Medicine and Health Sciences Commons^™

Hiv Symptom Burden And Anemia Among Hiv-Positive Individuals: Cross-Sectional Results Of A Community-Based Positive Living With Hiv (Polh) Study In Nepal, Catherine Martin, Kalpana Poudel-Tandukar, Krishna C. Poudel

Krishna C. Poudel

A Single Vertebrate Dna Virus Protein Disarms Invertebrate Immunity To Rna Virus Infection, Don B. Gammon, Sophie Duraffour, Daniel K. Rozelle, Heidi Hehnly, Rita Sharma, Michael E. Sparks, Cara C. West, Ying Chen, James J. Moresco, Graciela Andrei, John H. Connor, Darryl Conte Jr., Dawn E. Gundersen-Rindal, William L. Marshall, John R. Yates, Neal S. Silverman, Craig C. Mello

Neal Silverman

Virus-host interactions drive a remarkable diversity of immune responses and countermeasures. We found that two RNA viruses with broad host ranges, vesicular stomatitis virus (VSV) and Sindbis virus (SINV), are completely restricted in their replication after entry into Lepidopteran cells. This restriction is overcome when cells are co-infected with vaccinia virus (VACV), a vertebrate DNA virus. Using RNAi screening, we show that Lepidopteran RNAi, Nuclear Factor-kappaB, and ubiquitin-proteasome pathways restrict RNA virus infection. Surprisingly, a highly conserved, uncharacterized VACV protein, A51R, can partially overcome this virus restriction. We show that A51R is also critical for VACV replication in vertebrate cells …

Examining The Regulatory Value Of Multi-Route Mammalian Acute Systemic Toxicity Studies, Troy Seidle, Pilar Prieto, Anna Bulgheroni

Troy Seidle, PhD

Regulatory information requirements for pesticides call for submission of acute systemic toxicity data for up to three different exposure routes (oral, dermal, inhalation) for both active ingredients and formulated products. Similar multi-route testing is required in the European Union and elsewhere for industrial chemicals. To determine the value of acute toxicity testing by more than one route, oral-dermal and oralinhalation concordances among regulatory classifications were examined for large data sets of chemicals and pesticide active ingredients. Across all sectors examined, oral acute toxicity classifications for pure active substances were more severe than those derived from dermal data in more than …

Can Acute Dermal Systemic Toxicity Tests Be Replaced With Oral Tests? A Comparison Of Route-Specific Systemic Toxicity And Hazard Classifications Under The Globally Harmonized System Of Classification And Labelling Of Chemicals (Ghs), Nigel P. Moore, David J. Andrew, Donald L. Bjerke, Stuart Creton, David Dreher, Thomas Holmes, Pilar Prieto, Troy Seidle, Tim G. Rowan

Troy Seidle, PhD

Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification …

An Evaluation Of The Us High Production Volume (Hpv) Chemical-Testing Programme: A Study In (Ir)Relevance, Redundancy And Retro Thinking, Andrew Nicholson, Jessica Sandler, Troy Seidle

Troy Seidle, PhD

Under the US Environmental Protection Agency (EPA) High Production Volume (HPV) Challenge Programme, chemical companies have volunteered to conduct screening-level toxicity tests on approximately 2800 widely-used industrial chemicals. Participating companies are committed to providing available toxicity information to the EPA and presenting testing proposals for review by the EPA and posting on the EPA Web site as public information. People for the Ethical Treatment of Animals (PETA) and a coalition of animal protection organisations have reviewed all the test plans submitted by the participating chemical companies for compliance with the original HPV framework, as well as with animal welfare guidelines …

Cross-Sector Review Of Drivers And Available 3rs Approaches For Acute Systemic Toxicity Testing, Troy Seidle, Sally Robinson, Tom Holmes, Stuart Creton, Pilar Prieto, Julia Scheel, Magda Chlebus

Troy Seidle, PhD

Acute systemic toxicity studies are carried out in many sectors in which synthetic chemicals are manufactured or used and are among the most criticized of all toxicology tests on both scientific and ethical grounds. A review of the drivers for acute toxicity testing within the pharmaceutical industry led to a paradigm shift whereby in vivo acute toxicity data are no longer routinely required in advance of human clinical trials. Based on this experience, the following review was undertaken to identify (1) regulatory and scientific drivers for acute toxicity testing in other industrial sectors, (2) activities aimed at replacing, reducing, or …

The Development Of New Concepts For Assessing Reproductive Toxicity Applicable To Large Scale Toxicological Programmes, S. Bremer, C. Pellizzer, S. Hoffmann, T. Seidle, T. Hartung

Troy Seidle, PhD

Large scale toxicological testing programmes which are currently ongoing such as the new European chemical legislation REACH require the development of new integrated testing strategies rather than applying traditional testing schemes to thousands of chemicals. The current practice of requiring in vivo testing for every possible adverse effect endanger the success of these programmes due (i) to limited testing facilities and sufficient capacity of scientific/technical knowledge for reproductive toxicity; (ii) an unacceptable number of laboratory animals involved (iii) an intolerable number of chemicals classified as false positive.

A key aspect of the implementation of new testing strategies is the determination …

Bringing Toxicology Into The 21st Century: A Global Call To Action, Troy Seidle, Martin Stephens

Troy Seidle, PhD

Conventional toxicological testing methods are often decades old, costly and low-throughput, with questionable relevance to the human condition. Several of these factors have contributed to a backlog of chemicals that have been inadequately assessed for toxicity. Some authorities have responded to this challenge by implementing large-scale testing programmes. Others have concluded that a paradigm shift in toxicology is warranted. One such call came in 2007 from the United States National Research Council (NRC), which articulated a vision of ‘‘21st century toxicology” based predominantly on non-animal techniques. Potential advantages of such an approach include the capacity to examine a far greater …

A Modular One-Generation Reproduction Study As A Flexible Testing System For Regulatory Safety Assessment, Richard Vogel, Troy Seidle, Horst Spielmann

Troy Seidle, PhD

The European Union’s Registration, Evaluation and Authorisation of Chemicals (REACH) legislation mandates testing and evaluation of approximately 30,000 existing substances within a short period of time, beginning with the most widely used “high production volume” (HPV) chemicals. REACH testing requirements for the roughly 3000 HPV chemicals specify three separate tests for reproductive toxicity: two developmental toxicity studies on different animal species (OECD Test Guideline 414) and a two-generation reproduction toxicity study (OECD TG 416). These studies are highly costly in both economic and animal welfare terms. OECD TG 416 is a fertility study intended to evaluate reproductive performance of animals …

Ideology Masquerading As Science: The Case Of Endocrine Disrupter Screening Programmes, Troy Seidle

Troy Seidle, PhD

The global move to develop novel testing methods and strategies to identify suspected endocrine disrupting chemicals offers a unique opportunity to move away from traditional animal testing paradigms in this new area of regulatory concern. Regrettably, the programmes under development, both in the USA and internationally through the OECD, have thus far failed to consider in vitro and other nonanimal test methods as more than “pre-screening” or “priority-setting” tools in a larger, animal-based testing strategy. Validation efforts to date have focused almost exclusively on the modification of existing animal tests to detect “endocrine effects”, with no demonstrable effort to promote …

Levels Of Citation Of Nonhuman Animal Studies Conducted At A Canadian Research Hospital, Anne Innis Dagg, Troy K. Seidle

Troy Seidle, PhD

The publication of scientific articles that receive few or no citations raises questions of the appropriate use of resources as well as ethics. In the case of animal research, the ethics issue extends beyond human patients to nonhuman animals, as the research subjects them to pain and, typically, to death. This study is a citation analysis of animal research conducted at Toronto's Hospital for Sick Children (HSC). Of the 594 publications (1990 to 1995) on animal research by affiliates of HSC, 29% received Iower than 10 citations in a 10-year period. We compare the research history of 13 "best" and …

Humane Society International’S Global Campaign To End Animal Testing, Troy Seidle

Troy Seidle, PhD

The Research & Toxicology Department of Humane Society International (HSI) operates a multifaceted and science-driven global programme aimed at ending the use of animals in toxicity testing and research. The key strategic objectives include: a) ending cosmetics animal testing worldwide, via the multinational Be Cruelty-Free campaign; b) achieving near-term reductions in animal testing requirements through revision of product sector regulations; and c) advancing humane science by exposing failing animal models of human disease and shifting science funding toward human biology-based research and testing tools fit for the 21st century. HSI was instrumental in ensuring the implementation of the March 2013 …

Brain And Law: An Eeg Study Of How We Decide Or Not To Implement A Law, Armando Rocha, Eduardo Massad, Fábio Rocha, Marcelo Buratini

Armando F Rocha

Brazil has introduced a referendum regarding the prohibition of firearm commerce and propaganda arguments has invoked socially and personally driven issues in the promotion of voting in favor of and against firearm control, respectively. Here, we used different techniques to study the brain activity associated with a voter’s perception of the truthfulness of these arguments and their influence on voting decisions. Low Resolution Tomography was used to identify the possible different sets of neurons activated in the analysis of the different types of propaganda. Linear correlation was used to calculate the amount information provided by different electrodes about how these …

The Fine-Scale Habitat Use Of Risso’S Dolphins Off Bardsey Island, Cardigan Bay (Uk), Marijke N. De Boer, Sonja Eisfeld, Mark P. Simmonds

Mark P. Simmonds, OBE

The main objectives of this study were (1) to estimate the population size of Risso’s dolphins off Bardsey Island using mark-recapture techniques (De Boer et al., 2013); and (2) to study habitat-use in relation to fine-scale oceanographic features. This work provides preliminary information on the habitat-use of Risso’s dolphins and will benefit future studies, along with the development of effective conservation measures for this species throughout the region.

Photo-Identification Methods Reveal Seasonal And Long-Term Site-Fidelity Of Risso’S Dolphins (Grampus Griseus) In Shallow Waters (Cardigan Bay, Wales), Marijke N. De Boer, Josephine Clark, Mardik F. Leopold, Mark P. Simmonds, Peter J.H. Reijnders

Mark P. Simmonds, OBE

A photo-identification study on Risso’s dolphins was carried out off Bardsey Island in Wales (July to September, 1997-2007). Their local abundance was estimated using two different analytical techniques: 1) mark-recapture of well-marked dolphins using a “closed-population” model; and 2) a census technique based on the total number of iden-tified individual dolphins sighted over the study period. The mark-recapture estimates of 121 (left sides; 64 - 178, 95% CI; CV 0.24) and 145 dolphins (right sides; 78 - 213, 95% CI; CV 0.24) closely matched the census technique estimates (population size of 90 - 151). It was found that the dolphins …

Cetaceans And Marine Debris: The Great Unknown, Mark Peter Simmonds

Mark P. Simmonds, OBE

Plastics and other marine debris have been found in the gastrointestinal tracts of cetaceans, including instances where large quantities of material have been found that are likely to cause impairment to digestive processes and other examples, where other morbidity and even death have resulted. In some instances, debris may have been ingested as a result of the stranding process and, in others, it may have been ingested when feeding. Those species that are suction or “ram” feeders may be most at risk. There is also evidence of entanglement of cetaceans in marine debris. However, it is usually difficult to distinguish …

Bacterial Rna:Dna Hybrids Are Activators Of The Nlrp3 Inflammasome, Sivapriya Kailasan Vanaja, Vijay A. K. Rathinam, Maninjay K. Atianand, Parisa Kalantari, Brian M. Skehan, Katherine A. Fitzgerald, John M. Leong

Katherine A. Fitzgerald

Enterohemorrhagic Escherichia coli (EHEC) is an extracellular pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. The proinflammatory cytokine, interleukin-1beta, has been linked to hemolytic uremic syndrome. Here we identify the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome as an essential mediator of EHEC-induced IL-1beta. Whereas EHEC-specific virulence factors were dispensable for NLRP3 activation, bacterial nucleic acids such as RNA:DNA hybrids and RNA gained cytosolic access and mediated inflammasome-dependent responses. Consistent with a direct role for RNA:DNA hybrids in inflammasome activation, delivery of synthetic EHEC RNA:DNA hybrids into the cytosol triggered NLRP3-dependent responses, …

Dual Engagement Of The Nlrp3 And Aim2 Inflammasomes By Plasmodium-Derived Hemozoin And Dna During Malaria, Parisa Kalantari, Rosane B. Deoliveira, Jennie Chan, Yolanda Corbett, Vijay A. K. Rathinam, Andrea Stutz, Eicke Latz, Ricardo T. Gazzinelli, Douglas T. Golenbock, Katherine A. Fitzgerald

Katherine A. Fitzgerald

Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and …

Malaria-Induced Nlrp12/Nlrp3-Dependent Caspase-1 Activation Mediates Inflammation And Hypersensitivity To Bacterial Superinfection, Marco A. Ataide, Warrison A. Andrade, Dario S. Zamboni, Donghai Wang, Maria Do Carmo Souza, Bernardo S. Franklin, Samir Elian, Flaviano S. Martins, Dhelio Pereira, George W. Reed, Katherine A. Fitzgerald, Douglas T. Golenbock, Ricardo T. Gazzinelli

Katherine A. Fitzgerald

Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1beta. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-gamma-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1beta expression required a second stimulation with LPS and was also dependent on IFN-gamma-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1beta upon a second …

The Swedish Studies Of The Adopted Children Of Alcoholics, Jill Littrell

jill l littrell Dr.

The authors of the widely cited studies analyzing the Swedish adoption records of the children of alcoholics have advanced the notion that there are three distinct paths for the inheritance of alcoholism. One path results in moderate alcoholism in men and a form of somatization but no alcoholism in women. A second path results in severe and mild alcoholism in men and alcoholism in women. The third path results in a particular variety of alcohol abuse in men and a particular variety of somatization in women. This article analyzes the authors' claims. It is argued that the data were improperly …

Incorporating Information From Neuroscience And Endocrinology Regarding Sexual Orientation Into Social Work Education, Jill Littrell

jill l littrell Dr.

The brains of heterosexual males and heterosexual females are different. Moreover, the brains of gay men are similar to heterosexual females whereas the brains of lesbians are similar to heterosexual males. Neuroscience research supporting these postulates is reviewed. The gestational processes that might explain the differences in brain structure and function corresponding with gender are reviewed. Following a discussion of the physiological bases for sexual orientation, a discussion of the physiological bases for the expression of gender related traits and a discussion of factors contributing to sexual identity are provided. Throughout the article, alternative ways to think about gender are …

Is There Evidence For The Bipolar Spectrum And The Safety Of Pharmaceutical Interventions?, Jill Littrell

jill l littrell Dr.

Social workers constitute a high proportion of mental health professionals and a high percentage of social workers provide mental health care. Thus, psychiatric diagnoses and pharmaceutical interventions are relevant for many social workers. This paper reviews the rise in the diagnoses of Bipolar spectrum disorders for both children and adults. It considers the safety of antipsychotic medications, a mainstay of treatment for children and adults, which, in addition to other well-documented negative side effects, have recently been shown to decrease brain volume by a significant percent. These issues are particularly relevant for children in the foster care system.

Controversies In Psychiatry And Dsm-5: The Relevance For Social Work (Occasional Essay), Jill Littrell, Jeffrey R. Lacasse

jill l littrell Dr.

This essay addresses recent controversies surrounding the forthcoming fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5—the first major revision of the DSM since 1994), as well as questions regarding the safety and efficacy of psychotropic medications discussed in the public domain. Mental health professionals across a wide range of professions have signed a petition to the DSM-5 Task Force protesting changes in the new edition, and critiques of psychiatric medications are increasingly disseminated in the media. These issues have particular relevance for children in foster care, who receive diagnoses and medication at high rates. The general …

Taking The Perspective That A Depressive State Reflects Inflammation: Implications For The Use Of Antidepressants, Jill Littrell

jill l littrell Dr.

This paper reviews both the evidence that supports the characterization of depression as an inflammatory disorder and the different biochemical mechanisms that have been postulated for the connection between inflammation and depression. This association offers credible explanation for the short term efficacy of antidepressants, which have short term anti-inflammatory effects. Evidence for those anti-inflammatory effects is discussed. Evidence of the contrary long-term effects of antidepressants, which increase rather than decrease inflammation, is also reviewed. It is argued that this increase in inflammation would predict an increase in chronicity among depressed patients that have been treated with antidepressants drugs, which has …

The Controversy Over Antidepressant Drugs In An Era Of Evidence-Based Practice, Jill Littrell, Jeffrey Lacasse

jill l littrell Dr.

Questions regarding the efficacy of antidepressant drugs have been a recent focus of attention in the national news both in print and in the television media. Many clients will have questions regarding what they can believe and how they can address mood problems. Social workers constitute a greater percentage of the mental health work force than any other profession. Thus, social workers will probably be asked by clients about these issues. This article presents information on the efficacy of antidepressants for both the short and long term. It covers adverse effects and withdrawal symptoms. Clients' self-determination should be honored. However, …

Perspectives Emerging From Neuroscience On Why People Become Addicted And What To Do About It, Jill Littrell

jill l littrell Dr.

This paper reviews the new ideas emerging from neuroscience regarding the question of why some people are compelled to use drugs. During the process of drug exposure, the brain’s motivational system is changed in ways that co-opts the individual’s motivational system. Changes in the brain’s motivational structures along with changes in the brain’s self-regulatory structures compel an individual to drug use. Ways to reverse those changes in an addicted brain have been identified, as have ways to enhance self-regulatory control. The information from neuroscience offers a new perspective on “loss of control” as well as offering implications for treatment.

Can A Diagnosis Be Epidemic, With Therapeutic Efforts The Catastrophe?, Jill Littrell

jill l littrell Dr.

The diagnosis of Bipolar Spectrum Disorders (BSD) given for office visits has risen 40 fold for children and has risen dramatically for adults as well. Some of the growth may have been fueled by re-categorization of individuals who would previously have received diagnoses of major depression along with the widening of diagnostic criteria for BSD. Concomitant with the rise in BSD diagnoses, the number of adults and children receiving atypical antipsychotics has increased dramatically. Recent evidence finds that atypical antipsychotics cause considerable reduction in brain volume. It is thus imperative to ensure that those with diagnoses comprising BSD—Bipolar I, Bipolar …

How Addiction Happens, How Change Happens, And What Social Workers Need To Know To Be Effective Facilitators Of Change, Jill Littrell

jill l littrell Dr.

During the last two decades, neuroscience research has proliferated examining brain mechanisms that explain why some people are compelled to pursue drugs and alcohol. The findings suggest that addiction is independent of pleasure, and that drug seeking can be triggered outside of conscious awareness (Berridge, Robinson, & Aldridge, 2009; Goldstein et al., 2009; Kalivas, Volkow, & Seamans, 2005). The observations and conclusions from this research can be used to advantage in treating addiction. The use of social psychological principles, in the context of motivational interviewing, offers a platform for taking advantage of these new insights. After a brief sketch of …

Children In Foster Care And Excessive Medications, Jill Littrell

jill l littrell Dr.

Children in foster care system are more likely to receive diagnoses of major mental illness and to be medicated with powerful medications such as antipsychotic drugs. Reasons for the increased risk of the actual mental illnesses and for the diagnoses of illness among children in foster care are reviewed. The reliabilities of various diagnoses are considered. The legitimacy of the rationale for early medications to prevent later disability is discussed. The very real hazards of medicating with antipsychotics, anticonvulsants, stimulants, mood stabilizers and antidepressants are reviewed. A discussion of advocacy efforts occurring around the United States on behalf of medicated …

Book Review: “Mental Illness In The Family: Issues And Trends”, Jill Littrell

jill l littrell Dr.

No abstract provided.