis that MYCN amplification alters p53 transcriptional activity in neuroblastoma. Interestingly, we found that MYCN directly binds to the tetrameric form of p53 at its C-terminal domain, and this interaction is independent of MYCN/MAX heterodimer formation. Chromatin analysis of MYCN and p53 targets reveals dramatic changes in binding, as well as co-localization of the MYCN-p53 complex at p53-REs and E-boxes of genes critical to DNA damage responses and cell cycle progression. RNA sequencing studies show that MYCN-p53 co-localization significantly modulated the expression of p53 target genes. Furthermore, MYCN-p53 interaction leads to regulation of alternative p53 targets not regulated in the presence of low MYCN levels. These novel targets include a number of genes involved in lipid metabolism, DNA repair, and apoptosis. Taken together, our findings demonstrate a novel oncogenic role of MYCN as a transcriptional co-regulator of p53 in high-risk MYCN amplified neuroblastoma. Targeting this novel oncogenic function of MYCN may enhance p53-mediated responses and sensitize MYCN amplified tumors to chemotherapy.

Differential Activation of Human Keratinocytes by Leishmania Species Causing Localized or Disseminated Disease.

PubMed

Scorza, Breanna M; Wacker, Mark A; Messingham, Kelly; Kim, Peter; Klingelhutz, Aloysius; Fairley, Janet; Wilson, Mary E

2017-10-01

All Leishmania species parasites are introduced into mammalian skin through a sand fly bite, but different species cause distinct clinical outcomes. Mouse studies suggest that early responses are critical determinants of subsequent adaptive immunity in leishmaniasis, yet few studies address the role of keratinocytes, the most abundant cell in the epidermis. We hypothesized that Leishmania infection causes keratinocytes to produce immunomodulatory factors that influence the outcome of infection. Incubation of primary or immortalized human keratinocytes with Leishmania infantum or Leishmania major, which cause visceral or cutaneous leishmaniasis, respectively, elicited dramatically different responses. Keratinocytes incubated with L. infantum significantly increased expression of proinflammatory genes for IL-6, IL-8, tumor necrosis factor, and IL-1B, whereas keratinocytes exposed to several L. major isolates did not. Furthermore, keratinocyte-monocyte co-incubation studies across a 4 µM semipermeable membrane suggested that L. infantum-exposed keratinocytes release soluble factors that enhance monocyte control of intracellular L. infantum replication (P < 0.01). L. major-exposed keratinocytes had no comparable effect. These data suggest that L. infantum and L. major differentially activate keratinocytes to release factors that limit infection in monocytes. We propose that keratinocytes initiate or withhold a proinflammatory response at the site of infection, generating a microenvironment uniquely tailored to each Leishmania species that may affect the course of disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The importance of context in the evolution of health promotion.

PubMed

Sparks, Michael

2013-06-01

The world has changed dramatically since the Ottawa Charter was developed in 1986. Contemporary health promotion responses continue to evolve and become more sophisticated in response to the multiple challenges created by an ever-changing world. This commentary discusses some of the challenges facing health promotion professionals today and some of the responses that are being developed to address them. The importance of contextual considerations for both the worker and the work of health promotion are emphasised. The author then suggests ways that organisations and individuals can meet modern-day health promotion challenges through specific courses of action.

SIGIRR, a negative regulator of TLR/IL-1R signalling promotes Microbiota dependent resistance to colonization by enteric bacterial pathogens.

PubMed

Sham, Ho Pan; Yu, Emily Yi Shan; Gulen, Muhammet F; Bhinder, Ganive; Stahl, Martin; Chan, Justin M; Brewster, Lara; Morampudi, Vijay; Gibson, Deanna L; Hughes, Michael R; McNagny, Kelly M; Li, Xiaoxia; Vallance, Bruce A

2013-01-01

Enteric bacterial pathogens such as enterohemorrhagic E. coli (EHEC) and Salmonella Typhimurium target the intestinal epithelial cells (IEC) lining the mammalian gastrointestinal tract. Despite expressing innate Toll-like receptors (TLRs), IEC are innately hypo-responsive to most bacterial products. This is thought to prevent maladaptive inflammatory responses against commensal bacteria, but it also limits antimicrobial responses by IEC to invading bacterial pathogens, potentially increasing host susceptibility to infection. One reason for the innate hypo-responsiveness of IEC is their expression of Single Ig IL-1 Related Receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and TLR signaling. To address whether SIGIRR expression and the innate hypo-responsiveness of IEC impacts on enteric host defense, Sigirr deficient (-/-) mice were infected with the EHEC related pathogen Citrobacter rodentium. Sigirr -/- mice responded with accelerated IEC proliferation and strong pro-inflammatory and antimicrobial responses but surprisingly, Sigirr -/- mice proved dramatically more susceptible to infection than wildtype mice. Through haematopoietic transplantation studies, it was determined that SIGIRR expression by non-haematopoietic cells (putative IEC) regulated these responses. Moreover, the exaggerated responses were found to be primarily dependent on IL-1R signaling. Whilst exploring the basis for their susceptibility, Sigirr -/- mice were found to be unusually susceptible to intestinal Salmonella Typhimurium colonization, developing enterocolitis without the typical requirement for antibiotic based removal of competing commensal microbes. Strikingly, the exaggerated antimicrobial responses seen in Sigirr -/- mice were found to cause a rapid and dramatic loss of commensal microbes from the infected intestine. This depletion appears to reduce the ability of the microbiota to compete for space and nutrients (colonization resistance) with the invading pathogens, leaving the intestine highly susceptible to pathogen colonization. Thus, SIGIRR expression by IEC reflects a strategy that sacrifices maximal innate responsiveness by IEC in order to promote commensal microbe based colonization resistance against bacterial pathogens.

Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis.

PubMed

Ward, Jeanine; Kanchagar, Chitra; Veksler-Lublinsky, Isana; Lee, Rosalind C; McGill, Mitchell R; Jaeschke, Hartmut; Curry, Steven C; Ambros, Victor R

2014-08-19

We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.

CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE QUALITY OF DXA SCANS AND REPORTS.

PubMed

Licata, Angelo A; Binkley, Neil; Petak, Steven M; Camacho, Pauline M

2018-02-01

High-quality dual-energy X-ray absorptiometry (DXA) scans are necessary for accurate diagnosis of osteoporosis and monitoring of therapy; however, DXA scan reports may contain errors that cause confusion about diagnosis and treatment. This American Association of Clinical Endocrinologists/American College of Endocrinology consensus statement was generated to draw attention to many common technical problems affecting DXA report conclusions and provide guidance on how to address them to ensure that patients receive appropriate osteoporosis care. The DXA Writing Committee developed a consensus based on discussion and evaluation of available literature related to osteoporosis and osteodensitometry. Technical errors may include errors in scan acquisition and/or analysis, leading to incorrect diagnosis and reporting of change over time. Although the International Society for Clinical Densitometry advocates training for technologists and medical interpreters to help eliminate these problems, many lack skill in this technology. Suspicion that reports are wrong arises when clinical history is not compatible with scan interpretation (e.g., dramatic increase/decrease in a short period of time; declines in previously stable bone density after years of treatment), when different scanners are used, or when inconsistent anatomic sites are used for monitoring the response to therapy. Understanding the concept of least significant change will minimize erroneous conclusions about changes in bone density. Clinicians must develop the skills to differentiate technical problems, which confound reports, from real biological changes. We recommend that clinicians review actual scan images and data, instead of relying solely on the impression of the report, to pinpoint errors and accurately interpret DXA scan images. AACE = American Association of Clinical Endocrinologists; BMC = bone mineral content; BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; ISCD = International Society for Clinical Densitometry; LSC = least significant change; TBS = trabecular bone score; WHO = World Health Organization.

Estuarine response in northeastern Florida Bay to major hurricanes in 2005: Chapter 6I in Science and the storms-the USGS response to the hurricanes of 2005

USGS Publications Warehouse

Woods, Jeff; Zucker, Mark

2007-01-01

Hurricanes and tropical storms are critical components of the south Florida hydrologic cycle. These storms cause dramatic and often rapid changes in water level of, salinity of, and discharge into northeastern Florida Bay as well as into adjacent marine estuaries. During 2005, two major hurricanes (Katrina and Wilma) crossed the southern estuaries of the Everglades and had substantial impacts on hydrologic conditions.

Neurotechnology and Society: Strengthening Responsible Innovation in Brain Science.

PubMed

Garden, Hermann; Bowman, Diana M; Haesler, Sebastian; Winickoff, David E

2016-11-02

Technological advances have the potential to dramatically increase our understanding of the human brain, treat and cure injury and disease, and enhance our general well-being. While advances in neuroscience hold great promise, they also raise profound ethical, legal, and social questions. In this vein, the Organization for Economic Co-operation and Development (OECD) convened an international workshop in September 2016 to explore responsible research and innovation in brain science. Copyright © 2016 OECD. Published by Elsevier Inc. All rights reserved.

Daytime Unresponsiveness of the Human and Syrian Hamster Pineal to Adrenergic Stimulation

DTIC Science & Technology

1989-01-01

exposure) raises pineal melatonin content; injection outside this sensitive period does not. (CajP-" This dramatic change in response of the pineal gland ...1988, 264 (abstract976). Binkley, S. (1976): Comprative biochemistry of the pineal glands of birds and mammals. Am. Zool. 16, 57-65. Bowers, C.V., an...R.J. (1982): In vivo responses of the pineal gland of the Syrian hamster to isoproterenol or -or-epinephrine. In The Pineal and Its Hormones, pp 107

Response to eperisone in patients of therapy-resistant dissociative convulsions: A report of two cases.

PubMed

Jha, Vijendra Nath; Singh, Pramod Kumar

2017-01-01

Dissociative convulsions or pseudoseizures are a difficult to treat common psychiatric condition. In a subset of these patients, the chief complaint is clenching of teeth with apparent nonresponsiveness alone. Neither drugs nor psychotherapeutic interventions have been found to be of much help in its management. Report of two such subsets of cases is presented, in which patients with dissociative convulsions showed sudden, dramatic, and sustained good response to the addition of a muscle relaxant eperisone.

Dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor T790M mutation: A case report

PubMed Central

Uemura, Takehiro; Oguri, Tetsuya; Okayama, Minami; Furuta, Hiromi; Kanemitsu, Yoshihiro; Takakuwa, Osamu; Ohkubo, Hirotsugu; Takemura, Masaya; Maeno, Ken; Ito, Yutaka; Niimi, Akio

2017-01-01

We herein report a case of dramatic intracranial response to osimertinib in a poor performance status patient with lung adenocarcinoma harboring the epidermal growth factor receptor (EGFR) T790M mutation encoded in exon 20. The patient was a 59-year-old woman with EGFR exon 19 deletion-positive lung adenocarcinoma, who relapsed with multiple brain metastases. Computed tomography-guided biopsy of the left pleural tumor revealed adenocarcinoma harboring an EGFR exon 19 deletion and an EGFR T790M mutation encoded in exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor. Two days after treatment initiation, the patient displayed profound disturbance of consciousness, possibly due to carcinomatous meningitis, and treatment had to be discontinued due to difficulty in taking osimertinib. However, the patient gradually started to recover consciousness and, after 3 days, she was again able to take osimertinib. One month after the initiation of osimertinib treatment, magnetic resonance imaging revealed an apparent reduction in brain metastases. The patient is currently under continued treatment with osimertinib. At the last follow-up (February, 2017) she exhibited partial response to the treatment. PMID:28413660

In Vivo Rodent Models of Skeletal Muscle Adaptation to Decreased Use.

PubMed

Cho, Su Han; Kim, Jang Hoe; Song, Wook

2016-03-01

Skeletal muscle possesses plasticity and adaptability to external and internal physiological changes. Due to these characteristics, skeletal muscle shows dramatic changes depending on its response to stimuli such as physical activity, nutritional changes, disease status, and environmental changes. Modulation of the rate of protein synthesis/degradation plays an important role in atrophic responses. The purpose of this review is to describe different features of skeletal muscle adaptation with various models of deceased use. In this review, four models were addressed: immobilization, spinal cord transection, hindlimb unloading, and aging. Immobilization is a form of decreased use in which skeletal muscle shows electrical activity, tension development, and motion. These results differ by muscle group. Spinal cord transection was selected to simulate spinal cord injury. Similar to the immobilization model, dramatic atrophy occurs in addition to fiber type conversion in this model. Despite the fact that electromyography shows unremarkable changes in muscle after hindlimb unloading, decreased muscle mass and contractile force are observed. Lastly, aging significantly decreases the numbers of muscle fibers and motor units. Skeletal muscle responses to decreased use include decreased strength, decreased fiber numbers, and fiber type transformation. These four models demonstrated different changes in the skeletal muscle. This review elucidates the different skeletal muscle adaptations in these four decreased use animal models and encourages further studies.

Necrotizing Fasciitis in Aesthetic Surgery: A Review of the Literature.

PubMed

Marchesi, Andrea; Marcelli, Stefano; Parodi, Pier C; Perrotta, Rosario E; Riccio, Michele; Vaienti, Luca

2017-04-01

Necrotizing fasciitis (NF) is a rare, potentially fatal, infective complication that can occur after surgery. Diagnosis is still difficult and mainly based on clinical data. Only a prompt pharmacological and surgical therapy can avoid dramatic consequences. There are few reports regarding NF as a complication after aesthetic surgical procedures, and a systematic review still lacks. We have performed a systematic review of English literature on PubMed, covering a period of 30 years. Keywords used were "necrotising fasciitis" matched with "aesthetic surgery complications", "breast surgery", "mammoplasty", "blepharoplasty", "liposuction", "facelift", "rhinoplasty fasciitis", "arm lift", "thigh lift", "otoplasty" and "abdominoplasty fasciitis". No additional search and temporal limitation were set. Among 3782 papers concerning NF, only 18 were related to NF after an aesthetic surgical procedure. Liposuction was the most affected procedure, with buttocks and lower extremity the most involved anatomical regions. The majority of the infections were monomicrobial, promoted by Streptococcus pyogenes. In most cases, NF occurred within the third post-operative day with non-specific signs and symptoms. In 14 cases, a single or multiple surgical interventions were performed and survival was achieved in 11 patients. In case of infection after aesthetic surgery, we should always bear in mind NF. Clinical hallmarks still guide NF management. Because early signs and symptoms are usually non-specific, a strict clinical control is highly suggested. Once clinical suspicion is raised, prompt antibacterial therapy should be administered, followed by surgical debridement in case of ineffective response. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Targeting epidermal growth factor receptor in the treatment of non-small-cell lung cancer.

PubMed

Kotsakis, Athanasios; Georgoulias, Vassilis

2010-10-01

The management of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade, with the survival advantage demonstrated by the incorporation of anti-epidermal growth factor receptor (EGFR) agents to the standard treatment of advanced/metastatic NSCLC. We review the existing data regarding the distinct anti-EGFR agents in the NSCLC treatment and the potential role of the investigated biomarkers in the clinical outcome. Tyrosine kinase inhibitors have been used in first-line, second-line and more settings with extremely good results in a subgroup of patients. Cetuximab remains the only anti-EGFR monoclonal antibody to show survival benefit when combined with a cytotoxic agent in the front-line setting. Anti-EGFR treatment is associated with a dramatic clinical benefit in a subgroup of patients, emphasizing the importance of customizing treatment. Several biomarkers have been investigated for their predictive or prognostic value. Validation of identification of biomarkers remains a focus of intense research that may ultimately guide therapeutic decision making, as none of these is considered ideal to discriminate responding from non-responding patients. However, the current evidence of the EGFR mutation analysis from a recent randomised trial suggests that EGFR mutation analysis is quite a good predictive marker for responsiveness to anti-EGFR TKIs. Moreover, the identification of surrogate markers to indicate optimal activity of the anti-EGFR agent is also needed. This review article provides data from large clinical trials using anti-EGFR agents and correlates these results with the tested biomarkers. EGFR inhibition has shown very encouraging results and has improved the outcome of the NSCLC treatment. However, a plateau of significant clinical benefit seems to have been reached and we believe that the time to move away from the traditional treatment approach to more individualizing therapies has come.

Preclinical Evaluation of Sequential Combination of Oncolytic Adenovirus Delta-24-RGD and Phosphatidylserine-Targeting Antibody in Pancreatic Ductal Adenocarcinoma.

PubMed

Dai, Bingbing; Roife, David; Kang, Ya'an; Gumin, Joy; Rios Perez, Mayrim V; Li, Xinqun; Pratt, Michael; Brekken, Rolf A; Fueyo-Margareto, Juan; Lang, Frederick F; Fleming, Jason B

2017-04-01

Delta-24-RGD (DNX-2401) is a conditional replication-competent oncolytic virus engineered to preferentially replicate in and lyse tumor cells with abnormality of p16/RB/E2F pathway. In a phase I clinical trial, Delta-24-RGD has shown favorable safety profile and promising clinical efficacy in brain tumor, which prompted us to evaluate its anticancer activity in pancreatic ductal adenocarcinoma (PDAC), which also has high frequency of homozygous deletion and promoter methylation of CDKN2A encoding the p16 protein. Our results demonstrate that Delta-24-RGD can induce dramatic cytotoxicity in a subset of PDAC cell lines with high cyclin D1 expression. Induction of autophagy and apoptosis by Delta-24-RGD in sensitive PDAC cells was confirmed with LC3B-GFP autophagy reporter and acridine orange staining as well as Western blotting analysis of LC3B-II expression. Notably, we found that Delta-24-RGD induced phosphatidylserine exposure in infected cells independent of cells' sensitivity to Delta-24-RGD, which renders a rationale for combination of Delta-24-RGD viral therapy and phosphatidylserine targeting antibody for PDAC. In a mouse PDAC model derived from a liver metastatic pancreatic cancer cell line, Delta-24-RGD significantly inhibited tumor growth compared with control ( P < 0.001), and combination of phosphatidylserine targeting antibody 1N11 further enhanced its anticancer activity ( P < 0.01) possibly through inducing synergistic anticancer immune responses. Given that these 2 agents are currently in clinical evaluation, our study warrants further clinical evaluation of this novel combination strategy in pancreatic cancer therapy. Mol Cancer Ther; 16(4); 662-70. ©2016 AACR . ©2017 American Association for Cancer Research.

Sustained improvements in plasma ACTH and clinical status in a patient with Nelson's syndrome treated with pasireotide LAR, a multireceptor somatostatin analog.

PubMed

Katznelson, Laurence

2013-05-01

Nelson's syndrome refers to aggressive pituitary corticotroph adenoma growth after bilateral adrenalectomy for treatment of Cushing's disease (CD). Pasireotide, a novel somatostatin analog, has been effective in treating CD. Here, the first case report of a patient with Nelson's syndrome treated with pasireotide is presented. A 55-year-old female was diagnosed with CD in 1973 at age 15 years and underwent bilateral adrenalectomy 1 year later. She subsequently developed Nelson's syndrome and underwent multiple surgeries and radiotherapy for adenoma growth. After presentation with ocular pain, third cranial nerve palsy, and a finding of suprasellar tumor enlargement with hemorrhage, she began pasireotide long-acting release 60 mg/28 days im. At baseline, fasting plasma ACTH was 42 710 pg/mL (normal, 5-27 pg/mL), and fasting plasma glucose was 98 mg/dL. After 1 month, ACTH declined to 4272 pg/mL, and it has remained stable over 19 months of follow-up. Hyperpigmentation progressively improved. Magnetic resonance imaging scans show reduction in the suprasellar component. Fasting plasma glucose increased to 124 mg/dL, and the patient underwent diabetes management. In this clinical case seminar, the current understanding of the treatment of Nelson's syndrome and the use of pasireotide in CD are summarized. A case of Nelson's syndrome with clinically significant and dramatic biochemical and clinical responses to pasireotide administration is reported. Hyperglycemia was noted after pasireotide administration. Pasireotide may represent a useful tool in the medical management of Nelson's syndrome. Further study of the potential benefits and risks of pasireotide in this population is necessary.

Hemodynamic and permeability characteristics of acute experimental necrotizing enterocolitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, M.J.; Adams, J.; Gu, X.A.

1990-10-01

We examined the local hemodynamic response of intestinal loops during acute necrotizing enterocolitis (NEC) in anesthetized rabbits. NEC was induced in ileal loops by transmural injection of a solution containing casein (10 mg/ml) and calcium gluconate (50 mg/ml) acidified to pH 4.0 with propionic or acetic acid. Control loops received casein only (pH 5.0). Mucosal damage was quantified by the blood-to-lumen movement of (51Cr)EDTA, fluid shifts into the lumen, and histology. Mean arterial pressure and loop blood flow were steady over the 3-hr period, loop fluid volume decreased, and there was no evidence of necrosis or epithelial damage. In loopsmore » receiving acidified casein and calcium gluconate, there was an immediate dramatic increase in loop blood flow that returned to baseline by 50 min. In addition, loop fluid volume was dramatically increased, necrosis was noted in the form of blunting and loss of villi, and sevenfold increase in (51Cr)EDTA permeability was evident. Administration of CV 1808 (30 mg/kg/hr), a selective adenosine2 agonist, which maintained and elevated loop blood flow throughout the 3 hr protocol, failed to alter the changes in loop fluid volume or prevent necrosis. Histamine levels in loop fluid levels were significantly elevated 20-30 min after NEC induction when compared to saline controls, indicating an early activation of mucosal defenses with this luminal insult. Thus, this model of NEC is characterized by a transient, acute hyperemia, increased intestinal permeability, and histamine release. As mucosal damage was independent of ischemia and could not be prevented by vasodilatory therapy, this model supports the clinical findings that NEC is correlated with luminal factors related to feeding and independent of cardiovascular stress.« less

Temporal trends in the use of drug-eluting stents for approved and off-label indications: a longitudinal analysis of a large multicenter percutaneous coronary intervention registry.

PubMed

Gualano, Sarah K; Gurm, Hitinder S; Share, David; Smith, Dean; Aronow, Herbert D; LaLonde, Thomas; Bates, Eric R; Changezi, Hameem; McNamara, Richard; Moscucci, Mauro

2010-02-01

We sought to examine the temporal variations in the rate of both bare-metal stent (BMS) and drug-eluting stent (DES) use for off-label indications after the reports of an increased risk of very late stent thrombosis in patients with DES at the 2006 meeting of the European Society of Cardiology (ESC). To determine whether the decrease in use of DES has affected both on and off-label indications. The study cohort included patients undergoing coronary intervention in a large regional registry, the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2). Patient demographic and clinical characteristics for patients with DES in the third quarter of 2006 (pre-ESC) were compared to those from the fourth quarter of 2008 (post-guideline changes). Use of DES for off-label indications, such as ST-segment elevation myocardial infarction (STEMI), in-stent restenosis (ISR), and saphenous vein graft (SVG) interventions, were evaluated. The overall deployment of DES fell sharply from 83% pre-ESC to a plateau of 58% in the first quarter of 2008. This corresponded to a rise in BMS use, while angioplasty procedures stayed the same. The STEMI subgroup showed the most dramatic change, from 78% to only 36%. Off-label use in SVGs showed a similar trend, from 74% to 43%. Drug-eluting stent deployment for ISR was less affected, though it also fell 25% (from 79%-56%). The use of DES has fallen dramatically from June 2006 to December 2008, particularly for nonapproved indications. Our study provides a real-world assessment of contemporary change in DES use in response to the presentation of negative observational studies. Copyright 2010 Wiley Periodicals, Inc.

Family Matters: An Approach to the Theatre and to Theatre Research.

ERIC Educational Resources Information Center

Addington, David W.

The relational concepts developed in mathematics and psychology are used in this paper to explicate the needs and responsibilities of dramatic acting and theatre research. A parallel is constructed between the emergence of the mathematical concept of function, the awakening of psychology to the concept of relationship (especially regarding family…

The Ketogenic Diet Improves Recently Worsened Focal Epilepsy

ERIC Educational Resources Information Center

Villeneuve, Nathalie; Pinton, Florence; Bahi-Buisson, Nadia; Dulac, Olivier; Chiron, Catherine; Nabbout, Rima

2009-01-01

Aim: We observed a dramatic response to the ketogenic diet in several patients with highly refractory epilepsy whose seizure frequency had recently worsened. This study aimed to identify whether this characteristic was a useful indication for the ketogenic diet. Method: From the 70 patients who received the ketogenic diet during a 3-year period at…

Tag-based Heart Rate Measurements of Harbor Porpoises During Normal and Noise-exposed Dives to Study Stress Responses

DTIC Science & Technology

2014-09-30

mammals face potentially dramatic changes in the environment, as well as continued disturbances of their ocean habitat from shipping, sonar, fisheries... Cheetahs of the deep sea: deep foraging sprints in short-finned pilot whales off Tenerife (Canary Islands). Journal of Animal Ecology 77:936-947.

Guardian Caps: What's the Impact?

ERIC Educational Resources Information Center

Jenny, Seth E.; Rouse, Wardell; Seibles, Ashlie

2017-01-01

Reported sport-related concussion rates have dramatically increased recently. In response, the Guardian company has emerged as a leading manufacturer of soft-shell helmet covers. The "Guardian Cap" is a foam padded covering that fits over a helmet that aims to reduce the impact of collisions and lessen the chance of a concussion. The…

Learning Sustainability by Developing a Solar Dryer for Microalgae Retrieval

ERIC Educational Resources Information Center

Malheiro, Benedita; Ribeiro, Cristina; Silva, Manuel F.; Caetano, Nídia; Paulo Ferreira,; Guedes, Pedro

2015-01-01

The development of nations depends on energy consumption, which is generally based on fossil fuels. This dependency produces irreversible and dramatic effects on the environment, e.g. large greenhouse gas emissions, which in turn cause global warming and climate changes, responsible for the rise of the sea level, floods, and other extreme weather…

Crisis at a Bronx Junior High: Responding to School-Related Violence.

ERIC Educational Resources Information Center

Seltzer, Joel A.

Responding to dramatically increased levels of urban violence, inner-city school districts have recognized the need to address the psychological impact of violent events by organizing Crisis Response Teams. In New York's south Bronx neighborhoods, where violence appears endemic, the schools often serve children's basic needs by providing a safe…

Teaching Bad Apples: A Fun Way to Tackle Difficult Teaching Situations

ERIC Educational Resources Information Center

Turcotte, Nathaniel; Betrus, Anthony

2016-01-01

"Teaching Bad Apples" is a game developed in 2014 for current and future teachers. It plays much like "Apples to Apples" or "Cards Against Humanity," with each player in turn reading a situation card, followed by the other players choosing their response cards. Each situation, however dramatic or bizarre, is…

A Case Study in Organizational Change: Evaluation in Cooperative Extension

ERIC Educational Resources Information Center

Rennekamp, Roger A.; Engle, Molly

2008-01-01

This chapter examines how factors both internal and external to Cooperative Extension have influenced its commitment and capability to assess the quality and impact of its programs. The authors begin by documenting how the nature of Extension programming has changed dramatically in response to societal needs over the course of the organization's…

A view of Antarctic ice-sheet evolution from sea-level and deep-sea Isotope Changes During the Late Cretaceous-Cenozoic

USGS Publications Warehouse

Miller, K.G.; Wright, J.D.; Katz, M.E.; Browning, J.V.; Cramer, B.S.; Wade, B.S.; Mizintseva, S.F.

2007-01-01

18O increase. This large ice sheet became a driver of climate change, not just a response to it, causing increased latitudinal thermal gradients and a spinning up of the oceans that, in turn, caused a dramatic reorganization of ocean circulation and chemistry.

College Environment, Student Involvement, and Intellectual Development: Evidence in China

ERIC Educational Resources Information Center

Chi, Xianglan; Liu, Jinlan; Bai, Yin

2017-01-01

China's higher education system has been marked by dramatic growth since 1999. In response to calls for quality assurance, substantial efforts have been made to improve collegiate environments and enhance student learning. However, only limited empirical research has been conducted to investigate the effects of the college environment on student…

Principals' Perceptions of the Influence of Central Office

ERIC Educational Resources Information Center

Russell, Barbara A.

2013-01-01

In response to the No Child Left Behind legislation (NCLB, 2001), there has been a dramatic shift in schools toward improving student outcomes in the areas of reading and math. NCLB mandates that states establish specified levels of achievement for all students in these content areas and holds them accountable yearly via state assessments…

Recolonization by warmwater fishes and crayfishes after severe drought in upper coastal plain hill streams

Treesearch

Susan B. Adams; Melvin L. Warren

2005-01-01

Extreme hydrologic disturbance, such as a supraseasonal drought, can dramatically influence aquatic communities. Documentation of the responses of aquatic communities after such disturbances provides insight into the timing, order, and mechanisms of recolonization. Postdisturbance recolonization of streams depends on many factors, including the region and...

Apology and Redress: Escaping the Dustbin of History in the Postsegregationist South

ERIC Educational Resources Information Center

Fine, Gary Alan

2013-01-01

How at moments of dramatic change and a shifting social context do political actors alter their public identities? Put differently, how do political figures respond when positions with which they have been closely identified are no longer morally and electorally defensible and must be altered? Responses to identity challenge within institutional…

A Journey with Chronic Pain: Self-Directed Learning as Survival

ERIC Educational Resources Information Center

King, Kathleen P.

2014-01-01

Over the past 20 years in the USA, increased insurance control of healthcare decisions, litigation and regulations, have contributed to a dramatic shift in the doctor-patient relationship and respective responsibilities. This paper presents an autoethnographic study of the self-directed learning (SDL) strategies and patterns used by an individual…

Children's Theatre Review, Volume XXX, Number 2, Spring 1981. Research Edition.

ERIC Educational Resources Information Center

Ritch, Pamela, Ed.

1981-01-01

This special journal edition contains research reports on children and the theatre. The seven articles discuss the following subjects: (1) how audiences function in participation plays for young people, (2) creative dramatics and handicapped children, (3) the effect of advance organizers on children's responses to theatre viewing, (4) a Piagetian…

Etiological and therapeutical observations in a case of belly dancer's dyskinesia.

PubMed

Linazasoro, Girutz; Van Blercom, Nadège; Lasa, Asier; Fernández, José Manuel; Aranzábal, Inés

2005-02-01

We report on the case of a woman with belly dancer's syndrome. This case presented two peculiarities: (1) the condition was induced by the chronic use of clebopride, and (2) abdominal dyskinesias showed a dramatic response to the application of transcutaneous electrical nerve stimulation. Copyright 2004 Movement Disorder Society.

Climate change induced invasions by native and exotic pests

Treesearch

Jesse A. Logan

2007-01-01

The importance of effective risk assessment for introduction and establishment of exotic pest species has dramatically increased with an expanded global economy and the accompanying increase in international trade. Concurrently, recent climate warming has resulted in potential invasion of new habitats by native pest species. The time frame of response to changing...

John Collier's Crusade for Indian Reform: 1920-1954.

ERIC Educational Resources Information Center

Philp, Kenneth R.

For many years federal government policy sought to break up Indian communal land holdings, destroy tribal communities, and absorb Indians into the mainstream of American Society. This policy changed dramatically in the 1920's and 30's, and John Collier stands at the forefront of those responsible. Collier questioned the wisdom of a policy which…

Dollars and Sense: Budgeting for Today's Campus.

ERIC Educational Resources Information Center

Budig, Gene A., Ed.

Budgeting is examined in view of the increasingly complex relationship between colleges and universities and state governments. It is noted that there needs to be dramatic revisions to improve the responsiveness of state government to the needs of society, and institutions of higher learning have a stake in the outcome of this so-called…

The Big, Bad Wolf Goes Trick-or-Treating.

ERIC Educational Resources Information Center

Joy, Flora; And Others

1994-01-01

This adaptation of the "Three Little Pigs" story is suitable for performance in elementary grades, especially around Halloween. The story comes with step-by-step directions for how to dramatize the action for maximum audience participation and response and with suggestions for optional learning activities that can be used with the story.…

The Impact of the Sarbanes-Oxley Act of 2002 on the Business and Accounting Curriculums

ERIC Educational Resources Information Center

Reed, Ronald O.; Bullock, Charles; Johnson, Gene; Iyer, Vish

2007-01-01

Business and accounting curriculums are designed to educate and train future business professionals and leaders. When Congress passed SOX in 2002, it dramatically impacted the responsibilities of corporate executives and CPAs and consequently required corresponding changes in the business schools prepare students to assume these roles. Because the…

Marketing Adult Literacy Programs: Meeting the Challenges in the Twenty-First Century. Research to Practice.

ERIC Educational Resources Information Center

Michael, Steve Olu; Hogard, Elaine

In the current environment of increasing competition for shrinking resources and the dramatic changes in educational service delivery in response to recent technological advances, marketing is becoming increasingly important to the success of adult literacy programs. Individual attitudes toward marketing in the educational sector differ greatly…

The Use of Latex Gloves in the School Setting

ERIC Educational Resources Information Center

Purcell, Cathy Koeppen

2006-01-01

In 1987, when the U.S. Centers for Disease Control and Prevention recommended the use of universal precautions in response to the HIV/AIDS epidemic, the demand for medical gloves dramatically increased. Unfortunately, the manufacturing techniques for the most widely-used gloves--natural rubber latex--also changed, in order to expedite production.…

Educational Films: Writing, Directing, and Producing for Classroom, Television, and Industry.

ERIC Educational Resources Information Center

Herman, Lewis

Intended for beginning and nonprofessional film makers interested in making the educational film, this book explains the technical aspects of film making, the roles of the specialists responsible for it, the types of film treatments (expository, narrative, and dramatic), and the various types of educational films. Some of the technical aspects…

Between a Rock and a Hard Place: Organizational Change and Performance under Conditions of Fundamental Environmental Transformation.

ERIC Educational Resources Information Center

Haveman, Heather A.

1992-01-01

Organizational change may benefit performance and survival chances if it occurs in response to dramatic restructuring of environmental conditions and builds on established routines and competencies. These propositions are tested on the savings and loan industry in California, which has experienced technological, economic, and regulatory shifts…

Strategies Leaders Can Use to Improve Rigor in Their Schools

ERIC Educational Resources Information Center

Williamson, Ronald; Blackburn, Barbara R.

2009-01-01

Concern about rigor is not new. Since the release of "A Nation At Risk" (National Commission on Excellence in Education, 1983) the debate about the quality of America's schools has grown exponentially. This debate calls for dramatically different schools, schools that are much more responsive to student need, and provide a rigorous…

USGS Arctic Science Strategy

USGS Publications Warehouse

Shasby, Mark; Smith, Durelle

2015-07-17

The United States is one of eight Arctic nations responsible for the stewardship of a polar region undergoing dramatic environmental, social, and economic changes. Although warming and cooling cycles have occurred over millennia in the Arctic region, the current warming trend is unlike anything recorded previously and is affecting the region faster than any other place on Earth, bringing dramatic reductions in sea ice extent, altered weather, and thawing permafrost. Implications of these changes include rapid coastal erosion threatening villages and critical infrastructure, potentially significant effects on subsistence activities and cultural resources, changes to wildlife habitat, increased greenhouse-gas emissions from thawing permafrost, threat of invasive species, and opening of the Arctic Ocean to oil and gas exploration and increased shipping. The Arctic science portfolio of the U.S. Geological Survey (USGS) and its response to climate-related changes focuses on landscapescale ecosystem and natural resource issues and provides scientific underpinning for understanding the physical processes that shape the Arctic. The science conducted by the USGS informs the Nation's resource management policies and improves the stewardship of the Arctic Region.

Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages.

PubMed

Lichtenstein, Laeticia; Mattijssen, Frits; de Wit, Nicole J; Georgiadi, Anastasia; Hooiveld, Guido J; van der Meer, Roelof; He, Yin; Qi, Ling; Köster, Anja; Tamsma, Jouke T; Tan, Nguan Soon; Müller, Michael; Kersten, Sander

2010-12-01

Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we study the role of the lipoprotein lipase inhibitor Angptl4 in the response to dietary saturated fat. Strikingly, in mice lacking Angptl4, saturated fat induces a severe and lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid-laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced foam cell formation, inflammatory gene expression, and chyle-induced activation of ER stress. Induction of macrophage Angptl4 by fatty acids is part of a mechanism that serves to reduce postprandial lipid uptake from chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled saturated fat-induced inflammation. Copyright © 2010 Elsevier Inc. All rights reserved.

Genetic testing in nephrotic syndrome--challenges and opportunities.

PubMed

Gbadegesin, Rasheed A; Winn, Michelle P; Smoyer, William E

2013-03-01

Monogenic nephrotic syndrome (nephrotic syndrome caused by a single gene defect) is responsible for only a small percentage of cases of nephrotic syndrome, but information from studies of the unique cohort of patients with this form of the disease has dramatically improved our understanding of the disease pathogenesis. The use of genetic testing in the management of children and adults with nephrotic syndrome poses unique challenges for clinicians in terms of who to test and how to use the information obtained from testing in the clinical setting. In our view, not enough data exist at present to justify the routine genetic testing of all patients with nephrotic syndrome. Testing is warranted, however, in patients with congenital nephrotic syndrome (onset at 0-3 months), infantile nephrotic syndrome (onset at 3-12 months), a family history of nephrotic syndrome, and those in whom nephrotic syndrome is associated with other congenital malformations. The family and/or the patient should be given complete and unbiased information on the potential benefits and risks associated with therapy, including the reported outcomes of treatment in patients with similar mutations. Based on the data available in the literature so far, intensive immunosuppressive treatment is probably not indicated in monogenic nephrotic syndrome if complete or partial remission has not been achieved within 6 weeks of starting treatment. We advocate that family members of individuals with genetic forms of nephrotic syndrome undergo routine genetic testing prior to living-related kidney transplantation. Prospective, multicentre studies are needed to more completely determine the burden of disease caused by monogenic nephrotic syndrome, and randomized controlled trials are needed to clarify the presence or absence of clinical responses of monogenic nephrotic syndrome to available therapies.

Care of HIV-Infected Pregnant Women in Maternal–Fetal Medicine Programs

PubMed Central

Bathgate, Susanne L.; Young, Heather A.; Parenti, David M.

2001-01-01

Objective: To survey the evolution over the past decade of attitudes and practices of obstetricians in maternal–fetal medicine fellowship programs regarding the management of human immunodeficiency virus (HIV)-infected pregnant women. Methods: Directors of all 65 approved maternal–fetal medicine training programs were sent questionnaires, responses to which were to reflect the consensus among members of their faculties. Programs were stratified based upon the number of HIV-infected pregnant patients cared for in the previous year. Results: Responses reflect experience with over 1000 infected pregnantwomen per year, nearly one-quarter with advanced disease. Combination antiretroviral therapy was prescribed by all respondents, universally in the 2nd and 3rd trimesters. A three-drug regimen (often containing a protease inhibitor) was used more often by those who treated at least 20 HIV-infected pregnant patients per year than by those programs seeing a lower number of patients (80 vs 59%).Despite the known and unknown risks of the use of antiretrovirals during pregnancy, only half of all responding programs report adverse events to the Antiretroviral Pregnancy Registry; reporting was more common among the institutions seeing a higher number of patients (61 vs 45%). Seventy-eight percent of higher volume programs enroll their patients in clinical studies, usually multicenter, versus 35% of lower volume programs. Conclusions: Care for HIV² pregnant women has dramatically changed over the past decade. Antiretroviral therapy is now universally prescribed by physicians involved in maternal–fetal medicine training programs. Given limited experience with these agents in the setting of pregnancy, it is essential for maternal–fetal medicine practitioners to actively report on adverse events and participate in clinical trials. PMID:11495558

Nonsteroidal Anti-Inflammatory Drugs Quickly Resolve Symptoms Associated with EBV-Induced Infectious Mononucleosis in Patients with Atopic Predispositions

PubMed Central

Kazama, Itsuro; Miura, Chieko; Nakajima, Toshiyuki

2016-01-01

Case series Patient: Female, 24 • Male, 35 Final Diagnosis: EBV-induced infectious mononucleosis Symptoms: Fever • general malaise • lymphadenopathy Medication: — Clinical Procedure: Physical examination and serological testing Specialty: Infectious diseases Objective: Rare co-existance of disease or pathology Background: Infectious mononucleosis is a clinical syndrome most commonly associated with primary Epstein-Barr virus (EBV) infection. In adults, the symptoms can often be severe and prolonged, sometimes causing serious complications. Analgesic or antipyretic drugs are normally used to relieve the symptoms. However, there is no causal treatment for the disease. Case Report: Two cases of adult patients with atopic predispositions developed nocturnal fever, general fatigue, pharyngitis and lymphadenopathy after an exacerbation of atopic symptoms or those of allergic rhinitis. Due to the positive results for EBV viral-capsid antigen (VCA) IgM and negative results for EBV nuclear antigen (EBNA) IgG, diagnoses of infectious mononucleosis induced by EBV were made in both cases. Although oral antibiotics or acetaminophen alone did not improve the deteriorating symptoms, including fever, headache and general fatigue, nonsteroidal anti-inflammatory drugs (NSAIDs), such as tiaramide or loxoprofen, completely improved the symptoms quickly after the initiation. Conclusions: In these cases, given the atopic predispositions of the patients, an enhanced immunological response was likely to be mainly responsible for the pathogenesis of the symptoms. In such cases, NSAIDs, that are known to reduce the activity of EBV, may dramatically improve the deteriorating symptoms quickly after the initiation. In the present cases, the immunosuppressive property of these drugs was considered to suppress the activity of lymphocytes and thus provide the rapid and persistent remission of the disease. PMID:26874639

Efficacy of infliximab on MRI-determined bone oedema in psoriatic arthritis.

PubMed

Marzo-Ortega, Helena; McGonagle, Dennis; Rhodes, Laura A; Tan, Ai Lyn; Conaghan, Philip G; O'Connor, Philip; Tanner, Steven F; Fraser, Alexander; Veale, Douglas; Emery, Paul

2007-06-01

Psoriatic arthritis (PsA) is commonly associated with bone pathology, including entheseal new bone formation and osteolysis. On MRI, areas of active clinical involvement are represented by bone oedema and synovitis. To assess the impact of infliximab on bone oedema in PsA as shown by MRI. 18 patients with joint swelling, psoriasis and seronegativity for rheumatoid factor received four infusions of infliximab, 3 mg/kg, in combination with methotrexate. MRI of the affected hand (12 patients) or knee joints (6 patients) was performed before and after treatment. The primary outcome was the assessment of bone oedema and synovitis at 20 weeks as shown by MRI. Secondary outcomes included the American College of Rheumatology (ACR) response criteria, psoriasis skin scores (Psoriasis Area and Severity Index (PASI)) and a quality of life measure (Psoriatic Arthritis Quality of Life (PsAQoL)). At baseline, bone oedema was seen in 50% of patients (seven hands and two knees) in 30% of scanned joints, and this improved or resolved in all cases in the hand joints (p = 0.018) and in one knee joint at 20 weeks. Synovitis was found to be reduced in 90% of cases on MRI. Likewise, a significant improvement in all clinical outcomes, including PASI (p = 0.003) and PsAQoL (p = 0.006) was seen at week 20. 65% (n = 11) of the patients achieved an ACR response, of whom 45% had ACR70 or above and 54% had ACR20 or ACR50. Infliximab treatment is associated with dramatic improvements in MRI-determined bone oedema in PsA in the short term. It remains to be determined whether infliiximib treatment is the cause for prevention of new bone formation, bone fusion or osteolysis in PsA as shown by radiography.

Uncoupling primer and releaser responses to pheromone in honey bees

NASA Astrophysics Data System (ADS)

Grozinger, Christina M.; Fischer, Patrick; Hampton, Jacob E.

2007-05-01

Pheromones produce dramatic behavioral and physiological responses in a wide variety of species. Releaser pheromones elicit rapid responses within seconds or minutes, while primer pheromones produce long-term changes which may take days to manifest. Honeybee queen mandibular pheromone (QMP) elicits multiple distinct behavioral and physiological responses in worker bees, as both a releaser and primer, and thus produces responses on vastly different time scales. In this study, we demonstrate that releaser and primer responses to QMP can be uncoupled. First, treatment with the juvenile hormone analog methoprene leaves a releaser response (attraction to QMP) intact, but modulates QMP’s primer effects on sucrose responsiveness. Secondly, two components of QMP (9-ODA and 9-HDA) do not elicit a releaser response (attraction) but are as effective as QMP at modulating a primer response, downregulation of foraging-related brain gene expression. These results suggest that different responses to a single pheromone may be produced via distinct pathways.

The impact of psychopharmacology on contemporary clinical psychiatry.

PubMed

Vázquez, Gustavo H

2014-08-01

Clinical psychiatric evaluations of patients have changed dramatically in recent decades. Both initial assessments and follow-up visits have become brief and superficial, focused on searching for categorical diagnostic criteria from checklists, with limited inquiry into patient-reported symptomatic status and tolerability of treatments. The virtually exclusive therapeutic task has become selecting a plausible psychotropic, usually based on expert consensus guidelines. These guidelines and practice patterns rest mainly on published monotherapy trials that may or may not be applicable to particular patients but are having a profound impact, not only on modern psychiatric practice but also on psychiatric education, research, and theory.

Boxing-related head injuries.

PubMed

Jayarao, Mayur; Chin, Lawrence S; Cantu, Robert C

2010-10-01

Fatalities in boxing are most often due to traumatic brain injury that occurs in the ring. In the past 30 years, significant improvements in ringside and medical equipment, safety, and regulations have resulted in a dramatic reduction in the fatality rate. Nonetheless, the rate of boxing-related head injuries, particularly concussions, remains unknown, due in large part to its variability in clinical presentation. Furthermore, the significance of repeat concussions sustained when boxing is just now being understood. In this article, we identify the clinical manifestations, pathophysiology, and management of boxing-related head injuries, and discuss preventive strategies to reduce head injuries sustained by boxers.

Vaginal Epithelial Cell-Derived S100 Alarmins Induced by Candida albicans via Pattern Recognition Receptor Interactions Are Sufficient but Not Necessary for the Acute Neutrophil Response during Experimental Vaginal Candidiasis

PubMed Central

Yano, Junko; Palmer, Glen E.; Eberle, Karen E.; Peters, Brian M.; Vogl, Thomas; McKenzie, Andrew N.

2014-01-01

Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects women worldwide. Animal and clinical studies suggest that the immunopathogenic inflammatory condition of VVC is initiated by S100 alarmins in response to C. albicans, which stimulate polymorphonuclear neutrophil (PMN) migration to the vagina. The purpose of this study was to extend previous in vitro data and determine the requirement for the alarmin S100A8 in the PMN response and to evaluate pattern recognition receptors (PRRs) that initiate the response. For the former, PMN migration was evaluated in vitro or in vivo in the presence or absence of S100 alarmins initiated by several approaches. For the latter, vaginal epithelial cells were evaluated for PRR expression and C. albicans-induced S100A8 and S100A9 mRNAs, followed by evaluation of the PMN response in inoculated PRR-deficient mice. Results revealed that, consistent with previously reported in vitro data, eukaryote-derived S100A8, but not prokaryote-derived recombinant S100A8, induced significant PMN chemotaxis in vivo. Conversely, a lack of biologically active S100A8 alarmin, achieved by antibody neutralization or by using S100A9−/− mice, had no effect on the PMN response in vivo. In PRR analyses, whereas Toll-like receptor 4 (TLR4)- and SIGNR1-deficient vaginal epithelial cells showed a dramatic reduction in C. albicans-induced S100A8/S100A9 mRNAs in vitro, inoculated mice deficient in these PRRs showed PMN migration similar to that in wild-type controls. These results suggest that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during VVC and that the vaginal PMN response to C. albicans involves PRRs in addition to SIGNR1 and TLR4, or other induction pathways. PMID:24478092

Vaginal epithelial cell-derived S100 alarmins induced by Candida albicans via pattern recognition receptor interactions are sufficient but not necessary for the acute neutrophil response during experimental vaginal candidiasis.

PubMed

Yano, Junko; Palmer, Glen E; Eberle, Karen E; Peters, Brian M; Vogl, Thomas; McKenzie, Andrew N; Fidel, Paul L

2014-02-01

Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects women worldwide. Animal and clinical studies suggest that the immunopathogenic inflammatory condition of VVC is initiated by S100 alarmins in response to C. albicans, which stimulate polymorphonuclear neutrophil (PMN) migration to the vagina. The purpose of this study was to extend previous in vitro data and determine the requirement for the alarmin S100A8 in the PMN response and to evaluate pattern recognition receptors (PRRs) that initiate the response. For the former, PMN migration was evaluated in vitro or in vivo in the presence or absence of S100 alarmins initiated by several approaches. For the latter, vaginal epithelial cells were evaluated for PRR expression and C. albicans-induced S100A8 and S100A9 mRNAs, followed by evaluation of the PMN response in inoculated PRR-deficient mice. Results revealed that, consistent with previously reported in vitro data, eukaryote-derived S100A8, but not prokaryote-derived recombinant S100A8, induced significant PMN chemotaxis in vivo. Conversely, a lack of biologically active S100A8 alarmin, achieved by antibody neutralization or by using S100A9(-/-) mice, had no effect on the PMN response in vivo. In PRR analyses, whereas Toll-like receptor 4 (TLR4)- and SIGNR1-deficient vaginal epithelial cells showed a dramatic reduction in C. albicans-induced S100A8/S100A9 mRNAs in vitro, inoculated mice deficient in these PRRs showed PMN migration similar to that in wild-type controls. These results suggest that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during VVC and that the vaginal PMN response to C. albicans involves PRRs in addition to SIGNR1 and TLR4, or other induction pathways.

Responsive Block Copolymer and Gold Nanoparticle Hybrid Nanotubes.

NASA Astrophysics Data System (ADS)

Chang, Sehoon; Singamaneni, Srikanth; Young, Seth; Tsukruk, Vladimir

2009-03-01

We demonstrate the facile fabrication of responsive polymer and metal nanoparticle composite nanotube structures. The nanotubes are comprised of responsive block copolymer, polystyrene-block-poly (2-vinylpyridine) (PS-b-P2VP), and gold nanoparticles. PS-b-P2VP nanotubes were fabricated using porous alumina template and in situ reduction of the gold nanoparticles in P2VP domains. Owing to the pH sensitive nature of P2VP (anionic polymer with a pKa of 3.8), the nanotubes exhibit a dramatic change in topology in response to the changes in the external pH. Furthermore, the gold nanoparticles in the responsive block exhibit a reversible aggregation, causing a reversible change in optical properties such as absorption.

Evolutionary history and stress regulation of plant receptor-like kinase/pelle genes.

PubMed

Lehti-Shiu, Melissa D; Zou, Cheng; Hanada, Kousuke; Shiu, Shin-Han

2009-05-01

Receptor-Like Kinase (RLK)/Pelle genes play roles ranging from growth regulation to defense response, and the dramatic expansion of this family has been postulated to be crucial for plant-specific adaptations. Despite this, little is known about the history of or the factors that contributed to the dramatic expansion of this gene family. In this study, we show that expansion coincided with the establishment of land plants and that RLK/Pelle subfamilies were established early in land plant evolution. The RLK/Pelle family expanded at a significantly higher rate than other kinases, due in large part to expansion of a few subfamilies by tandem duplication. Interestingly, these subfamilies tend to have members with known roles in defense response, suggesting that their rapid expansion was likely a consequence of adaptation to fast-evolving pathogens. Arabidopsis (Arabidopsis thaliana) expression data support the importance of RLK/Pelles in biotic stress response. We found that hundreds of RLK/Pelles are up-regulated by biotic stress. Furthermore, stress responsiveness is correlated with the degree of tandem duplication in RLK/Pelle subfamilies. Our findings suggest a link between stress response and tandem duplication and provide an explanation for why a large proportion of the RLK/Pelle gene family is found in tandem repeats. In addition, our findings provide a useful framework for potentially predicting RLK/Pelle stress functions based on knowledge of expansion pattern and duplication mechanism. Finally, we propose that the detection of highly variable molecular patterns associated with specific pathogens/parasites is the main reason for the up-regulation of hundreds of RLK/Pelles under biotic stress.

From ClinicalTrials.gov trial registry to an analysis-ready database of clinical trial results.

PubMed

Cepeda, M Soledad; Lobanov, Victor; Berlin, Jesse A

2013-04-01

The ClinicalTrials.gov web site provides a convenient interface to look up study results, but it does not allow downloading data in a format that can be readily used for quantitative analyses. To develop a system that automatically downloads study results from ClinicalTrials.gov and provides an interface to retrieve study results in a spreadsheet format ready for analysis. Sherlock(®) identifies studies by intervention, population, or outcome of interest and in seconds creates an analytic database of study results ready for analyses. The outcome classification algorithms used in Sherlock were validated against a classification by an expert. Having a database ready for analysis that can be updated automatically, dramatically extends the utility of the ClinicalTrials.gov trial registry. It increases the speed of comparative research, reduces the need for manual extraction of data, and permits answering a vast array of questions.

Artificial intelligence guides system's best practices, cutting costs and improving services.

PubMed

1999-06-01

One for the history books. Clinical care improvement initiatives guided by a sophisticated artificial intelligence program have helped a major Virginia integrated health system make dramatic improvements in the cost and quality of its health care services. Find out how the technological innovation has earned Sentara Health System a place in the permanent collection of the Smithsonian's National Museum of American History.

Acute organic brain syndrome due to drug-induced eosinophilia.

PubMed

Ng, S C; Lee, M K; Teh, A

1989-11-01

A 72 year old man developed acute organic brain syndrome associated with marked eosinophilia following self medication with a variety of drugs. Investigations revealed no other known causes of eosinophilia. Withdrawal of drugs resulted in dramatic drop in eosinophil count paralleled by clinical resolution of neurological problems. To our knowledge drug-induced eosinophilia has not previously been associated with acute organic brain syndrome.

Acute organic brain syndrome due to drug-induced eosinophilia.

PubMed Central

Ng, S. C.; Lee, M. K.; Teh, A.

1989-01-01

A 72 year old man developed acute organic brain syndrome associated with marked eosinophilia following self medication with a variety of drugs. Investigations revealed no other known causes of eosinophilia. Withdrawal of drugs resulted in dramatic drop in eosinophil count paralleled by clinical resolution of neurological problems. To our knowledge drug-induced eosinophilia has not previously been associated with acute organic brain syndrome. PMID:2616421

Infrared imaging enhances retinal crystals in Bietti’s crystalline dystrophy

PubMed Central

Brar, Vikram S; Benson, William H

2015-01-01

Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti’s crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time. PMID:25931805

The preconception care experiences of women with epilepsy on sodium valproate.

PubMed

Lawther, Lorna; Dolk, Helen; Sinclair, Marlene; Morrow, Jim

2018-05-16

To understand the preconception experiences of women with epilepsy who have been taking the teratogenic drug valproate. Seven women were recruited, three from a preconception clinic and four from an antenatal clinic in a region of the UK. All had taken valproate preconceptionally. Three preconception clinic encounters were observed and audio-recorded. Interviews with all women were analysed using Interpretative Phenomenological Analysis (IPA). Women experienced a "trajectory of balance". Women moved from "maintaining balance" by using valproate to control seizures, to a "shattering of harmony" at the prospect of changing medication and as a result of the physical and mental effects of changing medication, to "restoring balance" which could involve "a new self" due to dramatic changes. Women balanced their health needs with those of their baby, and took responsibility for medication decision-making. They found it difficult to see "who is looking after me" in the healthcare system, either to access preconception care, or to support them through the stress of changing medication. Their journey ended with coming to terms with a variety of experiences: choosing not to have a baby due to unsuccessful change from valproate, recognising that a child from a previous pregnancy had been harmed by valproate or that the current pregnancy might be at risk, or successful medication change in preparation for pregnancy. A clear and adequately funded preconception care pathway is needed from epilepsy diagnosis, including support for stress. Understanding what influences maternalisation may help understand uptake of preconception care. Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

A web-based incident reporting system and multidisciplinary collaborative projects for patient safety in a Japanese hospital

PubMed Central

Nakajima, K; Kurata, Y; Takeda, H

2005-01-01



Problem: When patient safety programs were mandated for Japanese health care institutions, a safety culture, a tool for collecting incident reports, an organizational arrangement for multidisciplinary collaboration, and interventional methods for improvement had to be established. Design: Observational study of effects of new patient safety programs. Setting: Osaka University Hospital, a large government-run teaching hospital. Strategy for change: A voluntary and anonymous web-based incident reporting system was introduced. For the new organizational structure a clinical risk management committee, a department of clinical quality management, and area clinical risk managers were established with their respective roles clearly defined to advance the plan-do-study-act cycle and to integrate efforts. For preventive action, alert procedures, staff education, ward rounds by peers, a system oriented approach for reducing errors, and various feedback channels were introduced. Effects of change: Continuous incident reporting by all hospital staff has been observed since the introduction of the new system. Several error inducing situations have been improved: wrong choice of drug in computer prescribing, maladministration of drugs due to a look-alike appearance or confusion about the manipulation of a medical device, and poor after hours service of the blood transfusion unit. Staff participation in educational seminars has been dramatically improved. Ward rounds have detected problematic procedures which needed to be dealt with. Lessons learnt: Patient safety programs based on a web-based incident reporting system, responsible persons, staff education, and a variety of feedback procedures can help promote a safety culture, multidisciplinary collaboration, and strong managerial leadership resulting in system oriented improvement. PMID:15805458

Centralization of a regional clinical microbiology service: The Calgary experience

PubMed Central

Church, Deirdre L; Hall, Paula

1999-01-01

Diagnostic laboratory services in Alberta have been dramatically restructured over the past five years. In 1994, Alberta Health embarked on an aggressive laboratory restructuring that cut back approximately 30% of the overall monies previously paid to the laboratory service sector in Calgary. A unique service delivery model consolidated all institutional and community-based diagnostic testing in a company called Calgary Laboratory Services (CLS) in late 1996. CLS was formed by a public/private partnership between the Calgary Regional Health Care Authority (CRHA) and MDS-Kasper Laboratories. By virtue of its customer service base and scope of testing, CLS provides comprehensive regional laboratory services to the entire populace. Regional microbiology services within CLS have been successfully consolidated over the past three years into a centralized high volume laboratory (HVL). Because the HVL is not located in a hospital, rapid response laboratories (RRLs) are operated at each acute care site. Although the initial principle behind the proposed test menus for the RRLs was that only procedures requiring a clinical turnaround time of more than 2 h stay on-site, many other principles had to be used to develop and implement an efficient and clinically relevant RRL model for microbiology. From these guiding principles, a detailed assessment of the needs of each institution and extensive networking with user groups, the functions of the microbiology RRLs were established and a detailed implementation plan drawn up. The experience at CLS with regards to restructuring a regional microbiology service is described herein. A post-hoc analysis provides the pros and cons of directing and operating a regionalized microbiology service. PMID:22346397

Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy.

PubMed

Baek, Jin Hyen; D'Agnillo, Felice; Vallelian, Florence; Pereira, Claudia P; Williams, Matthew C; Jia, Yiping; Schaer, Dominik J; Buehler, Paul W

2012-04-01

Massive transfusion of blood can lead to clinical complications, including multiorgan dysfunction and even death. Such severe clinical outcomes have been associated with longer red blood cell (rbc) storage times. Collectively referred to as the rbc storage lesion, rbc storage results in multiple biochemical changes that impact intracellular processes as well as membrane and cytoskeletal properties, resulting in cellular injury in vitro. However, how the rbc storage lesion triggers pathophysiology in vivo remains poorly defined. In this study, we developed a guinea pig transfusion model with blood stored under standard blood banking conditions for 2 (new), 21 (intermediate), or 28 days (old blood). Transfusion with old but not new blood led to intravascular hemolysis, acute hypertension, vascular injury, and kidney dysfunction associated with pathophysiology driven by hemoglobin (Hb). These adverse effects were dramatically attenuated when the high-affinity Hb scavenger haptoglobin (Hp) was administered at the time of transfusion with old blood. Pathologies observed after transfusion with old blood, together with the favorable response to Hp supplementation, allowed us to define the in vivo consequences of the rbc storage lesion as storage-related posttransfusion hemolysis producing Hb-driven pathophysiology. Hb sequestration by Hp might therefore be a therapeutic modality for enhancing transfusion safety in severely ill or massively transfused patients.

Demethylation of induced pluripotent stem cells from type 1 diabetic patients enhances differentiation into functional pancreatic β cells.

PubMed

Manzar, Gohar S; Kim, Eun-Mi; Zavazava, Nicholas

2017-08-25

Type 1 diabetes (T1D) can be managed by transplanting either the whole pancreas or isolated pancreatic islets. However, cadaveric pancreas is scarcely available for clinical use, limiting this approach. As such, there is a great need to identify alternative sources of clinically usable pancreatic tissues. Here, we used induced pluripotent stem (iPS) cells derived from patients with T1D to generate glucose-responsive, insulin-producing cells (IPCs) via 3D culture. Initially, T1D iPS cells were resistant to differentiation, but transient demethylation treatment significantly enhanced IPC yield. The cells responded to high-glucose stimulation by secreting insulin in vitro The shape, size, and number of their granules, as observed by transmission electron microscopy, were identical to those found in cadaveric β cells. When the IPCs were transplanted into immunodeficient mice that had developed streptozotocin-induced diabetes, they promoted a dramatic decrease in hyperglycemia, causing the mice to become normoglycemic within 28 days. None of the mice died or developed teratomas. Because the cells are derived from "self," immunosuppression is not required, providing a much safer and reliable treatment option for T1D patients. Moreover, these cells can be used for drug screening, thereby accelerating drug discovery. In conclusion, our approach eliminates the need for cadaveric pancreatic tissue.

Gender-dimorphic effects of adipose-derived stromal vascular fractions on HUVECs exposed to oxidative stress.

PubMed

Lim, Soyeon; Kim, Il-Kwon; Choi, Jung-Won; Seo, Hyang-Hee; Lim, Kyu Hee; Lee, Seahyoung; Lee, Hoon-Bum; Kim, Sang Woo; Hwang, Ki-Chul

2017-01-01

Stromal vascular fractions (SVFs) are a heterogeneous collection of cells within adipose tissue that are being studied for various clinical indications. In this study, we aimed to determine whether SVF transplantation into impaired tissues has differential effects on inflammatory and angiogenetic properties with regard to gender. As reactive oxygen species have been implicated in cardiovascular disease development, we investigated differences in gene and protein expression related to inflammation and angiogenesis in HUVECs co-cultured with adipose-derived SVFs from male (M group) and female (F group) individuals under oxidative stress conditions. The expression of several inflammatory (interleukin (IL)-33) and angiogenetic (platelet-derived growth factor (PDGF)) factors differed dramatically between male and female donors. Anti-inflammatory and pro-angiogenetic responses were observed in HUVECs co-cultured with SVFs under oxidative stress conditions, and these characteristics may exhibit partially differential effects according to gender. Using network analysis, we showed that co-culturing HUVECs with SVFs ameliorated pyroptosis/apoptosis via an increase in oxidative stress. Activation of caspase-1 and IL-1B was significantly altered in HUVECs co-cultured with SVFs from female donors. These findings regarding gender-dimorphic regulation of adipose-derived SVFs provide valuable information that can be used for evidence-based gender-specific clinical treatment of SVF transplantation for understanding of cardiovascular disease, allowing for the development of additional treatment.

Prognostic significance of catalase expression and its regulatory effects on hepatitis B virus X protein (HBx) in HBV-related advanced hepatocellular carcinomas

PubMed Central

Cho, Mi-Young; Cheong, Jae Youn; Lim, Wonchung; Jo, Sujin; Lee, Youngsoo; Wang, Hee-Jung; Han, Kyou-Hoon; Cho, Hyeseong

2014-01-01

Hepatitis B virus X protein (HBx) plays a role in liver cancer development. We previously showed that ROS increased HBx levels and here, we investigated the role of antioxidants in the regulation of HBx expression and their clinical relevance. We found that overexpression of catalase induced a significant loss in HBx levels. The cysteine null mutant of HBx (Cys−) showed a dramatic reduction in its protein stability. In clonogenic proliferation assays, Huh7-X cells produced a significant number of colonies whereas Huh7-Cys− cells failed to generate them. The Cys at position 69 of HBx was crucial to maintain its protein stability and transactivation function in response to ROS. Among 50 HBV-related hepatocellular carcinoma (HCC) specimens, 72% of HCCs showed lower catalase levels than those of surrounding non-tumor tissues. In advanced stage IV, catalase levels in non-tumor tissues were increased whereas those in tumors were further reduced. Accordingly, patients with a high T/N ratio for catalase showed significantly longer survival than those with a low T/N ratio. Together, catalase expression in HCC patients can be clinically useful for prediction of patient survival, and restoration of catalase expression in HCCs could be an important strategy for intervention in HBV-induced liver diseases. PMID:25361011

Role of Cholestyramine in Refractory Hyperthyroidism: A Case Report and Literature Review

PubMed Central

Alswat, Khaled A.

2015-01-01

Patient: Female, 52 Final Diagnosis: Refractory iodine induced hyperthyroidism Symptoms: Neck swelling • shortness of breath Medication: Cholestyramine Clinical Procedure: Total thyroidectomy Specialty: Endocrinology and Metabolic Objective: Unusual clinical course Background: Hyperthyroidism is a common disease that usually responds to the conventional therapy of anti-thyroidal medications (methimazole or PTU) and beta-blocker. Refractory hyperthyroidism is a rare condition in which hyperthyroidism fails to respond to the above therapy. Cholestyramine has been shown to decrease thyroid hormone level when added to the ongoing anti-thyroidal medications. Case Report: A 52-year-old woman with past medical history of enlarging goiter presented with obstructive symptoms of worsening shortness of breath and snoring. Admission thyroid function test showed mild hyperthyroidism (suppressed TSH, slightly high FT4, and high normal FT3) that worsened after she received a CT scan with contrast and failed to respond to a 3-week course of high-dose dexamethasone, high-dose carbimazole, and up-titrated propranolol. Five days after cholestyramine was added, her FT4 decreased by 30% and normalized after 12 days. The patient underwent total thyroidectomy as definitive treatment for the hyperthyroidism and for the obstructive symptoms. Conclusions: Cholestyramine is an effective additional treatment for hyperthyroidism and may be an effective treatment for refractory iodine-induced hyperthyroidism. The possibility of self-remission (natural course) is less likely given the dramatic and rapid response to cholestyramine. PMID:26207323

Short- and long-term outcomes of AL amyloidosis patients admitted into intensive care units.

PubMed

Guinault, Damien; Canet, Emmanuel; Huart, Antoine; Jaccard, Arnaud; Ribes, David; Lavayssiere, Laurence; Venot, Marion; Cointault, Olivier; Roussel, Murielle; Nogier, Marie-Béatrice; Pichereau, Claire; Lemiale, Virginie; Arnulf, Bertrand; Attal, Michel; Chauveau, Dominique; Azoulay, Elie; Faguer, Stanislas

2016-09-01

Amyloidosis is a rare and threatening condition that may require intensive care because of amyloid deposit-related organ dysfunction or therapy-related adverse events. Although new multiple myeloma drugs have dramatically improved outcomes in AL amyloidosis, the outcomes of AL patients admitted into intensive care units (ICUs) remain largely unknown. Admission has been often restricted to patients with low Mayo Clinic staging and/or with a complete or very good immunological response at admission. In a retrospective multicentre cohort of 66 adult AL (n = 52) or AA (n = 14) amyloidosis patients, with similar causes of admission to an ICU, the 28-d and 6-month survival rates of AA patients were significantly higher compared to AL patients (93% vs. 60%, P = 0·03; 71% vs. 45%, P = 0·02, respectively). In AL patients, the simplified Index of Gravity Score (IGS2) was the only independent predictive factor for death by day 28, whereas the Mayo-Clinic classification stage had no influence. In Cox's multivariate regression model, only cardiac arrest and on-going chemotherapy at ICU admission significantly predicted death at 6 months. Short-term outcomes of AL patients admitted into an ICU were mainly related to the severity of the acute medical condition, whereas on-going chemotherapy for active amyloidosis impacted on long-term outcomes. © 2016 John Wiley & Sons Ltd.

Hospital clonal dissemination of Enterobacter aerogenes producing carbapenemase KPC-2 in a Chinese teaching hospital.

PubMed

Qin, Xiaohua; Yang, Yang; Hu, Fupin; Zhu, Demei

2014-02-01

Carbapenems are first-line agents for the treatment of serious nosocomial infections caused by multidrug-resistant Enterobacteriaceae. However, resistance to carbapenems has increased dramatically among Enterobacteriaceae in our hospital. In this study, we report clonal dissemination caused by carbapenem-resistant Enterobacter aerogenes (CREA). In 2011, CREA was identified from 12 patients admitted to the neurosurgical ward. All 12 clinical isolates were non-susceptible to cefotaxime, ceftazidime, cefoxitin, ertapenem, imipenem or meropenem. All isolates carried the gene encoding Klebsiella pneumoniae carbapenemase-2 (KPC-2), except for the isolate E4. However, a remarkably lower expression level of the porin OmpF was detected in the non-KPC-2-producing isolate E4 on SDS-PAGE compared with the carbapenem-susceptible isolate. Epidemiological and molecular investigations showed that a single E. aerogenes strain (PFGE type A), including seven KPC-2-producing clinical isolates, was primarily responsible for the first isolation and subsequent dissemination. In a case-control study, we identified risk factors for infection/colonization with CREA. Mechanical ventilation, the changing of sickbeds and previous use of broad-spectrum antibiotics were identified as potential risk factors. Our findings suggest that further studies should focus on judicious use of available antibiotics, implementation of active antibiotic resistance surveillance and strict implementation of infection-control measures to avoid the rapid spread or clonal dissemination caused by carbapenem-resistant Enterobacteriaceae in healthcare facilities.

Clinical roundtable monograph: Emerging treatment options for TKI-resistant chronic myelogenous leukemia.

PubMed

Cortes, Jorge; Radich, Jerald; Mauro, Michael J

2012-10-01

The development of tyrosine kinase inhibitors (TKIs) that inhibit signaling of the constitutive BCR-ABL protein revolutionized the treatment of chronic myelogenous leukemia (CML). These agents have dramatically changed the treatment landscape for CML, shifting the use of allogeneic stem cell transplantation to selected patients in the salvage setting. Four BCR-ABL TKIs are now commercially available for the treatment of CML: the first-generation TKI imatinib, and the second-generation TKIs dasatinib, nilotinib, and bosutinib. Continuous treatment with these agents induces durable responses in a high proportion of patients with chronic-phase CML. Research is focused on identifying which patients can discontinue therapy without a recurrence of disease. For the group of patients with resistance to TKIs, multiple alternative therapies are being evaluated. The third-generation TKI ponatinib is a BCR-ABL inhibitor that has demonstrated significant activity, including in patients with the TKI resistance mutation T315I. The homoharringtonine derivative omacetaxine mepesuccinate, which inhibits protein synthesis, has also demonstrated clinical activity in CML, including in patients with TKI resistance due to T315I and in patients who have TKI resistance despite no evidence of ABL mutations. It is essential that clinicians implement these new agents with care and change therapies only when appropriate in order to preserve as many options as possible for future use if needed.

Conducting Clinical Research Using Crowdsourced Convenience Samples.

PubMed

Chandler, Jesse; Shapiro, Danielle

2016-01-01

Crowdsourcing has had a dramatic impact on the speed and scale at which scientific research can be conducted. Clinical scientists have particularly benefited from readily available research study participants and streamlined recruiting and payment systems afforded by Amazon Mechanical Turk (MTurk), a popular labor market for crowdsourcing workers. MTurk has been used in this capacity for more than five years. The popularity and novelty of the platform have spurred numerous methodological investigations, making it the most studied nonprobability sample available to researchers. This article summarizes what is known about MTurk sample composition and data quality with an emphasis on findings relevant to clinical psychological research. It then addresses methodological issues with using MTurk--many of which are common to other nonprobability samples but unfamiliar to clinical science researchers--and suggests concrete steps to avoid these issues or minimize their impact.

Forest responses to changing climate: lessons from the past and uncertainty for the future

Treesearch

Donald H. DeHayes; George L., Jr. Jacobson; Paul G. Schaberg; Bruce Bongarten; Louis Iverson; Ann C. Dieffenbacher-Krall

2000-01-01

The earth's climate has undergone dramatic and long-term changes through natural processes many millennia before humans influenced global climate. Considerable evidence indicates that increasing concentrations of carbon dioxide and other greenhouse gases in the earth's atmosphere will lead to near-term warming, perhaps as much as 2 to 4°C in...

Problems in Calculating and Comparing Dropout Rates. ERS Research Digest.

ERIC Educational Resources Information Center

Ligon, Glynn; And Others

1990-01-01

This paper dramatizes the complexity and the problems involved in calculating the rates of student dropouts from school. To compare the dropout formulas used by various agencies, states, and local school systems, responses from a national survey are presented and used to calculate a range of dropout rates for the Austin (Texas) public schools. By…

Response of Fuelbed Characteristics to Restoration Treatments in Pinyon-Juniper-Encroached Shrublands on the Shivwits Plateau, Arizona

Treesearch

Helen Y. Smith; Sharon Hood; Matt Brooks; JR Matchett; Curt Deuser

2006-01-01

The recent encroachment of piñon (Pinus edulis) and juniper trees (Juniperus osteosperma) into historically shrub- and grass-dominated landscapes has caused major changes in ecosystem structure and function, including dramatic changes in fuel structure and fire regimes. Such encroachment is currently occurring on thousands of acres...

Opening Gates: On Celebrating Creative Commons and Flexing the Fair Use Muscle

ERIC Educational Resources Information Center

Valenza, Joyce Kasman

2011-01-01

The landscape surrounding the use of intellectual property has shifted dramatically over the past couple of years. Teacher librarians, responsible for guiding learners of all ages toward practicing digital citizenship, should be aware of the new rules for playing, living, and working in a new intellectual property sandbox. In the past, librarians…

The Schoolwide Cluster Grouping Model: Restructuring Gifted Education Services for the 21st Century

ERIC Educational Resources Information Center

Brulles, Dina; Winebrenner, Susan

2011-01-01

Schools today are experiencing dramatic changes in how they serve gifted students. Gifted programs that have prevailed for years are disappearing. In response, an increasing number of schools are turning to the Schoolwide Cluster Grouping Model (SCGM) to serve their gifted students. When implemented well, the SCGM represents one viable solution…