Human factors and ergonomics as a patient safety practice

PubMed Central

Carayon, Pascale; Xie, Anping; Kianfar, Sarah

2014-01-01

Background Human factors and ergonomics (HFE) approaches to patient safety have addressed five different domains: usability of technology; human error and its role in patient safety; the role of healthcare worker performance in patient safety; system resilience; and HFE systems approaches to patient safety. Methods A review of various HFE approaches to patient safety and studies on HFE interventions was conducted. Results This paper describes specific examples of HFE-based interventions for patient safety. Studies show that HFE can be used in a variety of domains. Conclusions HFE is a core element of patient safety improvement. Therefore, every effort should be made to support HFE applications in patient safety. PMID:23813211

Human Factors Engineering Program Review Model (NUREG-0711)Revision 3: Update Methodology and Key Revisions

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

OHara J. M.; Higgins, J.; Fleger, S.

The U.S. Nuclear Regulatory Commission (NRC) reviews the human factors engineering (HFE) programs of applicants for nuclear power plant construction permits, operating licenses, standard design certifications, and combined operating licenses. The purpose of these safety reviews is to help ensure that personnel performance and reliability are appropriately supported. Detailed design review procedures and guidance for the evaluations is provided in three key documents: the Standard Review Plan (NUREG-0800), the HFE Program Review Model (NUREG-0711), and the Human-System Interface Design Review Guidelines (NUREG-0700). These documents were last revised in 2007, 2004 and 2002, respectively. The NRC is committed to the periodicmore » update and improvement of the guidance to ensure that it remains a state-of-the-art design evaluation tool. To this end, the NRC is updating its guidance to stay current with recent research on human performance, advances in HFE methods and tools, and new technology being employed in plant and control room design. NUREG-0711 is the first document to be addressed. We present the methodology used to update NUREG-0711 and summarize the main changes made. Finally, we discuss the current status of the update program and the future plans.« less

A systematic review of mixed methods research on human factors and ergonomics in health care.

PubMed

Carayon, Pascale; Kianfar, Sarah; Li, Yaqiong; Xie, Anping; Alyousef, Bashar; Wooldridge, Abigail

2015-11-01

This systematic literature review provides information on the use of mixed methods research in human factors and ergonomics (HFE) research in health care. Using the PRISMA methodology, we searched four databases (PubMed, PsycInfo, Web of Science, and Engineering Village) for studies that met the following inclusion criteria: (1) field study in health care, (2) mixing of qualitative and quantitative data, (3) HFE issues, and (4) empirical evidence. Using an iterative and collaborative process supported by a structured data collection form, the six authors identified a total of 58 studies that primarily address HFE issues in health information technology (e.g., usability) and in the work of healthcare workers. About two-thirds of the mixed methods studies used the convergent parallel study design where quantitative and qualitative data were collected simultaneously. A variety of methods were used for collecting data, including interview, survey and observation. The most frequent combination involved interview for qualitative data and survey for quantitative data. The use of mixed methods in healthcare HFE research has increased over time. However, increasing attention should be paid to the formal literature on mixed methods research to enhance the depth and breadth of this research. Copyright © 2015. Published by Elsevier Ltd.

Factors affecting the appreciation generated through applying human factors/ergonomics (HFE) principles to systems of work.

PubMed

So, R H Y; Lam, S T

2014-01-01

This retrospective study examined the levels of appreciation (applause) given by clients to Human Factors/Ergonomic (HFE) specialists after they have modified the systems of work. Thirteen non-academic projects were chosen because the HFE interventions involved changed the way workers work at their workplaces. Companies involved range from multi-national corporations and military organizations with thousands of employees to small trading companies with less than 10 employees. In 5 cases the HFE recommendations were fully adopted and well appreciated. In 4 they were largely ignored and not appreciated, with partial adoption and some appreciation in the other 4 cases. Three factors that predict appreciation were identified: (i) alignment between the benefits HFE can provide and the project's key performance indices; (ii) awareness of HFE among the client's senior management; and (iii) a team organization appropriate for applying HFE recommendations. Having an HFE specialist on the client's side can greatly increase levels of appreciation, but lack of such a specialist will not affect levels of appreciation. A clear contractual requirement for HFE intervention does not promote appreciation significantly, but its absence can greatly reduce levels of appreciation. These relationships are discussed using the Kano's model of quality. Means to generate greater appreciation of the benefits of HFE are discussed. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Hype, harmony and human factors: applying user-centered design to achieve sustainable telehealth program adoption and growth.

PubMed

Rossos, P G; St-Cyr, O; Purdy, B; Toenjes, C; Masino, C; Chmelnitsky, D

2015-01-01

Despite decades of international experience with the use of information and communication technologies in healthcare delivery, widespread telehealth adoption remains limited and progress slow. Escalating health system challenges related to access, cost and quality currently coincide with rapid advancement of affordable and reliable internet based communication technologies creating unprecedented opportunities and incentives for telehealth. In this paper, we will describe how Human Factors Engineering (HFE) and user-centric elements have been incorporated into the establishment of telehealth within a large academic medical center to increase acceptance and sustainability. Through examples and lessons learned we wish to increase awareness of HFE and its importance in the successful implementation, innovation and growth of telehealth programs.

Color-coding and human factors engineering to improve patient safety characteristics of paper-based emergency department clinical documentation.

PubMed

Kobayashi, Leo; Boss, Robert M; Gibbs, Frantz J; Goldlust, Eric; Hennedy, Michelle M; Monti, James E; Siegel, Nathan A

2011-01-01

Investigators studied an emergency department (ED) physical chart system and identified inconsistent, small font labeling; a single-color scheme; and an absence of human factors engineering (HFE) cues. A case study and description of the methodology with which surrogate measures of chart-related patient safety were studied and subsequently used to reduce latent hazards are presented. Medical records present a challenge to patient safety in EDs. Application of HFE can improve specific aspects of existing medical chart organization systems as they pertain to patient safety in acute care environments. During 10 random audits over 5 consecutive days (573 data points), 56 (9.8%) chart binders (range 0.0-23%) were found to be either misplaced or improperly positioned relative to other chart binders; 12 (21%) were in the critical care area. HFE principles were applied to develop an experimental chart binder system with alternating color-based chart groupings, simple and prominent identifiers, and embedded visual cues. Post-intervention audits revealed significant reductions in chart binder location problems overall (p < 0.01), for Urgent Care A and B pods (6.4% to 1.2%; p < 0.05), Fast Track C pod (19.3% to 0.0%; p < 0.05) and Behavioral/Substance Abuse D pod (15.7% to 0.0%; p < 0.05) areas of the ED. The critical care room area did not display an improvement (11.4% to 13.2%; p = 0.40). Application of HFE methods may aid the development, assessment, and modification of acute care clinical environments through evidence-based design methodologies and contribute to safe patient care delivery.

A strategy for human factors/ergonomics: developing the discipline and profession.

PubMed

Dul, Jan; Bruder, Ralph; Buckle, Peter; Carayon, Pascale; Falzon, Pierre; Marras, William S; Wilson, John R; van der Doelen, Bas

2012-01-01

Human factors/ergonomics (HFE) has great potential to contribute to the design of all kinds of systems with people (work systems, product/service systems), but faces challenges in the readiness of its market and in the supply of high-quality applications. HFE has a unique combination of three fundamental characteristics: (1) it takes a systems approach (2) it is design driven and (3) it focuses on two closely related outcomes: performance and well-being. In order to contribute to future system design, HFE must demonstrate its value more successfully to the main stakeholders of system design. HFE already has a strong value proposition (mainly well-being) and interactivity with the stakeholder group of 'system actors' (employees and product/service users). However, the value proposition (mainly performance) and relationships with the stakeholder groups of 'system experts' (experts fromtechnical and social sciences involved in system design), and 'system decision makers' (managers and other decision makers involved in system design, purchase, implementation and use), who have a strong power to influence system design, need to be developed. Therefore, the first main strategic direction is to strengthen the demand for high-quality HFE by increasing awareness among powerful stakeholders of the value of high-quality HFE by communicating with stakeholders, by building partnerships and by educating stakeholders. The second main strategic direction is to strengthen the application of high-quality HFE by promoting the education of HFE specialists, by ensuring high-quality standards of HFE applications and HFE specialists, and by promoting HFE research excellence at universities and other organisations. This strategy requires cooperation between the HFE community at large, consisting of the International Ergonomics Association (IEA), local (national and regional) HFE societies, and HFE specialists. We propose a joint world-wide HFE development plan, in which the IEA takes a leadership role. Human factors/ergonomics (HFE) has much to offer by addressing major business and societal challenges regarding work and product/service systems. HFE potential, however, is underexploited. This paper presents a strategy for the HFE community to strengthen demand and application of high-quality HFE, emphasising its key elements: systems approach, design driven, and performance and well-being goals.

HFE Process Guidance and Standards for potential application to updating NRC guidance

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

Jacques Hugo; J. J. Persensky

2012-07-01

The U.S. Nuclear Regulatory Commission (NRC) reviews and evaluates the human factors engineering (HFE) programs of applicants for nuclear power plant construction permits, operating licenses, standard design certifications, and combined operating licenses. The purpose of these safety reviews is to help ensure that personnel performance and reliability are appropriately supported. Detailed design review procedures and guidance for the evaluations is provided in three key documents: the Standard Review Plan (NUREG-0800), the HFE Program Review Model (NUREG-0711), and the Human-System Interface Design Review Guidelines (NUREG-0700). These documents were last revised in 2007, 2004 and 2002, respectively. The NRC is committed tomore » the periodic update and improvement of these guidance documents to ensure that they remain state-of-the-art design evaluation tools. Thus, the NRC has initiated a project with BNL to update the NRC guidance to remain current with recent research on human performance, advances in HFE methods and tools, and new technology. INL supported Brookhaven National Lab (BNL) to update the detailed HFE review criteria contained in NUREG-0711 and NUREG-0700 based on (1) feedback obtained from end users, (2) the results of NRC research and development efforts supporting the NRC staff’s HFE safety reviews, and (3) other material the project staff identify as applicable to the update effort. INL submitted comments on development plans and sections of NUREGs 0800, 0711, and 0700. The contractor prepared the report attached here as the deliverable for this work.« less

A Virtual Campus Based on Human Factor Engineering

ERIC Educational Resources Information Center

Yang, Yuting; Kang, Houliang

2014-01-01

Three Dimensional or 3D virtual reality has become increasingly popular in many areas, especially in building a digital campus. This paper introduces a virtual campus, which is based on a 3D model of The Tourism and Culture College of Yunnan University (TCYU). Production of the virtual campus was aided by Human Factor and Ergonomics (HF&E), an…

Human factors and ergonomics for primary care.

PubMed

Bowie, Paul; Jeffcott, Shelly

2016-03-01

In the second paper of this series, we provide a brief overview of the scientific discipline of human factors and ergonomics (HFE). Traditionally the HFE focus in healthcare has been in acute hospital settings which are perceived to exhibit characteristics more similar to other high-risk industries already applying related principles and methods. This paper argues that primary care is an area which could benefit extensively from an HFE approach, specifically in improving the performance and well-being of people and organisations. To this end, we define the purpose of HFE, outline its three specialist sub-domains (physical, cognitive and organisational HFE) and provide examples of guiding HFE principles and practices. Additionally, we describe HFE issues of significance to primary care education, improvement and research and outline early plans for building capacity and capability in this setting.

NRC Reviewer Aid for Evaluating the Human Factors Engineering Aspects of Small Modular Reactors

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

OHara J. M.; Higgins, J.C.

Small modular reactors (SMRs) are a promising approach to meeting future energy needs. Although the electrical output of an individual SMR is relatively small compared to that of typical commercial nuclear plants, they can be grouped to produce as much energy as a utility demands. Furthermore, SMRs can be used for other purposes, such as producing hydrogen and generating process heat. The design characteristics of many SMRs differ from those of current conventional plants and may require a distinct concept of operations (ConOps). The U.S. Nuclear Regulatory Commission (NRC) conducted research to examine the human factors engineering (HFE) and themore » operational aspects of SMRs. The research identified thirty potential human-performance issues that should be considered in the NRC's reviews of SMR designs and in future research activities. The purpose of this report is to support NRC HFE reviewers of SMR applications by identifying some of the questions that can be asked of applicants whose designs have characteristics identified in the issues. The questions for each issue were identified and organized based on the review elements and guidance contained in Chapter 18 of the Standard Review Plan (NUREG-0800), and the Human Factors Engineering Program Review Model (NUREG-0711).« less

APPLICATION OF EYE TRACKING FOR MEASUREMENT AND EVALUATION IN HUMAN FACTORS STUDIES IN CONTROL ROOM MODERNIZATION

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

Kovesdi, C.; Spielman, Z.; LeBlanc, K.

An important element of human factors engineering (HFE) pertains to measurement and evaluation (M&E). The role of HFE-M&E should be integrated throughout the entire control room modernization (CRM) process and be used for human-system performance evaluation and diagnostic purposes with resolving potential human engineering deficiencies (HEDs) and other human machine interface (HMI) design issues. NUREG-0711 describes how HFE in CRM should employ a hierarchical set of measures, particularly during integrated system validation (ISV), including plant performance, personnel task performance, situation awareness, cognitive workload, and anthropometric/ physiological factors. Historically, subjective measures have been primarily used since they are easier to collectmore » and do not require specialized equipment. However, there are pitfalls with relying solely on subjective measures in M&E such that negatively impact reliability, sensitivity, and objectivity. As part of comprehensively capturing a diverse set of measures that strengthen findings and inferences made of the benefits from emerging technologies like advanced displays, this paper discusses the value of using eye tracking as an objective method that can be used in M&E. A brief description of eye tracking technology and relevant eye tracking measures is provided. Additionally, technical considerations and the unique challenges with using eye tracking in full-scaled simulations are addressed. Finally, this paper shares preliminary findings regarding the use of a wearable eye tracking system in a full-scale simulator study. These findings should help guide future full-scale simulator studies using eye tracking as a methodology to evaluate human-system performance.« less

Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients.

PubMed

Vieira, Fatima Mendonça Jorge; Nakhle, Maria Cristina; Abrantes-Lemos, Clarice Pires; Cançado, Eduardo Luiz Rachid; Reis, Vitor Manoel Silva dos

2013-01-01

Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations. An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR. Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors. Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients.

Improving Safety through Human Factors Engineering.

PubMed

Siewert, Bettina; Hochman, Mary G

2015-10-01

Human factors engineering (HFE) focuses on the design and analysis of interactive systems that involve people, technical equipment, and work environment. HFE is informed by knowledge of human characteristics. It complements existing patient safety efforts by specifically taking into consideration that, as humans, frontline staff will inevitably make mistakes. Therefore, the systems with which they interact should be designed for the anticipation and mitigation of human errors. The goal of HFE is to optimize the interaction of humans with their work environment and technical equipment to maximize safety and efficiency. Special safeguards include usability testing, standardization of processes, and use of checklists and forcing functions. However, the effectiveness of the safety program and resiliency of the organization depend on timely reporting of all safety events independent of patient harm, including perceived potential risks, bad outcomes that occur even when proper protocols have been followed, and episodes of "improvisation" when formal guidelines are found not to exist. Therefore, an institution must adopt a robust culture of safety, where the focus is shifted from blaming individuals for errors to preventing future errors, and where barriers to speaking up-including barriers introduced by steep authority gradients-are minimized. This requires creation of formal guidelines to address safety concerns, establishment of unified teams with open communication and shared responsibility for patient safety, and education of managers and senior physicians to perceive the reporting of safety concerns as a benefit rather than a threat. © RSNA, 2015.

A systematic review of Human Factors and Ergonomics (HFE)-based healthcare system redesign for quality of care and patient safety

PubMed Central

Xie, Anping; Carayon, Pascale

2014-01-01

Healthcare systems need to be redesigned to provide care that is safe, effective and efficient, and meets the multiple needs of patients. This systematic review examines how Human Factors and Ergonomics (HFE) is applied to redesign healthcare work systems and processes and improve quality and safety of care. We identified twelve projects representing 23 studies and addressing different physical, cognitive and organizational HFE issues in a variety of healthcare systems and care settings. Some evidence exists for the effectiveness of HFE-based healthcare system redesign in improving process and outcome measures of quality and safety of care. We assessed risk of bias in 16 studies reporting the impact of HFE-based healthcare system redesign and found varying quality across studies. Future research should further assess the impact of HFE on quality and safety of care, and clearly define the mechanisms by which HFE-based system redesign can improve quality and safety of care. Practitioner Summary Existing evidence shows that HFE-based healthcare system redesign has the potential to improve quality of care and patient safety. Healthcare organizations need to recognize the importance of HFE-based healthcare system redesign to quality of care and patient safety, and invest resources to integrate HFE in healthcare improvement activities. PMID:25323570

Tents and Shelters

DTIC Science & Technology

2010-07-15

Electromagnetic Interference ( EMI ), Transportability, Environmental, Human Factors Engineering (HFE), Reliability, Availability and Maintainability (RAM), and...vehicles and trailers to store, protect, and secure equipment, tools, and other theft-prone items. CBCs are designed not to interfere with the carrier’s...Transportability Test Facility. d. Electromagnetic Interference ( EMI ) Test Facility. e. Areas capable of conducting Blackout, Sound, Sand and Dust tests

Precipitating factors of porphyria cutanea tarda in Brazil with emphasis on hemochromatosis gene (HFE) mutations. Study of 60 patients*

PubMed Central

Vieira, Fatima Mendonça Jorge; Nakhle, Maria Cristina; Abrantes-Lemos, Clarice Pires; Cançado, Eduardo Luiz Rachid; dos Reis, Vitor Manoel Silva

2013-01-01

BACKGROUND Porphyria cutanea tarda is the most common form of porphyria, characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with porphyria cutanea tarda worldwide, although up to date only one study has been conducted in Brazil. OBJECTIVES Investigation of porphyria cutanea tarda association with C282Y and H63D mutations in the HFE gene. Identification of precipitating factors (hepatitis C, HIV, alcoholism and estrogen) and their link with HFE mutations. METHODS An ambispective study of 60 patients with PCT was conducted during the period from 2003 to 2012. Serological tests for hepatitis C and HIV were performed and histories of alcohol abuse and estrogen intake were investigated. HFE mutations were identified with real-time PCR. RESULTS Porphyria cutanea tarda predominated in males and alcohol abuse was the main precipitating factor. Estrogen intake was the sole precipitating factor present in 25% of female patients. Hepatitis C was present in 41.7%. All HIV-positive patients (15.3%) had a history of alcohol abuse. Allele frequency for HFE mutations, i.e., C282Y (p = 0.0001) and H63D (p = 0.0004), were significantly higher in porphyria cutanea tarda patients, compared to control group. HFE mutations had no association with the other precipitating factors. CONCLUSIONS Alcohol abuse, hepatitis C and estrogen intake are prevalent precipitating factors in our porphyria cutanea tarda population; however, hemochromatosis in itself can also contribute to the outbreak of porphyria cutanea tarda, which makes the research for HFE mutations necessary in these patients PMID:24068123

A systematic review of human factors and ergonomics (HFE)-based healthcare system redesign for quality of care and patient safety.

PubMed

Xie, Anping; Carayon, Pascale

2015-01-01

Healthcare systems need to be redesigned to provide care that is safe, effective and efficient, and meets the multiple needs of patients. This systematic review examines how human factors and ergonomics (HFE) is applied to redesign healthcare work systems and processes and improve quality and safety of care. We identified 12 projects representing 23 studies and addressing different physical, cognitive and organisational HFE issues in a variety of healthcare systems and care settings. Some evidence exists for the effectiveness of HFE-based healthcare system redesign in improving process and outcome measures of quality and safety of care. We assessed risk of bias in 16 studies reporting the impact of HFE-based healthcare system redesign and found varying quality across studies. Future research should further assess the impact of HFE on quality and safety of care, and clearly define the mechanisms by which HFE-based system redesign can improve quality and safety of care.

Human factors/ergonomics as a systems discipline? "The human use of human beings" revisited.

PubMed

Hollnagel, Erik

2014-01-01

Discussions of the possible future of Human factors/ergonomics (HFE) usually take the past for granted in the sense that the future of HFE is assumed to be more of the same. This paper argues that the nature of work in the early 2010s is so different from the nature of work when HFE was formulated 60-70 years ago that a critical reassessment of the basis for HFE is needed. If HFE should be a systems discipline, it should be a soft systems rather than a hard systems discipline. It is not enough for HFE to seek to improve performance and well-being through systems design, since any change to the work environment in principle alters the very basis for the change. Instead HFE should try to anticipate how the nature of work will change so that it can both foresee what work will be and propose what work should be. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

HFE gene variants affect iron in the brain.

PubMed

Nandar, Wint; Connor, James R

2011-04-01

Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.

HFE Genotyping in Patients with Elevated Serum Iron Indices and Liver Diseases

PubMed Central

Evangelista, Andreia Silva; de Araújo, Thiago Ferreira; Abrantes-Lemos, Clarice Pires; Deguti, Marta Mitiko; Cançado, Eduardo Luiz Rachid

2015-01-01

Iron abnormalities in chronic liver disease may be the result of genetic diseases or secondary factors. The present study aimed to identify subjects with HFE-HH in order to describe the frequency of clinical manifestations, identify risk factors for iron elevation, and compare the iron profile of HFE-HH to other genotypes in liver disease patients. A total of 108 individuals with hepatic disease, transferrin saturation (TS) > 45%, and serum ferritin (SF) > 350 ng/mL were tested for HFE mutations. Two groups were characterized: C282Y/C282Y or C282Y/H63D genotypes (n = 16) were the HFE hereditary hemochromatosis (HFE-HH) group; and C282Y and H63D single heterozygotes, the H63D/H63D genotype, and wild-type were considered group 2 (n = 92). Nonalcoholic liver disease, alcoholism, and chronic hepatitis C were detected more frequently in group 2, whereas arthropathy, hepatocarcinoma, diabetes, and osteoporosis rates were significantly higher in the HFE-HH group. TS > 82%, SF > 2685 ng/mL, and serum iron > 178 μg/dL were the cutoffs for diagnosis of HFE-HH in patients with liver disease. Thus, in non-Caucasian populations with chronic liver disease, HFE-HH diagnosis is more predictable in those with iron levels higher than those proposed in current guidelines for the general population. PMID:25654085

What do human factors and ergonomics professionals value in research publications? Re-examining the research-practice gap.

PubMed

Chung, Amy Z Q; Williamson, Ann; Shorrock, Steven T

2014-01-01

The research-practice gap is of concern in human factors/ergonomics (HF/E) as there is a belief that HF/E research may not be making an impact on practice in the 'real world'. A potential issue is what researchers and practitioners perceive as important in HF/E journal articles as a primary means of conveying research findings to practitioners. This study examined the characteristics that make scientific journal articles appeal to HF/E researchers and practitioners using a web-based survey. HF/E researchers and practitioners were more similar than expected in judgements of important attributes and the selection of articles. Both practitioners and researchers considered practical significance to be more important than theoretical significance, in direct contrast to professionals from a related discipline--psychology. Well-written articles were appreciated across disciplines. The results signal a strong interest in practical applications in HF/E, but a relative lack of focus on development of theories that should be the basis for practical applications.

Human Factors Engineering. Part 1. Test Procedures

DTIC Science & Technology

1990-05-15

b, given to offset mem ’,ry effects, and all participants should begin the test at the same i~erneral level of familiarity with the item. The HFE...Pop ohp l _________________________ CL PUWH p@e flpSI _____________ o AwjiqjIsA poonpojj x x x x x x P L)56MIS P*otnpo8 LIJ U Alijoixec3 poonpoW x x x

The development and piloting of electronic standardized measures on nursing work: combining engineering and nursing knowledge.

PubMed

Bragadóttir, Helga; Gunnarsdóttir, Sigrún; Ingason, Helgi T

2013-05-01

This paper describes the development and piloting of electronic standardized measures on nursing work (e-SMNW) for rich data gathering on the work and work environment of registered nurses (RNs) and practical nurses (PNs). Efficient and valid methods are needed to measure nursing work to enhance the optimal use of the nursing workforce for safe patient care. The study combined human factors engineering (HFE) and nursing knowledge to develop electronic standardized measures for observational studies on nursing work in acute care. The work and work environment of RNs and PNs in acute care medical and surgical inpatient units was successfully measured using e-SMNW. With predetermined items of work activities and influencing factors in the work of nurses, and full use of computer technology, multi-layered rich standardized data were gathered, analysed and displayed. The combination of nursing knowledge, HFE and computer technology enables observational data collection for a rich picture of the complex work of nursing. Information collected by standardized and multi-layered measures makes it easier to identify potential improvements, with regard to influencing factors and management of the work and work environment of nurses. Further use of computer technology in health services research is encouraged. © 2012 Blackwell Publishing Ltd.

Effect of pH on the stability of hemochromatosis factor E: a combined spectroscopic and molecular dynamics simulation-based study.

PubMed

Khan, Parvez; Shandilya, Ashutosh; Jayaram, B; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

2017-05-01

Hereditary hemochromatosis is an iron overburden condition, which is mainly governed by hereditary hemochromatosis factor E (HFE), a member of major histocompatibility complex class I. To understand the effect of pH on the structure and stability of HFE, we have cloned, expressed, and purified the HFE in the bacterial system and performed circular dichroism, fluorescence, and absorbance measurements at a wide pH range (pH 3.0-11.0). We found that HFE remains stable in the pH range 7.5-11.0 and gets completely acid denatured at low pH values. In this work, we also analyzed the contribution of salt bridges to the stability of HFE. We further performed molecular dynamics simulations for 80 ns at different pH values. An excellent agreement was observed between results from biophysical and MD simulation studies. At lower pH, HFE undergoes denaturation and may be driven toward a degradation pathway, such as ubiquitination. Hence, HFE is not available to bind again with transferrin receptor1 to negatively regulate iron homeostasis. Further we postulated that, might be low pH of cancerous cells helps them to meet their high iron requirement.

A human factors analysis of EVA time requirements

NASA Technical Reports Server (NTRS)

Pate, D. W.

1996-01-01

Human Factors Engineering (HFE), also known as Ergonomics, is a discipline whose goal is to engineer a safer, more efficient interface between humans and machines. HFE makes use of a wide range of tools and techniques to fulfill this goal. One of these tools is known as motion and time study, a technique used to develop time standards for given tasks. A human factors motion and time study was initiated with the goal of developing a database of EVA task times and a method of utilizing the database to predict how long an ExtraVehicular Activity (EVA) should take. Initial development relied on the EVA activities performed during the STS-61 mission (Hubble repair). The first step of the analysis was to become familiar with EVAs and with the previous studies and documents produced on EVAs. After reviewing these documents, an initial set of task primitives and task time modifiers was developed. Videotaped footage of STS-61 EVAs were analyzed using these primitives and task time modifiers. Data for two entire EVA missions and portions of several others, each with two EVA astronauts, was collected for analysis. Feedback from the analysis of the data will be used to further refine the primitives and task time modifiers used. Analysis of variance techniques for categorical data will be used to determine which factors may, individually or by interactions, effect the primitive times and how much of an effect they have.

HFE gene mutations and Wilson's disease in Sardinia.

PubMed

Sorbello, Orazio; Sini, Margherita; Civolani, Alberto; Demelia, Luigi

2010-03-01

Hypocaeruloplasminaemia can lead to tissue iron storage in Wilson's disease and the possibility of iron overload in long-term overtreated patients should be considered. The HFE gene encodes a protein that is intimately involved in intestinal iron absorption. The aim of this study was to determine the prevalence of the HFE gene mutation, its role in iron metabolism of Wilson's disease patients and the interplay of therapy in copper and iron homeostasis. The records of 32 patients with Wilson's disease were reviewed for iron and copper indices, HFE gene mutations and liver biopsy. Twenty-six patients were negative for HFE gene mutations and did not present significant alterations of iron metabolism. The HFE mutation was significantly associated with increased hepatic iron content (P<0.02) and transferrin saturation index (P<0.03). After treatment period, iron indices were significantly decreased only in HFE gene wild-type. The HFE gene mutations may be an addictional factor in iron overload in Wilson's disease. Our results showed that an adjustment of dosage of drugs could prevent further iron overload induced by overtreatment only in patients HFE wild-type. 2009. Published by Elsevier Ltd.

State of science: human factors and ergonomics in healthcare.

PubMed

Hignett, Sue; Carayon, Pascale; Buckle, Peter; Catchpole, Ken

2013-01-01

The past decade has seen an increase in the application of human factors and ergonomics (HFE) techniques to healthcare delivery in a broad range of contexts (domains, locations and environments). This paper provides a state of science commentary using four examples of HFE in healthcare to review and discuss analytical and implementation challenges and to identify future issues for HFE. The examples include two domain areas (occupational ergonomics and surgical safety) to illustrate a traditional application of HFE and the area that has probably received the most research attention. The other two examples show how systems and design have been addressed in healthcare with theoretical approaches for organisational and socio-technical systems and design for patient safety. Future opportunities are identified to develop and embed HFE systems thinking in healthcare including new theoretical models and long-term collaborative partnerships. HFE can contribute to systems and design initiatives for both patients and clinicians to improve everyday performance and safety, and help to reduce and control spiralling healthcare costs. There has been an increase in the application of HFE techniques to healthcare delivery in the past 10 years. This paper provides a state of science commentary using four illustrative examples (occupational ergonomics, design for patient safety, surgical safety and organisational and socio-technical systems) to review and discuss analytical and implementation challenges and identify future issues for HFE.

Development and Application of a Clinical Microsystem Simulation Methodology for Human Factors-Based Research of Alarm Fatigue.

PubMed

Kobayashi, Leo; Gosbee, John W; Merck, Derek L

2017-07-01

(1) To develop a clinical microsystem simulation methodology for alarm fatigue research with a human factors engineering (HFE) assessment framework and (2) to explore its application to the comparative examination of different approaches to patient monitoring and provider notification. Problems with the design, implementation, and real-world use of patient monitoring systems result in alarm fatigue. A multidisciplinary team is developing an open-source tool kit to promote bedside informatics research and mitigate alarm fatigue. Simulation, HFE, and computer science experts created a novel simulation methodology to study alarm fatigue. Featuring multiple interconnected simulated patient scenarios with scripted timeline, "distractor" patient care tasks, and triggered true and false alarms, the methodology incorporated objective metrics to assess provider and system performance. Developed materials were implemented during institutional review board-approved study sessions that assessed and compared an experimental multiparametric alerting system with a standard monitor telemetry system for subject response, use characteristics, and end-user feedback. A four-patient simulation setup featuring objective metrics for participant task-related performance and response to alarms was developed along with accompanying structured HFE assessment (questionnaire and interview) for monitor systems use testing. Two pilot and four study sessions with individual nurse subjects elicited true alarm and false alarm responses (including diversion from assigned tasks) as well as nonresponses to true alarms. In-simulation observation and subject questionnaires were used to test the experimental system's approach to suppressing false alarms and alerting providers. A novel investigative methodology applied simulation and HFE techniques to replicate and study alarm fatigue in controlled settings for systems assessment and experimental research purposes.

Human factors/ergonomics implications of big data analytics: Chartered Institute of Ergonomics and Human Factors annual lecture.

PubMed

Drury, Colin G

2015-01-01

In recent years, advances in sensor technology, connectedness and computational power have come together to produce huge data-sets. The treatment and analysis of these data-sets is known as big data analytics (BDA), and the somewhat related term data mining. Fields allied to human factors/ergonomics (HFE), e.g. statistics, have developed computational methods to derive meaningful, actionable conclusions from these data bases. This paper examines BDA, often characterised by volume, velocity and variety, giving examples of successful BDA use. This examination provides context by considering examples of using BDA on human data, using BDA in HFE studies, and studies of how people perform BDA. Significant issues for HFE are the reliance of BDA on correlation rather than hypotheses and theory, the ethics of BDA and the use of HFE in data visualisation.

Positive influences of home food environment on primary-school children's diet and weight status: a structural equation model approach.

PubMed

Ong, Jia Xin; Ullah, Shahid; Magarey, Anthea; Leslie, Eva

2016-10-01

The mechanism by which the home food environment (HFE) influences childhood obesity is unclear. The present study aimed to investigate the relationship between HFE and childhood obesity as mediated by diet in primary-school children. Cross-sectional data collected from parents and primary-school children participating in the Obesity Prevention and Lifestyle Evaluation Project. Only children aged 9-11 years participated in the study. Matched parent/child data (n 3323) were analysed. Exploratory factor analysis underlined components of twenty-one HFE items; these were linked to child diet (meeting guidelines for fruit, vegetable and non-core food intakes) and measured child BMI, in structural equation modelling, adjusting for confounders. Twenty geographically bounded metropolitan and regional South Australian communities. School children and their parents from primary schools in selected communities. In the initial exploratory factor analysis, nineteen items remaining extracted eight factors with eigenvalues >1·0 (72·4 % of total variance). A five-factor structure incorporating ten items described HFE. After adjusting for age, gender, socio-economic status and physical activity all associations in the model were significant (P<0·05), explaining 9·3 % and 4·5 % of the variance in child diet and BMI, respectively. A more positive HFE was directly and indirectly associated with a lower BMI in children through child diet. The robust statistical methodology used in the present study provides support for a model of direct and indirect dynamics between the HFE and childhood obesity. The model can be tested in future longitudinal and intervention studies to identify the most effective components of the HFE to target in childhood obesity prevention efforts.

Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis.

PubMed

Duarte, Tiago L; Caldas, Carolina; Santos, Ana G; Silva-Gomes, Sandro; Santos-Gonçalves, Andreia; Martins, Maria João; Porto, Graça; Lopes, José Manuel

2017-04-01

In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe -/- mice (an established model of human HFE-hemochromatosis). Wild-type, Nrf2 -/- , Hfe -/- and double knockout (Hfe/Nrf2 -/- ) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12-18 (middle-aged) or 24 months (old) for evaluation of liver pathology. Despite the parenchymal iron accumulation, Hfe -/- mice presented no liver injury. The combination of iron overload (Hfe -/- ) and defective antioxidant defences (Nrf2 -/- ) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe -/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

HFE gene mutation is a risk factor for tissue iron accumulation in hemodialysis patients.

PubMed

Turkmen, Ercan; Yildirim, Tolga; Yilmaz, Rahmi; Hazirolan, Tuncay; Eldem, Gonca; Yilmaz, Engin; Aybal Kutlugun, Aysun; Altindal, Mahmut; Altun, Bulent

2017-07-01

HFE gene mutations are responsible from iron overload in general population. Studies in hemodialysis patients investigated the effect of presence of HFE gene mutations on serum ferritin and transferrin saturation (TSAT) with conflicting results. However effect of HFE mutations on iron overload in hemodialysis patients was not previously extensively studied. 36 hemodialysis patients (age 51.3 ± 15.6, (18/18) male/female) and 44 healthy control subjects included in this cross sectional study. Hemoglobin, ferritin, TSAT in the preceding 2 years were recorded. Iron and erythropoietin (EPO) administered during this period were calculated. Iron accumulation in heart and liver was detected by MRI. Relationship between HFE gene mutation, hemoglobin, iron parameters and EPO doses, and tissue iron accumulation were determined. Iron overload was detected in nine (25%) patients. Hemoglobin, iron parameters, weekly EPO doses, and monthly iron doses of patients with and without iron overload were similar. There was no difference between control group and hemodialysis patients with respect to the prevalence of HFE gene mutations. Iron overload was detected in five of eight patients who had HFE gene mutations, but iron overload was present in 4 of 28 patients who had no mutations (P = 0.01). Hemoglobin, iron parameters, erythropoietin, and iron doses were similar in patients with and without gene mutations. HFE gene mutations remained the main determinant of iron overload after multivariate logistic regression analysis (P = 0.02; OR, 11.6). Serum iron parameters were not adequate to detect iron overload and HFE gene mutation was found to be an important risk factor for iron accumulation. © 2017 International Society for Hemodialysis.

H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment.

PubMed

Ali-Rahmani, Fatima; Grigson, Patricia S; Lee, Sang; Neely, Elizabeth; Connor, James R; Schengrund, Cara-Lynne

2014-06-01

The H63D variant of the hemochromatosis (HFE) gene, when expressed in carriers of the apolipoprotein E4 allele, is implicated as a risk factor for earlier onset of Alzheimer's disease (AD). We tested the hypothesis that like expression of apolipoprotein E4, expression of H63D-HFE disrupts cholesterol metabolism contributing to an increase in neurodegeneration and memory deficits. Analysis of SH-SY5Y human neuroblastoma cells transfected to stably express either wild type- (WT) or H63D-HFE indicated about a 50% reduction in cholesterol content in cells expressing H63D-HFE. This was accompanied by a significant decrease in expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and a significant increase in expression of cholesterol 24-hydroxylase. Consistent with these studies, H67D-HFE (orthologous to human H63D-HFE) knock-in mice, showed a greater age dependent decline in brain cholesterol than WT-HFE animals and changes in expression of proteins regulating cholesterol metabolism. Brains of aged H67D-HFE mice also exhibited a significant decrease in expression of synapse proteins and a significant increase in caspase-3 expression relative to WT-HFE controls. H67D-HFE mice also had a greater reduction in brain volume and poorer recognition and spatial memory than WT-HFE mice, symptoms associated with AD. These results indicate that the alterations in cholesterol metabolism associated with expression of H63D-HFE may contribute to the development of AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Diabetes in HFE Hemochromatosis

PubMed Central

Acton, Ronald T.

2017-01-01

Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis. PMID:28331855

HFE polymorphisms influence the response to chemotherapeutic agents via induction of p16INK4A.

PubMed

Lee, Sang Y; Liu, Siying; Mitchell, Ryan M; Slagle-Webb, Becky; Hong, Young-Soo; Sheehan, Jonas M; Connor, James R

2011-11-01

HFE is a protein that impacts cellular iron uptake. HFE gene variants are identified as risk factors or modifiers for multiple diseases. Using HFE stably transfected human neuroblastoma cells, we found that cells carrying the C282Y HFE variant do not differentiate when exposed to retinoic acid. Therefore, we hypothesized HFE variants would impact response to therapeutic agents. Both the human neuroblastoma and glioma cells that express the C282Y HFE variant are resistant to Temodar, geldanamycin and γ-radiation. A gene array analysis revealed that p16INK4A (p16) expression was increased in association with C282Y expression. Decreasing p16 protein by siRNA resulted in increased vulnerability to all of the therapeutic agents suggesting that p16 is responsible for the resistance. Decreasing HFE expression by siRNA resulted in a 85% decrease in p16 expression in the neuroblastoma cells but not the astrocytoma cells. These data suggest a potential direct relationship between HFE and p16 that may be cell specific or mediated by different pathways in the different cell types. In conclusion, the C282Y HFE variant impacts the vulnerability of cancer cells to current treatment strategies apparently by increasing expression of p16. Although best known as a tumor suppressor, there are multiple reports that p16 is elevated in some forms of cancer. Given the frequency of the HFE gene variants, as high as 10% of the Caucasian population, these data provide compelling evidence that the C282Y HFE variant should be part of a pharmacogenetic strategy for evaluating treatment efficacy in cancer cells. Copyright © 2011 UICC.

Human Factors Engineering Integration Project, Phase 1 Report

DTIC Science & Technology

1976-07-01

HFE. ESSEX CORPORATION Essex Corporation, Alexandria, Virginia, was selected to be the integration contractor. The primary role of the integration...having primary cognizance for the individual phases of the process. u PAS-75-52 ■ fay^a^^ja^^ aiiijlaiiaiiiig^^ a W’IPlJW’wi’UlWBII» ^■JWrtB^r...alternative ships. Implication for HFEI The design aspects of this stage can be characterized as addressing primary payload and performance features (speed

A mutation in the HFE gene is associated with altered brain iron profiles and increased oxidative stress in mice.

PubMed

Nandar, Wint; Neely, Elizabeth B; Unger, Erica; Connor, James R

2013-06-01

Because of the increasing evidence that H63D HFE polymorphism appears in higher frequency in neurodegenerative diseases, we evaluated the neurological consequences of H63D HFE in vivo using mice that carry H67D HFE (homologous to human H63D). Although total brain iron concentration did not change significantly in the H67D mice, brain iron management proteins expressions were altered significantly. The 6-month-old H67D mice had increased HFE and H-ferritin expression. At 12 months, H67D mice had increased H- and L-ferritin but decreased transferrin expression suggesting increased iron storage and decreased iron mobilization. Increased L-ferritin positive microglia in H67D mice suggests that microglia increase iron storage to maintain brain iron homeostasis. The 6-month-old H67D mice had increased levels of GFAP, increased oxidatively modified protein levels, and increased cystine/glutamate antiporter (xCT) and hemeoxygenase-1 (HO-1) expression indicating increased metabolic and oxidative stress. By 12 months, there was no longer increased astrogliosis or oxidative stress. The decrease in oxidative stress at 12 months could be related to an adaptive response by nuclear factor E2-related factor 2 (Nrf2) that regulates antioxidant enzymes expression and is increased in the H67D mice. These findings demonstrate that the H63D HFE impacts brain iron homeostasis, and promotes an environment of oxidative stress and induction of adaptive mechanisms. These data, along with literature reports on humans with HFE mutations provide the evidence to overturn the traditional paradigm that the brain is protected from HFE mutations. The H67D knock-in mouse can be used as a model to evaluate how the H63D HFE mutation contributes to neurodegenerative diseases. Copyright © 2013 Elsevier B.V. All rights reserved.

[The polymorphism of catechol-O-methyltransferase (COMT) and hemochromatosis (HFE) genes in the radiocontaminated regions residents with different chromosome aberration frequency].

PubMed

Ivanova, T I; Kondrashova, T V; Krikunova, L I; Smirnova, I A; Shentereva, N I; Sychenkova, N I; Rykova, E V; Zharikova, I A; Khorokhorina, V A; Riabchenko, N I; Zamulaeva, I A

2010-01-01

The association between polymorphisms in genes COMT, HFE that takes part in oxidative stress regulation, and chromosome aberration frequency in lymphocytes was assessed in 278 female residents of radiation polluted regions of Central Russia: Bryansk (322 kBk/m2) and Tula Districts (137Cs - 171 kBk/m2). The C187G, G845A genotyping of HFE and G1947A (H/L) of COMT was done by means of polymerase chain reaction-restriction fragment length polymorphism. Studied population was divided into 3 subgroups by level of chromosome aberrations per cell (0-2, 3-4, >5). There was shown statistically significant difference in distribution of COMTand HFE genotypes between the groups. The high frequency of chromosome aberrations (> or = 5%) was associated with homozygotes of the high activity COMT G/G and HFE CC. Heterozygotes for G1947A COMT and C187G HFE reveal negative association with the high frequency of chromosome aberrations and correspond to "resistance factors".

Evidence for the Influence of the Iron Regulatory MHC Class I Molecule HFE on Tumor Progression in Experimental Models and Clinical Populations

PubMed Central

Weston, Cody; Connor, James

2014-01-01

Proteins involved in iron regulation are modifiers of cancer risk and progression. Of these, the HFE protein (high iron gene and its protein product) is of particular interest because of its interaction with both iron handling and immune function and the high rate of genetic polymorphisms resulting in a mutant protein. Clinical studies suggest that HFE polymorphisms increase the risk of certain cancers, but the inconsistent outcomes suggest a more nuanced effect, possibly interacting with other genetic or environmental factors. Some basic science research has been conducted to begin to understand the implications of variant HFE genotype on cancer, but the story is far from complete. In particular, putative mechanisms exist for HFE to affect tumor progression through its role in iron handling and its major histocompatibility complex class I structural features. In this review, the current understanding of the role of HFE in cancer is described and models for future directions are identified. PMID:25520556

HFE (Human Factors Engineering) Technology for Navy Weapon System Acquisition.

DTIC Science & Technology

1979-07-01

requirements 2-31 to electrical components using: Failure Modes and Effects Analysis ( FMEA ) and LOR data, component design requirements and a selected...3- 60 * ,.- .- I; L , , _ m m _ --- : " I. I ._ . - I- The use of SAINT can specify various outputs of the simulation, histograms, plots, summary...Electro Safety . 60 .98 .95 .65 .92 .70 .42 .62 Personnel Relationships .74 .70 .79 .63 .40 .77 .85 .80 Electro Circuit Analysis .63 .90 .95 .58 .40

HFE gene variants modify the association between maternal lead burden and infant birthweight: a prospective birth cohort study in Mexico City, Mexico.

PubMed

Cantonwine, David; Hu, Howard; Téllez-Rojo, Martha Maria; Sánchez, Brisa N; Lamadrid-Figueroa, Héctor; Ettinger, Adrienne S; Mercado-García, Adriana; Hernández-Avila, Mauricio; Wright, Robert O

2010-07-26

Neonatal growth is a complex process involving genetic and environmental factors. Polymorphisms in the hemochromatosis (HFE) iron regulatory genes have been shown to modify transport and toxicity of lead which is known to affect birth weight. We investigated the role of HFE C282Y, HFE H63 D, and transferrin (TF) P570 S gene variants in modifying the association of lead and infant birthweight in a cohort of Mexican mother-infant pairs. Subjects were initially recruited between 1994-1995 from three maternity hospitals in Mexico City and 411 infants/565 mothers had archived blood available for genotyping. Multiple linear regression models, stratified by either maternal/infant HFE or TF genotype and then combined with interaction terms, were constructed examining the association of lead and birthweight after controlling for covariates. 3.1%, 16.8% and 17.5% of infants (N=390) and 1.9%, 14.5% and 18.9% of mothers (N=533) carried the HFE C282Y, HFE H63D, and TF P570 S variants, respectively. The presence of infant HFE H63 D variants predicted 110.3 g (95% CI -216.1, -4.6) decreases in birthweight while maternal HFE H63 D variants predicted reductions of 52.0 g (95% CI -147.3 to 43.2). Interaction models suggest that both maternal and infant HFE H63 D genotype may modify tibia lead's effect on infant birthweight in opposing ways. In our interaction models, maternal HFE H63 D variant carriers had a negative association between tibia lead and birthweight. These results suggest that the HFE H63 D genotype modifies lead's effects on infant birthweight in a complex fashion that may reflect maternal-fetal interactions with respect to the metabolism and transport of metals.

A Human Factors Analysis of EVA Time Requirements

NASA Technical Reports Server (NTRS)

Pate, Dennis W.

1997-01-01

Human Factors Engineering (HFE) is a discipline whose goal is to engineer a safer, more efficient interface between humans and machines. HFE makes use of a wide range of tools and techniques to fulfill this goal. One of these tools is known as motion and time study, a technique used to develop time standards for given tasks. During the summer of 1995, a human factors motion and time study was initiated with the goals of developing a database of EVA task times and developing a method of utilizing the database to predict how long an EVA should take. Initial development relied on the EVA activities performed during the STS-61 (Hubble) mission. The first step of the study was to become familiar with EVA's, the previous task-time studies, and documents produced on EVA's. After reviewing these documents, an initial set of task primitives and task-time modifiers was developed. Data was collected from videotaped footage of two entire STS-61 EVA missions and portions of several others, each with two EVA astronauts. Feedback from the analysis of the data was used to further refine the primitives and modifiers used. The project was continued during the summer of 1996, during which data on human errors was also collected and analyzed. Additional data from the STS-71 mission was also collected. Analysis of variance techniques for categorical data was used to determine which factors may affect the primitive times and how much of an effect they have. Probability distributions for the various task were also generated. Further analysis of the modifiers and interactions is planned.

Iron dysregulation combined with aging prevents sepsis-induced apoptosis.

PubMed

Javadi, Pardis; Buchman, Timothy G; Stromberg, Paul E; Turnbull, Isaiah R; Vyas, Dinesh; Hotchkiss, Richard S; Karl, Irene E; Coopersmith, Craig M

2005-09-01

Sepsis, iron loading, and aging cause independent increases in gut epithelial and splenic apoptosis. It is unknown how their combination will affect apoptosis and systemic cytokine levels. Hfe-/- mice (a murine homologue of hemochromatosis) abnormally accumulate iron in their tissues. Aged (24-26 months) or mature (16-18 months) Hfe-/- mice and wild type (WT) littermates were subjected to cecal ligation and puncture (CLP) or sham laparotomy. Intestine, spleen, and blood were harvested 24 h later and assessed for apoptosis and cytokine levels. Gut epithelial and splenic apoptosis were low in both aged septic and sham Hfe-/- mice, regardless of the amount of iron in their diet. Mature septic WT mice had increased apoptosis compared to age-matched sham WT mice. Mature septic Hfe-/- mice had similar levels of intestinal cell death to age-matched septic WT mice but higher levels of splenic apoptosis. Apoptosis was significantly lower in septic aged Hfe-/- mice than septic mature Hfe-/- animals. Interleukin-6 was elevated in septic aged Hfe-/- mice compared to sham mice. Although sepsis, chronic iron dysregulation, and aging each increase gut and splenic apoptosis, their combination yields cell death levels similar to sham animals despite the fact that aged Hfe-/- mice are able to mount an inflammatory response following CLP and mature Hfe-/- mice have elevated sepsis-induced apoptosis. Combining sepsis with two risk factors that ordinarily increase cell death and increase mortality in CLP yields an apoptotic response that could not have been predicted based upon each element in isolation.

Hepcidin regulation in wild-type and Hfe knockout mice in response to alcohol consumption: evidence for an alcohol-induced hypoxic response.

PubMed

Heritage, Mandy L; Murphy, Therese L; Bridle, Kim R; Anderson, Gregory J; Crawford, Darrell H G; Fletcher, Linda M

2009-08-01

Expression of Hamp1, the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE-associated hereditary hemochromatosis and Hfe knockout mice (Hfe(-/-)). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe(-/-) mice. Hfe(-/-) and C57BL/6 (wild-type) mice were pair-fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT-PCR and protein expression of hypoxia inducible factor-1 alpha (HIF-1alpha) was measured by western blot. Hamp1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol-fed wild-type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe(-/-) mice fed on the control diet compared with wild-type animals and alcohol further exacerbated these effects. HIF-1alpha protein levels were elevated in alcohol-fed wild-type animals compared with controls. Alcohol may decrease Hamp1 gene expression independently of the HFE pathway possibly via alcohol-induced hypoxia.

C282Y-HFE Gene Variant Affects Cholesterol Metabolism in Human Neuroblastoma Cells

PubMed Central

Ali-Rahmani, Fatima; Huang, Michael A.; Schengrund, C.-L.; Connor, James R.; Lee, Sang Y.

2014-01-01

Although disruptions in the maintenance of iron and cholesterol metabolism have been implicated in several cancers, the association between variants in the HFE gene that is associated with cellular iron uptake and cholesterol metabolism has not been studied. The C282Y-HFE variant is a risk factor for different cancers, is known to affect sphingolipid metabolism, and to result in increased cellular iron uptake. The effect of this variant on cholesterol metabolism and its possible relevance to cancer phenotype was investigated using wild type (WT) and C282Y-HFE transfected human neuroblastoma SH-SY5Y cells. Expression of C282Y-HFE in SH-SY5Y cells resulted in a significant increase in total cholesterol as well as increased transcription of a number of genes involved in its metabolism compared to cells expressing WT-HFE. The marked increase in expression of NPC1L1 relative to that of most other genes, was accompanied by a significant increase in expression of NPC1, a protein that functions in cholesterol uptake by cells. Because inhibitors of cholesterol metabolism have been proposed to be beneficial for treating certain cancers, their effect on the viability of C282Y-HFE neuroblastoma cells was ascertained. C282Y-HFE cells were significantly more sensitive than WT-HFE cells to U18666A, an inhibitor of desmosterol Δ24-reductase the enzyme catalyzing the last step in cholesterol biosynthesis. This was not seen for simvastatin, ezetimibe, or a sphingosine kinase inhibitor. These studies indicate that cancers presenting in carriers of the C282Y-HFE allele might be responsive to treatment designed to selectively reduce cholesterol content in their tumor cells. PMID:24533143

C282Y-HFE gene variant affects cholesterol metabolism in human neuroblastoma cells.

PubMed

Ali-Rahmani, Fatima; Huang, Michael A; Schengrund, C-L; Connor, James R; Lee, Sang Y

2014-01-01

Although disruptions in the maintenance of iron and cholesterol metabolism have been implicated in several cancers, the association between variants in the HFE gene that is associated with cellular iron uptake and cholesterol metabolism has not been studied. The C282Y-HFE variant is a risk factor for different cancers, is known to affect sphingolipid metabolism, and to result in increased cellular iron uptake. The effect of this variant on cholesterol metabolism and its possible relevance to cancer phenotype was investigated using wild type (WT) and C282Y-HFE transfected human neuroblastoma SH-SY5Y cells. Expression of C282Y-HFE in SH-SY5Y cells resulted in a significant increase in total cholesterol as well as increased transcription of a number of genes involved in its metabolism compared to cells expressing WT-HFE. The marked increase in expression of NPC1L1 relative to that of most other genes, was accompanied by a significant increase in expression of NPC1, a protein that functions in cholesterol uptake by cells. Because inhibitors of cholesterol metabolism have been proposed to be beneficial for treating certain cancers, their effect on the viability of C282Y-HFE neuroblastoma cells was ascertained. C282Y-HFE cells were significantly more sensitive than WT-HFE cells to U18666A, an inhibitor of desmosterol Δ24-reductase the enzyme catalyzing the last step in cholesterol biosynthesis. This was not seen for simvastatin, ezetimibe, or a sphingosine kinase inhibitor. These studies indicate that cancers presenting in carriers of the C282Y-HFE allele might be responsive to treatment designed to selectively reduce cholesterol content in their tumor cells.

MTHFR and HFE, but not preproghrelin and LBP, polymorphisms as risk factors for all-cause end-stage renal disease development.

PubMed

Bloudíčková, S; Kuthanová, L; Hubáček, J A

2014-01-01

End-stage renal disease (ESRD) is a serious health problem worldwide. The high prevalence of cardiovascular diseases and chronic inflammation remains a major cause of morbidity and mortality in haemodialysed patients. Beside some external factors, genetic predisposition both to renal failure and poor prognosis has been assumed. We have collected a total of 1,014 haemodialysed patients and 2,559 unrelated healthy Caucasians. Single-nucleotide polymorphisms (SNPs) in genes for preproghrelin (GHRL), lipopolysaccharide-binding protein (LBP), HFE and MTHFR were genotyped. In the group of patients, significantly more carriers presented the MTHFR T667T (P = 0.002) and HFE Asp63Asp (P = 0.001) and Cys282Cys (P = 0.01) genotypes. The frequencies of individual SNPs within GHRL and LBP genes did not differ between the patients and controls. The trends in genotype frequencies did not differ between the subgroups of patients with different time on haemodialysis. Common variants in MTHFR and HFE could be a risk factor for all-cause ESRD development, but are not predictors for the survival on haemodialysis.

Theory versus practice in the human factors and ergonomics discipline: Trends in journal publications from 1960 to 2010.

PubMed

Chung, Amy Z Q; Williamson, Ann

2018-01-01

The research-practice gap has been highlighted as a barrier to effective practice in human factors and ergonomics (HFE). There is also evidence of a theory-research gap that may be limiting the scientific evidence base of HFE. The purpose of this study was to examine trends in journal publications, especially relating to the research-practice gap and the involvement of theory over time. A content analysis was conducted on 425 journal articles published in Human Factors, Ergonomics, and Applied Ergonomics from 1960 to 2010. Results showed evidence of growth in applied research with increasing collaborative research between research and industry, larger research teams, and more empirical research-especially on applied problems. While there has been a corresponding increase in the involvement of theory in HFE publications, around half of the publications failed to acknowledge theory. This calls into question whether the HFE discipline may be missing the benefits of theory to guide research and subsequent practice, and to enhance the development of new ideas. Copyright © 2017 Elsevier Ltd. All rights reserved.

Understanding the Current State of Infection Prevention to Prevent Clostridium difficile Infection: A Human Factors and Systems Engineering Approach

PubMed Central

Yanke, Eric; Zellmer, Caroline; Van Hoof, Sarah; Moriarty, Helene; Carayon, Pascale; Safdar, Nasia

2015-01-01

Background Achieving and sustaining high levels of healthcare worker (HCW) compliance with contact isolation precautions is challenging. The aim of this study was to determine HCW work system barriers to, and facilitators of, adherence to contact isolation for patients with suspected or confirmed Clostridium difficile infection (CDI) using a human factors and systems engineering approach. Methods Prospective cohort study from September 2013 to November 2013 at a large academic medical center (hospital A) and an affiliated Veterans Administration (VA) hospital (hospital B). A human factors engineering (HFE) model for patient safety – the Systems Engineering Initiative for Patient Safety (SEIPS) model – was used to guide work system analysis and direct observation data collection. 288 observations were conducted. HCWs and visitors were assessed for compliance with all components of contact isolation precautions (hand hygiene, gowning, and gloving) before and after patient contact. Time required to complete contact isolation precautions was measured and adequacy of contact isolation supplies was assessed. Results Full compliance with contact isolation precautions was low at both hospitals: hospital A, 7%; hospital B, 22%. Lack of appropriate hand hygiene prior to room entry (Compliance: hospital A, 18%; hospital B, 29%) was the most common reason for lack of full compliance. More time was required for full compliance as compared to compliance with no components of contact isolation precautions before patient room entry, inside patient room, and after patient room exit (59.9 sec vs. 3.2 sec; P < .001; 507.3 sec vs. 149.7 sec; P = .006; 15.2 sec vs. 1.3 sec; P < .001). Compliance was lower when contact isolation supplies were inadequate (4% vs. 16%; P = .005). Conclusions Adherence to contact isolation precautions for CDI is a complex, time-consuming process. HFE analysis indicates multiple work system components serve as barriers and facilitators to full compliance with contact isolation precautions and should be addressed further to prevent CDI. PMID:25728149

Understanding the current state of infection prevention to prevent Clostridium difficile infection: a human factors and systems engineering approach.

PubMed

Yanke, Eric; Zellmer, Caroline; Van Hoof, Sarah; Moriarty, Helene; Carayon, Pascale; Safdar, Nasia

2015-03-01

Achieving and sustaining high levels of health care worker (HCW) compliance with contact isolation precautions is challenging. The aim of this study was to determine HCW work system barriers to and facilitators of adherence to contact isolation for patients with suspected or confirmed Clostridium difficile infection (CDI) using a human factors and systems engineering approach. This prospective cohort study took place between September 2013 and November 2013 at a large academic medical center (hospital A) and an affiliated Veterans Administration hospital (hospital B). A human factors engineering (HFE) model for patient safety, the Systems Engineering Initiative for Patient Safety model, was used to guide work system analysis and direct observation data collection. There were 288 observations conducted. HCWs and visitors were assessed for compliance with all components of contact isolation precautions (hand hygiene, gowning, and gloving) before and after patient contact. Time required to complete contact isolation precautions was measured, and adequacy of contact isolation supplies was assessed. Full compliance with contact isolation precautions was low at both hospitals A (7%) and B (22%). Lack of appropriate hand hygiene prior to room entry (compliance for hospital A: 18%; compliance for hospital B: 29%) was the most common reason for lack of full compliance. More time was required for full compliance compared with compliance with no components of contact isolation precautions before patient room entry, inside patient room, and after patient room exit (59.9 vs 3.2 seconds, P < .001; 507.3 vs 149.7 seconds, P = .006; 15.2 vs 1.3 seconds, P < .001, respectively). Compliance was lower when contact isolation supplies were inadequate (4% vs 16%, P = .005). Adherence to contact isolation precautions for CDI is a complex, time-consuming process. HFE analysis indicates that multiple work system components serve as barriers and facilitators to full compliance with contact isolation precautions and should be addressed further to prevent CDI. Published by Elsevier Inc.

Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age.

PubMed

Shi, Zumin; Johnstone, Daniel; Talseth-Palmer, Bente A; Evans, Tiffany-Jane; Spigelman, Allan D; Groombridge, Claire; Milward, Elizabeth A; Olynyk, John K; Suchy, Janina; Kurzawski, Grzegorz; Lubinski, Jan; Scott, Rodney J

2009-07-01

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes; however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 individuals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian sample only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC.

Human factors and ergonomics in home care: Current concerns and future considerations for health information technology

PubMed Central

Or, Calvin K.L.; Valdez, Rupa S.; Casper, Gail R.; Carayon, Pascale; Burke, Laura J.; Brennan, Patricia Flatley; Karsh, Ben-Tzion

2010-01-01

Sicker patients with greater care needs are being discharged to their homes to assume responsibility for their own care with fewer nurses available to aid them. This situation brings with it a host of human factors and ergonomic (HFE) concerns, both for the home care nurse and the home dwelling patient, that can affect quality of care and patient safety. Many of these concerns are related to the critical home care tasks of information access, communication, and patient self-monitoring and self-management. Currently, a variety of health information technologies (HITs) are being promoted as possible solutions to those problems, but those same technologies bring with them a new set of HFE concerns. This paper reviews the HFE considerations for information access, communication, and patients self-monitoring and self-management, discusses how HIT can potentially mitigate current problems, and explains how the design and implementation of HIT itself requires careful HFE attention. PMID:19713630

Human Factors and Ergonomics in the Design of Health Information Technology: Trends and Progress in 2014

PubMed Central

Ong, MS.

2015-01-01

Summary Objective To summarize significant contributions to the research on human factors and organizational issues in medical informatics. Methods An extensive search using PubMed/Medline and Web of Science® was conducted to identify the scientific contributions, published in 2014, to human factors and organizational issues in medical informatics, with a focus on health information technology (HIT) usability. The selection process comprised three steps: (i) 15 candidate best papers were selected by the two section editors, (ii) external reviewers from a pool of international experts reviewed each candidate best paper, and (iii) the final selection of three best papers was made by the editorial board of the IMIA Yearbook. Results Noteworthy papers published in 2014 describe an efficient, easy to implement, and useful process for detecting and mitigating human factors and ergonomics (HFE) issues of HIT. They contribute to promote the HFE approach with interventions based on rigorous and well-conducted methods when designing and implementing HIT. Conclusion The application of HFE in the design and implementation of HIT remains limited, and the impact of incorporating HFE principles on patient safety is understudied. Future works should be conducted to advance this field of research, so that the safety and quality of patient care are not compromised by the increasing adoption of HIT. PMID:26293852

HFE gene polymorphism defined by sequence-based typing of the Brazilian population and a standardized nomenclature for HFE allele sequences.

PubMed

Campos, W N; Massaro, J D; Martinelli, A L C; Halliwell, J A; Marsh, S G E; Mendes-Junior, C T; Donadi, E A

2017-10-01

The HFE molecule controls iron uptake from gut, and defects in the molecule have been associated with iron overload, particularly in hereditary hemochromatosis. The HFE gene including both coding and boundary intronic regions were sequenced in 304 Brazilian individuals, encompassing healthy individuals and patients exhibiting hereditary or acquired iron overload. Six sites of variation were detected: (1) H63D C>G in exon 2, (2) IVS2 (+4) T>C in intron 2, (3) a C>G transversion in intron 3, (4) C282Y G>A in exon 4, (5) IVS4 (-44) T>C in intron 4, and (6) a new guanine deletion (G>del) in intron 5, which were used for haplotype inference. Nine HFE alleles were detected and six of these were officially named on the basis of the HLA Nomenclature, defined by the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System, and published via the IPD-IMGT/HLA website. Four alleles, HFE*001, *002, *003, and *004 exhibited variation within their exon sequences. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A sustainable system of systems approach: a new HFE paradigm.

PubMed

Thatcher, Andrew; Yeow, Paul H P

2016-01-01

Sustainability issues such as natural resource depletion, pollution and poor working conditions have no geographical boundaries in our interconnected world. To address these issues requires a paradigm shift within human factors and ergonomics (HFE), to think beyond a bounded, linear model understanding towards a broader systems framework. For this reason, we introduce a sustainable system of systems model that integrates the current hierarchical conceptualisation of possible interventions (i.e., micro-, meso- and macro-ergonomics) with important concepts from the sustainability literature, including the triple bottom line approach and the notion of time frames. Two practical examples from the HFE literature are presented to illustrate the model. The implications of this paradigm shift for HFE researchers and practitioners are discussed and include the long-term sustainability of the HFE community and comprehensive solutions to problems that consider the emergent issues that arise from this interconnected world. A sustainable world requires a broader systems thinking than that which currently exists in ergonomics. This study proposes a sustainable system of systems model that incorporates ideas from the ecological sciences, notably a nested hierarchy of systems and a hierarchical time dimension. The implications for sustainable design and the sustainability of the HFE community are considered.

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

Roger Lew; Ronald L. Boring; Thomas A. Ulrich

Operators of critical processes, such as nuclear power production, must contend with highly complex systems, procedures, and regulations. Developing human-machine interfaces (HMIs) that better support operators is a high priority for ensuring the safe and reliable operation of critical processes. Human factors engineering (HFE) provides a rich and mature set of tools for evaluating the performance of HMIs, but the set of tools for developing and designing HMIs is still in its infancy. Here we propose that Microsoft Windows Presentation Foundation (WPF) is well suited for many roles in the research and development of HMIs for process control.

Viewing Prevention of Catheter-Associated Urinary Tract Infection as a System: Using Systems Engineering and Human Factors Engineering in a Quality Improvement Project in an Academic Medical Center.

PubMed

Rhee, Chanhaeng; Phelps, M Eleanor; Meyer, Bruce; Reed, W Gary

2016-01-01

Urinary tract infections (UTIs) are the most commonly reported health care-associated infection (HAI) in the United States. Among UTIs acquired in the hospital, approximately 75% are associated with urinary catheters, with an estimated 15%-25% of all hospitalized patients receiving urinary catheters during their hospitalization. Despite ambitious national goals to reduce these infections, catheter-associated urinary tract infection (CAUTI) has not decreased in the United States. Systems engineering (SE) and human factors engi- neering (HFE) methods were used to reduce urinary catheter utilization and CAUTIs in a three-year (June 1, 2012-May 31, 2015) quality improvement project in a 610-bed academic medical center. These methods were used to define the factors leading to CAUTI and promote standardization of urinary catheter utilization, insertion, and maintenance. The total systemwide CAUTI count decreased from 135 cases at baseline to 74 cases at the end of the project's Year 1, to 59 cases at the end of Year 2, and 25 cases at the end of Year 3-alone, an 81.5% reduction from baseline. The control chart showed a steady decline in the CAUTI count within a few months after the project's start. By the end of Year 3, on the basis of an average attributable-per-patient cost of CAUTI ($1,007 per case), the estimated annual avoidable CAUTI costs decreased from approximately $135,945 to $25,175 per year. Urinary catheter utilization decreased by 27.3% during the same three-year period, and the systemwide CAUTI standardized infection ratio (SIR) decreased from 3.2 to 0.51 (84.1% from baseline). SE and HFE methods and principles can effectively decrease urinary catheter utilization and CAUTI incidence in an academic medical center hospital environment.

HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis.

PubMed

Nelson, James E; Bhattacharya, Renuka; Lindor, Keith D; Chalasani, Naga; Raaka, Stuart; Heathcote, E Jenny; Miskovsky, Emil; Shaffer, Eldon; Rulyak, Stephen J; Kowdley, Kris V

2007-09-01

Previous studies examining the relationship between HFE mutations and severity of nonalcoholic steatohepatitis (NASH) have been limited by small sample size or ascertainment bias. The aim of this study was to examine the relationship between HFE mutations and histological severity in a large North American multicenter cohort with NASH. Data from 126 NASH patients were collected from 6 North American centers. Liver biopsy and genotyping for the C282Y and H63D HFE mutations were performed in all subjects. Serum transferrin-iron saturation and ferritin levels as well as hepatic iron content were recorded whenever available. Univariate and multivariate logistic regression analyses were performed to identify factors associated with advanced hepatic fibrosis. The prevalence of heterozygous C282Y and H63D HFE mutations was 14.3% and 21.4%, respectively, in the overall cohort. Among Caucasians, C282Y heterozygotes were more likely to have bridging fibrosis or cirrhosis (44% versus 21% [P = 0.05]) and stainable hepatic iron (50% versus 16% [P = 0.011]) compared with patients with other genotypes. Diabetes mellitus was the only independent predictor of advanced hepatic fibrosis (OR 4.37, 95% CI 1.41-13.54 [P = 0.010]) using multiple logistic regression analysis adjusting for age, sex, ethnicity, body mass index, and HFE genotype status. The HFE C282Y heterozygous mutation is associated with advanced fibrosis among Caucasians with NASH. Additional studies are warranted to examine the possible mechanisms for this relationship.

HFE gene: Structure, function, mutations, and associated iron abnormalities.

PubMed

Barton, James C; Edwards, Corwin Q; Acton, Ronald T

2015-12-15

The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload. Copyright © 2015 Elsevier B.V. All rights reserved.

Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease.

PubMed

Sandhu, Kam; Flintoff, Kaledas; Chatfield, Mark D; Dixon, Jeannette L; Ramm, Louise E; Ramm, Grant A; Powell, Lawrie W; Subramaniam, V Nathan; Wallace, Daniel F

2018-05-09

The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the HJV , HAMP or TFR2 genes. The purpose of this study was to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 subjects with non-HFE HH was extracted from 53 publications and compared with data from 984 subjects with HFE -p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP HH are phenotypically and clinically very similar and have the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH is more intermediate in its age of onset and severity. All clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy which were more commonly seen in HFE HH. This is the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH and the results will be valuable for the differential diagnosis and management of these conditions. Importantly, our analyses indicate that factors other than iron overload may be contributing to joint pathology in subjects with HFE HH. Copyright © 2018 American Society of Hematology.

Sample-to-SNP kit: a reliable, easy and fast tool for the detection of HFE p.H63D and p.C282Y variations associated to hereditary hemochromatosis.

PubMed

Nielsen, Peter B; Petersen, Maja S; Ystaas, Viviana; Andersen, Rolf V; Hansen, Karin M; Blaabjerg, Vibeke; Refstrup, Mette

2012-10-01

Classical hereditary hemochromatosis involves the HFE-gene and diagnostic analysis of the DNA variants HFE p.C282Y (c.845G>A; rs1800562) and HFE p.H63D (c.187C>G; rs1799945). The affected protein alters the iron homeostasis resulting in iron overload in various tissues. The aim of this study was to validate the TaqMan-based Sample-to-SNP protocol for the analysis of the HFE-p.C282Y and p.H63D variants with regard to accuracy, usefulness and reproducibility compared to an existing SNP protocol. The Sample-to-SNP protocol uses an approach where the DNA template is made accessible from a cell lysate followed by TaqMan analysis. Besides the HFE-SNPs other eight SNPs were used as well. These SNPs were: Coagulation factor II-gene F2 c.20210G>A, Coagulation factor V-gene F5 p.R506Q (c.1517G>A; rs121917732), Mitochondria SNP: mt7028 G>A, Mitochondria SNP: mt12308 A>G, Proprotein convertase subtilisin/kexin type 9-gene PCSK9 p.R46L (c.137G>T), Plutathione S-transferase pi 1-gene GSTP1 p.I105V (c313A>G; rs1695), LXR g.-171 A>G, ZNF202 g.-118 G>T. In conclusion the Sample-to-SNP kit proved to be an accurate, reliable, robust, easy to use and rapid TaqMan-based SNP detection protocol, which could be quickly implemented in a routine diagnostic or research facility. Copyright © 2012. Published by Elsevier B.V.

A question of our marketing or our preconceptions: commentary on the paper 'a strategy for human factors/ergonomics: developing the discipline and profession'.

PubMed

Nathanael, Dimitris; Marmaras, Nicolas

2012-01-01

The present paper is a commentary on the recently published IEA strategy for human factors/ergonomics (Dul, J., et al. (2012), A strategy for human factors/ergonomics: developing the discipline and profession. Ergonomics, 55(4), 377-395). Two main issues that demand attention are: (i) the way others understand our profession and discipline, and (ii) the way we understand our profession and added value to industry. First, it is advocated that the discussion on the future of human factors/ergonomics (HFE) should be focused more on the quality of the delivered value of HFE and less on its visibility and marketing. Second, the three fundamental characteristics of HFE, as proposed in the report, are discussed and the consequences of this proposal are further developed. Arguments are put forward on the endemic epistemological vagueness within the discipline and on the optimistic definition of its aim. Finally, a proposal is made at the epistemological level, which challenges some established convictions of the discipline. It is advocated that such an epistemological evolution may be necessary if HFE is to make progress towards contributing to system performance. The paper is a commentary on the IEA strategy for human factors/ergonomics. Issues discussed are, the way others understand our profession and the way we understand our profession and added value to industry. Some of the established convictions of the discipline are challenged and proposals are made to overcome these.

Measuring Resilience.

PubMed

Hoffman, Robert R; Hancock, P A

2017-06-01

As human factors and ergonomics (HF/E) moves to embrace a greater systems perspective concerning human-machine technologies, new and emergent properties, such as resilience, have arisen. Our objective here is to promote discussion as to how to measure this latter, complex phenomenon. Resilience is now a much-referenced goal for technology and work system design. It subsumes the new movement of resilience engineering. As part of a broader systems approach to HF/E, this concept requires both a definitive specification and an associated measurement methodology. Such an effort epitomizes our present work. Using rational analytic and synthetic methods, we offer an approach to the measurement of resilience capacity. We explicate how our proposed approach can be employed to compare resilience across multiple systems and domains, and emphasize avenues for its future development and validation. Emerging concerns for the promise and potential of resilience and associated concepts, such as adaptability, are highlighted. Arguments skeptical of these emerging dimensions must be met with quantitative answers; we advance one approach here. Robust and validated measures of resilience will enable coherent and rational discussions of complex emergent properties in macrocognitive system science.

Firefighting to Innovation: Using Human Factors and Ergonomics to Tackle Slip, Trip, and Fall Risks in Hospitals.

PubMed

Hignett, Sue; Wolf, Laurie; Taylor, Ellen; Griffiths, Paula

2015-11-01

The aim of this study was to use a theoretical model (bench) for human factors and ergonomics (HFE) and a comparison with occupational slips, trips, and falls (STFs) risk management to discuss patient STF interventions (bedside). Risk factors for patient STFs have been identified and reported since the 1950s and are mostly unchanged in the 2010s. The prevailing clinical view has been that STF events indicate underlying frailty or illness, and so many of the interventions over the past 60 years have focused on assessing and treating physiological factors (dizziness, illness, vision/hearing, medicines) rather than designing interventions to reduce risk factors at the time of the STF. Three case studies are used to discuss how HFE has been, or could be, applied to STF risk management as (a) a design-based (building) approach to embed safety into the built environment, (b) a staff- (and organization-) based approach, and (c) a patient behavior-based approach to explore and understand patient perspectives of STF events. The results from the case studies suggest taking a similar HFE integration approach to other industries, that is, a sustainable design intervention for the person who experiences the STF event-the patient. This paper offers a proactive problem-solving approach to reduce STFs by patients in acute hospitals. Authors of the three case studies use HFE principles (bench/book) to understand the complex systems for facility and equipment design and include the perspective of all stakeholders (bedside). © 2015, Human Factors and Ergonomics Society.

HJV and HFE Play Distinct Roles in Regulating Hepcidin.

PubMed

Wu, Qian; Wang, Hao; An, Peng; Tao, Yunlong; Deng, Jiali; Zhang, Zhuzhen; Shen, Yuanyuan; Chen, Caiyong; Min, Junxia; Wang, Fudi

2015-05-20

Hereditary hemochromatosis (HH) is an iron overload disease that is caused by mutations in HFE, HJV, and several other genes. However, whether HFE-HH and HJV-HH share a common pathway via hepcidin regulation is currently unclear. Recently, some HH patients have been reported to carry concurrent mutations in both the HFE and HJV genes. To dissect the roles and molecular mechanisms of HFE and/or HJV in the pathogenesis of HH, we studied Hfe(-/-), Hjv(-/-), and Hfe(-/-)Hjv(-/-) double-knockout mouse models. Hfe(-/-)Hjv(-/-) mice developed iron overload in multiple organs at levels comparable to Hjv(-/-) mice. After an acute delivery of iron, the expression of hepcidin (i.e., Hamp1 mRNA) was increased in the livers of wild-type and Hfe(-/-) mice, but not in either Hjv(-/-) or Hfe(-/-)Hjv(-/-) mice. Furthermore, iron-induced phosphorylation of Smad1/5/8 was not detected in the livers of Hjv(-/-) or Hfe(-/-)Hjv(-/-) mice. We generated and phenotypically characterized Hfe(-/-)Hjv(-/-) double-knockout mice. In addition, because they faithfully phenocopy clinical HH patients, these mouse models are an invaluable tool for mechanistically dissecting how HFE and HJV regulate hepcidin expression. Based on our results, we conclude that HFE may depend on HJV for transferrin-dependent hepcidin regulation. The presence of residual hepcidin in the absence of HFE suggests either the presence of an unknown regulator (e.g., TFR2) that is synergistic with HJV or that HJV is sufficient to maintain basal levels of hepcidin.

Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal).

PubMed

Branco, Claudia C; Gomes, Cidália T; De Fez, Laura; Bulhões, Sara; Brilhante, Maria José; Pereirinha, Tânia; Cabral, Rita; Rego, Ana Catarina; Fraga, Cristina; Miguel, António G; Brasil, Gracinda; Macedo, Paula; Mota-Vieira, Luisa

2015-01-01

Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations- c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family's HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40-2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins--the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C>G;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the São Miguel population. Independent replication studies in other populations are needed to confirm this association.

Carriers of the Complex Allele HFE c.[187C>G;340+4T>C] Have Increased Risk of Iron Overload in São Miguel Island Population (Azores, Portugal)

PubMed Central

Bulhões, Sara; Brilhante, Maria José; Pereirinha, Tânia; Cabral, Rita; Rego, Ana Catarina; Fraga, Cristina; Miguel, António G.; Brasil, Gracinda; Macedo, Paula; Mota-Vieira, Luisa

2015-01-01

Iron overload is associated with acquired and genetic conditions, the most common being hereditary hemochromatosis (HH) type-I, caused by HFE mutations. Here, we conducted a hospital-based case-control study of 41 patients from the São Miguel Island (Azores, Portugal), six belonging to a family with HH type-I pseudodominant inheritance, and 35 unrelated individuals fulfilling the biochemical criteria of iron overload compatible with HH type-I. For this purpose, we analyzed the most common HFE mutations– c.845G>A [p.Cys282Tyr], c.187C>G [p.His63Asp], and c.193A>T [p.Ser65Cys]. Results revealed that the family’s HH pseudodominant pattern is due to consanguineous marriage of HFE-c.845G>A carriers, and to marriage with a genetically unrelated spouse that is a -c.187G carrier. Regarding unrelated patients, six were homozygous for c.845A, and three were c.845A/c.187G compound heterozygous. We then performed sequencing of HFE exons 2, 4, 5 and their intron-flanking regions. No other mutations were observed, but we identified the -c.340+4C [IVS2+4C] splice variant in 26 (74.3%) patients. Functionally, the c.340+4C may generate alternative splicing by HFE exon 2 skipping and consequently, a protein missing the α1-domain essential for HFE/ transferrin receptor-1 interactions. Finally, we investigated HFE mutations configuration with iron overload by determining haplotypes and genotypic profiles. Results evidenced that carriers of HFE-c.187G allele also carry -c.340+4C, suggesting in-cis configuration. This data is corroborated by the association analysis where carriers of the complex allele HFE-c.[187C>G;340+4T>C] have an increased iron overload risk (RR = 2.08, 95% CI = 1.40−2.94, p<0.001). Therefore, homozygous for this complex allele are at risk of having iron overload because they will produce two altered proteins—the p.63Asp [c.187G], and the protein lacking 88 amino acids encoded by exon 2. In summary, we provide evidence that the complex allele HFE-c.[187C>G;340+4T>C] has a role, as genetic predisposition factor, on iron overload in the São Miguel population. Independent replication studies in other populations are needed to confirm this association. PMID:26501199

Formally verifying human–automation interaction as part of a system model: limitations and tradeoffs

PubMed Central

Bass, Ellen J.

2011-01-01

Both the human factors engineering (HFE) and formal methods communities are concerned with improving the design of safety-critical systems. This work discusses a modeling effort that leveraged methods from both fields to perform formal verification of human–automation interaction with a programmable device. This effort utilizes a system architecture composed of independent models of the human mission, human task behavior, human-device interface, device automation, and operational environment. The goals of this architecture were to allow HFE practitioners to perform formal verifications of realistic systems that depend on human–automation interaction in a reasonable amount of time using representative models, intuitive modeling constructs, and decoupled models of system components that could be easily changed to support multiple analyses. This framework was instantiated using a patient controlled analgesia pump in a two phased process where models in each phase were verified using a common set of specifications. The first phase focused on the mission, human-device interface, and device automation; and included a simple, unconstrained human task behavior model. The second phase replaced the unconstrained task model with one representing normative pump programming behavior. Because models produced in the first phase were too large for the model checker to verify, a number of model revisions were undertaken that affected the goals of the effort. While the use of human task behavior models in the second phase helped mitigate model complexity, verification time increased. Additional modeling tools and technological developments are necessary for model checking to become a more usable technique for HFE. PMID:21572930

SIMULATED HUMAN ERROR PROBABILITY AND ITS APPLICATION TO DYNAMIC HUMAN FAILURE EVENTS

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

Herberger, Sarah M.; Boring, Ronald L.

Abstract Objectives: Human reliability analysis (HRA) methods typically analyze human failure events (HFEs) at the overall task level. For dynamic HRA, it is important to model human activities at the subtask level. There exists a disconnect between dynamic subtask level and static task level that presents issues when modeling dynamic scenarios. For example, the SPAR-H method is typically used to calculate the human error probability (HEP) at the task level. As demonstrated in this paper, quantification in SPAR-H does not translate to the subtask level. Methods: Two different discrete distributions were generated for each SPAR-H Performance Shaping Factor (PSF) tomore » define the frequency of PSF levels. The first distribution was a uniform, or uninformed distribution that assumed the frequency of each PSF level was equally likely. The second non-continuous distribution took the frequency of PSF level as identified from an assessment of the HERA database. These two different approaches were created to identify the resulting distribution of the HEP. The resulting HEP that appears closer to the known distribution, a log-normal centered on 1E-3, is the more desirable. Each approach then has median, average and maximum HFE calculations applied. To calculate these three values, three events, A, B and C are generated from the PSF level frequencies comprised of subtasks. The median HFE selects the median PSF level from each PSF and calculates HEP. The average HFE takes the mean PSF level, and the maximum takes the maximum PSF level. The same data set of subtask HEPs yields starkly different HEPs when aggregated to the HFE level in SPAR-H. Results: Assuming that each PSF level in each HFE is equally likely creates an unrealistic distribution of the HEP that is centered at 1. Next the observed frequency of PSF levels was applied with the resulting HEP behaving log-normally with a majority of the values under 2.5% HEP. The median, average and maximum HFE calculations did yield different answers for the HFE. The HFE maximum grossly over estimates the HFE, while the HFE distribution occurs less than HFE median, and greater than HFE average. Conclusions: Dynamic task modeling can be perused through the framework of SPAR-H. Identification of distributions associated with each PSF needs to be defined, and may change depending upon the scenario. However it is very unlikely that each PSF level is equally likely as the resulting HEP distribution is strongly centered at 100%, which is unrealistic. Other distributions may need to be identified for PSFs, to facilitate the transition to dynamic task modeling. Additionally discrete distributions need to be exchanged for continuous so that simulations for the HFE can further advance. This paper provides a method to explore dynamic subtask to task translation and provides examples of the process using the SPAR-H method.« less

HFE interacts with the BMP type I receptor ALK3 to regulate hepcidin expression

PubMed Central

Wu, Xing-gang; Wang, Yang; Wu, Qian; Cheng, Wai-Hang; Liu, Wenjing; Zhao, Yueshui; Mayeur, Claire; Schmidt, Paul J.; Yu, Paul B.; Wang, Fudi

2014-01-01

Mutations in HFE are the most common cause of hereditary hemochromatosis (HH). HFE mutations result in reduced expression of hepcidin, a hepatic hormone, which negatively regulates iron absorption from the duodenum and iron release from macrophages. However, the mechanism by which HFE regulates hepcidin expression in hepatocytes is not well understood. It is known that the bone morphogenetic protein (BMP) pathway plays a central role in controlling hepcidin expression in the liver. Here we show that HFE overexpression increased Smad1/5/8 phosphorylation and hepcidin expression, whereas inhibition of BMP signaling abolished HFE-induced hepcidin expression in Hep3B cells. HFE was found to associate with ALK3, inhibiting ALK3 ubiquitination and proteasomal degradation and increasing ALK3 protein expression and accumulation on the cell surface. The 2 HFE mutants associated with HH, HFE C282Y and HFE H63D, regulated ALK3 protein ubiquitination and trafficking differently, but both failed to increase ALK3 cell-surface expression. Deletion of Hfe in mice resulted in a decrease in hepatic ALK3 protein expression. Our results provide evidence that HFE induces hepcidin expression via the BMP pathway: HFE interacts with ALK3 to stabilize ALK3 protein and increase ALK3 expression at the cell surface. PMID:24904118

Molecular basis of HFE-hemochromatosis

PubMed Central

Vujić, Maja

2014-01-01

Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies. PMID:24653703

Molecular basis of HFE-hemochromatosis.

PubMed

Vujić, Maja

2014-01-01

Iron-overload disorders owing to genetic misregulation of iron acquisition are referred to as hereditary hemochromatosis (HH). The most prevalent genetic iron overload disorder in Caucasians is caused by mutations in the HFE gene, an atypical MHC class I molecule. Recent studies classified HFE/Hfe-HH as a liver disease with the primarily failure in the production of the liver iron hormone hepcidin in hepatocytes. Inadequate hepcidin expression signals for excessive iron absorption from the diet and iron deposition in tissues causing multiple organ damage and failure. This review focuses on the molecular actions of the HFE/Hfe and hepcidin in maintaining systemic iron homeostasis and approaches undertaken so far to combat iron overload in HFE/Hfe-HH. In the light of the recent investigations, novel roles of extra-hepatocytic Hfe are discussed raising a question to the relevance of the multipurpose functions of Hfe for the understanding of HH-associated pathologies.

2008 High-Flow Experiment at Glen Canyon Dam-Morphologic Response of Eddy-Deposited Sandbars and Associated Aquatic Backwater Habitats along the Colorado River in Grand Canyon National Park

USGS Publications Warehouse

Grams, Paul E.; Schmidt, John C.; Andersen, Matthew E.

2010-01-01

The March 2008 high-flow experiment (HFE) at Glen Canyon Dam resulted in sandbar deposition and sandbar reshaping such that the area and volume of associated backwater aquatic habitat in Grand Canyon National Park was greater following the HFE. Analysis of backwater habitat area and volume for 116 locations at 86 study sites, comparing one month before and one month after the HFE, shows that total habitat area increased by 30 percent to as much as a factor of 3 and that volume increased by 80 percent to as much as a factor of 15. These changes resulted from an increase in the area and elevation of sandbars, which isolate backwaters from the main channel, and the scour of eddy return-current channels along the bank where the habitat occurs. Because of this greater relief on the sandbars, backwaters were present across a broader range of flows following the HFE than before the experiment. Reworking of sandbars during diurnal fluctuating flow operations in the first 6 months following the HFE caused sandbar erosion and a reduction of backwater size and abundance to conditions that were 5 to 14 percent greater than existed before the HFE. In the months following the HFE, erosion of sandbars and deposition in eddy return-current channels caused reductions of backwater area and volume. However, sandbar relief was still greater in October 2008 such that backwaters were present across a broader range of discharges than in February 2008. Topographic analyses of the sandbar and backwater morphologic data collected in this study demonstrate that steady flows are associated with a greater amount of continuously available backwater habitat than fluctuating flows, which result in a greater amount of intermittently available habitat. With the exception of the period immediately following the HFE, backwater habitat in 2008 was greater for steady flows associated with dam operations of relatively lower monthly volume (about 227 m3/s) than steady flows associated with dam operations of higher monthly volume. Similarly, there was greater habitat availability associated with lower monthly volume fluctuating flows (post-HFE through mid-April) compared to higher monthly volume fluctuating flows (after mid-April 2008). The sites monitored for this study represent about 20 percent of the 569 estimated number of potential sand-bounded backwaters that occur in eddies below Glen Canyon Dam in Grand Canyon National Park. Data from fish sampling in backwaters, by seining, demonstrates that both native and nonnative species were present in the backwaters monitored for this study.

Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice

PubMed Central

Alsulimani, Helal Hussain; Ye, Qi

2015-01-01

Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe-/-) and their control wild-type (Hfe+/+) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe+/+ mice, but not in Hfe-/- mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe+/+ compared with water-drinking Hfe+/+ mice. However, Mn-exposed Hfe-/- mice spent more time to find the target hole than Mn-drinking Hfe+/+ mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload disorders. PMID:26877837

Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice.

PubMed

Alsulimani, Helal Hussain; Ye, Qi; Kim, Jonghan

2015-12-01

Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (Hfe (-/-)) and their control wild-type (Hfe (+/+)) mice to MnCl2 in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in Hfe (+/+) mice, but not in Hfe (-/-) mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed Hfe (+/+) compared with water-drinking Hfe (+/+) mice. However, Mn-exposed Hfe (-/-) mice spent more time to find the target hole than Mn-drinking Hfe (+/+) mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload disorders.

HFE p.C282Y homozygosity predisposes to rapid serum ferritin rise after menopause: A genotype-stratified cohort study of hemochromatosis in Australian women.

PubMed

Warne, Charles D; Zaloumis, Sophie G; Bertalli, Nadine A; Delatycki, Martin B; Nicoll, Amanda J; McLaren, Christine E; Hopper, John L; Giles, Graham G; Anderson, Greg J; Olynyk, John K; Powell, Lawrie W; Allen, Katrina J; Gurrin, Lyle C

2017-04-01

Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations (HFE wild types) as comparison groups. A sample of the Melbourne Collaborative Cohort Study was selected for the "HealthIron" study (n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing. For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P < 0.001) during the first 10 years postmenopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between premenopausal and postmenopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 μg/L postmenopause, but the projected SF did not increase the risk of iron overload-related disease. These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

HFE gene mutations and iron status of Brazilian blood donors.

PubMed

Santos, P C J L; Cançado, R D; Terada, C T; Rostelato, S; Gonzales, I; Hirata, R D C; Hirata, M H; Chiattone, C S; Guerra-Shinohara, E M

2010-01-01

Mutations of the HFE and TFR2 genes have been associated with iron overload. HFE and TFR2 mutations were assessed in blood donors, and the relationship with iron status was evaluated. Subjects (N = 542) were recruited at the Hemocentro da Santa Casa de São Paulo, São Paulo, Brazil. Iron status was not influenced by HFE mutations in women and was independent of blood donation frequency. In contrast, men carrying the HFE 282CY genotype had lower total iron-binding capacity (TIBC) than HFE 282CC genotype carriers. Men who donated blood for the first time and were carriers of the HFE 282CY genotype had higher transferrin saturation values and lower TIBC concentrations than those with the homozygous wild genotype for the HFE C282Y mutation. Moreover, in this group of blood donors, carriers of HFE 63DD plus 63HD genotypes had higher serum ferritin values than those with the homozygous wild genotype for HFE H63D mutation. Multiple linear regression analysis showed that HFE 282CY leads to a 17.21% increase (P = 0.018) and a 83.65% decrease (P = 0.007) in transferrin saturation and TIBC, respectively. In addition, serum ferritin is influenced by age (3.91%, P = 0.001) and the HFE 63HD plus DD genotype (55.84%, P = 0.021). In conclusion, the HFE 282Y and 65C alleles were rare, while the HFE 63D allele was frequent in Brazilian blood donors. The HFE C282Y and H63D mutations were associated with alterations in iron status in blood donors in a gender-dependent manner.

Hepcidin expression does not rescue the iron-poor phenotype of Kupffer cells in Hfe-null mice after liver transplantation.

PubMed

Garuti, Cinzia; Tian, Yinghua; Montosi, Giuliana; Sabelli, Manuela; Corradini, Elena; Graf, Rolf; Ventura, Paolo; Vegetti, Alberto; Clavien, Pierre-Alain; Pietrangelo, Antonello

2010-07-01

Hemochromatosis is a common hereditary disease caused by mutations in HFE and characterized by increased absorption of iron in the intestine. However, the intestine does not appear to be the site of mutant HFE activity in the disease; we investigated the role of the liver-the source of the iron regulatory hormone hepcidin-in pathogenesis in mice. We exchanged livers between Hfe wild-type (+/+) and Hfe null (-/-) mice by orthotopic liver transplantation (OLT) and assessed histopathology, serum and tissue iron parameters, and hepatic hepcidin messenger RNA expression. At 6-8 months after OLT, Hfe(-/-) mice that received Hfe(-/-) livers maintained the hemochromatosis phenotype: iron accumulation in hepatocytes but not Kupffer cells (KC), increased transferrin levels, and low levels of iron in the spleen. Hfe(+/+) mice that received Hfe(-/-) livers had increased levels of iron in serum and liver and low levels of iron in spleen. However, they did not develop the iron-poor KCs that characterize hemochromatosis: KCs appeared iron rich, although hepatic hepcidin expression was low. Transplantation of Hfe(+/+) livers into Hfe(-/-) mice prevented hepatic iron accumulation but did not return spleen and plasma levels of iron to normal; KCs still appeared to be iron poor, despite normal hepcidin expression. In Hfe(-/-) mice, transplantation of livers from Hfe(+/+) mice reversed the iron-loading phenotype associated with hemochromatosis (regardless of Hfe expression in intestine). However, KCs still had low levels of iron that were not affected by hepatic hepcidin expression. These findings indicate an independent, iron-modifying effect of HFE in KCs. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

On the application of motivation theory to human factors/ergonomics: motivational design principles for human-technology interaction.

PubMed

Szalma, James L

2014-12-01

Motivation is a driving force in human-technology interaction. This paper represents an effort to (a) describe a theoretical model of motivation in human technology interaction, (b) provide design principles and guidelines based on this theory, and (c) describe a sequence of steps for the. evaluation of motivational factors in human-technology interaction. Motivation theory has been relatively neglected in human factors/ergonomics (HF/E). In both research and practice, the (implicit) assumption has been that the operator is already motivated or that motivation is an organizational concern and beyond the purview of HF/E. However, technology can induce task-related boredom (e.g., automation) that can be stressful and also increase system vulnerability to performance failures. A theoretical model of motivation in human-technology interaction is proposed, based on extension of the self-determination theory of motivation to HF/E. This model provides the basis for both future research and for development of practical recommendations for design. General principles and guidelines for motivational design are described as well as a sequence of steps for the design process. Human motivation is an important concern for HF/E research and practice. Procedures in the design of both simple and complex technologies can, and should, include the evaluation of motivational characteristics of the task, interface, or system. In addition, researchers should investigate these factors in specific human-technology domains. The theory, principles, and guidelines described here can be incorporated into existing techniques for task analysis and for interface and system design.

The perceptual significance of high-frequency energy in the human voice.

PubMed

Monson, Brian B; Hunter, Eric J; Lotto, Andrew J; Story, Brad H

2014-01-01

While human vocalizations generate acoustical energy at frequencies up to (and beyond) 20 kHz, the energy at frequencies above about 5 kHz has traditionally been neglected in speech perception research. The intent of this paper is to review (1) the historical reasons for this research trend and (2) the work that continues to elucidate the perceptual significance of high-frequency energy (HFE) in speech and singing. The historical and physical factors reveal that, while HFE was believed to be unnecessary and/or impractical for applications of interest, it was never shown to be perceptually insignificant. Rather, the main causes for focus on low-frequency energy appear to be because the low-frequency portion of the speech spectrum was seen to be sufficient (from a perceptual standpoint), or the difficulty of HFE research was too great to be justifiable (from a technological standpoint). The advancement of technology continues to overcome concerns stemming from the latter reason. Likewise, advances in our understanding of the perceptual effects of HFE now cast doubt on the first cause. Emerging evidence indicates that HFE plays a more significant role than previously believed, and should thus be considered in speech and voice perception research, especially in research involving children and the hearing impaired.

The perceptual significance of high-frequency energy in the human voice

PubMed Central

Monson, Brian B.; Hunter, Eric J.; Lotto, Andrew J.; Story, Brad H.

2014-01-01

While human vocalizations generate acoustical energy at frequencies up to (and beyond) 20 kHz, the energy at frequencies above about 5 kHz has traditionally been neglected in speech perception research. The intent of this paper is to review (1) the historical reasons for this research trend and (2) the work that continues to elucidate the perceptual significance of high-frequency energy (HFE) in speech and singing. The historical and physical factors reveal that, while HFE was believed to be unnecessary and/or impractical for applications of interest, it was never shown to be perceptually insignificant. Rather, the main causes for focus on low-frequency energy appear to be because the low-frequency portion of the speech spectrum was seen to be sufficient (from a perceptual standpoint), or the difficulty of HFE research was too great to be justifiable (from a technological standpoint). The advancement of technology continues to overcome concerns stemming from the latter reason. Likewise, advances in our understanding of the perceptual effects of HFE now cast doubt on the first cause. Emerging evidence indicates that HFE plays a more significant role than previously believed, and should thus be considered in speech and voice perception research, especially in research involving children and the hearing impaired. PMID:24982643

Development of a transgenic zebrafish model expressing GFP in the notochord, somite and liver directed by the hfe2 gene promoter.

PubMed

Bian, Yue-Hong; Xu, Cheng; Li, Junling; Xu, Jin; Zhang, Hongwei; Du, Shao Jun

2011-08-01

Hemojuvelin, also known as RGMc, is encoded by hfe2 gene that plays an important role in iron homeostasis. hfe2 is specifically expressed in the notochord, developing somite and skeletal muscles during development. The molecular regulation of hfe2 expression is, however, not clear. We reported here the characterization of hfe2 gene expression and the regulation of its tissue-specific expression in zebrafish embryos. We demonstrated that the 6 kb 5'-flanking sequence upstream of the ATG start codon in the zebrafish hfe2 gene could direct GFP specific expression in the notochord, somites, and skeletal muscle of zebrafish embryos, recapitulating the expression pattern of the endogenous gene. However, the Tg(hfe2:gfp) transgene is also expressed in the liver of fish embryos, which did not mimic the expression of the endogenous hfe2 at the early stage. Nevertheless, the Tg(hfe2:gfp) transgenic zebrafish provides a useful model to study liver development. Treating Tg(hfe2:gfp) transgenic zebrafish embryos with valproic acid, a liver development inhibitor, significantly inhibited GFP expression in zebrafish. Together, these data indicate that the tissue specific expression of hfe2 in the notochord, somites and muscles is regulated by regulatory elements within the 6 kb 5'-flanking sequence of the hfe2 gene. Moreover, the Tg(hfe2:gfp) transgenic zebrafish line provides a useful model system for analyzing liver development in zebrafish.

Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data.

PubMed

Lee, Sang Y; Zhu, Junjia; Salzberg, Anna C; Zhang, Bo; Liu, Dajiang J; Muscat, Joshua E; Langan, Sara T; Connor, James R

2017-01-01

Human hemochromatosis protein (HFE) is involved in iron metabolism. Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers. Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM). However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied. To expand our finding in a larger sample, and to identify other HFE SNV, we analyzed the frequency of somatic SNV in HFE gene and its relationship to survival in GBM patients using The Cancer Genome Atlas (TCGA) GBM (Caucasian only) database. We found 9 SNVs with increased frequency in blood normal of TCGA GBM patients compared to the 1000Genome. Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene. The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119-0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474-0.1159) HFE polymorphisms than 1000Genome. The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients. In addition, there was no difference in the survival of male/female GBM patients based on HFE genotype. There was no correlation between HFE expression and survival. In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients' survival in the TCGA data set of GBM.

Loss of hfe function reverses impaired recognition memory caused by olfactory manganese exposure in mice.

PubMed

Ye, Qi; Kim, Jonghan

2015-03-01

Excessive manganese (Mn) in the brain promotes a variety of abnormal behaviors, including memory deficits, decreased motor skills and psychotic behavior resembling Parkinson's disease. Hereditary hemochromatosis (HH) is a prevalent genetic iron overload disorder worldwide. Dysfunction in HFE gene is the major cause of HH. Our previous study has demonstrated that olfactory Mn uptake is altered by HFE deficiency, suggesting that loss of HFE function could alter manganese-associated neurotoxicity. To test this hypothesis, Hfe-knockout (Hfe (-/-)) and wild-type (Hfe (+/+)) mice mice were intranasally-instilled with manganese chloride (MnCl2 5 mg/kg) or water daily for 3 weeks and examined for memory function. Olfactory Mn diminished both short-term recognition and spatial memory in Hfe (+/+) mice, as examined by novel object recognition task and Barnes maze test, respectively. Interestingly, Hfe (-/-) mice did not show impaired recognition memory caused by Mn exposure, suggesting a potential protective effect of Hfe deficiency against Mn-induced memory deficits. Since many of the neurotoxic effects of manganese are thought to result from increased oxidative stress, we quantified activities of anti-oxidant enzymes in the prefrontal cortex (PFC). Mn instillation decreased superoxide dismutase 1 (SOD1) activity in Hfe (+/+) mice, but not in Hfe (-/-) mice. In addition, Hfe deficiency up-regulated SOD1 and glutathione peroxidase activities. These results suggest a beneficial role of Hfe deficiency in attenuating Mn-induced oxidative stress in the PFC. Furthermore, Mn exposure reduced nicotinic acetylcholine receptor levels in the PFC, indicating that blunted acetylcholine signaling could contribute to impaired memory associated with intranasal manganese. Together, our model suggests that disrupted cholinergic system in the brain is involved in airborne Mn-induced memory deficits and loss of HFE function could in part prevent memory loss via a potential up-regulation of anti-oxidant enzymes in the PFC.

Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin.

PubMed

Kent, Patricia; Wilkinson, Nicole; Constante, Marco; Fillebeen, Carine; Gkouvatsos, Konstantinos; Wagner, John; Buffler, Marzell; Becker, Christiane; Schümann, Klaus; Santos, Manuela M; Pantopoulos, Kostas

2015-05-01

Functional inactivation of HFE or hemojuvelin (HJV) is causatively linked to adult or juvenile hereditary hemochromatosis, respectively. Systemic iron overload results from inadequate expression of hepcidin, the iron regulatory hormone. While HJV regulates hepcidin by amplifying bone morphogenetic protein (BMP) signaling, the role of HFE in the hepcidin pathway remains incompletely understood. We investigated the pathophysiological implications of combined Hfe and Hjv ablation in mice. Isogenic Hfe (-)/(-) and Hjv (-)/(-) mice were crossed to generate double Hfe (-)/(-) Hjv (-)/(-) progeny. Wild-type control and mutant mice of all genotypes were analyzed for serum, hepatic, and splenic iron content, expression of iron metabolism proteins, and expression of hepcidin and Smad signaling in the liver, in response to a standard or an iron-enriched diet. As expected, Hfe (-)/(-) and Hjv (-)/(-) mice developed relatively mild or severe iron overload, respectively, which corresponded to the degree of hepcidin inhibition. The double Hfe (-)/(-) Hjv (-)/(-) mice exhibited an indistinguishable phenotype to single Hjv (-)/(-) counterparts with regard to suppression of hepcidin, serum and hepatic iron overload, splenic iron deficiency, tissue iron metabolism, and Smad signaling, under both dietary regimens. We conclude that the hemochromatotic phenotype caused by disruption of Hjv is not further aggravated by combined Hfe/Hjv deficiency. Our results provide genetic evidence that Hfe and Hjv operate in the same pathway for the regulation of hepcidin expression and iron metabolism. Combined disruption of Hfe and Hjv phenocopies single Hjv deficiency. Single Hjv(-)/(-) and double Hfe(-)/(-)Hjv(-)/(-) mice exhibit comparable iron overload. Hfe and Hjv regulate hepcidin via the same pathway.

Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn's Disease Patients.

PubMed

Repnik, Katja; Koder, Silvo; Skok, Pavel; Ferkolj, Ivan; Potočnik, Uroš

2016-08-01

Tumor necrosis factor α inhibitors (anti-TNF) have improved treatment of several complex diseases, including Crohn's disease (CD). However, the effect varies and approximately one-third of the patients do not respond. Since blood parameters as well as genetic factors have shown a great potential to predict response during treatment, the aim of the study was to evaluate response to anti-TNF treatment with adalimumab (ADA) between genes HFE and TF and haematological parameters in Slovenian refractory CD patients. Single nucleotide polymorphisms (SNPs) rs1799852 in gene TF and rs2071303 in gene HFE were genotyped in 68 refractory CD patients for which response has been measured using inflammatory bowel disease questionnaire (IBDQ) index. Haematological parameters and IBDQ index were determined before therapy and after 4, 12, 20 and 30 weeks. We found novel strong association between SNP rs2071303 in gene HFE and response to ADA treatment, particularly patients with G allele comparing to A allele had better response after 20 weeks (p = 0.008). Further, we found strong association between transferrin level at baseline and treatment response after 12, 20 and 30 weeks, where average transferrin level before therapy was lower in responders (2.38 g/L) compared to non-responders (2.89 g/L, p = 0.005). Association was found between transferrin level in week 30 and SNP rs1799852 (p = 0.023), and between MCHC level before treatment and SNP rs2071303 (p = 0.007). Our results suggest that SNP in gene HFE as well as haematological markers serve as promising prognostic markers of response to anti-TNF treatment in CD patients.

Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis

PubMed Central

Ramos, Pedro; Guy, Ella; Chen, Nan; Proenca, Catia C.; Gardenghi, Sara; Casu, Carla; Follenzi, Antonia; Van Rooijen, Nico; Grady, Robert W.; de Sousa, Maria

2011-01-01

In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis. We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and β-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis. PMID:21059897

Effects of an Advanced Reactor’s Design, Use of Automation, and Mission on Human Operators

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

Jeffrey C. Joe; Johanna H. Oxstrand

The roles, functions, and tasks of the human operator in existing light water nuclear power plants (NPPs) are based on sound nuclear and human factors engineering (HFE) principles, are well defined by the plant’s conduct of operations, and have been validated by years of operating experience. However, advanced NPPs whose engineering designs differ from existing light-water reactors (LWRs) will impose changes on the roles, functions, and tasks of the human operators. The plans to increase the use of automation, reduce staffing levels, and add to the mission of these advanced NPPs will also affect the operator’s roles, functions, and tasks.more » We assert that these factors, which do not appear to have received a lot of attention by the design engineers of advanced NPPs relative to the attention given to conceptual design of these reactors, can have significant risk implications for the operators and overall plant safety if not mitigated appropriately. This paper presents a high-level analysis of a specific advanced NPP and how its engineered design, its plan to use greater levels of automation, and its expanded mission have risk significant implications on operator performance and overall plant safety.« less

Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis

PubMed Central

Ben-Arieh, Sayeh Vahdati; Zimerman, Baruch; Smorodinsky, Nechama I.; Yaacubovicz, Margalit; Schechter, Chana; Bacik, Igor; Gibbs, Jim; Bennink, Jack R.; Yewdell, Jon W.; Coligan, John E.; Firat, Hüseyin; Lemonnier, François; Ehrlich, Rachel

2001-01-01

HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/β2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses. PMID:11581431

Structural basis of urea-induced unfolding: Unraveling the folding pathway of hemochromatosis factor E.

PubMed

Khan, Parvez; Prakash, Amresh; Haque, Md Anzarul; Islam, Asimul; Hassan, Md Imtaiyaz; Ahmad, Faizan

2016-10-01

Hereditary hemochromatosis factor E (HFE) is a type 1 transmembrane protein, and acts as a negative regulator of iron-uptake. The equilibrium unfolding and conformational stability of the HFE protein was examined in the presence of urea. The folding and unfolding transitions were monitored with the help of circular dichroism (CD), intrinsic fluorescence and absorption spectroscopy. Analysis of transition curves revealed that the folding of HFE is not a two-state process. However, it involved stable intermediates. Transition curves (plot of fluorescence (F346) and CD signal at 222nm (θ222) versus [Urea], the molar urea concentration) revealed a biphasic transition with midpoint (Cm) values at 2.88M and 4.95M urea. Whereas, absorption analysis shows one two-state transition centered at 2.96M. To estimate the protein stability, denaturation curves were analyzed for Gibbs free energy change in the absence of urea (ΔGD(0)) associated with the equilibrium of denaturation exist between native state↔denatured state. The intermediate state was further characterized by hydrophobic probe, 1-anilinonaphthalene-8-sulfonic acid (ANS-binding). For seeing the effect of urea on the structure and dynamics of HFE, molecular dynamics simulation for 60ns was also performed. A clear correspondence was established between the in vitro and in silico studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Differential HFE Gene Expression Is Regulated by Alternative Splicing in Human Tissues

PubMed Central

Proença, Daniela; Faustino, Paula

2011-01-01

Background The pathophysiology of HFE-derived Hereditary Hemochromatosis and the function of HFE protein in iron homeostasis remain uncertain. Also, the role of alternative splicing in HFE gene expression regulation and the possible function of the corresponding protein isoforms are still unknown. The aim of this study was to gain insights into the physiological significance of these alternative HFE variants. Methodology/Principal Findings Alternatively spliced HFE transcripts in diverse human tissues were identified by RT-PCR, cloning and sequencing. Total HFE transcripts, as well as two alternative splicing transcripts were quantified using a real-time PCR methodology. Intracellular localization, trafficking and protein association of GFP-tagged HFE protein variants were analysed in transiently transfected HepG2 cells by immunoprecipitation and immunofluorescence assays. Alternatively spliced HFE transcripts present both level- and tissue-specificity. Concerning the exon 2 skipping and intron 4 inclusion transcripts, the liver presents the lowest relative level, while duodenum presents one of the highest amounts. The protein resulting from exon 2 skipping transcript is unable to associate with β2M and TfR1 and reveals an ER retention. Conversely, the intron 4 inclusion transcript gives rise to a truncated, soluble protein (sHFE) that is mostly secreted by cells to the medium in association with β2M. Conclusions/Significance HFE gene post-transcriptional regulation is clearly affected by a tissue-dependent alternative splicing mechanism. Among the corresponding proteins, a sHFE isoform stands out, which upon being secreted into the bloodstream, may act in remote tissues. It could be either an agonist or antagonist of the full length HFE, through hepcidin expression regulation in the liver or by controlling dietary iron absorption in the duodenum. PMID:21407826

Differential HFE gene expression is regulated by alternative splicing in human tissues.

PubMed

Martins, Rute; Silva, Bruno; Proença, Daniela; Faustino, Paula

2011-03-03

The pathophysiology of HFE-derived Hereditary Hemochromatosis and the function of HFE protein in iron homeostasis remain uncertain. Also, the role of alternative splicing in HFE gene expression regulation and the possible function of the corresponding protein isoforms are still unknown. The aim of this study was to gain insights into the physiological significance of these alternative HFE variants. Alternatively spliced HFE transcripts in diverse human tissues were identified by RT-PCR, cloning and sequencing. Total HFE transcripts, as well as two alternative splicing transcripts were quantified using a real-time PCR methodology. Intracellular localization, trafficking and protein association of GFP-tagged HFE protein variants were analysed in transiently transfected HepG2 cells by immunoprecipitation and immunofluorescence assays. Alternatively spliced HFE transcripts present both level- and tissue-specificity. Concerning the exon 2 skipping and intron 4 inclusion transcripts, the liver presents the lowest relative level, while duodenum presents one of the highest amounts. The protein resulting from exon 2 skipping transcript is unable to associate with β2M and TfR1 and reveals an ER retention. Conversely, the intron 4 inclusion transcript gives rise to a truncated, soluble protein (sHFE) that is mostly secreted by cells to the medium in association with β2M. HFE gene post-transcriptional regulation is clearly affected by a tissue-dependent alternative splicing mechanism. Among the corresponding proteins, a sHFE isoform stands out, which upon being secreted into the bloodstream, may act in remote tissues. It could be either an agonist or antagonist of the full length HFE, through hepcidin expression regulation in the liver or by controlling dietary iron absorption in the duodenum.

Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data

PubMed Central

Zhang, Bo; Liu, Dajiang J.; Muscat, Joshua E.; Langan, Sara T.; Connor, James R.

2017-01-01

Human hemochromatosis protein (HFE) is involved in iron metabolism. Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers. Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM). However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied. To expand our finding in a larger sample, and to identify other HFE SNV, we analyzed the frequency of somatic SNV in HFE gene and its relationship to survival in GBM patients using The Cancer Genome Atlas (TCGA) GBM (Caucasian only) database. We found 9 SNVs with increased frequency in blood normal of TCGA GBM patients compared to the 1000Genome. Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene. The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119–0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474–0.1159) HFE polymorphisms than 1000Genome. The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients. In addition, there was no difference in the survival of male/female GBM patients based on HFE genotype. There was no correlation between HFE expression and survival. In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients’ survival in the TCGA data set of GBM. PMID:28358914

In Situ Proximity Ligation Assays Indicate That Hemochromatosis Proteins Hfe and Transferrin Receptor 2 (Tfr2) Do Not Interact

PubMed Central

Rishi, Gautam; Crampton, Emily M.; Wallace, Daniel F.; Subramaniam, V. Nathan

2013-01-01

The hemochromatosis associated proteins HFE and Transferrin Receptor 2 (TFR2) have been shown to be important for the proper regulation of hepcidin. A number of in vitro studies using transient overexpression systems have suggested that an interaction between HFE and TFR2 is required for the regulation of hepcidin. This model of iron sensing which centers upon the requirement for an interaction between HFE and TFR2 has recently been questioned with in vivo studies in mice from our laboratory and others which suggest that Hfe and Tfr2 can regulate hepcidin independently of each other. To re-examine the postulated interaction between Hfe and Tfr2 we developed a novel expression system in which both proteins are stably co-expressed and used the proximity ligation assay to examine the interactions between Hfe, Tfr1 and Tfr2 at a cellular level. We were able to detect the previously described interaction between Hfe and Tfr1, and heterodimers between Tfr1 and Tfr2; however no interaction between Hfe and Tfr2 was observed in our system. The results from this study indicate that Hfe and Tfr2 do not interact with each other when they are stably expressed at similar levels. Furthermore, these results support in vivo studies which suggest that Hfe and Tfr2 can independently regulate hepcidin. PMID:24155934

Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2.

PubMed

Schmidt, Paul J; Fleming, Mark D

2012-06-01

Hereditary hemochomatosis (HH) is caused by mutations in several genes, including HFE and transferrin receptor-2 (TFR2). Loss of either protein decreases expression of the iron regulatory hormone hepcidin by the liver, leading to inappropriately high iron uptake from the diet, and resulting in systemic iron overload. In tissue culture, overexpressed HFE and TFR2 physically interact. Hepatocellular overexpression of Hfe in vivo increases hepcidin expression, despite an associated decrease in Tfr2. On this basis, we hypothesized that Tfr2 would not be required for Hfe-dependent up-regulation of hepcidin. We show that hepatocellular overexpression of Hfe in Tfr2(Y245X/Y245X) mice leads to hepcidin induction eventuating in iron deficiency and a hypochromic, microcytic anemia. Furthermore, coimmunoprecipitation studies using liver lysates did not provide evidence for physical interaction between Hfe and Tfr2 in vivo. In conclusion, we demonstrate that Tfr2 is not essential for Hfe-mediated induction of hepcidin expression, supporting the possibility that TFR2 may regulate iron metabolism in an HFE-independent manner. Copyright © 2012 Wiley Periodicals, Inc.

Transgenic HFE-dependent induction of hepcidin in mice does not require transferrin receptor-2

PubMed Central

Schmidt, Paul J.; Fleming, Mark D.

2012-01-01

Hereditary hemochomatosis (HH) is caused by mutations in several genes, including HFE and transferrin receptor-2 (TFR2). Loss of either protein decreases expression of the iron regulatory hormone hepcidin by the liver, leading to inappropriately high iron uptake from the diet, and resulting in systemic iron overload. In tissue culture, overexpressed HFE and TFR2 physically interact. Hepatocellular overexpression of Hfe in vivo increases hepcidin expression, despite an associated decrease in Tfr2. On this basis, we hypothesized that Tfr2 would not be required for Hfe-dependent up-regulation of hepcidin. We show that hepatocellular overexpression of Hfe in Tfr2Y245X/Y245X mice leads to hepcidin induction eventuating in iron deficiency and a hypochromic, microcytic anemia. Furthermore, co-immunoprecipitation studies using liver lysates did not provide evidence for physical interaction between Hfe and Tfr2 in vivo. In conclusion, we demonstrate that Tfr2 is not essential for Hfe-mediated induction of hepcidin expression, supporting the possibility that TFR2 may regulate iron metabolism in an HFE-independent manner. PMID:22460705

Health Care Human Factors/Ergonomics Fieldwork in Home and Community Settings

PubMed Central

Valdez, Rupa S.; Holden, Richard J.

2017-01-01

Feature at a glance Designing innovations aligned with patients’ needs and workflow requires human factors and ergonomics (HF/E) fieldwork in home and community settings. Fieldwork in these extra-institutional settings is challenged by a need to balance the occasionally competing priorities of patient and informal caregiver participants, study team members, and the overall project. We offer several strategies that HF/E professionals can use before, during, and after home and community site visits to optimize fieldwork and mitigate challenges in these settings. Strategies include interacting respectfully with participants, documenting the visit, managing the study team-participant relationship, and engaging in dialogue with institutional review boards. PMID:28781512

Regulation of HFE expression by Poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter

PubMed Central

Rodova, Marianna; Rudolph, Angela; Chipps, Elizabeth; Islam, M. Rafiq

2013-01-01

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700 bp (−1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression. PMID:24184271

Rare HFE variants are the most frequent cause of hemochromatosis in non-c282y homozygous patients with hemochromatosis.

PubMed

Hamdi-Rozé, Houda; Beaumont-Epinette, Marie-Pascale; Ben Ali, Zeineb; Le Lan, Caroline; Loustaud-Ratti, Véronique; Causse, Xavier; Loreal, Olivier; Deugnier, Yves; Brissot, Pierre; Jouanolle, Anne-Marie; Bardou-Jacquet, Edouard

2016-12-01

p.Cys282Tyr (C282Y) homozygosity explains most cases of HFE-related hemochromatosis, but a significant number of patients presenting with typical type I hemochromatosis phenotype remain unexplained. We sought to describe the clinical relevance of rare HFE variants in non-C282Y homozygotes. Patients referred for hemochromatosis to the National Reference Centre for Rare Iron Overload Diseases from 2004 to 2010 were studied. Sequencing was performed for coding region and intronic flanking sequences of HFE, HAMP, HFE2, TFR2, and SLC40A1. Nine private HFE variants were identified in 13 of 206 unrelated patients. Among those, five have not been previously described: p.Leu270Argfs*4, p.Ala271Valfs*25, p.Tyr52*, p.Lys166Asn, and p.Asp141Tyr. Our results show that rare HFE variants are identified more frequently than variants in the other genes associated with iron overload. Rare HFE variants are therefore the most frequent cause of hemochromatosis in non-C282Y homozygote HFE patients. Am. J. Hematol. 91:1202-1205, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Regulation of HFE expression by poly(ADP-ribose) polymerase-1 (PARP1) through an inverted repeat DNA sequence in the distal promoter.

PubMed

Pelham, Christopher; Jimenez, Tamara; Rodova, Marianna; Rudolph, Angela; Chipps, Elizabeth; Islam, M Rafiq

2013-12-01

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron overload among Caucasians of northern European descent. Over 85% of all cases with HH are due to mutations in the hemochromatosis protein (HFE) involved in iron metabolism. Although the importance in iron homeostasis is well recognized, the mechanism of sensing and regulating iron absorption by HFE, especially in the absence of iron response element in its gene, is not fully understood. In this report, we have identified an inverted repeat sequence (ATGGTcttACCTA) within 1700bp (-1675/+35) of the HFE promoter capable to form cruciform structure that binds PARP1 and strongly represses HFE promoter. Knockdown of PARP1 increases HFE mRNA and protein. Similarly, hemin or FeCl3 treatments resulted in increase in HFE expression by reducing nuclear PARP1 pool via its apoptosis induced cleavage, leading to upregulation of the iron regulatory hormone hepcidin mRNA. Thus, PARP1 binding to the inverted repeat sequence on the HFE promoter may serve as a novel iron sensing mechanism as increased iron level can trigger PARP1 cleavage and relief of HFE transcriptional repression. © 2013.

Effects of strain and age on hepatic gene expression profiles in murine models of HFE-associated hereditary hemochromatosis.

PubMed

Lee, Seung-Min; Loguinov, Alexandre; Fleming, Robert E; Vulpe, Christopher D

2015-01-01

Hereditary hemochromatosis is an iron overload disorder most commonly caused by a defect in the HFE gene. While the genetic defect is highly prevalent, the majority of individuals do not develop clinically significant iron overload, suggesting the importance of genetic modifiers. Murine hfe knockout models have demonstrated that strain background has a strong effect on the severity of iron loading. We noted that hepatic iron loading in hfe-/- mice occurs primarily over the first postnatal weeks (loading phase) followed by a timeframe of relatively static iron concentrations (plateau phase). We thus evaluated the effects of background strain and of age on hepatic gene expression in Hfe knockout mice (hfe-/-). Hepatic gene expression profiles were examined using cDNA microarrays in 4- and 8-week-old hfe-/- and wild-type mice on two different genetic backgrounds, C57BL/6J (C57) and AKR/J (AKR). Genes differentially regulated in all hfe-/- mice groups, compared with wild-type mice, including those involved in cell survival, stress and damage responses and lipid metabolism. AKR strain-specific changes in lipid metabolism genes and C57 strain-specific changes in cell adhesion and extracellular matrix protein genes were detected in hfe-/- mice. Mouse strain and age are each significantly associated with hepatic gene expression profiles in hfe-/- mice. These affects may underlie or reflect differences in iron loading in these mice.

Bone morphogenetic protein signaling is impaired in an Hfe knockout mouse model of hemochromatosis

PubMed Central

Corradini, Elena; Garuti, Cinzia; Montosi, Giuliana; Ventura, Paolo; Andriopoulos, Billy; Lin, Herbert Y.; Pietrangelo, Antonello; Babitt, Jodie L.

2009-01-01

Background and Aims Mutations in HFE are the most common cause of the iron-overload disorder hereditary hemochromatosis (HH). Levels of the main iron regulatory hormone, hepcidin, are inappropriately low in HH mouse models and patients with HFE mutations, indicating that HFE regulates hepcidin. The bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway is an important endogenous regulator of hepcidin expression. We investigated whether HFE is involved in BMP6-SMAD regulation of hepcidin expression. Methods The BMP6-SMAD pathway was examined in Hfe knockout (KO) mice and in wild-type (WT) mice as controls. Mice were placed on diets of varying iron content. Hepcidin induction by BMP6 was examined in primary hepatocytes from Hfe KO mice; data were compared with those of WT mice. Results Liver levels of Bmp6 mRNA were higher in Hfe KO mice; these were appropriate for the increased hepatic levels of iron in these mice, compared with WT mice. However, levels of hepatic phosphorylated Smad 1/5/8 protein (an intracellular mediator of Bmp6 signaling) and Id1 mRNA (a target gene of Bmp6) were inappropriately low for the body iron burden and Bmp6 mRNA levels in Hfe KO, compared with WT mice. BMP6 induction of hepcidin expression was reduced in Hfe KO hepatocytes compared with WT hepatocytes. Conclusions HFE is not involved in regulation of BMP6 by iron, but does regulate the downstream signals of BMP6 that are triggered by iron. PMID:19591830

A REVIEW OF HUMAN-SYSTEM INTERFACE DESIGN ISSUES OBSERVED DURING ANALOG-TO-DIGITAL AND DIGITAL-TO-DIGITAL MIGRATIONS IN U.S. NUCLEAR POWER PLANTS

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

Kovesdi, C.; Joe, J.

The United States (U.S.) Department of Energy (DOE) Light Water Reactor Sustainability (LWRS) program is developing a scientific basis through targeted research and development (R&D) to support the U.S. nuclear power plant (NPP) fleet in extending their existing licensing period and ensuring their long-term reliability, productivity, safety, and security. Over the last several years, human factors engineering (HFE) professionals at the Idaho National Laboratory (INL) have supported the LWRS Advanced Instrumentation, Information, and Control (II&C) System Technologies pathway across several U.S. commercial NPPs in analog-to-digital migrations (i.e., turbine control systems) and digital-to-digital migrations (i.e., Safety Parameter Display System). These effortsmore » have included in-depth human factors evaluation of proposed human-system interface (HSI) design concepts against established U.S. Nuclear Regulatory Commission (NRC) design guidelines from NUREG-0700, Rev 2 to inform subsequent HSI design prior to transitioning into Verification and Validation. This paper discusses some of the overarching design issues observed from these past HFE evaluations. In addition, this work presents some observed challenges such as common tradeoffs utilities are likely to face when introducing new HSI technologies into NPP hybrid control rooms. The primary purpose of this work is to distill these observed design issues into general HSI design guidance that industry can use in early stages of HSI design.« less

Hormone Replacement Therapy, Iron, and Breast Cancer

DTIC Science & Technology

2005-10-01

tested in cell culture model systems and in an iron loaded transgenic mouse model. Since iron slowly accumulates due to the mutation of the HFE gene ...murine HFE gene is structurally similar to the human gene . Four different HFE gene disruptions have been reported in the mouse: an exon 4 knockout...Ex3 F Hfe Ex 5 R Figure 1. HFE gene knockout. Huang, X., DAMD-17-03-1-0717 5 mice provided by Dr. Nancy Andrews of the Howard Hughes Medical

Enhanced ergonomics approaches for product design: a user experience ecosystem perspective and case studies.

PubMed

Xu, Wei

2014-01-01

This paper first discusses the major inefficiencies faced in current human factors and ergonomics (HFE) approaches: (1) delivering an optimal end-to-end user experience (UX) to users of a solution across its solution lifecycle stages; (2) strategically influencing the product business and technology capability roadmaps from a UX perspective and (3) proactively identifying new market opportunities and influencing the platform architecture capabilities on which the UX of end products relies. In response to these challenges, three case studies are presented to demonstrate how enhanced ergonomics design approaches have effectively addressed the challenges faced in current HFE approaches. Then, the enhanced ergonomics design approaches are conceptualised by a user-experience ecosystem (UXE) framework, from a UX ecosystem perspective. Finally, evidence supporting the UXE, the advantage and the formalised process for executing UXE and methodological considerations are discussed. Practitioner Summary: This paper presents enhanced ergonomics approaches to product design via three case studies to effectively address current HFE challenges by leveraging a systematic end-to-end UX approach, UX roadmaps and emerging UX associated with prioritised user needs and usages. Thus, HFE professionals can be more strategic, creative and influential.

A novel homozygous stop-codon mutation in human HFE responsible for nonsense-mediated mRNA decay.

PubMed

Padula, Maria Carmela; Martelli, Giuseppe; Larocca, Marilena; Rossano, Rocco; Olivieri, Attilio

2014-09-01

HFE-hemochromatosis (HH) is an autosomal disease characterized by excessive iron absorption. Homozygotes for H63D variant, and still less H63D heterozygotes, generally do not express HH phenotype. The data collected in our previous study in the province of Matera (Basilicata, Italy) underlined that some H63D carriers showed altered iron metabolism, without additional factors. In this study, we selected a cohort of 10/22 H63D carriers with severe biochemical iron overload (BIO). Additional analysis was performed for studying HFE exons, exon-intron boundaries, and untranslated regions (UTRs) by performing DNA extraction, PCR amplification and sequencing. The results showed a novel substitution (NM_000410.3:c.847C>T) in a patient exon 4 (GenBankJQ478433); it introduces a premature stop-codon (PTC). RNA extraction and reverse-transcription were also performed. Quantitative real-time PCR was carried out for verifying if our aberrant mRNA is targeted for nonsense-mediated mRNA decay (NMD); we observed that patient HFE mRNA was expressed much less than calibrator, suggesting that the mutated HFE protein cannot play its role in iron metabolism regulation, resulting in proband BIO. Our finding is the first evidence of a variation responsible for a PTC in iron cycle genes. The genotype-phenotype correlation observed in our cases could be related to the additional mutation. Copyright © 2014 Elsevier Inc. All rights reserved.

Absorption of Manganese and Iron in a Mouse Model of Hemochromatosis

PubMed Central

Kim, Jonghan; Buckett, Peter D.; Wessling-Resnick, Marianne

2013-01-01

Hereditary hemochromatosis, an iron overload disease associated with excessive intestinal iron absorption, is commonly caused by loss of HFE gene function. Both iron and manganese absorption are regulated by iron status, but the relationships between the transport pathways of these metals and how they are affected by HFE-associated hemochromatosis remain poorly understood. Loss of HFE function is known to alter the intestinal expression of DMT1 (divalent metal transporter-1) and Fpn (ferroportin), transporters that have been implicated in absorption of both iron and manganese. Although the influence of HFE deficiency on dietary iron absorption has been characterized, potential effects on manganese metabolism have yet to be explored. To investigate the role of HFE in manganese absorption, we characterized the uptake and distribution of the metal in Hfe −/− knockout mice after intravenous, intragastric, and intranasal administration of 54Mn. These values were compared to intravenous and intragastric administration of 59Fe. Intestinal absorption of 59Fe was increased and clearance of injected 59Fe was also increased in Hfe−/− mice compared to controls. Hfe −/− mice displayed greater intestinal absorption of 54Mn compared to wild-type Hfe+/+ control mice. After intravenous injection, the distribution of 59Fe to heart and liver was greater in Hfe −/− mice but no remarkable differences were observed for 54Mn. Although olfactory absorption of 54Mn into blood was unchanged in Hfe −/− mice, higher levels of intranasally-instilled 54Mn were associated with Hfe−/− brain compared to controls. These results show that manganese transport and metabolism can be modified by HFE deficiency. PMID:23705020

An extensive analysis of the hereditary hemochromatosis gene HFE and neighboring histone genes: associations with childhood leukemia.

PubMed

Davis, Charronne F; Dorak, M Tevfik

2010-04-01

The most common mutation of the HFE gene C282Y has shown a risk association with childhood acute lymphoblastic leukemia (ALL) in Welsh and Scottish case-control studies. This finding has not been replicated outside Britain. Here, we present a thorough analysis of the HFE gene in a panel of HLA homozygous reference cell lines and in the original population sample from South Wales (117 childhood ALL cases and 414 newborn controls). The 21 of 24 variants analyzed were from the HFE gene region extending 52 kb from the histone gene HIST1H1C to HIST1H1T. We identified the single-nucleotide polymorphism (SNP) rs807212 as a tagging SNP for the most common HFE region haplotype, which contains wild-type alleles of all HFE variants examined. This intergenic SNP rs807212 yielded a strong male-specific protective association (per allele OR = 0.38, 95% CI = 0.22-0.64, P (trend) = 0.0002; P = 0.48 in females), which accounted for the original C282Y risk association. In the HapMap project data, rs807212 was in strong linkage disequilibrium with 25 other SNPs spanning 151 kb around HFE. Minor alleles of these 26 SNPs characterized the most common haplotype for the HFE region, which lacked all disease-associated HFE variants. The HapMap data suggested positive selection in this region even in populations where the HFE C282Y mutation is absent. These results have implications for the sex-specific associations observed in this region and suggest the inclusion of rs807212 in future studies of the HFE gene and the extended HLA class I region.

HFE and Spherical Cryostats MC Study

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

Brodsky, Jason P.

2016-09-26

The copper vessel containing the nEXO TPC is surrounded by a buffer of HFE, a liquid refrigerant with very low levels of radioactive element contamination. The HFE is contained within the cryostat’s inner vessel, which is in turn inside the outer vessel. While some HFE may be necessary for stable cooling of nEXO, it is possible that using substantially more than necessary for thermal reasons will help reduce backgrounds originating in the cryostats. Using a larger amount of HFE is accomplished by making the cryostat vessels larger. By itself, increasing the cryostat size somewhat increases the background rate, as themore » thickness of the cryostat wall must increase at larger sizes. However, the additional space inside the cryostat will be filled with HFE which can absorb gamma rays headed for the TPC. As a result, increasing the HFE reduces the number of backgrounds reaching the TPC. The aim of this study was to determine the relationship between HFE thickness and background rate. Ultimately, this work should support choosing a cryostat and HFE size that satisfies nEXO’s background budget. I have attempted to account for every consequence of changing the cryostat size, although naturally this remains a work in progress until a final design is achieved. At the moment, the scope of the study includes only the spherical cryostat design. This study concludes that increasing cryostat size reduces backgrounds, reaching neglible backgrounds originating from the cryostat at the largest sizes. It also shows that backgrounds originating from the inherent radioactivity of the HFE plateau quickly, so may be considered essentially fixed at any quantity of HFE.« less

Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda.

PubMed

Stölzel, Ulrich; Köstler, Erich; Schuppan, Detlef; Richter, Matthias; Wollina, Uwe; Doss, Manfred O; Wittekind, Christian; Tannapfel, Andrea

2003-03-01

To examine the role of hemochromatosis (HFE) gene mutations, which are associated with porphyria cutanea tarda (PCT), in the therapeutic response to chloroquine. We retrospectively analyzed a database (Excel version 2001 [Microsoft Excel, Redmond, Wash]; date range of search, 1985-1999) of chloroquine-treated patients with PCT on whether HFE mutations (C282Y and H63D) might have influenced the clinical response, urinary porphyrin excretion, liver enzyme activities, and serum iron markers. Serum samples and corresponding complete sets of data before and after therapy were available in 62 of 207 patients with PCT who were treated exclusively with chloroquine. Academic teaching hospital. For treatment, low-dose chloroquine diphosphate, 125 to 250 mg twice weekly, was used during a median time of 16 months (range, 12-26 months). Of the 62 German patients with PCT, 37 (60%) carries HFE mutations. Chloroquine therapy was accompanied by clinical remission and reduced urinary porphyrin excretion (P<.001) in the 24 patients (39%) with HFE wild type as well as in 35 HFE heterozygous patients with PCT (56%). Decreases of serum iron markers following chloroquine therapy were limited to patients with PCT and HFE wild type. All patients homozygous for the C282Y mutation (3 [5%] of 62) had high serum iron, ferritin, and transferrin saturation and failed to respond to chloroquine treatment. The therapeutic response to chloroquine was not compromised by C282Y heterozygosity and compound heterozygosity of HFE mutations. Because HFE C282Y homozygotes (+/+) did not respond to chloroquine and a decrease in serum iron concentration was limited to patients with PCT and HFE wild type, phlebotomy should be first-line therapy in patients with PCT and HFE mutations.

HFE gene mutations in patients with primary iron overload: is there a significant improvement in molecular diagnosis yield with HFE sequencing?

PubMed

Santos, Paulo C J L; Pereira, Alexandre C; Cançado, Rodolfo D; Schettert, Isolmar T; Sobreira, Tiago J P; Oliveira, Paulo S L; Hirata, Rosario D C; Hirata, Mario H; Figueiredo, Maria Stella; Chiattone, Carlos S; Krieger, Jose E; Guerra-Shinohara, Elvira M

2010-12-15

Rare HFE variants have been shown to be associated with hereditary hemochromatosis (HH), an iron overload disease. The low frequency of the HFE p.C282Y mutation in HH-affected Brazilian patients may suggest that other HFE-related mutations may also be implicated in the pathogenesis of HH in this population. The main aim was to screen for new HFE mutations in Brazilian individuals with primary iron overload and to investigate their relationship with HH. Fifty Brazilian patients with primary iron overload (transferrin saturation>50% in females and 60% in males) were selected. Subsequent bidirectional sequencing for each HFE exon was performed. The effect of HFE mutations on protein structure were analyzed by molecular dynamics simulation and free binding energy calculations. p.C282Y in homozygosis or in heterozygosis with p.H63D were the most frequent genotypic combinations associated with HH in our sample population (present in 17 individuals, 34%). Thirty-six (72.0%) out of the 50 individuals presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n=11, 22.0%). One novel mutation (p.V256I) was indentified in heterozygosis with the p.H63D mutation. In silico modeling analysis of protein behavior indicated that the p.V256I mutation does not reduce the binding affinity between HFE and β2-microglobulin (β2M) in the same way the p.C282Y mutation does compared with the native HFE protein. In conclusion, screening of HFE through direct sequencing, as compared to p.C282Y/p.H63D genotyping, was not able to increase the molecular diagnosis yield of HH. The novel p.V256I mutation could not be implicated in the molecular basis of the HH phenotype, although its role cannot be completely excluded in HH-phenotype development. Our molecular modeling analysis can help in the analysis of novel, previously undescribed, HFE mutations. Copyright © 2010 Elsevier Inc. All rights reserved.

Pathophysiology of Hereditary Hemochromatosis

PubMed Central

Fleming, Robert E.; Britton, Robert S.; Waheed, Abdul; Sly, William S.; Bacon, Bruce R.

2008-01-01

Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. The most common form of this disorder is HFE-related HH, nearly always caused by homozygosity for the C282Y mutation. A substantial proportion of C282Y homozygotes do not develop clinically significant iron overload, suggesting roles for environmental factors and modifier genes in determining the phenotype. Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE. PMID:16315135

Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

PubMed

Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

2016-06-01

Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis.

PubMed

Sangiuolo, Federica; Puxeddu, Ermanno; Pezzuto, Gabriella; Cavalli, Francesco; Longo, Giuliana; Comandini, Alessia; Di Pierro, Donato; Pallante, Marco; Sergiacomi, Gianluigi; Simonetti, Giovanni; Zompatori, Maurizio; Orlandi, Augusto; Magrini, Andrea; Amicosante, Massimo; Mariani, Francesca; Losi, Monica; Fraboni, Daniela; Bisetti, Alberto; Saltini, Cesare

2015-02-01

In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage. The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation. Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (p<0.05). The frequency of C282Y, S65C and H63D HFE allelic variants was markedly higher in IPF compared with controls (40.4% versus 22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4±56.0, HFE wild type (wt) 59.4±36.4 and controls 16.7±11.8 fluorescence units per 10(5) BAL cells; p=0.028 HFE variant versus HFE wt, p=0.006 HFE wt versus controls). The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF. Copyright ©ERS 2015.

The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data.

PubMed

Wallace, Daniel F; Subramaniam, V Nathan

2016-06-01

The prevalence of HFE-related hereditary hemochromatosis (HH) among European populations has been well studied. There are no prevalence data for atypical forms of HH caused by mutations in HFE2, HAMP, TFR2, or SLC40A1. The purpose of this study was to estimate the population prevalence of these non-HFE forms of HH. A list of HH pathogenic variants in publically available next-generation sequence (NGS) databases was compiled and allele frequencies were determined. Of 161 variants previously associated with HH, 43 were represented among the NGS data sets; an additional 40 unreported functional variants also were identified. The predicted prevalence of HFE HH and the p.Cys282Tyr mutation closely matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2-, HFE2-, and HAMP-related forms are predicted to be rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. Significantly, SLC40A1 variants that have been previously associated with autosomal-dominant ferroportin disease were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans. We have, for the first time, estimated the population prevalence of non-HFE HH. This methodology could be applied to estimate the population prevalence of a wide variety of genetic disorders.Genet Med 18 6, 618-626.

The hemochromatosis protein HFE 20 years later: An emerging role in antigen presentation and in the immune system

PubMed Central

Chung, Jacqueline W.; Santos, Manuela M.

2017-01-01

Abstract Introduction Since its discovery, the hemochromatosis protein HFE has been primarily defined by its role in iron metabolism and homeostasis, and its involvement in the genetic disease termed hereditary hemochromatosis (HH). While HH patients are typically afflicted by dysregulated iron levels, many are also affected by several immune defects and increased incidence of autoimmune diseases that have thereby implicated HFE in the immune response. Growing evidence has supported an immunological role for HFE with recent studies describing HFE specifically as it relates to MHC I antigen presentation. Methods/Results Here, we present a comprehensive overview of the relationship between iron metabolism, HFE, and the immune system to better understand the origin and cause of immune defects in HH patients. We further describe the role of HFE in MHC I antigen presentation and its potential to impair autoimmune responses in homeostatic conditions, a mechanism which may be exploited by tumors to evade immune surveillance. Conclusion Overall, this increased understanding of the role of HFE in the immune response sets the stage for better treatment and management of HH and other iron‐related diseases, as well as of the immune defects related to this condition. PMID:28474781

Hereditary hemochromatosis: awareness and genetic testing acceptability in Western Romania.

PubMed

Neghina, Adriana Maria; Anghel, Andrei

2010-12-01

a public health strategy to promote early diagnosis of hemochromatosis gene (HFE)-related hemochromatosis (HFE-HH) largely depends on people's acceptance of available screening tests. The present study aimed at evaluating patient awareness of HFE-HH and their acceptance of DNA testing in western Romania. a total of 221 participants were randomly recruited from the ambulatory unit of the Emergency County Hospital in Timisoara, Romania. They received brief information on HFE-HH and were assessed for the signs and symptoms of hemochromatosis. HFE genotyping was offered to all of them. Only two cases (0.9%) had previous knowledge of HFE-HH. Twenty-one cases (9.5%) underwent genetic testing. Characteristics associated with test acceptance were age <45 years, male gender, and educational attainment. Acceptance was associated with a desire to know if they had HFE-HH (85.7%). The most prevalent refusal reason was a desire for more information (41%). larger educational programs are required to increase people's awareness about HFE-HH in western Romania. Nevertheless, within health care settings, the importance of disease detection and patient's educational background appear to be essential for achieving high rates of participation in the genetic test.

HFE gene variants, iron, and lipids: a novel connection in Alzheimer's disease.

PubMed

Ali-Rahmani, Fatima; Schengrund, Cara-Lynne; Connor, James R

2014-01-01

Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer's disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases.

HFE gene variants, iron, and lipids: a novel connection in Alzheimer’s disease

PubMed Central

Ali-Rahmani, Fatima; Schengrund, Cara-Lynne; Connor, James R.

2014-01-01

Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer’s disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases. PMID:25071582

Alternative Polyadenylation and Nonsense-Mediated Decay Coordinately Regulate the Human HFE mRNA Levels

PubMed Central

Martins, Rute; Proença, Daniela; Silva, Bruno; Barbosa, Cristina; Silva, Ana Luísa; Faustino, Paula; Romão, Luísa

2012-01-01

Nonsense-mediated decay (NMD) is an mRNA surveillance pathway that selectively recognizes and degrades defective mRNAs carrying premature translation-termination codons. However, several studies have shown that NMD also targets physiological transcripts that encode full-length proteins, modulating their expression. Indeed, some features of physiological mRNAs can render them NMD-sensitive. Human HFE is a MHC class I protein mainly expressed in the liver that, when mutated, can cause hereditary hemochromatosis, a common genetic disorder of iron metabolism. The HFE gene structure comprises seven exons; although the sixth exon is 1056 base pairs (bp) long, only the first 41 bp encode for amino acids. Thus, the remaining downstream 1015 bp sequence corresponds to the HFE 3′ untranslated region (UTR), along with exon seven. Therefore, this 3′ UTR encompasses an exon/exon junction, a feature that can make the corresponding physiological transcript NMD-sensitive. Here, we demonstrate that in UPF1-depleted or in cycloheximide-treated HeLa and HepG2 cells the HFE transcripts are clearly upregulated, meaning that the physiological HFE mRNA is in fact an NMD-target. This role of NMD in controlling the HFE expression levels was further confirmed in HeLa cells transiently expressing the HFE human gene. Besides, we show, by 3′-RACE analysis in several human tissues that HFE mRNA expression results from alternative cleavage and polyadenylation at four different sites – two were previously described and two are novel polyadenylation sites: one located at exon six, which confers NMD-resistance to the corresponding transcripts, and another located at exon seven. In addition, we show that the amount of HFE mRNA isoforms resulting from cleavage and polyadenylation at exon seven, although present in both cell lines, is higher in HepG2 cells. These results reveal that NMD and alternative polyadenylation may act coordinately to control HFE mRNA levels, possibly varying its protein expression according to the physiological cellular requirements. PMID:22530027

Human Factors and Ergonomics for the Dental Profession.

PubMed

Ross, Al

2016-09-01

This paper proposes that the science of Human Factors and Ergonomics (HFE) is suitable for wide application in dental education, training and practice to improve safety, quality and efficiency. Three areas of interest are highlighted. First it is proposed that individual and team Non-Technical Skills (NTS), such as communication, leadership and stress management can improve error rates and efficiency of procedures. Secondly, in a physically and technically challenging environment, staff can benefit from ergonomic principles which examine design in supporting safe work. Finally, examination of organizational human factors can help anticipate stressors and plan for flexible responses to multiple, variable demands, and fluctuating resources. Clinical relevance: HFE is an evidence-based approach to reducing error rates and procedural complications, and avoiding problems associated with stress and fatigue. Improved teamwork and organizational planning and efficiency can impact directly on patient outcomes.

Non-HFE haemochromatosis

PubMed Central

Wallace, Daniel F; Subramaniam, V Nathan

2007-01-01

Non-HFE hereditary haemochromatosis (HH) refers to a genetically heterogeneous group of iron overload disorders that are unlinked to mutations in the HFE gene. The four main types of non-HFE HH are caused by mutations in the hemojuvelin, hepcidin, transferrin receptor 2 and ferroportin genes. Juvenile haemochromatosis is an autosomal recessive disorder and can be caused by mutations in either hemojuvelin or hepcidin. An adult onset form of HH similar to HFE-HH is caused by homozygosity for mutations in transferrin receptor 2. The autosomal dominant iron overload disorder ferroportin disease is caused by mutations in the iron exporter ferroportin. The clinical characteristics and molecular basis of the various types of non-HFE haemochromatosis are reviewed. The study of these disorders and the molecules involved has been invaluable in improving our understanding of the mechanisms involved in the regulation of iron metabolism. PMID:17729390

Human factors engineering verification and validation for APR1400 computerized control room

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

Shin, Y. C.; Moon, H. K.; Kim, J. H.

2006-07-01

This paper introduces the Advanced Power Reactor 1400 (APR1400) HFE V and V activities the Korea Hydro Nuclear Plant Co. LTD. (KHNP) has performed for the last 10 years and some of the lessons learned through these activities. The features of APR1400 main control room include large display panel, redundant compact workstations, computer-based procedure, and safety console. Several iterations of human factors evaluations have been performed from small scale proof of concept tests to large scale integrated system tests for identifying human engineering deficiencies in the human system interface design. Evaluations in the proof of concept test were focused onmore » checking the presence of any show stopper problems in the design concept. Later evaluations were mostly for finding design problems and for assuring the resolution of human factors issues of advanced control room. The results of design evaluations were useful not only for refining the control room design, but also for licensing the standard design. Several versions of APR1400 mock-ups with dynamic simulation models of currently operating Korea Standard Nuclear Plant (KSNP) have been used for the evaluations with the participation of operators from KSNP plants. (authors)« less

Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

PubMed Central

Whittlesey, Rebecca L.; Andrews, Nancy C.

2011-01-01

The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe−/− mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/Smad target genes. In contrast, neither genetic loss of Hfe nor hepatic Hfe overexpression modulated the hepcidin elevation and systemic iron deficiency of Tmprss6−/− mice. These results indicate that genetic loss of Tmprss6 increases Bmp/Smad signaling in an Hfe-independent manner that can restore Bmp/Smad signaling in Hfe−/− mice. Furthermore, these results suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-associated hereditary hemochromatosis, raising the possibility that pharmacologic inhibition of TMPRSS6 could attenuate iron loading in this disorder. PMID:21355094

The WT hemochromatosis protein HFE inhibits CD8⁺ T-lymphocyte activation.

PubMed

Reuben, Alexandre; Phénix, Mikaël; Santos, Manuela M; Lapointe, Réjean

2014-06-01

MHC class I (MHC I) antigen presentation is a ubiquitous process by which cells present endogenous proteins to CD8(+) T lymphocytes during immune surveillance and response. Hereditary hemochromatosis protein, HFE, is involved in cellular iron uptake but, while structurally homologous to MHC I, is unable to bind peptides. However, increasing evidence suggests a role for HFE in the immune system. Here, we investigated the impact of HFE on CD8(+) T-lymphocyte activation. Using transient HFE transfection assays in a model of APCs, we show that WT HFE (HFEWT ), but not C282Y-mutated HFE, inhibits secretion of MIP-1β from antigen-specific CD8(+) T lymphocytes. HFEWT expression also resulted in major decreases in CD8(+) T-lymphocyte activation as measured by 4-1BB expression. We further demonstrate that inhibition of CD8(+) T-lymphocyte activation was independent of MHC I surface levels, β2-m competition, HFE interaction with transferrin receptor, antigen origin, or epitope affinity. Finally, we identified the α1-2 domains of HFEWT as being responsible for inhibiting CD8(+) T-lymphocyte activation. Our data imply a new role for HFEWT in altering CD8(+) T-lymphocyte reactivity, which could modulate antigen immunogenicity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hormone Replacement Therapy, Iron, and Breast Cancer

DTIC Science & Technology

2004-11-01

accumulates due to the mutation of the HFE gene (hemochromatosis EeJ, iron elevated in the mouse body mimics the post-menopausal condition. In the present...model. Since iron slowly accumulates due to the mutation of the HFE gene (hemochromatosis Fe), iron elevated in the mouse body mimics the post...menopausal condition. Development of iron overloaded transgenic mice: The murine HFE gene is structurally similar to the human gene . Four different HFE gene

Environmental risk assessment of hydrofluoroethers (HFEs).

PubMed

Tsai, Wen-Tien

2005-03-17

Hydrofluoroethers (HFEs) are being used as third generation replacements to chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) and perfluorocarbons (PFCs) because of their nearly zero stratospheric ozone depletion and relatively low global warming potential. HFEs have been developed under commercial uses as cleaning solvents (incl., HFE-7500, C7F15OC2H5; HFE-7200, C4F9OC2H5; HFE-7100, C4F9CH3; HFE-7000, n-C3F7OCH3), blowing agents (incl., HFE-245mc, CF3CF2OCH3; HFC-356mec, CF3CHFCF2OCH3), refrigerants (incl., HFE-143a, CF3OCH3; HFE-134, CHF2OCHF2; HFE-245mc, CF3CF2OCH3), and dry etching agents in semiconductor manufacturing, (incl., HFE-227me, CF3OCHFCF3). From the environmental, ecological, and health points of view, it is important to understand their environmental risks for these HFEs from a diversity of commercial applications and industrial processes. This paper aims to introduce these HFEs with respect to physiochemical properties, commercial uses, and environmental hazards (i.e. global warming, photochemical potential, fire and explosion hazard, and environmental partition). Further, it addresses the updated data on the human toxicity, occupational exposure and potential health risk of commercial HFEs. It is concluded that there are few HFEs that still possess some environmental hazards, including global warming, flammability hazard and adverse effect of exposure. The partition coefficient for these HFEs has been estimated using the group contribution method; the values of logKow for commercial HFEs have been estimated to be below 3.5.

The Study of HFE Genotypes and Its Expression Effect on Iron Status of Iranian Haemochromatosis, Iron Deficiency Anemia Patients, Iron-Taker and Non Iron-Taker Controls.

PubMed

Beiranvand, Elham; Abediankenari, Saeid; Rostamian, Mosayeb; Beiranvand, Behnoush; Naazeri, Saeed

2015-01-01

The role of HFE gene mutations or its expression in regulation of iron metabolism of hereditary haemochromatosis (HH) patients is remained controversial. Therefore here the correlation between two common HFE genotype (p.C282Y, p.H63D) and HFE gene expression with iron status in HH, iron deficiency anemia (IDA) and healthy Iranian participants was studied. For this purpose genotype determination was done by polymerase chain reaction--restriction fragment length polymorphism (PCR-RFLP). Real-Time PCR was applied for evaluation of HFE gene expression. Biochemical parameters and iron consumption were also assessed. Homozygote p.H63D mutation was seen in all HH patients and p.C282Y was not observed in any member of the population. A significant correlation was observed between serum ferritin (SF) level and gender or age of HH patients. p.H63D homozygote was seen to be able to significantly increase SF and transferrin saturation (TS) level without affecting on liver function. Our results also showed that iron consumption affects on TS level increasing. HFE gene expression level of IDA patients was significantly higher than other groups. Also the HFE gene expression was negatively correlated with TS. Finally, the main result of our study showed that loss of HFE function in HH is not derived from its gene expression inhibition and much higher HFE gene expression might lead to IDA. However we propose repeating of the study for more approval of our finding.

Mutant HFE H63D Protein Is Associated with Prolonged Endoplasmic Reticulum Stress and Increased Neuronal Vulnerability*

PubMed Central

Liu, Yiting; Lee, Sang Y.; Neely, Elizabeth; Nandar, Wint; Moyo, Mthabisi; Simmons, Zachary; Connor, James R.

2011-01-01

A specific polymorphism in the hemochromatosis (HFE) gene, H63D, is over-represented in neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer disease. Mutations of HFE are best known as being associated with cellular iron overload, but the mechanism by which HFE H63D might increase the risk of neuron degeneration is unclear. Here, using an inducible expression cell model developed from a human neuronal cell line SH-SY5Y, we reported that the presence of the HFE H63D protein activated the unfolded protein response (UPR). This response was followed by a persistent endoplasmic reticulum (ER) stress, as the signals of UPR sensors attenuated and followed by up-regulation of caspase-3 cleavage and activity. Our in vitro findings were recapitulated in a transgenic mouse model carrying Hfe H67D, the mouse equivalent of the human H63D mutation. In this model, UPR activation was detected in the lumbar spinal cord at 6 months then declined at 12 months in association with increased caspase-3 cleavage. Moreover, upon the prolonged ER stress, the number of cells expressing HFE H63D in early apoptosis was increased moderately. Cell proliferation was decreased without increased cell death. Additionally, despite increased iron level in cells carrying HFE H63D, it appeared that ER stress was not responsive to the change of cellular iron status. Overall, our studies indicate that the HFE H63D mutant protein is associated with prolonged ER stress and chronically increased neuronal vulnerability. PMID:21349849

Chemical chaperones reduce endoplasmic reticulum stress and prevent mutant HFE aggregate formation.

PubMed

de Almeida, Sérgio F; Picarote, Gonçalo; Fleming, John V; Carmo-Fonseca, Maria; Azevedo, Jorge E; de Sousa, Maria

2007-09-21

HFE C282Y, the mutant protein associated with hereditary hemochromatosis (HH), fails to acquire the correct conformation in the endoplasmic reticulum (ER) and is targeted for degradation. We have recently shown that an active unfolded protein response (UPR) is present in the cells of patients with HH. Now, by using HEK 293T cells, we demonstrate that the stability of HFE C282Y is influenced by the UPR signaling pathway that promotes its degradation. Treatment of HFE C282Y-expressing cells with tauroursodeoxycholic acid (TUDCA), a bile acid derivative with chaperone properties, or with the chemical chaperone sodium 4-phenylbutyrate (4PBA) impeded the UPR activation. However, although TUDCA led to an increased stability of the mutant protein, 4PBA contributed to a more efficient disposal of HFE C282Y to the degradation route. Fluorescence microscopy and biochemical analysis of the subcellular localization of HFE revealed that a major portion of the C282Y mutant protein forms intracellular aggregates. Although neither TUDCA nor 4PBA restored the correct folding and intracellular trafficking of HFE C282Y, 4PBA prevented its aggregation. These data suggest that TUDCA hampers the UPR activation by acting directly on its signal transduction pathway, whereas 4PBA suppresses ER stress by chemically enhancing the ER capacity to cope with the expression of misfolded HFE, facilitating its degradation. Together, these data shed light on the molecular mechanisms involved in HFE C282Y-related HH and open new perspectives on the use of orally active chemical chaperones as a therapeutic approach for HH.

The Effect of the Hemochromatosis (HFE) Genotype on Lead Load and Iron Metabolism among Lead Smelter Workers

PubMed Central

Fan, Guangqin; Du, Guihua; Li, Huijun; Lin, Fen; Sun, Ziyong; Yang, Wei; Feng, Chang; Zhu, Gaochun; Li, Yanshu; Chen, Ying; Jiao, Huan; Zhou, Fankun

2014-01-01

Background Both an excess of toxic lead (Pb) and an essential iron disorder have been implicated in many diseases and public health problems. Iron metabolism genes, such as the hemochromatosis (HFE) gene, have been reported to be modifiers for lead absorption and storage. However, the HFE gene studies among the Asian population with occupationally high lead exposure are lacking. Objectives To explore the modifying effects of the HFE genotype (wild-type, H63D variant and C282Y variant) on the Pb load and iron metabolism among Asian Pb-workers with high occupational exposure. Methods Seven hundred and seventy-one employees from a lead smelter manufacturing company were tested to determine their Pb intoxication parameters, iron metabolic indexes and identify the HFE genotype. Descriptive and multivariate analyses were conducted. Results Forty-five H63D variant carriers and no C282Y variant carrier were found among the 771 subjects. Compared with subjects with the wild-type genotype, H63D variant carriers had higher blood lead levels, even after controlling for factors such as age, sex, marriage, education, smoking and lead exposure levels. Multivariate analyses also showed that the H63D genotype modifies the associations between the blood lead levels and the body iron burden/transferrin. Conclusions No C282Y variant was found in this Asian population. The H63D genotype modified the association between the lead and iron metabolism such that increased blood lead is associated with a higher body iron content or a lower transferrin in the H63D variant. It is indicated that H63D variant carriers may be a potentially highly vulnerable sub-population if they are exposed to high lead levels occupationally. PMID:24988074

The effect of the hemochromatosis (HFE) genotype on lead load and iron metabolism among lead smelter workers.

PubMed

Fan, Guangqin; Du, Guihua; Li, Huijun; Lin, Fen; Sun, Ziyong; Yang, Wei; Feng, Chang; Zhu, Gaochun; Li, Yanshu; Chen, Ying; Jiao, Huan; Zhou, Fankun

2014-01-01

Both an excess of toxic lead (Pb) and an essential iron disorder have been implicated in many diseases and public health problems. Iron metabolism genes, such as the hemochromatosis (HFE) gene, have been reported to be modifiers for lead absorption and storage. However, the HFE gene studies among the Asian population with occupationally high lead exposure are lacking. To explore the modifying effects of the HFE genotype (wild-type, H63D variant and C282Y variant) on the Pb load and iron metabolism among Asian Pb-workers with high occupational exposure. Seven hundred and seventy-one employees from a lead smelter manufacturing company were tested to determine their Pb intoxication parameters, iron metabolic indexes and identify the HFE genotype. Descriptive and multivariate analyses were conducted. Forty-five H63D variant carriers and no C282Y variant carrier were found among the 771 subjects. Compared with subjects with the wild-type genotype, H63D variant carriers had higher blood lead levels, even after controlling for factors such as age, sex, marriage, education, smoking and lead exposure levels. Multivariate analyses also showed that the H63D genotype modifies the associations between the blood lead levels and the body iron burden/transferrin. No C282Y variant was found in this Asian population. The H63D genotype modified the association between the lead and iron metabolism such that increased blood lead is associated with a higher body iron content or a lower transferrin in the H63D variant. It is indicated that H63D variant carriers may be a potentially highly vulnerable sub-population if they are exposed to high lead levels occupationally.

Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis.

PubMed

Del-Castillo-Rueda, Alejandro; Moreno-Carralero, María-Isabel; Cuadrado-Grande, Nuria; Alvarez-Sala-Walther, Luis-Antonio; Enríquez-de-Salamanca, Rafael; Méndez, Manuel; Morán-Jiménez, María-Josefa

2012-10-15

Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. Copyright © 2012. Published by Elsevier B.V.

The role of genetic factors in patients with hepatocellular carcinoma and iron overload - a prospective series of 234 patients.

PubMed

Funakoshi, Natalie; Chaze, Iphigénie; Alary, Anne-Sophie; Tachon, Gaëlle; Cunat, Séverine; Giansily-Blaizot, Muriel; Bismuth, Michael; Larrey, Dominique; Pageaux, Georges-Philippe; Schved, Jean-François; Donnadieu-Rigole, Hélène; Blanc, Pierre; Aguilar-Martinez, Patricia

2016-05-01

Iron overload (IO) in HFE-related hereditary haemochromatosis is associated with increased risk of liver cancer. This study aimed to investigate the role of other genes involved in hereditary IO among patients with hepatocellular carcinoma (HCC). Patients with HCC diagnosed in our institution were included in this prospective study. Those with ferritin levels ≥300 μg/L (males) or ≥200 μg/L (females) and/or transferrin saturation ≥50% (males) or ≥45% (females) had liver iron concentration (LIC) evaluated by MRI. HFE C282Y and H63D mutations were screened. Genetic analyses of genes involved in hereditary IO (HFE, HJV/HFE2, HAMP, TFR2, SLC40A1, GNPAT) were performed in patients with increased LIC. A total of 234 patients were included; 215 (92%) had common acquired risk factors of HCC (mainly alcoholism or chronic viral hepatitis). 119 patients had abnormal iron parameters. Twelve (5.1%) were C282Y homozygotes, three were compound C282Y/H63D heterozygotes. LIC was measured by MRI in 100 patients. Thirteen patients with a LIC>70 μmol/g were enrolled in further genetic analyses: two unrelated patients bore the HAMP:c.-153C>T mutation at the heterozygous state, which is associated with increased risk of IO and severe haemochromatosis. Specific haplotypes of SLC40A1 were also studied. Additional genetic risk factors of IO were found in 18 patients (7.7%) among a large series of 234 HCC patients. Screening for IO and the associated at-risk genotypes in patients who have developed HCC, is useful for both determining etiologic diagnosis and enabling family screening and possibly primary prevention in relatives. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Towards a sustainable world through human factors and ergonomics: it is all about values.

PubMed

Lange-Morales, Karen; Thatcher, Andrew; García-Acosta, Gabriel

2014-01-01

In this paper, we analyse two approaches that attempt to address how a human factors and ergonomics (HFE) perspective can contribute to the sustainability of the human race. We outline the principles, purposes and fields of application of ergoecology and green ergonomics, and thereafter deal with their context of emergence, and the overlaps in purpose, and principles. Shared values are deduced and related to socio-technical principles for systems' design. Social responsibility and environmental/ecospheric responsibility are the leading threads of ergoecology and green ergonomics, giving rise to the values of: respect for human rights, respect for the Earth, respect for ethical decision-making, appreciation of complexity, respect for transparency and openness, and respect for diversity. We discuss the consequences of considering these values in HFE theory and practice.

Differences in hepatic phenotype between hemochromatosis patients with HFE C282Y homozygosity and other HFE genotypes.

PubMed

Cheng, Raymond; Barton, James C; Morrison, Elizabeth D; Phatak, Pradyumna D; Krawitt, Edward L; Gordon, Stuart C; Kowdley, Kris V

2009-07-01

There are limited data comparing hepatic phenotype among hemochromatosis patients with different HFE genotypes. The goal of this study was to compare hepatic histopathologic features and hepatic iron concentration (HIC) among patients with phenotypic hemochromatosis and different HFE genotypes. We studied 182 US patients with phenotypic hemochromatosis. Degree of hepatic fibrosis, pattern of iron deposition, presence of steatosis or necroinflammation, and HIC were compared among different HFE genotypes. C282Y/H63D compound heterozygotes and patients with HFE genotypes other than C282Y/C282Y were more likely to have stainable Kupffer cell iron (31.1% vs. 9.5%; P=0.02), portal or lobular inflammation (28.9% vs. 15.6%; P=0.03), and steatosis (33.3% vs. 10.2%; P<0.01) on liver biopsy than C282Y homozygotes. Mean log10 HIC (P<0.05) and log10 ferritin (P<0.05) were higher among C282Y homozygotes than in patients with other HFE genotypes. In a logistic regression analysis using age, sex, HFE genotype, log10 ferritin, and log10 HIC as independent variables, log10 serum ferritin (P=0.0008), male sex (P=0.0086), and log10 HIC (P=0.047), but not HFE genotype (P=0.0554) were independently associated with presence or absence of advanced hepatic fibrosis. C282Y/H63D compound heterozygotes and other non-C282Y homozygotes which express the hepatic hemochromatosis phenotype frequently have evidence of steatosis or chronic hepatitis and lower body iron stores than C282Y homozygotes. These data suggest that presence of concomitant liver disease may explain expression of the hemochromatosis phenotype among non-C282Y homozygotes. Increased age, HIC, and ferritin are associated with advanced hepatic fibrosis, regardless of HFE genotype.

Increased duodenal DMT-1 expression and unchanged HFE mRNA levels in HFE-associated hereditary hemochromatosis and iron deficiency.

PubMed

Byrnes, V; Barrett, S; Ryan, E; Kelleher, T; O'Keane, C; Coughlan, B; Crowe, J

2002-01-01

HFE-associated hereditary hemochromatosis is characterized by imbalances of iron homeostasis and alterations in intestinal iron absorption. The identification of the HFE gene and the apical iron transporter divalent metal transporter-1, DMT-1, provide a direct method to address the mechanisms of iron overload in this disease. The aim of this study was to evaluate the regulation of duodenal HFE and DMT-1 gene expression in HFE-associated hereditary hemochromatosis. Small bowel biopsies and serum iron indices were obtained from a total of 33 patients. The study population comprised 13 patients with hereditary hemochromatosis (C282Y homozygous), 10 patients with iron deficiency anemia, and 10 apparently healthy controls, all of whom were genotyped for the two common mutations in the HFE gene (C282Y and H63D). Total RNA was isolated from tissue and amplified via RT-PCR for HFE, DMT-1, and the internal control GAPDH. DMT-1 protein expression was additionally assessed by immunohistochemistry. Levels of HFE mRNA did not differ significantly between patient groups (P = 0.09), specifically between C282Y homozygotes and iron deficiency anemic patients, when compared to controls (P = 0.09, P = 0.9, respectively). In contrast, DMT-1 mRNA levels were at least twofold greater in patients with hereditary hemochromatosis and iron deficiency anemia when compared to controls (P = 0.02, P = 0.01, respectively). Heightened DMT-1 protein expression correlated with mRNA levels in all patients. Loss of HFE function in hereditary hemochromatosis is not derived from inhibition of its gene expression. DMT-1 expression in C282Y homozygote subjects is consistent with the hypothesis of a "paradoxical" duodenal iron deficiency in hereditary hemochromatosis. The observed twofold upregulation of the DMT-1 is consistent with the slow but steady increase in body iron stores observed in those presenting with clinical features of hereditary hemochromatosis.

Detection of high-frequency energy level changes in speech and singing

PubMed Central

Monson, Brian B.; Lotto, Andrew J.; Story, Brad H.

2014-01-01

Previous work has shown that human listeners are sensitive to level differences in high-frequency energy (HFE) in isolated vowel sounds produced by male singers. Results indicated that sensitivity to HFE level changes increased with overall HFE level, suggesting that listeners would be more “tuned” to HFE in vocal production exhibiting higher levels of HFE. It follows that sensitivity to HFE level changes should be higher (1) for female vocal production than for male vocal production and (2) for singing than for speech. To test this hypothesis, difference limens for HFE level changes in male and female speech and singing were obtained. Listeners showed significantly greater ability to detect level changes in singing vs speech but not in female vs male speech. Mean differences limen scores for speech and singing were about 5 dB in the 8-kHz octave (5.6–11.3 kHz) but 8–10 dB in the 16-kHz octave (11.3–22 kHz). These scores are lower (better) than those previously reported for isolated vowels and some musical instruments. PMID:24437780

Hemochromatosis

MedlinePlus

... and S65C HFE gene mutations, diet, and life-style factors on iron status in the general Mediterranean ... Health Information Diabetes Digestive Diseases Kidney Disease Weight Management Liver Disease Urologic Diseases Endocrine Diseases Diet & Nutrition ...

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

White, Michael K.; Brown, Jason R.; Thornberg, Steven Michael

HFE-7100 and FC-72 fluorinert are two fluids used during weapon component manufacturing. HFE-7100 is a solvent used in the cleaning of parts, and FC-72 is the blowing agent of a polymeric removable foam. The presence of either FC-72 or HFE-7100 gas in weapon components can provide valuable information as to the stability of the materials. Therefore, gas standards are needed so HFE-7100 and FC-72 gas concentrations can be accurately measured. There is no current established procedure for generating gas standards of either HFE-7100 or FC-72. This report outlines the development of a method to generate gas standards ranging in concentrationmore » from 0.1 ppm to 10% by volume. These standards were then run on a Jeol GC-Mate II mass spectrometer and analyzed to produce calibration curves. We present a manifold design that accurately generates gas standards of HFE-7100 and FC-72 and a procedure that allows the amount of each to be determined.« less

Identification of novel mutations in HFE, HFE2, TfR2, and SLC40A1 genes in Chinese patients affected by hereditary hemochromatosis.

PubMed

Wang, Yongwei; Du, Yali; Liu, Gang; Guo, Shanshan; Hou, Bo; Jiang, Xianyong; Han, Bing; Chang, Yanzhong; Nie, Guangjun

2017-04-01

Hereditary hemochromatosis (HH) is a group of inherited iron-overload disorders associated with pathogenic defects in the genes encoding hemochromatosis (HFE), hemojuvelin (HJV/HFE2), hepcidin (HAMP), transferrin receptor 2 (TfR2), and ferroportin (FPN1/SLC40A1) proteins, and the clinical features are well described. However, there have been only a few detailed reports of HH in Chinese populations. Thus, there is insufficient patient information for population-based analyses in Chinese populations or comparative studies among different ethical groups. In the current work, we describe eight Chinese cases of hereditary hemochromatosis. Gene sequencing results revealed eight mutations (five novel mutations) in HFE, HFE2, TfR2, and SLC40A1 genes in these Chinese HH patients. In addition, we used Polymorphism Phenotyping v2 (Polyphen), Sorting Intolerant From Tolerant (SIFT), and a sequence alignment program to predict the molecular consequences of missense mutations.

Preliminary investigation of bottlenose dolphins (Tursiops truncatus) for hfe gene-related hemochromatosis.

PubMed

Phillips, Brianne E; Venn-Watson, Stephanie; Archer, Linda L; Nollens, Hendrik H; Wellehan, James F X

2014-10-01

Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.

Analysis of high-frequency energy in long-term average spectra of singing, speech, and voiceless fricatives.

PubMed

Monson, Brian B; Lotto, Andrew J; Story, Brad H

2012-09-01

The human singing and speech spectrum includes energy above 5 kHz. To begin an in-depth exploration of this high-frequency energy (HFE), a database of anechoic high-fidelity recordings of singers and talkers was created and analyzed. Third-octave band analysis from the long-term average spectra showed that production level (soft vs normal vs loud), production mode (singing vs speech), and phoneme (for voiceless fricatives) all significantly affected HFE characteristics. Specifically, increased production level caused an increase in absolute HFE level, but a decrease in relative HFE level. Singing exhibited higher levels of HFE than speech in the soft and normal conditions, but not in the loud condition. Third-octave band levels distinguished phoneme class of voiceless fricatives. Female HFE levels were significantly greater than male levels only above 11 kHz. This information is pertinent to various areas of acoustics, including vocal tract modeling, voice synthesis, augmentative hearing technology (hearing aids and cochlear implants), and training/therapy for singing and speech.

The Human Factors and Ergonomics of P300-Based Brain-Computer Interfaces

PubMed Central

Powers, J. Clark; Bieliaieva, Kateryna; Wu, Shuohao; Nam, Chang S.

2015-01-01

Individuals with severe neuromuscular impairments face many challenges in communication and manipulation of the environment. Brain-computer interfaces (BCIs) show promise in presenting real-world applications that can provide such individuals with the means to interact with the world using only brain waves. Although there has been a growing body of research in recent years, much relates only to technology, and not to technology in use—i.e., real-world assistive technology employed by users. This review examined the literature to highlight studies that implicate the human factors and ergonomics (HFE) of P300-based BCIs. We assessed 21 studies on three topics to speak directly to improving the HFE of these systems: (1) alternative signal evocation methods within the oddball paradigm; (2) environmental interventions to improve user performance and satisfaction within the constraints of current BCI systems; and (3) measures and methods of measuring user acceptance. We found that HFE is central to the performance of P300-based BCI systems, although researchers do not often make explicit this connection. Incorporation of measures of user acceptance and rigorous usability evaluations, increased engagement of disabled users as test participants, and greater realism in testing will help progress the advancement of P300-based BCI systems in assistive applications. PMID:26266424

UXO Discrimination in Cases with Overlapping Signatures

DTIC Science & Technology

2007-03-07

13. APPENDIX B: HFE -BIEM ..........................................................................................................290 - 7...First principals numerical solutions developed were a Hybrid Finite Element – Boundary Integral Equation Method ( HFE -BIEM) body of revolution (BOR...attacks, namely the Method of Auxiliary Sources (MAS) and the Hybrid Finite Element – Boundary Integral Equation Method ( HFE -BIEM). These work

HFE Genotype Restricts the Response to Paraquat in a Mouse Model of Neurotoxicity.

PubMed

Nixon, Anne M; Meadowcroft, Mark D; Neely, Elizabeth B; Snyder, Amanda M; Purnell, Carson J; Wright, Justin; Lamendella, Regina; Nandar, Wint; Huang, Xuemei; Connor, James R

2018-05-01

Parkinson's disease is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra and iron accumulation in the substantia nigra. The driver underlying iron accumulation remains unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R 2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R 2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for Parkinson's disease. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants. © 2018 International Society for Neurochemistry.

The impact of H63D HFE gene carriage on hemoglobin and iron status in children.

PubMed

Barbara, Kaczorowska-Hac; Marcin, Luszczyk; Jedrzej, Antosiewicz; Wieslaw, Ziolkowski; Elzbieta, Adamkiewicz-Drozynska; Malgorzata, Mysliwiec; Ewa, Milosz; Jacek, Kaczor Jan

2016-12-01

The molecular mechanism that regulates iron homeostasis is based on a network of signals, which reflect on the iron requirements of the body. Hereditary hemochromatosis is a heterogenic metabolic syndrome which is due to unchecked transfer of iron into the bloodstream and its toxic effects on parenchymatous organs. It is caused by the mutation of genes that encode proteins that help hepcidin to monitor serum iron. These proteins include the human hemochromatosis protein -HFE, transferrin-receptor 2, hemojuvelin in rare instances, and ferroportin. HFE-related hemochromatosis is the most frequent form of the disease. Interestingly, the low penetrance of polymorphic HFE genes results in rare clinical presentation of the disease, predominantly in middle-aged males. Taking into account the wide dispersion of HFE mutation in our population and also its unknown role in heterozygotes, we analyzed the impact of H63D HFE carriage in the developmental age, with respect to gender, on the iron status and hemoglobin concentration of carriers in comparison to those of wild-type HFE gene (12.7 ± 3.07 years, 42 boys and 41 girls). H63D carriers presented higher blood iron, transferrin saturation, and ferritin concentration than wild-type probands (p < 0.05.) Interestingly, male H63D carriers showed higher hemoglobin concentration than the unburdened children. Moreover, in the H63D carrier group, a positive correlation between iron and hemoglobin was noted. In conclusion, this study demonstrates that changes in iron metabolism occur at a young age in HFE heterozygotes.

Analysis of high-frequency energy in long-term average spectra of singing, speech, and voiceless fricatives

PubMed Central

Monson, Brian B.; Lotto, Andrew J.; Story, Brad H.

2012-01-01

The human singing and speech spectrum includes energy above 5 kHz. To begin an in-depth exploration of this high-frequency energy (HFE), a database of anechoic high-fidelity recordings of singers and talkers was created and analyzed. Third-octave band analysis from the long-term average spectra showed that production level (soft vs normal vs loud), production mode (singing vs speech), and phoneme (for voiceless fricatives) all significantly affected HFE characteristics. Specifically, increased production level caused an increase in absolute HFE level, but a decrease in relative HFE level. Singing exhibited higher levels of HFE than speech in the soft and normal conditions, but not in the loud condition. Third-octave band levels distinguished phoneme class of voiceless fricatives. Female HFE levels were significantly greater than male levels only above 11 kHz. This information is pertinent to various areas of acoustics, including vocal tract modeling, voice synthesis, augmentative hearing technology (hearing aids and cochlear implants), and training/therapy for singing and speech. PMID:22978902

Prevalence of C282Y, H63D, and S65C mutations in hereditary HFE-hemochromatosis gene in Lithuanian population.

PubMed

Kucinskas, Laimutis; Juzenas, Simonas; Sventoraityte, Jurgita; Cedaviciute, Ruta; Vitkauskiene, Astra; Kalibatas, Vytenis; Kondrackiene, Jurate; Kupcinskas, Limas

2012-04-01

HFE-hemochromatosis is a common autosomal recessive disease caused by HFE gene mutations and characterized as iron overload and failure of different organs. The aim of this study was to determine the prevalence of C282Y (c.845 G>A), H63D (c.187 C>G), and S65C (c.193A>T) alleles of HFE gene in the Lithuanian population. One thousand and eleven healthy blood donors of Lithuanian nationality were examined in four different ethnic Lithuanian regions to determine HFE gene alleles and genotype frequencies. The samples of DNA were analyzed for the presence of restriction fragment length polymorphism and validated by DNA sequencing. Among 1,011 blood donors tested, the frequency of C282Y, H63D, and S65C alleles were 2.6%, 15.9%, and 1.9%, respectively. One third of the tested subjects (n = 336) had at least one of the C282Y or H63D HFE gene mutations. The screening of Lithuanian blood donors has detected 13 (1.3%) subjects with a genotype C282Y/C282Y or C282Y/H63D responsible for the development of HFE-hemochromatosis. The prevalence of C282Y mutation was significantly higher among the inhabitants of Zemaitija (Somogitia) at the Baltic Sea area (5.9%) in comparison to the regions of continental part of Lithuania (2.4% in Dzukija, 2.3% in Aukstaitija, and 2% in Suvalkija, p < 0.05). These data support the hypothesis that the p.C282Y mutation originated from Scandinavia and spread with the Vikings along the Baltic Sea coast. The first epidemiological investigation of HFE gene mutations in ethnic Lithuanians showed that the frequencies of H63D, C282Y, and S65C of HFE gene alleles are similar to the other North-Eastern Europeans, especially in the Baltic region (Estonia, Latvia), Poland, and part of Russia (Moscow region).

HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosis.

PubMed

Allen, Katrina J; Bertalli, Nadine A; Osborne, Nicholas J; Constantine, Clare C; Delatycki, Martin B; Nisselle, Amy E; Nicoll, Amanda J; Gertig, Dorota M; McLaren, Christine E; Giles, Graham G; Hopper, John L; Anderson, Gregory J; Olynyk, John K; Powell, Lawrie W; Gurrin, Lyle C

2010-09-01

Hemochromatosis gene (HFE)-associated hereditary hemochromatosis (HH) is a genetic predisposition to iron overload and subsequent signs and symptoms of disease that potentially affects approximately 80,000 persons in Australia and almost 1 million persons in the United States. Most clinical cases are homozygous for the Cys282Tyr (C282Y) mutation in the HFE gene, with serum ferritin (SF) concentration >1000 microg/L as the strongest predictor of cirrhosis. The optimal treatment regimen for those with SF concentrations above the normal range but <1000 microg/L is unknown. We assessed HFE mutations in a prospective cohort of 31,192 participants of northern European descent, aged 40-69 years. An HFE-stratified random sample of 1438 participants including all C282Y homozygotes with iron studies 12 years apart were examined by physicians blinded to participants' HFE genotype. All previously undiagnosed C282Y homozygotes (35 male, 67 female) and all HFE wild-types (131 male, 160 female) with baseline and follow-up SF concentrations <1000 microg/L were assessed for HH-associated signs and symptoms including abnormal second/third metacarpophalangeal joints (MCP2/3), raised liver enzymes, hepatomegaly, and self-reported liver disease, fatigue, diabetes mellitus, and use of arthritis medication. The prevalence of HH-associated signs and symptoms was similar for C282Y homozygotes and HFE wild-types for both normal and moderately elevated SF concentrations. The maximum prevalence difference between HFE genotype groups with moderately elevated SF was 11% (MCP2/3, 95% confidence interval = -6%, 29%; P = 0.22) and for normal SF was 6% (arthritis medicine use, 95% confidence interval = -3%, 16%; P = 0.11). Previously undiagnosed C282Y homozygotes with SF concentrations that remain below 1000 microg/L are at low risk of developing HH-associated signs and symptoms at an age when disease would be expected to have developed. These observations have implications for the management of C282Y homozygotes.

Electronic Master Monitor and Advisory Display System, Human Engineering Summary Report.

DTIC Science & Technology

1981-06-01

Communications, Sensors Instrumentation Division IS. NUMBER OF PAGES Fort Monmouth, NJ 0770M 226 14. MONITORING AGENCY NAME & ADORESS{I1 differel from...quantized each indication according to electrical signal, sensor type, display type, operating ranges, etc. The HFE evaluation sought to categorize the...was based on: " Frequency of the suggestion across crews * Relative potential for reducing workload " The need for sophisticated sensors for

Iron overload and HFE gene mutations in Czech patients with chronic liver diseases.

PubMed

Dostalikova-Cimburova, Marketa; Kratka, Karolina; Stransky, Jaroslav; Putova, Ivana; Cieslarova, Blanka; Horak, Jiri

2012-01-01

The aim of the study was to identify the prevalence of HFE gene mutations in Czech patients with chronic liver diseases and the influence of the mutations on iron status. The presence of HFE gene mutations (C282Y, H63D, and S65C) analyzed by the PCR-RFLP method, presence of cirrhosis, and serum iron indices were compared among 454 patients with different chronic liver diseases (51 with chronic hepatitis B, 122 with chronic hepatitis C, 218 with alcoholic liver disease, and 63 patients with hemochromatosis). Chronic liver diseases patients other than hemochromatics did not have an increased frequency of HFE gene mutations compared to controls. Although 33.3% of patients with hepatitis B, 43% of patients with hepatitis C, and 73.2% of patients with alcoholic liver disease had elevated transferrin saturation or serum ferritin levels, the presence of HFE gene mutations was not significantly associated with iron overload in these patients. Additionally, patients with cirrhosis did not have frequencies of HFE mutations different from those without cirrhosis. This study emphasizes the importance, not only of C282Y, but also of the H63D homozygous genetic constellation in Czech hemochromatosis patients. Our findings show that increased iron indices are common in chronic liver diseases but {\\it HFE} mutations do not play an important role in the pathogenesis of chronic hepatitis B, chronic hepatitis C, and alcoholic liver disease.

The hepcidin gene promoter nc.-1010C > T; -582A > G haplotype modulates serum ferritin in individuals carrying the common H63D mutation in HFE gene.

PubMed

Silva, Bruno; Pita, Lina; Gomes, Susana; Gonçalves, João; Faustino, Paula

2014-12-01

Hereditary hemochromatosis is an autosomal recessive disorder characterized by severe iron overload. It is usually associated with homozygosity for the HFE gene mutation c.845G > A; p.C282Y. However, in some cases, another HFE mutation (c.187C > G; p.H63D) seems to be associated with the disease. Its penetrance is very low, suggesting the possibility of other iron genetic modulators being involved. In this work, we have screened for HAMP promoter polymorphisms in 409 individuals presenting normal or increased serum ferritin levels together with normal or H63D-mutated HFE genotypes. Our results show that the hepcidin gene promoter TG haplotype, originated by linkage of the nc.-1010C > T and nc.-582A > G polymorphisms, is more frequent in the HFE_H63D individuals presenting serum ferritin levels higher than 300 μg/L than in those presenting the HFE_H63D mutation but with normal serum ferritin levels or in the normal control group.Moreover, it was observed that the TG haplotype was associated to increased serum ferritin levels in the overall pool of HFE_H63D individuals. Thus, our data suggest that screening for these polymorphisms could be of interest in order to explain the phenotype. However, this genetic condition seems to have no clinical significance.

Risk factors for development of dementia in a unique six-year cohort study. I. An exploratory, pilot study of involvement of the E4 allele of apolipoprotein E, mutations of the hemochromatosis-HFE gene, type 2 diabetes, and stroke.

PubMed

Percy, Maire; Somerville, Martin J; Hicks, Mark; Garcia, Angeles; Colelli, Teresa; Wright, Emily; Kitaygorodsky, Julia; Jiang, Amy; Ho, Valerie; Parpia, Alyssa; Wong, Michael K

2014-01-01

Risk factors for dementia development are not well-defined. We evaluated several factors alone and in combination in a unique cohort of Caucasian volunteers over an approximately 6-year observation window using a nested case/control design. Factors included: apolipoprotein E (ApoE) gene variants (the E4 allele is the strongest confirmed genetic predisposing factor for Alzheimer's disease), the hemochromatosis-HFE gene mutations (H63D and C282Y), diabetes, and stroke. At study entry, subjects were ≥65 years of age (M ± SD = 73.0 ± 4.9), had an MMSE score ≥24, and no evidence of cerebrovascular disease or current depression. Genotyping was completed on 163 available DNA samples from three different groups at the study end: those who still had normal cognitive function; those who had developed dementia; and those with Mild Cognitive Impairment (MCI). Analyses were interpreted at the 95% confidence level without Bonferroni corrections. In the subgroup with dementia, all cases of diabetes were type 2 and present at study entry, whereas all strokes occurred during the study. The results highlight apparently synergistic interactions between genetic and medical risk factors for dementia development, gender differences in risk factors, and involvement of HFE mutations. Having E4 (i.e., either of E3/4 or E4/4), C282Y, H63D, diabetes, or stroke alone did not attain significance. Significant predisposing factors with post-hoc power ≥80% were: E4 homozygosity (E4/4)males+females, odds ratio (OR) = 56.0); E4+diabetes (males+females, OR = 13.7; E4+H63D+diabetes (females, OR = 52.0); E4+stroke (males, OR = 46.5). The importance of preventing diabetes and stroke to ward off dementia and the possible role of iron dysmetabolism in dementia are discussed.

Human-system Interfaces to Automatic Systems: Review Guidance and Technical Basis

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

OHara, J.M.; Higgins, J.C.

Automation has become ubiquitous in modern complex systems and commercial nuclear power plants are no exception. Beyond the control of plant functions and systems, automation is applied to a wide range of additional functions including monitoring and detection, situation assessment, response planning, response implementation, and interface management. Automation has become a 'team player' supporting plant personnel in nearly all aspects of plant operation. In light of the increasing use and importance of automation in new and future plants, guidance is needed to enable the NRC staff to conduct safety reviews of the human factors engineering (HFE) aspects of modern automation.more » The objective of the research described in this report was to develop guidance for reviewing the operator's interface with automation. We first developed a characterization of the important HFE aspects of automation based on how it is implemented in current systems. The characterization included five dimensions: Level of automation, function of automation, modes of automation, flexibility of allocation, and reliability of automation. Next, we reviewed literature pertaining to the effects of these aspects of automation on human performance and the design of human-system interfaces (HSIs) for automation. Then, we used the technical basis established by the literature to develop design review guidance. The guidance is divided into the following seven topics: Automation displays, interaction and control, automation modes, automation levels, adaptive automation, error tolerance and failure management, and HSI integration. In addition, we identified insights into the automaton design process, operator training, and operations.« less

HJV and HFE Play Distinct Roles in Regulating Hepcidin

PubMed Central

Wu, Qian; Wang, Hao; An, Peng; Tao, Yunlong; Deng, Jiali; Zhang, Zhuzhen; Shen, Yuanyuan; Chen, Caiyong

2015-01-01

Abstract Aims: Hereditary hemochromatosis (HH) is an iron overload disease that is caused by mutations in HFE, HJV, and several other genes. However, whether HFE-HH and HJV-HH share a common pathway via hepcidin regulation is currently unclear. Recently, some HH patients have been reported to carry concurrent mutations in both the HFE and HJV genes. To dissect the roles and molecular mechanisms of HFE and/or HJV in the pathogenesis of HH, we studied Hfe−/−, Hjv−/−, and Hfe−/−Hjv−/− double-knockout mouse models. Results: Hfe−/−Hjv−/− mice developed iron overload in multiple organs at levels comparable to Hjv−/− mice. After an acute delivery of iron, the expression of hepcidin (i.e., Hamp1 mRNA) was increased in the livers of wild-type and Hfe−/− mice, but not in either Hjv−/− or Hfe−/−Hjv−/− mice. Furthermore, iron-induced phosphorylation of Smad1/5/8 was not detected in the livers of Hjv−/− or Hfe−/−Hjv−/− mice. Innovation: We generated and phenotypically characterized Hfe−/−Hjv−/− double-knockout mice. In addition, because they faithfully phenocopy clinical HH patients, these mouse models are an invaluable tool for mechanistically dissecting how HFE and HJV regulate hepcidin expression. Conclusions: Based on our results, we conclude that HFE may depend on HJV for transferrin-dependent hepcidin regulation. The presence of residual hepcidin in the absence of HFE suggests either the presence of an unknown regulator (e.g., TFR2) that is synergistic with HJV or that HJV is sufficient to maintain basal levels of hepcidin. Antioxid. Redox Signal. 22, 1325–1336. PMID:25608116

Financial Analysis of Experimental Releases Conducted at Glen Canyon Dam during Water Year 2015

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

Graziano, D. J.; Poch, L. A.; Veselka, T. D.

This report examines the financial implications of experimental flows conducted at the Glen Canyon Dam (GCD) in water year (WY) 2015. It is the seventh report in a series examining the financial implications of experimental flows conducted since the Record of Decision (ROD) was adopted in February 1997 (Reclamation 1996). A report released in January 2011 examined WYs 1997 to 2005 (Veselka et al. 2011); a report released in August 2011 examined WYs 2006 to 2010 (Poch et al. 2011); a report released June 2012 examined WY 2011 (Poch et al. 2012); a report released April 2013 examined WY 2012more » (Poch et al. 2013); a report released June 2014 examined WY 2013 (Graziano et al. 2014); and a report released September 2015 examined WY 2014 (Graziano et al. 2015). An experimental release may have either a positive or negative impact on the financial value of energy production. Only one experimental release was conducted at GCD in WY 2015; specifically, a high flow experimental (HFE) release conducted in November 2014. For this experimental release, financial costs of approximately $2.1 million were incurred because the HFE required sustained water releases that exceeded the powerplant’s maximum flow rate. In addition, during the month of the experiment, operators were not allowed to shape GCD power production to either follow firm power customer loads or to respond to market prices. This study identifies the main factors that contribute to HFE costs and examines the interdependencies among these factors. It applies an integrated set of tools to estimate financial impacts by simulating the GCD operations under two scenarios: (1) a baseline scenario that mimics both HFE operations during the experiment and during the rest of the year when it complies with the 1996 ROD operating criteria, and (2) a “without experiments” scenario that is identical to the baseline except it assumes that the HFE did not occur. The Generation and Transmission Maximization (GTMax) model was the main simulation tool used to simulate the dispatch of hydropower plants at GCD and other plants that comprise the Salt Lake City Area Integrated Projects (SLCA/IP). The research team used extensive data sets and historical information on SLCA/IP powerplant characteristics, hydrologic conditions, and Western Area Power Administration’s (WAPA’s) power purchase prices in the modeling process. In addition to estimating the financial impact of the HFE, the team used the GTMax model to gain insights into the interplay among ROD operating criteria, exceptions that were made to criteria to accommodate the experimental releases, and WAPA operating practices.« less

Heritability of Serum Iron Measures in the Hemochromatosis and Iron Overload Screening (HEIRS) Family Study

PubMed Central

McLaren, Christine E.; Barton, James C.; Eckfeldt, John H.; McLaren, Gordon D.; Acton, Ronald T.; Adams, Paul C.; Henkin, Leora F.; Gordeuk, Victor R.; Vulpe, Chris D.; Harris, Emily L.; Harrison, Barbara W.; Reiss, Jacob A.; Snively, Beverly M.

2013-01-01

Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The HEIRS Family Study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 μg/L, men; SF > 200 μg/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N=942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) y; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (p=0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and non-genetic sources of variation. PMID:20095037

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

Redondo, Pilar; Barrientos, Carmen; Largo, Antonio, E-mail: predondo@qf.uva.es

Iron is the most abundant transition metal in space. Its abundance is similar to that of magnesium, and until today only, FeO and FeCN have been detected. However, magnesium-bearing compounds such as MgCN, MgNC, and HMgNC are found in IRC+10216. It seems that the hydrides of iron cyanide/isocyanide could be good candidates to be present in space. In the present work we carried out a characterization of the different minima on the quintet and triplet [C, Fe, H, N] potential energy surfaces, employing several theoretical approaches. The most stable isomers are predicted to be hydride of iron cyanide HFeCN, andmore » isocyanide HFeNC, in their {sup 5}Δ states. Both isomers are found to be quasi-isoenergetics. The HFeNC isomer is predicted to lie about 0.5 kcal/mol below HFeCN. The barrier for the interconversion process is estimated to be around 6.0 kcal/mol, making this process unfeasible under low temperature conditions, such as those in the interstellar medium. Therefore, both HFeCN and HFeNC could be candidates for their detection. We report geometrical parameters, vibrational frequencies, and rotational constants that could help with their experimental characterization.« less

Reduction of Skeletal Muscle Power in Adolescent Males Carrying H63D Mutation in the HFE Gene.

PubMed

Luszczyk, Marcin; Kaczorowska-Hac, Barbara; Milosz, Ewa; Adamkiewicz-Drozynska, Elzbieta; Ziemann, Ewa; Laskowski, Radoslaw; Flis, Damian; Rokicka-Hebel, Magdalena; Antosiewicz, Jedrzej

2017-01-01

Iron overload resulting from the mutation of genes involved in iron metabolism or excess dietary intake has been reported to negatively influence human physical performance. The aim of this study was to test the hypothesis that adolescents bearing a hemochromatosis gene (HFE) mutation in contrast to adults with the same mutation will not experience iron accumulation and their aerobic capacity will be similar to that of age-matched controls. Thirteen boys participated in the study. Seven of them are carriers of H63D mutation in the HFE gene and six were wild type. Fitness levels were assessed using the cardiopulmonary exercise test. In addition, iron status and inflammatory markers were determined. We observed that cardiovascular fitness was significantly lower in the group bearing the HFE mutation compared to the control group. Moreover, the HFE mutation group achieved lower maximal power output compared to the control group. There were no differences in blood ferritin concentrations between the two groups which indicates similar amounts of stored iron. Obtained data do not confirm our hypothesis. On the contrary, it was demonstrated that HFE mutation is associated with a lower level of aerobic capacity, even in the absence of iron accumulation.

[Effect of high frequency electrotherapy on caspase-3 and ultra microstructure of hippocampus in rats following cerebral ischemia/reperfusion].

PubMed

Fan, Yongmei; Wang, Rumi; Zhang, Changjie; Peng, Wenna; Yin, Jing; Hu, Zhiping

2017-01-28

To investigate the effect of high frequency electrotherapy (HFE) on rat hippocampus after cerebral ischemia/reperfusion (I/R).
 Methods: A rat model of cerebral I/R injury was established. The rats were randomly divided into a sham group, an I/R group and an HFE group. The HFE group received thearapy daily for different sessions for 1, 3, 7 d. Neuronal deficit score,neuron ultra microstructure in the hippocampus and caspase-3 protein expression were measured on 1 st, 3 th and 7th d.
 Results: Compared with the I/R group, the HFE group showed the decreased neurological deficit scores, with significant differences between the 2 groups (P<0.05). The injury in HFE group was reduced compared with that in the I/R group based on the electron microscope test, with significant difference. Caspase-3 protein in brain tissue in the HFE group also downregulated compared with that in the I/R group (P<0.05).
 Conclusion: High frequency electrotherapy can improve neural function, suppress caspase-3 expression and apoptosis in nerve cells and improve the ultra microstructure of neurons, displaying a protective effect on cerebral I/R injury in rats.

Fast estimation of Colles' fracture load of the distal section of the radius by homogenized finite element analysis based on HR-pQCT.

PubMed

Hosseini, Hadi S; Dünki, Andreas; Fabech, Jonas; Stauber, Martin; Vilayphiou, Nicolas; Pahr, Dieter; Pretterklieber, Michael; Wandel, Jasmin; Rietbergen, Bert van; Zysset, Philippe K

2017-04-01

Fractures of the distal section of the radius (Colles' fractures) occur earlier in life than other osteoporotic fractures. Therefore, they can be interpreted as a warning signal for later, more deleterious fractures of vertebral bodies or the femoral neck. In the past decade, the advent of HR-pQCT allowed a detailed architectural analysis of the distal radius and an automated but time-consuming estimation of its strength with linear micro-finite element (μFE) analysis. Recently, a second generation of HR-pQCT scanner (XtremeCT II, SCANCO Medical, Switzerland) with a resolution beyond 61 μm became available for even more refined biomechanical investigations in vivo. This raises the question how biomechanical outcome variables compare between the original (LR) and the new (HR) scanner resolution. Accordingly, the aim of this work was to validate experimentally a patient-specific homogenized finite element (hFE) analysis of the distal section of the human radius for the fast prediction of Colles' fracture load based on the last generation HR-pQCT. Fourteen pairs of fresh frozen forearms (mean age = 77.5±9) were scanned intact using the high (61 μm) and the low (82 μm) resolution protocols that correspond to the new and original HR-pQCT systems. From each forearm, the 20mm most distal section of the radius were dissected out, scanned with μCT at 16.4 μm and tested experimentally under compression up to failure for assessment of stiffness and ultimate load. Linear and nonlinear hFE models together with linear micro finite element (μFE) models were then generated based on the μCT and HR-pQCT reconstructions to predict the aforementioned mechanical properties of 24 sections. Precision errors of the short term reproducibility of the FE analyses were measured based on the repeated scans of 12 sections. The calculated failure loads correlated strongly with those measured in the experiments: accounting for donor as a random factor, the nonlinear hFE provided a marginal coefficient of determination (R m 2 ) of 0.957 for the high resolution (HR) and 0.948 for the low resolution (LR) protocols, the linear hFE with R m 2 of 0.957 for the HR and 0.947 for the LR protocols. Linear μFE predictions of the ultimate load were similar with an R m 2 of 0.950 for the HR and 0.954 for the LR protocols, respectively. Nonlinear hFE strength computation led to precision errors of 2.2 and 2.3% which were higher than the ones calculated based on the linear hFE (1.6 and 1.9%) and linear μFE (1.2 and 1.6%) for the HR and LR protocols respectively. Computation of the fracture load with nonlinear hFE demanded in average 6h of CPU time which was 3 times faster than with linear μFE, while computation with linear hFE took only a few minutes. This study delivers an extensive experimental and numerical validation for the application of an accurate and fast hFE diagnostic tool to help in identifying individuals who may be at risk of an osteoporotic wrist fracture and to follow up pharmacological and other treatments in such patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE hemochromatosis.

PubMed

Bardou-Jacquet, Edouard; Morcet, Jeff; Manet, Ghislain; Lainé, Fabrice; Perrin, Michèle; Jouanolle, Anne-Marie; Guyader, Dominique; Moirand, Romain; Viel, Jean-François; Deugnier, Yves

2015-03-01

Mortality studies in patients with hemochromatosis give conflicting results especially with respect to extrahepatic causes of death. Our objective was to assess mortality and causes of death in a cohort of patients homozygous for the C282Y mutation in the HFE gene, diagnosed since the availability of HFE testing. We studied 1085 C282Y homozygotes, consecutively diagnosed from 1996 to 2009, and treated according to current recommendations. Mortality and causes of death were obtained from death certificates and compared to those of the general population. Standardized mortality ratios (SMRs) were used to assess specific causes of death and the Cox model was used to identify prognostic factors for death. Patients were followed for 8.3±3.9 years. Overall the SMR was the same as in the general population (0.94 CI: 0.71-1.22). Patients with serum ferritin⩾2000 μg/L had increased liver-related deaths (SMR: 23.9 CI: 13.9-38.2), especially due to hepatic cancer (SMR: 49.1 CI: 24.5-87.9). Patients with serum ferritin between normal and 1000 μg/L had a lower mortality than the general population (SMR: 0.27 CI: 0.1-0.5), due to a decreased mortality, related to reduced cardiovascular events and extrahepatic cancers in the absence of increased liver-related mortality. Age, diabetes, alcohol consumption, and hepatic fibrosis were independent prognostic factors of death. In treated HFE hemochromatosis, only patients with serum ferritin higher than 2000 μg/L have an increased mortality, mainly related to liver diseases. Those with mild iron burden have a decreased overall mortality in relation to reduced cardiovascular and extrahepatic cancer-related events. These results support a beneficial effect of early and sustained management of patients with iron excess, even when mild. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

An Evaluation of the Effects of Human Factors and Ergonomics on Health Care and Patient Safety Practices: A Systematic Review

PubMed Central

Zhang, Longhao; Zhao, Pujing; Chen, Ying; Zhang, Mingming

2015-01-01

Background From the viewpoint of human factors and ergonomics (HFE), errors often occur because of the mismatch between the system, technique and characteristics of the human body. HFE is a scientific discipline concerned with understanding interactions between human behavior, system design and safety. Objective To evaluate the effectiveness of HFE interventions in improving health care workers’ outcomes and patient safety and to assess the quality of the available evidence. Methods We searched databases, including MEDLINE, EMBASE, BIOSIS Previews and the CBM (Chinese BioMedical Literature Database), for articles published from 1996 to Mar.2015. The quality assessment tool was based on the risk of bias criteria developed by the Cochrane Effective Practice and Organization of Care (EPOC) Group. The interventions of the included studies were categorized into four relevant domains, as defined by the International Ergonomics Association. Results For this descriptive study, we identified 8, 949 studies based on our initial search. Finally, 28 studies with 3,227 participants were included. Among the 28 included studies, 20 studies were controlled studies, two of which were randomized controlled trials. The other eight studies were before/after surveys, without controls. Most of the studies were of moderate or low quality. Five broad categories of outcomes were identified in this study: 1) medical errors or patient safety, 2) health care workers’ quality of working life (e.g. reduced fatigue, discomfort, workload, pain and injury), 3) user performance (e.g., efficiency or accuracy), 4) health care workers’ attitudes towards the interventions(e.g., satisfaction and preference), and 5) economic evaluations. Conclusion The results showed that the interventions positively affected the outcomes of health care workers. Few studies considered the financial merits of these interventions. Most of the included studies were of moderate quality. This review highlights the need for scientific and standardized guidelines regarding how HFE should be implemented in health care. PMID:26067774

Home food environment in relation to children's diet quality and weight status.

PubMed

Couch, Sarah C; Glanz, Karen; Zhou, Chuan; Sallis, James F; Saelens, Brian E

2014-10-01

The objective of this cohort study was to explore relationships among the home food environment (HFE), child/parent characteristics, diet quality, and measured weight status among 699 child-parent pairs from King County, WA, and San Diego County, CA. HFE variables included parenting style/feeding practices, food rules, frequency of eating out, home food availability, and parents' perceptions of food costs. Child dietary intake was measured by 3-day recall and diet quality indicators included fruits and vegetables, sweet/savory snacks, high-calorie beverages, and Dietary Approaches to Stop Hypertension (DASH) score. Individual linear regression models were run in which child BMI z score and child diet quality indicators were dependent variables and HFE variables and child/parent characteristics were independent variables of interest. Fruit and vegetable consumption was associated with parental encouragement/modeling (β=.68, P<0.001) and unhealthful food availability (-0.27, P<0.05); DASH score with food availability (healthful: 1.3, P<0.01; unhealthful: -2.25, P<0.001), food rules (0.45, P<0.01), and permissive feeding style (-1.04, P<0.05); high-calorie beverages with permissive feeding style (0.14, P<0.01) and unhealthful food availability (0.21, P<0.001); and sweet/savory snacks with healthful food availability (0.26, P<0.05; unexpectedly positive). Children's BMI z score was positively associated with parent's use of food restriction (0.21, P<0.001), permissive feeding style (0.16, P<0.05), and concern for healthy food costs (0.10, P<0.01), but negatively with verbal encouragement/modeling (-0.17, P<0.05), and pressure to eat (-0.34, P<0.001). Various HFE factors associated with parenting around eating and food availability are related to child diet quality and weight status. These factors should be considered when designing interventions for improving child health. Copyright © 2014 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

PubMed Central

Hollerer, Ina; Bachmann, André; Muckenthaler, Martina U.

2017-01-01

Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers. PMID:28280078

IDHEAS – A NEW APPROACH FOR HUMAN RELIABILITY ANALYSIS

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

G. W. Parry; J.A Forester; V.N. Dang

2013-09-01

This paper describes a method, IDHEAS (Integrated Decision-Tree Human Event Analysis System) that has been developed jointly by the US NRC and EPRI as an improved approach to Human Reliability Analysis (HRA) that is based on an understanding of the cognitive mechanisms and performance influencing factors (PIFs) that affect operator responses. The paper describes the various elements of the method, namely the performance of a detailed cognitive task analysis that is documented in a crew response tree (CRT), and the development of the associated time-line to identify the critical tasks, i.e. those whose failure results in a human failure eventmore » (HFE), and an approach to quantification that is based on explanations of why the HFE might occur.« less

The association between the C282Y and H63D polymorphisms of HFE gene and the risk of Parkinson's disease: A meta-analysis.

PubMed

Xia, Jianjian; Xu, Huamin; Jiang, Hong; Xie, Junxia

2015-05-19

Impaired brain iron homeostasis has been considered as an important mechanism in Parkinson's diseases (PD). There are indications that C282Y and H63D polymorphisms of HFE genes involved in iron metabolism might contribute to the pathogenesis of PD in some cases. However, the investigation of the relationship between PD and the two polymorphisms had produced contradictory results. We performed a meta-analysis to assess the C282Y and H63D polymorphisms of HFE in PD susceptibility. PubMed, EMBASE and Web of Science were systematically searched to identify relevant researches. The strict selection criteria and exclusion standard were applied. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A fixed-effect or random-effect model was selected, depending on the results of the heterogeneity test. Fifteen studies were included in the meta-analysis (eight studies with 1631 cases and 4548 controls for C282Y; seven studies with 1192 cases and 4065 controls for H63D). For the C282Y polymorphism, significant associations were observed in the Recessive model (YY vs CY+CC: OR=0.22, 95% CI=0.09-0.57, P=0.002). This indicated that the C282Y polymorphism in HFE might be a potential protective factor for PD. However, no significant associations were found for any genetic model for the H63D polymorphism, suggesting that the H63D polymorphism might not be associated with PD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Meta-analyses of HFE variants in coronary heart disease.

PubMed

Lian, Jiangfang; Xu, Limin; Huang, Yi; Le, Yanping; Jiang, Danjie; Yang, Xi; Xu, Weifeng; Huang, Xiaoyan; Dong, Changzheng; Ye, Meng; Zhou, Jianqing; Duan, Shiwei

2013-09-15

HFE gene variants can cause hereditary hemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD. We conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. Meta-analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P=0.02, odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01-1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta-analyses (all P values>0.05). In addition, the results of our case-control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese. Our meta-analysis suggested that a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese. Copyright © 2013 Elsevier B.V. All rights reserved.

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children.

PubMed

Kaczorowska-Hac, Barbara; Luszczyk, Marcin; Antosiewicz, Jedrzej; Ziolkowski, Wieslaw; Adamkiewicz-Drozynska, Elzbieta; Mysliwiec, Malgorzata; Milosz, Ewa; Kaczor, Jan J

2017-07-01

Iron participates in oxygen transport, energetic, metabolic, and immunologic processes. There are 2 main causes of iron overload: hereditary hemochromatosis which is a primary cause, is a metabolic disorder caused by mutations of genes that control iron metabolism and secondary hemochromatosis caused by multitransfusions, chronic hemolysis, and intake of iron rich food. The most common type of hereditary hemochromatosis is caused by HFE gene mutation. In this study, we analyzed iron metabolism in 100 healthy Polish children in relation to their HFE gene status. The wild-type HFE gene was predominant being observed in 60 children (60%). Twenty-five children (25%), presented with heterozygotic H63D mutation, and 15 children (15%), presented with other mutations (heterozygotic C282Y and S65C mutation, compound heterozygotes C282Y/S65C, C282Y/H63D, H63D homozygote). The mean concentration of iron, the level of ferritin, and transferrin saturation were statistically higher in the group of HFE variants compared with the wild-type group. H63D carriers presented with higher mean concentration of iron, ferritin levels, and transferrin saturation compared with the wild-type group. Male HFE carriers presented with higher iron concentration, transferrin saturation, and ferritin levels than females. This preliminary investigation demonstrates allelic impact on potential disease progression from childhood.

Contributions of β2-microglobulin–dependent molecules and lymphocytes to iron regulation: insights from HfeRag1−/− and β2mRag1−/− double knock-out mice

PubMed Central

Miranda, Carlos J.; Makui, Hortence; Andrews, Nancy C.; Santos, Manuela M.

2010-01-01

Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, coding for a β2-microglobulin (β2m)–associated major histocompatibility complex class I-like protein. However, iron accumulation in patients with HH can be highly variable. Previously, analysis of β2mRag1−/− double-deficient mice, lacking all β2m-dependent molecules and lymphocytes, demonstrated increased iron accumulation in the pancreas and heart compared with β2m single knock-out mice. To evaluate whether the observed phenotype in β2mRag1−/− mice was due solely to the absence of Hfe or to other β2m-dependent molecules, we generated HfeRag1−/− double-deficient mice. Our studies revealed that introduction of Rag1 deficiency in Hfe knock-out mice leads to heightened iron overload, mainly in the liver, whereas the heart and pancreas are relatively spared compared with β2mRag1−/− mice. These results suggest that other β2m-interacting protein(s) may be involved in iron regulation and that in the absence of functional Hfe molecules lymphocyte numbers may influence iron overload severity. PMID:14656877

Reaction of ferrate (VI)/ferrate (V) with hydrogen peroxide and superoxide anion--a stopped-flow and premix pulse radiolysis study.

PubMed

Rush, J D; Zhao, Z; Bielski, B H

1996-03-01

The reduction of ferrate(VI) to ferrate(V) by superoxide ions was studied over the pH range 2.6-13.0 using the premix pulse radiolysis technique. The pH dependence indicates that only the unstable protonated forms of ferrate, H2FeO4 (pKa3.5) and HFeO4- (pKa7.3) are reactive, k(HFeO4(-) + O2) = (1.7 +/- 0.2) x 10(7) M-1 s-1. The stable ferrate ion, FeO4(2-), showed no significant reactivity towards either hydrogen peroxide or superoxide anion. The rate constants for the spontaneous dimerization and decomposition of the protonated ferrates, e.g. k(HFeO4(-) + HFe04) approximately 250 M-1s-1, are orders of magnitude slower than their corresponding reduction reduction by superoxide indicating an outer-sphere mode of electron transfer for the latter process. In contrast the ferrate(VI) species H3FeO4+ (pKa = 1.6 +/- 0.2), H2FeO4, and HFeO4- oxidize hydrogen peroxide, e.g. k(HFeO4(-) + H2O2) = 170 M-1 s-1), at rates which correspond closely to their dimerization rates suggesting an inner-sphere controlled mechanism.

C282Y polymorphism in the HFE gene is associated with risk of breast cancer.

PubMed

Liu, Xiaoyan; Lv, Chunlei; Luan, Xiaorong; Lv, Ming

2013-10-01

The C282Y and H63D polymorphisms in the HFE gene have been implicated in susceptibility of breast cancer, but a number of studies have reported inconclusive results. The aim of this study is to investigate the association between the C282Y and H63D polymorphisms in the HFE gene and breast cancer risk by meta-analysis. We searched PubMed and Embase databases, covering all related studies until March 2, 2013. Statistical analysis was performed using STATA 10.0. A total of 7 studies including 1,720 cases and 18,296 controls for HFE C282Y polymorphism and 5 studies including 942 cases and 1,571 controls for HFE H63D polymorphism were included in the meta-analysis. The results showed that HFE C282Y polymorphism was significantly associated with increased risk of breast cancer under homozygotes vs. wild-type model (OR = 2.06, 95%CI = 1.19-3.58) and recessive model (OR = 1.98, 95%CI = 1.14-3.44) but not under heterozygotes vs. wild-type model (OR = 0.97, 95%CI = 0.70-1.35), dominant model (OR = 1.00, 95%CI = 0.72-1.40) and multiplicative model (OR = 1.04, 95%CI = 0.76-1.42). However, we did not find any association between HFE H63D polymorphism and breast cancer risk under all genetic models. This current meta-analysis suggested that C282Y polymorphism rather than H63D might be associated with increased risk of breast cancer.

Changes in the highest frequency of breath sounds without wheezing during methacholine inhalation challenge in children.

PubMed

Habukawa, Chizu; Murakami, Katsumi; Mochizuki, Hiroyuki; Takami, Satoru; Muramatsu, Reiko; Tadaki, Hiromi; Hagiwara, Satomi; Mizuno, Takahisa; Arakawa, Hirokazu; Nagasaka, Yukio

2010-04-01

It is difficult for clinicians to identify changes in breath sounds caused by bronchoconstriction when wheezing is not audible. A breath sound analyser can identify changes in the frequency of breath sounds caused by bronchoconstriction. The present study aimed to identify the changes in the frequency of breath sounds during bronchoconstriction and bronchodilatation using a breath sound analyser. Thirty-six children (8.2 +/- 3.7 years; males : females, 22 : 14) underwent spirometry, methacholine inhalation challenge and breath sound analysis. Methacholine inhalation challenge was performed and baseline respiratory resistance, minimum dose of methacholine (bronchial sensitivity) and speed of bronchoconstriction in response to methacholine (Sm: bronchial reactivity) were calculated. The highest frequency of inspiratory breath sounds (HFI), the highest frequency of expiratory breath sounds (HFE) and the percentage change in HFI and HFE were determined. The HFI and HFE were compared before methacholine inhalation (pre-HFI and pre-HFE), when respiratory resistance reached double the baseline value (max HFI and max HFE), and after bronchodilator inhalation (post-HFI and post-HFE). Breath sounds increased during methacholine-induced bronchoconstriction. Max HFI was significantly greater than pre-HFI (P < 0.001), and decreased to the basal level after bronchodilator inhalation. Post-HFI was significantly lower than max HFI (P < 0.001). HFI and HFE were also significantly changed (P < 0.001). The percentage change in HFI showed a significant correlation with the speed of bronchoconstriction in response to methacholine (P = 0.007). Methacholine-induced bronchoconstriction significantly increased HFI, and the increase in HFI was correlated with bronchial reactivity.

Iron overload in HFE C282Y heterozygotes at first genetic testing: a strategy for identifying rare HFE variants.

PubMed

Aguilar-Martinez, Patricia; Grandchamp, Bernard; Cunat, Séverine; Cadet, Estelle; Blanc, François; Nourrit, Marlène; Lassoued, Kaiss; Schved, Jean-François; Rochette, Jacques

2011-04-01

Heterozygotes for the p.Cys282Tyr (C282Y) mutation of the HFE gene do not usually express a hemochromatosis phenotype. Apart from the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele, other rare HFE mutations can be found in trans on chromosome 6. We performed molecular investigation of the genes implicated in hereditary hemochromatosis in six patients who presented with iron overload but were simple heterozygotes for the HFE C282Y mutation at first genetic testing. Functional impairment of new variants was deduced from computational methods including molecular modeling studies. We identified four rare HFE mutant alleles, three of which have not been previously described. One mutation is a 13-nucleotide deletion in exon 6 (c.1022_1034del13, p.His341_Ala345 > LeufsX119), which is predicted to lead to an elongated and unstable protein. The second one is a substitution of the last nucleotide of exon 2 (c.340G > A, p.Glu114Lys) which modifies the relative solvent accessibility in a loop interface. The third mutation, p.Arg67Cys, also lies in exon 2 and introduces a destabilization of the secondary structure within a loop of the α1 domain. We also found the previously reported c.548T > C (p.Leu183Pro) missense mutation in exon 3. No other known iron genes were mutated. We present an algorithm at the clinical and genetic levels for identifying patients deserving further investigation. Conclusions Our results suggest that additional mutations in HFE may have a clinical impact in C282Y carriers. In conjunction with results from previously described cases we conclude that an elevated transferrin saturation level and elevated hepatic iron index should indicate the utility of searching for further HFE mutations in C282Y heterozygotes prior to other iron gene studies.

HFE mRNA expression is responsive to intracellular and extracellular iron loading: short communication.

PubMed

Mehta, Kosha J; Farnaud, Sebastien; Patel, Vinood B

2017-10-01

In liver hepatocytes, the HFE gene regulates cellular and systemic iron homeostasis by modulating cellular iron-uptake and producing the iron-hormone hepcidin in response to systemic iron elevation. However, the mechanism of iron-sensing in hepatocytes remain enigmatic. Therefore, to study the effect of iron on HFE and hepcidin (HAMP) expressions under distinct extracellular and intracellular iron-loading, we examined the effect of holotransferrin treatment (1, 2, 5 and 8 g/L for 6 h) on intracellular iron levels, and mRNA expressions of HFE and HAMP in wild-type HepG2 and previously characterized iron-loaded recombinant-TfR1 HepG2 cells. Gene expression was analyzed by real-time PCR and intracellular iron was measured by ferrozine assay. Data showed that in the wild-type cells, where intracellular iron content remained unchanged, HFE expression remained unaltered at low holotransferrin treatments but was upregulated upon 5 g/L (p < 0.04) and 8 g/L (p = 0.05) treatments. HAMP expression showed alternating elevations and increased upon 1 g/L (p < 0.05) and 5 g/L (p < 0.05). However, in the recombinant cells that showed higher intracellular iron levels than wild-type cells, HFE and HAMP expressions were elevated only at low 1 g/L treatment (p < 0.03) and were repressed at 2 g/L treatment (p < 0.03). Under holotransferrin-untreated conditions, the iron-loaded recombinant cells showed higher expressions of HFE (p < 0.03) and HAMP (p = 0.05) than wild-type cells. HFE mRNA was independently elevated by extracellular and intracellular iron-excess. Thus, it may be involved in sensing both, extracellular and intracellular iron. Repression of HAMP expression under simultaneous intracellular and extracellular iron-loading resembles non-hereditary iron-excess pathologies.

Iron overload and HFE gene mutations in Polish patients with liver cirrhosis.

PubMed

Sikorska, Katarzyna; Romanowski, Tomasz; Stalke, Piotr; Iżycka-Świeszewska, Ewa; Bielawski, Krzysztof Piotr

2011-06-01

Increased liver iron stores may contribute to the progression of liver injury and fibrosis, and are associated with a higher risk of hepatocellular carcinoma development. Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients. HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins. This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis. Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases. Liver function tests and serum iron markers were assessed in both groups. All patients were screened for HFE mutations (C282Y, H63D, S65C). Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes. The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis. There were no differences in the prevalence of all HFE mutations in both groups. In patients with a diagnosis of hepatocellular carcinoma, no significant associations with iron disorders and HFE gene mutations were found. Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations. Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis. As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease, there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis.

Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe

PubMed Central

Corradini, Elena; Rozier, Molly; Meynard, Delphine; Odhiambo, Adam; Lin, Herbert Y.; Feng, Qi; Migas, Mary C.; Britton, Robert S.; Babitt, Jodie L.; Fleming, Robert E.

2011-01-01

Background & Aims HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes. Methods Hepatic iron concentrations and mRNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad)1,5,8 and Id1 mRNA levels were measured as markers of Bmp/Smad signaling. Results While Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also demonstrated attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. Conclusions These observations demonstrate that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver BMP6 mRNA or steady-state P-Smad1,5,8 levels. PMID:21745449

Predictive models of safety based on audit findings: Part 2: Measurement of model validity.

PubMed

Hsiao, Yu-Lin; Drury, Colin; Wu, Changxu; Paquet, Victor

2013-07-01

Part 1 of this study sequence developed a human factors/ergonomics (HF/E) based classification system (termed HFACS-MA) for safety audit findings and proved its measurement reliability. In Part 2, we used the human error categories of HFACS-MA as predictors of future safety performance. Audit records and monthly safety incident reports from two airlines submitted to their regulatory authority were available for analysis, covering over 6.5 years. Two participants derived consensus results of HF/E errors from the audit reports using HFACS-MA. We adopted Neural Network and Poisson regression methods to establish nonlinear and linear prediction models respectively. These models were tested for the validity of prediction of the safety data, and only Neural Network method resulted in substantially significant predictive ability for each airline. Alternative predictions from counting of audit findings and from time sequence of safety data produced some significant results, but of much smaller magnitude than HFACS-MA. The use of HF/E analysis of audit findings provided proactive predictors of future safety performance in the aviation maintenance field. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Reactivities of Precision Cleaning Solvents with Hypergolic Propellants

NASA Technical Reports Server (NTRS)

Davis, Dennis D.; Delgado, Rafael H.; Williams, James H.

1999-01-01

The reactivities of several selected halogenated precision cleaning solvents with hypergolic propellants has been determined by analysis of the rates of formation of halide ion decomposition products. The solvents were Asahiklin AK 225, Asahiklin AK 225 AES, HFE 7100, HFE 7100 DE, Vertrel XF, Vertrel MCA, Vertrel MCA Plus, 1,1,2-trichloro-1,2,2-trifluoroethane (CFC-113), and trans-1,2-dichloroethylene (DCE). The propellants were hydrazine (HZ), monomethylhydrazine (MMH), and mixed oxides of nitrogen (MON-3). The Vertrel solvents showed significant reactivity with HZ. All of the solvents except DCE exhibited significant reactivity with MMH, particularly HFE 7100 DE and CFC-113. HFE 7100 DE, Vertrel MCA, and Vertrel MCA Plus also showed significant reactivity with MON-3 oxidizer.

High prevalence of fibromyalgia in patients with HFE-related hereditary hemochromatosis.

PubMed

Mohammad, Ausaf; Carey, John J; Storan, Eoin; Scarry, Margaret; Coughlan, Robert J; Lee, John M

2013-07-01

Subjects with HFE-related hereditary hemochromatosis (HH) may present with arthralgias, fatigue, and stiffness, yet little is known on the presence of fibromyalgia syndrome (FMS) in these subjects. We determined the prevalence of FMS in a cohort of subjects with HH and evaluated its relationship to subject demographics, disease status, and quality of life. In a cross-sectional study we collected data on 395 consecutive subjects diagnosed with HH who were attending a tertiary referral Hepatology outpatient clinic at Galway University Hospital, Ireland (between October 2009 and June 2010). Subjects underwent a standard assessment including history, clinical examination, and functional assessments for pain and disability. Univariate logistic regression was applied to determine risk factors independently associated with prevalent FMS in these subjects. Three hundred ninety-five subjects met the inclusion criteria. Mean age was 43 years (range, 21 to 59 y) and 260 (66%) were males. One hundred seventy (43%) of the subjects were diagnosed with FMS. Among those with fibromyalgia fatigue and ≥ 11 tender points were present in all of the subjects, widespread pain in 150 (88%), depression in 70 (41%), and arthralgia/joint stiffness in 70 (41%). In subjects with FMS 33% reported some functional impairment (HAQ-DI>0), with 10% reporting moderate-severe functional impairment (HAQ-DI ≥ 1.5). This study reveals a high prevalence of FMS (43%) among subjects with HFE-related hemochromatosis. Prospective studies are needed to better understand the risk factors for FMS in such patients.

Short-Term Effects of the 2008 High-Flow Experiment on Macroinvertebrates in Colorado River Below Glen Canyon Dam, Arizona

USGS Publications Warehouse

Rosi-Marshall, Emma J.; Kennedy, Theodore A.; Kincaid, Dustin W.; Cross, Wyatt F.; Kelly, Holly A.W.; Behn, Kathrine A.; White, Tyler; Hall, Robert O.; Baxter, Colden V.

2010-01-01

Glen Canyon Dam has dramatically altered the physical environment (especially discharge regime, water temperatures, and sediment inputs) of the Colorado River. High-flow experiments (HFE) that mimic one aspect of the natural hydrograph (floods) were implemented in 1996, 2004, and 2008. The primary goal of these experiments was to increase the size and total area of sandbar habitats that provide both camping sites for recreational users and create backwaters (areas of stagnant flow in the lee of return-current eddies) that may be important as rearing habitat for native fish. Experimental flows might also positively or negatively alter the rainbow trout (Oncorhynchus mykiss) sport fishery in the clear tailwater reach below Glen Canyon Dam, Ariz., and native fish populations in downstream reaches (for example, endangered humpback chub, Gila cypha) through changes in available food resources. We examined the short-term response of benthic macroinvertebrates to the March 2008 HFE at three sites [river mile 0 (RM 0, 15.7 miles downriver from the dam), RM 62, and RM 225] along the Colorado River downstream from Glen Canyon Dam by sampling immediately before and then 1, 7, 14, and 30 days after the HFE. We selected these sites because of their importance to management; RM 0 has a valuable trout fishery, and RM 62 is the location of the largest population of the endangered humpback chub in the Grand Canyon. In addition to the short-term collection of samples, as part of parallel investigations, we collected 3 years of monthly (quarterly for RM 62) benthic macroinvertebrate samples that included 15 months of post-HFE data for all three sites, but processing of the samples is only complete for one site (RM 0). At RM 0, the HFE caused an immediate 1.75 g AFDM/m2 (expressed as grams ash-free dry mass, or AFDM) reduction of macroinvertebrate biomass that was driven by significant reductions in the biomass of the two dominant taxa in this reach-Potamopyrgus antipodarum (New Zealand mud snails) and Gammarus lacustris (scuds or side-swimmers)-and also biomass reductions of other common taxa (worms in the families Lumbricidae and Tubificidae). Invertebrate drift estimates during the HFE suggest that reductions in biomass of some taxa were because of export from the reach. Reductions in biomass of P. antipodarum and G. lacustris persisted at least 15 months after the HFE, when this study concluded, and coincided with a significant decline in the annual production of these taxa: P. antipodarum production of 11 to 13 g AFDM/m2/yr in two pre-HFE years versus 2 g AFDM/m2/yr in the post-HFE year, and G. lacustris production of 7 to 8 g AFDM/m2/yr in two pre-HFE years versus 3 g AFDM/m2/yr in the post-HFE year. There were not changes in invertebrate feeding habits in response to the HFE, as our 3-year dataset of invertebrate diets indicated no substantial changes. Our long-term analysis of the composition of the drift indicates that because of a reduction in P. antipodarum in the drift relative to digestible taxa, the quality of the drift as a food resource for fishes increased. At downstream sites, total assemblage biomass did not decline, likely because assemblages were dominated by blackflies (Simulium arcticum), which were not affected by the HFE. Similar to RM 0, G. lacustris and Tubificidae had significantly lower biomass after the HFE at RM 62 and RM 225. Chironomids were also significantly lower following the flood at both downstream sites. Our findings demonstrate that the effects of a HFE on invertebrates may persist up to at least 15 months in the clear tailwater below the dam, whereas in downstream reaches impacts were more short lived. If controlling the abundance of P. antipodarum is a goal of managers, our findings indicate that periodic HFEs on the order of every 2 to 3 years may be an effective strategy for meeting that goal. More frequent HFEs may cause a shift in the state of the benthic invertebrate assemblage of the tailwa

Human factors engineering and design validation for the redesigned follitropin alfa pen injection device.

PubMed

Mahony, Mary C; Patterson, Patricia; Hayward, Brooke; North, Robert; Green, Dawne

2015-05-01

To demonstrate, using human factors engineering (HFE), that a redesigned, pre-filled, ready-to-use, pre-asembled follitropin alfa pen can be used to administer prescribed follitropin alfa doses safely and accurately. A failure modes and effects analysis identified hazards and harms potentially caused by use errors; risk-control measures were implemented to ensure acceptable device use risk management. Participants were women with infertility, their significant others, and fertility nurse (FN) professionals. Preliminary testing included 'Instructions for Use' (IFU) and pre-validation studies. Validation studies used simulated injections in a representative use environment; participants received prior training on pen use. User performance in preliminary testing led to IFU revisions and a change to outer needle cap design to mitigate needle stick potential. In the first validation study (49 users, 343 simulated injections), in the FN group, one observed critical use error resulted in a device design modification and another in an IFU change. A second validation study tested the mitigation strategies; previously reported use errors were not repeated. Through an iterative process involving a series of studies, modifications were made to the pen design and IFU. Simulated-use testing demonstrated that the redesigned pen can be used to administer follitropin alfa effectively and safely.

Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis.

PubMed

Praline, Julien; Blasco, Hélène; Vourc'h, Patrick; Rat, Valérian; Gendrot, Chantal; Camu, William; Andres, Christian R

2012-06-15

Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants. Copyright © 2012 Elsevier B.V. All rights reserved.

Two novel mutations in the SLC40A1 and HFE genes implicated in iron overload in a Spanish man.

PubMed

Del-Castillo-Rueda, Alejandro; Moreno-Carralero, María-Isabel; Alvarez-Sala-Walther, Luis-Antonio; Cuadrado-Grande, Nuria; Enríquez-de-Salamanca, Rafael; Méndez, Manuel; Morán-Jiménez, María-Josefa

2011-03-01

The most common form of hemochromatosis is caused by mutations in the HFE gene. Rare forms of the disease are caused by mutations in other genes. We present a patient with hyperferritinemia and iron overload, and facial flushing. Magnetic resonance imaging was performed to measure hepatic iron overload, and a molecular study of the genes involved in iron metabolism was undertaken. The iron overload was similar to that observed in HFE hemochromatosis, and the patient was double heterozygous for two novel mutations, c.-20G>A and c.718A>G (p.K240E), in the HFE and ferroportin (FPN1 or SLC40A1) genes, respectively. Hyperferritinemia and facial flushing improved after phlebotomy. Two of the patient's children were also studied, and the daughter was heterozygous for the mutation in the SLC40A1 gene, although she did not have hyperferritinemia. The patient presented a mild iron overload phenotype probably because of the two novel mutations in the HFE and SLC40A1 genes. © 2011 John Wiley & Sons A/S.

HFE p.C282Y gene variant is associated with varicose veins in Russian population.

PubMed

Sokolova, Ekaterina A; Shadrina, Alexandra S; Sevost'ianova, Kseniya S; Shevela, Andrey I; Soldatsky, Evgenii Yu; Seliverstov, Evgenii I; Demekhova, Marina Yu; Shonov, Oleg A; Ilyukhin, Evgenii A; Smetanina, Mariya A; Voronina, Elena N; Zolotukhin, Igor A; Filipenko, Maxim L

2016-08-01

Recently, the association of polymorphism rs1800562 (p.C282Y) in the hemochromatosis (HFE) gene with the increased risk of venous ulceration was shown. We hypothesized that HFE gene polymorphism might be involved not only in ulceration process, but also in susceptibility to primary varicose veins. We genotyped HFE p.C282Y (rs1800562) and p.H63D (rs1799945) variants in patients with primary varicose veins (n = 463) and in the control group (n = 754). In our study, p.282Y variant (rs1800562 A allele) was significantly associated with the risk of varicose veins (OR 1.79, 95 % CI = 1.11-2.89, P = 0.02). A borderline significant reverse association of p.63D variant (rs1799945 G allele) with venous leg ulcer development was revealed in Russians (OR 0.25, 95 % CI = 0.06-1.00, P = 0.05), but not in the meta-analysis (P = 0.56). We conclude that the HFE gene polymorphism can affect the risk of developing primary varicose veins.

Suitability of virtual prototypes to support human factors/ergonomics evaluation during the design.

PubMed

Aromaa, Susanna; Väänänen, Kaisa

2016-09-01

In recent years, the use of virtual prototyping has increased in product development processes, especially in the assessment of complex systems targeted at end-users. The purpose of this study was to evaluate the suitability of virtual prototyping to support human factors/ergonomics evaluation (HFE) during the design phase. Two different virtual prototypes were used: augmented reality (AR) and virtual environment (VE) prototypes of a maintenance platform of a rock crushing machine. Nineteen designers and other stakeholders were asked to assess the suitability of the prototype for HFE evaluation. Results indicate that the system model characteristics and user interface affect the experienced suitability. The VE system was valued as being more suitable to support the assessment of visibility, reach, and the use of tools than the AR system. The findings of this study can be used as a guidance for the implementing virtual prototypes in the product development process. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ethnic and genetic factors of iron status in women of reproductive age.

PubMed

Gordeuk, Victor R; Brannon, Patsy M

2017-12-01

Background: African Americans are at increased risk of iron deficiency (ID) but also have higher serum ferritin (SF) concentrations than those of the general population. The Hemochromatosis and Iron Overload Screening (HEIRS) Study was a multicenter study of ethnically diverse participants that tested for the hemochromatosis ( HFE ) C282Y genotype and iron status. Objective: We sought to determine the prevalence and predictors of ID (SF concentration ≤15 μg/L) and elevated iron stores (SF concentration >300 μg/L) in HEIRS women of reproductive age (25-44 y). Design: The HEIRS Study was a cross-sectional study of iron status and HFE mutations in primary care patients at 5 centers in the United States and Canada. We analyzed data for women of reproductive age according to whether or not they were pregnant or breastfeeding at the time of the study. Results: ID was present in 12.5% of 20,080 nonpregnant and nonbreastfeeding women compared with 19.2% of 1962 pregnant or breastfeeding women ( P < 0.001). Asian American ethnicity (OR ≤0.9; P ≤ 0.049) and HFE C282Y (OR ≤0.84; P ≤ 0.060) were independently associated with a decreased risk of ID in nonpregnant and nonbreastfeeding women and in pregnant or breastfeeding women. Hispanic ethnicity (OR: 1.8; P < 0.001) and African American ethnicity (OR: 1.6; P < 0.001) were associated with an increased risk of ID in nonpregnant and nonbreastfeeding women. Elevated iron stores were shown in 1.7% of nonpregnant and nonbreastfeeding women compared with 0.7% of pregnant or breastfeeding women ( P = 0.001). HFE C282Y homozygosity had the most marked independent association with elevated iron stores in nonpregnant and nonbreastfeeding women and in pregnant or breastfeeding women (OR >49.0; P < 0.001), but African American ethnicity was also associated with increased iron stores in both groups of women (OR >2.0; P < 0.001). Asian American ethnicity (OR: 1.8; P = 0.001) and HFE C282Y heterozygosity (OR: 1.9; P = 0.003) were associated with increased iron stores in nonpregnant and nonbreastfeeding women. Conclusions: Both ID and elevated iron stores are present in women of reproductive age and are influenced by ethnicity and HFE C282Y. Efforts to optimize iron status should keep these findings in view. This study was registered at clinicaltrials.gov as NCT03276247. © 2017 American Society for Nutrition.

Eighty percent of French sport winners in Olympic, World and Europeans competitions have mutations in the hemochromatosis HFE gene.

PubMed

Hermine, Olivier; Dine, Gérard; Genty, Vincent; Marquet, Laurie-Anne; Fumagalli, Gabriela; Tafflet, Muriel; Guillem, Flavia; Van Lierde, Françoise; Rousseaux-Blanchi, Marie-Philippe; Palierne, Christian; Lapostolle, Jean-Claude; Cervetti, Jean-Pierre; Frey, Alain; Jouven, Xavier; Noirez, Philippe; Toussaint, Jean-François

2015-12-01

The HFE gene encodes a protein involved in iron homeostasis; individuals with mutations in both alleles develop hemochromatosis. 27% of the French population is heterozygous for mutations in this gene. We found that 80% of the French athletes who won international competitions in rowing, Nordic skiing and judo display mutations in one allele of HFE, thus demonstrating the existence of a favourable phenotype linked to this heterozygosity. Copyright © 2015. Published by Elsevier B.V.

Hemochromatosis (HFE) gene mutations and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

PubMed

Agudo, Antonio; Bonet, Catalina; Sala, Núria; Muñoz, Xavier; Aranda, Núria; Fonseca-Nunes, Ana; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie Christine; Vineis, Paolo; Panico, Salvatore; Palli, Domenico; Tumino, Rosario; Grioni, Sara; Quirós, J Ramón; Molina, Esther; Navarro, Carmen; Barricarte, Aurelio; Chamosa, Saioa; Allen, Naomi E; Khaw, Kay-Tee; Bueno-de-Mesquita, H Bas; Siersema, Peter D; Numans, Mattijs E; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Kaaks, Rudof; Canzian, Federico; Boeing, Heiner; Meidtner, Karina; Johansson, Mattias; Sund, Malin; Manjer, Jonas; Overvad, Kim; Tjonneland, Anne; Lund, Eiliv; Weiderpass, Elisabete; Jenab, Mazda; Fedirko, Veronika; Offerhaus, G Johan A; Riboli, Elio; González, Carlos A; Jakszyn, Paula

2013-06-01

Hereditary hemochromatosis (HH) is a strong risk factor for hepatocellular cancer, and mutations in the HFE gene associated with HH and iron overload may be related to other tumors, but no studies have been reported for gastric cancer (GC). A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 365 incident gastric adenocarcinoma and 1284 controls matched by center, sex, age and date of blood collection. Genotype analysis was performed for two functional polymorphisms (C282Y/rs1800562 and H63D/rs1799945) and seven tagSNPs of the HFE genomic region. Association with all gastric adenocarcinoma, and according to anatomical localization and histological subtype, was assessed by means of the odds ratio (OR) and 95% confidence interval (CI) estimated by unconditional logistic regression adjusted for the matching variables. We observed a significant association for H63D with OR (per rare allele) of 1.32 (CI = 1.03-1.69). In subgroup analyses, the association was stronger for non-cardia anatomical subsite (OR = 1.60, CI = 1.16-2.21) and intestinal histological subtype (OR = 1.82, CI = 1.27-2.62). Among intestinal cases, two tagSNPs (rs1572982 and rs6918586) also showed a significant association that disappeared after adjustment for H63D. No association with tumors located in the cardia or with diffuse subtype was found for any of the nine SNPs analyzed. Our results suggest that H63D variant in HFE gene seems to be associated with GC risk of the non-cardia region and intestinal type, possibly due to its association with iron overload although a role for other mechanisms cannot be entirely ruled out.

Hyperferritinemia increases the risk of hyperuricemia in HFE-hereditary hemochromatosis.

PubMed

Flais, Jérémy; Bardou-Jacquet, Edouard; Deugnier, Yves; Coiffier, Guillaume; Perdriger, Aleth; Chalès, Gérard; Ropert, Martine; Loréal, Olivier; Guggenbuhl, Pascal

2017-05-01

Hyperuricemia is becoming increasingly frequent in the population, and is known to be sometimes the cause of gout. The impact of uric acid is still not clearly understood, however. The iron metabolism may interact with the uric acid metabolism. The aim of this study was to examine the relationship between the serum uric acid and serum ferritin levels in a cohort of hemochromatosis patients who were homozygous for the HFE p.Cys282Tyr mutation. 738 patients with the HFE gene mutation Cys282Tyr in the homozygous state were included in the study. The variables measured during the initial evaluation were compared in univariate analysis by Student's t test. In multivariate analysis, linear stepwise regression was used. In the group of hyperuricemic patients, ferritinemia was significantly higher than in the group of non-hyperuricemic patients (1576.7±1387.4μg/l vs. 1095.63±1319.24μg/l, P<0.005). With multivariate analysis, only ferritin and BMI independently explained the uricemia (R 2 =0.258) after adjustment for age, glycemia and CRP. The correlation between uricemia and log(ferritin) with partial regression correlation coefficients was 0.307 (P<0.01). The increase in uricemia is associated with the increase in ferritin in a population of patients who were homozygous for the HFE gene mutation p.Cys282Tyr and this independently of factors commonly associated with hyperuricemia. The increase in uric acid associated with hyperferritinemia, could be a response to the visceral toxicity of excess non-transferrin bound iron linked to oxidative stress via the antioxidant properties of uric acid. Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Predictors of haemoconcentration at delivery: association with low birth weight.

PubMed

Aranda, N; Ribot, B; Viteri, F; Cavallé, P; Arija, V

2013-09-01

[corrected] To assess the factors associated with risk of haemoconcentration at delivery, such as initial haemoglobin levels and alterations in the HFE gene, and its effect on low birth weight in pregnant women supplemented with moderate doses of iron. Case-control study nested in a longitudinal study conducted on 217 healthy pregnant women taking moderate iron supplementation and their newborns. Women were classified according to the risk of haemoconcentration at delivery, defined as Hb > 130 g/L. Each subject's obstetric and clinical history, smoking habit, and iron biochemical parameters (haemoglobin (Hb), serum ferritin and transferrin saturation) were recorded at 1st, 2nd and 3rd trimester and at delivery. Polymorphisms of the HFE gene (C282Y, H63D and S65C) were also measured. The average of iron supplementation of all the women was 43.9 mg/dia (geometric mean, 95 % CI: 43.6-44.1). Higher levels of Hb at early gestation and the presence of HFE mutations were associated with greater risk of haemoconcentration at delivery, adjusted odds ratios of 1.14 (95 % CI: 1.05-1.25) and 5.35 (95 % CI: 1.6-17.8). Haemoconcentration at delivery was associated with a greater risk of low birth weight, adjusted odd ratio of 11.48 (95 % CI: 1.13-116.6). Moderate daily doses of supplementary iron may be harmful for foetal growth in women with alterations in HFE gene and who started pregnancy with good haemoglobin levels. Overall, this suggests the importance of determining a woman's iron status early in her pregnancy in order to establish a more appropriate pattern of supplementation.

Maternal hemochromatosis gene H63D single-nucleotide polymorphism and lead levels of placental tissue, maternal and umbilical cord blood

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

Kayaalti, Zeliha, E-mail: kayaalti@ankara.edu.tr; Kaya-Akyüzlü, Dilek; Söylemez, Esma

Human hemochromatosis protein (HFE), a major histocompatibility complex class I-like integral membrane protein, participates in the down regulation of intestinal iron absorption by binding to transferrin receptor (TR). HFE competes with transferrin-bound iron for the TR and thus reduces uptake of iron into cells. On the other hand, a lack of HFE increases the intestinal absorption of iron similarly to iron deficiency associated with increasing in absorption and deposition of lead. During pregnancy, placenta cannot prevent transfer lead to the fetus; even low-level lead poisoning causes neurodevelopmental toxicity in children. The aim of this study was to determine the associationmore » between the maternal HFE H63D single-nucleotide polymorphism and lead levels in placental tissue, maternal blood and umbilical cord bloods. The study population comprised 93 mother–placenta pairs. Venous blood from mother was collected to investigate lead levels and HFE polymorphism that was detected by standard PCR–RFLP technique. Cord bloods and placentas were collected for lead levels which were analyzed by dual atomic absorption spectrometer system. The HFE H63D genotype frequencies of mothers were found as 75.3% homozygote typical (HH), 23.6% heterozygote (HD) and 1.1% homozygote atypical (DD). Our study results showed that the placental tissue, umbilical cord and maternal blood lead levels of mothers with HD+DD genotypes were significantly higher than those with HH genotype (p<0.05). The present study indicated for the first time that mothers with H63D gene variants have higher lead levels of their newborn's placentas and umbilical cord bloods. - Highlights: • Mothers with H63D gene variants have higher lead levels of their newborn's umbilical cord blood. • Unborn child of women with HD+DD genotypes may be at increased risk of internal exposure to lead. • Maternal HFE status may have an effect on increased placenta, maternal and cord blood lead levels. • Maternal HFE status may have an effect on lead transfer from maternal to fetal circulation. • Placental, maternal and cord blood lead levels were not correlated with mothers' age.« less

Detection of high-frequency energy changes in sustained vowels produced by singers

PubMed Central

Monson, Brian B.; Lotto, Andrew J.; Ternström, Sten

2011-01-01

The human voice spectrum above 5 kHz receives little attention. However, there are reasons to believe that this high-frequency energy (HFE) may play a role in perceived quality of voice in singing and speech. To fulfill this role, differences in HFE must first be detectable. To determine human ability to detect differences in HFE, the levels of the 8- and 16-kHz center-frequency octave bands were individually attenuated in sustained vowel sounds produced by singers and presented to listeners. Relatively small changes in HFE were in fact detectable, suggesting that this frequency range potentially contributes to the perception of especially the singing voice. Detection ability was greater in the 8-kHz octave than in the 16-kHz octave and varied with band energy level. PMID:21476681

HFE gene C282Y variant is associated with colorectal cancer in Caucasians: a meta-analysis.

PubMed

Chen, Weidong; Zhao, Hua; Li, Tiegang; Yao, Hongliang

2013-08-01

The HFE gene has been suggested to play an important role in the pathogenesis of colorectal cancer. However, the results have been conflicting. In this study, we performed a meta-analysis to clarify the association of HFE gene C282Y variant with colorectal cancer. PubMed and Embase were retrieved to identify the potential literature. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed- or random-effects model. A total of eight papers including nine studies (7,588 colorectal cancer cases and 81,571 controls) for HFE gene C282Y variant were included in the meta-analysis. The result indicated that HFE gene C282Y variant was significantly associated with colorectal cancer under recessive model (OR = 2.00, 95 % CI = 1.32-3.04), with no evidence of between-study heterogeneity (I (2) = 0.2 %, p = 0.432). Further subgroup analysis by number of cases suggested the effect was significant in studies with more than 500 cases (OR = 2.51, 95 % CI = 1.58-3.98, I (2) = 0.0 %, p = 0.921), but not in studies with less than 500 cases (OR = 0.75, 95 % CI = 0.28-1.97, I (2) = 0.0 %, p = 0.622). The current meta-analysis supported the positive association of HFE gene C282Y variant with colorectal cancer. Further large-scale studies with the consideration for gene-gene/gene-environment interactions should be conducted to investigate the association.

T lymphocyte-derived TNF and IFN-γ repress HFE expression in cancer cells.

PubMed

Reuben, Alexandre; Godin-Ethier, Jessica; Santos, Manuela M; Lapointe, Réjean

2015-06-01

The immune system and tumors are closely intertwined initially upon tumor development. During this period, tumors evolve to promote self-survival through immune escape, including by targeting crucial components involved in the presentation of antigens to the immune system in order to avoid recognition. Accordingly, components involved in MHC I presentation of tumor antigens are often mutated and down-regulated targets in tumors. On the other hand, the immune system has been shown to influence tumors through production of immunosuppressive cytokines, recruitment and polarization of cells favoring or impeding tumor escape or through production of anti-tumor cytokines promoting tumor rejection. We previously discovered that the hemochromatosis protein HFE, a negative regulator of iron absorption, dampens classical MHC I antigen presentation. In this study, we evaluated the impact of activated T lymphocytes purified from peripheral blood mononuclear cells (PBMC) on HFE expression in tumor cell lines. We co-cultured tumor cell lines from melanoma, lung, and kidney cancers with anti-CD3-activated PBMC and established that HFE expression is increased in tumor cell lines compared to healthy tissues, whilst being down-regulated significantly upon exposure to activated PBMC. HFE down-regulation was mediated by both CD4 and CD8 T lymphocytes, through production of soluble mediators, namely TNF and IFN-γ. These results suggest that the immune system may modulate tumor HFE expression in inflammatory conditions in order to regulate MHC I antigen presentation and promote tumor clearance. Copyright © 2015. Published by Elsevier Ltd.

Association of HFE gene C282Y and H63D mutations with liver cirrhosis in the Lithuanian population.

PubMed

Juzėnas, Simonas; Kupčinskas, Juozas; Valantienė, Irena; Šumskienė, Jolanta; Petrenkienė, Vitalija; Kondrackienė, Jūrate; Kučinskas, Laimutis; Kiudelis, Gediminas; Skiecevičienė, Jurgita; Kupčinskas, Limas

2016-01-01

Liver cirrhosis is the end-stage disease of chronic liver injury. Due to differences in the natural course of chronic liver diseases, identification of genetic factors that influence individual outcomes is warranted. HFE-linked hereditary hemochromatosis (HH) predisposes disease progression to cirrhosis; however, the role of heterozygous C282Y or H63D mutations in the development of cirrhosis in the presence of other etiological factors is still debated. The aim of this study was to determine the association between heterozygous C282Y and H63D mutations and non-HH liver cirrhosis in Lithuanian population. The patient cohort consisted of 209 individuals. Diagnosis of cirrhosis was confirmed by clinical, laboratory parameters, liver biopsy, and radiological imaging. Control samples were obtained from 1005 randomly selected unrelated healthy individuals. HFE gene mutations were determined using the PCR-RFLP method. The most common causes of cirrhosis were hepatitis C (33.9%), hepatitis B (13.6%), and alcohol (25.8%). C282Y allele was associated with the presence of cirrhosis (OR=2.07; P=0.005); this was also observed under recessive model for C282Y (OR=2.06, P=0.008). The prevalence of C282Y allele was higher in cirrhotic men than in controls (7.0% vs. 2.8%, P=0.002). The carriage of H63D risk allele (OR=1.54; P=0.02), heterozygous C282Y/wt and homozygous H63D/H63D genotypes were associated with liver cirrhosis in males (OR=2.48, P=0.008, and OR=4.13, P=0.005, respectively). Heterozygous C282Y mutation of the HFE gene was associated with liver cirrhosis in the Lithuanian population. In gender-related analysis, heterozygous C282Y and homozygous H63D mutations were linked to liver cirrhosis in men, not in women. Copyright © 2016 The Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Effects of High-Flow Experiments from Glen Canyon Dam on Abundance, Growth, and Survival Rates of Early Life Stages of Rainbow Trout in the Lees Ferry Reach of the Colorado River

USGS Publications Warehouse

Korman, Josh; Kaplinski, Matthew; Melis, Theodore S.

2010-01-01

High-flow experiments (HFEs) from Glen Canyon Dam are primarily intended to conserve fine sediment and improve habitat conditions for native fish in the Colorado River as it flows through Grand Canyon National Park, Arizona. These experimental flows also have the potential to affect the rainbow trout (Oncorhynchus mykiss) population in the Lees Ferry tailwater reach immediately below the dam, which supports a highly valued recreational fishery and likely influences the abundance of rainbow trout in Grand Canyon. Understanding how flow regimes affect the survival and growth of juvenile rainbow trout is critical to interpreting trends in adult abundance. This study reports on the effects of HFEs in 2004 and 2008 on early life stages of rainbow trout in the Lees Ferry reach on the basis of monthly sampling of redds (egg nests) and the abundance of the age-0 trout (fertilization to about 1 to 2 months from emergence) and their growth during a 7-year period between 2003 and 2009. Multiple lines of evidence indicate that the March 2008 HFE resulted in a large increase in early survival rates of age-0 trout because of an improvement in habitat conditions. A stock-recruitment analysis demonstrated that age-0 abundance in July 2008 was more than fourfold higher than expected, given the number of viable eggs that produced these fish. A hatch-date analysis showed that early survival rates were much higher for cohorts that hatched about 1 month after the 2008 HFE (about April 15, 2008) relative to those fish that hatched before this date. These cohorts, fertilized after the 2008 HFE, would have emerged into a benthic invertebrate community that had recovered, and was possibly enhanced by, the HFE. Interannual differences in growth of age-0 trout, determined on the basis of otolith microstructure, support this hypothesis. Growth rates in the summer and fall of 2008 (0.44 mm/day) were virtually the same as in 2006 (0.46 mm/day), the highest recorded during 6 years, even though abundance was eightfold greater in 2008. We speculate that the 60-hour-long 2008 HFE (with peak magnitude about twice that of the annual peak flow during the previous 4 years) increased interstitial spaces in the gravel bed substrate and food availability or quality, leading to higher early survival of recently emerged trout and better growth of these fish through summer and fall. Abundance in 2009 was more than twofold higher than expected, given the estimated number of viable eggs deposited in that year, perhaps indicating that the effect of the 2008 HFE on early life stages was somewhat persistent. In a 3-week interval that spanned the November 2004 HFE, abundance of age-0 trout that were approximately 7 months old from hatch experienced about a threefold decline, compared to the approximately twofold decrease observed between November and December 2008. Abundance of age-0 trout that were approximately 10 months old from hatch was very similar across sampling trips that spanned the March 2008 HFE. It is uncertain whether the decline in abundance after the November 2004 HFE was the result of higher flow-induced mortality or higher flow-induced downstream dispersal. A focused monitoring effort in Marble Canyon (the reach immediately downstream of the Lees Ferry tailwater) before and after future HFEs is recommended to resolve this uncertainty. Relatively detailed monitoring of early life stages-such as the program described in this study-is essential to establish linkages between Glen Canyon Dam operations, or possibly other factors, and trends in the abundance of important nonnative and native fish populations living downstream within Grand Canyon National Park.

The demands and benefits of ergonomics in Sri Lankan apparel industry: A case study at MAS holdings.

PubMed

Abeysekera, John; Illankoon, Prasanna

2016-10-17

Apparel exports bring in sizeable foreign income to Sri Lanka. To protect and promote this industry is a paramount need. This can be carried out by applying Human Factors/Ergonomics (HFE) which has proved to control negative effects at work places. This paper reports a case study which describes the demands and benefits of HFE in MAS Holdings which owns a large share of the apparel industry in Sri Lanka. The study consisted of walk through observation survey, a questionnaire survey and ergonomic work place analysis followed by a training programme to selected employees in three companies. Positive responses to questionnaires revealed good ergonomic practices in the work places surveyed. Ergonomically unfit chairs and potential hazards e.g. exposure to noise and hot environment were detected. It is seen that MAS have introduced strategies originated by Toyota Production System viz. 5S, Kaizen, six sigma etc., which are in fact ergonomic methods. A progressive project MAS boast of viz. 'MAS Operating System' (MOS) empowers training and development to employees. MAS Holdings has adequately realized the benefits of applying HFE as evident by the number of awards received. Relevant companies were advised to take appropriate corrective measures to control the potential hazards.

HFE genotype affects exosome phenotype in cancer.

PubMed

Mrowczynski, Oliver D; Madhankumar, A B; Slagle-Webb, Becky; Lee, Sang Y; Zacharia, Brad E; Connor, James R

2017-08-01

Neuroblastoma is the third most common childhood cancer, and timely diagnosis and sensitive therapeutic monitoring remain major challenges. Tumor progression and recurrence is common with little understanding of mechanisms. A major recent focus in cancer biology is the impact of exosomes on metastatic behavior and the tumor microenvironment. Exosomes have been demonstrated to contribute to the oncogenic effect on the surrounding tumor environment and also mediate resistance to therapy. The effect of genotype on exosomal phenotype has not yet been explored. We interrogated exosomes from human neuroblastoma cells that express wild-type or mutant forms of the HFE gene. HFE, one of the most common autosomal recessive polymorphisms in the Caucasian population, originally associated with hemochromatosis, has also been associated with increased tumor burden, therapeutic resistance boost, and negative impact on patient survival. Herein, we demonstrate that changes in genotype cause major differences in the molecular and functional properties of exosomes; specifically, HFE mutant derived exosomes have increased expression of proteins relating to invasion, angiogenesis, and cancer therapeutic resistance. HFE mutant derived exosomes were also shown to transfer this cargo to recipient cells and cause an increased oncogenic functionality in those recipient cells. Copyright © 2017. Published by Elsevier B.V.

A role for sex and a common HFE gene variant in brain iron uptake.

PubMed

Duck, Kari A; Neely, Elizabeth B; Simpson, Ian A; Connor, James R

2018-03-01

HFE (high iron) is an essential protein for regulating iron transport into cells. Mutations of the HFE gene result in loss of this regulation causing accumulation of iron within the cell. The mutated protein has been found increasingly in numerous neurodegenerative disorders in which increased levels of iron in the brain are reported. Additionally, evidence that these mutations are associated with elevated brain iron challenges the paradigm that the brain is protected by the blood-brain barrier. While much has been studied regarding the role of HFE in cellular iron uptake, it has remained unclear what role the protein plays in the transport of iron into the brain. We investigated regulation of iron transport into the brain using a mouse model with a mutation in the HFE gene. We demonstrated that the rate of radiolabeled iron ( 59 Fe) uptake was similar between the two genotypes despite higher brain iron concentrations in the mutant. However, there were significant differences in iron uptake between males and females regardless of genotype. These data indicate that brain iron status is consistently maintained and tightly regulated at the level of the blood-brain barrier.

HFE p.H63D polymorphism does not influence ALS phenotype and survival.

PubMed

Chiò, Adriano; Mora, Gabriele; Sabatelli, Mario; Caponnetto, Claudia; Lunetta, Christian; Traynor, Bryan J; Johnson, Janel O; Nalls, Mike A; Calvo, Andrea; Moglia, Cristina; Borghero, Giuseppe; Monsurrò, Maria Rosaria; La Bella, Vincenzo; Volanti, Paolo; Simone, Isabella; Salvi, Fabrizio; Logullo, Francesco O; Nilo, Riva; Giannini, Fabio; Mandrioli, Jessica; Tanel, Raffaella; Murru, Maria Rita; Mandich, Paola; Zollino, Marcella; Conforti, Francesca L; Penco, Silvana; Brunetti, Maura; Barberis, Marco; Restagno, Gabriella

2015-10-01

It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients. Copyright © 2015 Elsevier Inc. All rights reserved.

An Excel Macro to Plot the HFE-Diagram to Identify Sea Water Intrusion Phases.

PubMed

Giménez-Forcada, Elena; Sánchez San Román, F Javier

2015-01-01

A hydrochemical facies evolution diagram (HFE-D) is a multirectangular diagram, which is a useful tool in the interpretation of sea water intrusion processes. This method note describes a simple method for generating an HFE-D plot using the spreadsheet software package, Microsoft Excel. The code was applied to groundwater from the alluvial coastal plain of Grosseto (Tuscany, Italy), which is characterized by a complex salinization process in which sea water mixes with sulfate or bicarbonate recharge water. © 2014, National GroundWater Association.

Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis.

PubMed

Bittencourt, Paulo Lisboa; Marin, Maria Lúcia Carnevale; Couto, Cláudia Alves; Cançado, Eduardo Luiz Rachid; Carrilho, Flair José; Goldberg, Anna Carla

2009-01-01

Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH) are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2) and ferroportin 1 (SCL40A1). To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. Nineteen male subjects (median age 42 [range: 20-72] years) with HH were evaluated using the Haemochromatosis StripAssay A. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del. In our cohort, nine (47%) patients were homozygous for the C282Y mutation, two (11%) were heterozygous for the H63D mutation, and one each (5%) was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients. One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.

Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption.

PubMed

Ye, Kaixiong; Cao, Chang; Lin, Xu; O'Brien, Kimberly O; Gu, Zhenglong

2015-06-10

HFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. While the genetic variant under selection in Europeans (a non-synonymous mutation, C282Y) has been relatively well-studied, the adaptive variant in Asians and its functional consequences are still unknown. Identifying the adaptive HFE variants in Asians will not only elucidate the evolutionary history and the genetic basis of population difference in Fe status, but also assist the future practice of genome-informed dietary recommendation. Using data from the International HapMap Project, we confirmed the signatures of positive selection on HFE in Asian populations and identified a candidate adaptive haplotype that is common in Asians (52.35-54.71%) but rare in Europeans (5.98%) and Africans (4.35%). The T allele at tag SNP rs9366637 (C/T) captured 95.8% of this Asian-common haplotype. A significantly reduced HFE expression was observed in individuals carrying T/T at rs9366637 compared to C/C and C/T, indicating a possible role of gene regulation in adaptation. We recruited 57 women of Asian descent and measured Fe absorption using stable isotopes in those homozygous at rs9366637. We observed a 22% higher absorption in women homozygous for the Asian-common haplotype (T/T) compared to the control genotype (C/C). Additionally, compared with a group of age-matched Caucasian women, Asian women exhibited significantly elevated Fe absorption. Our results indicate parallel adaptation of HFE gene in Europeans and Asians with different genetic variants. Moreover, natural selection on HFE may have contributed to elevated Fe absorption in Asians. This study regarding population differences in Fe homeostasis has significant medical impact as high Fe level has been linked to an increased disease risk of metabolic syndromes.

[CCR5, CCR2, apoe, p53, ITGB3 and HFE gene polymorphism in Western Siberia long-livers].

PubMed

Ivanoshchuk, D E; Mikhaĭlova, S V; Kulikov, I V; Maksimov, V N; Voevoda, M I; Romashchenko, A G

2012-01-01

In order to estimate the distribution of some polymorphisms for the CCR5, CCR2, apoE, p53, ITGB3, and HFE genes in Russian long-livers from Western Siberia, a sample of 271 individuals (range 90-105 years) was examined. It was demonstrated that carriage of the delta32 polymorphism for the CCR5 gene, V64/polymorphism for the CCR2 gene, e2/e3/e4 for the apoE gene, L33P for the ITGB3 gene, as well as H63D and S65C polymorphisms for the HFE gene does not influence on predisposition to the longevity; carriage of the 282 Y allele for the HFE gene negatively influences on the longevity; carriage of the heterozygous genotype for the R72P polymorphism for the p53 gene correlates with the longevity of elderly people.

Association study between four polymorphisms in the HFE, TF and TFR genes and Parkinson's disease in southern Italy.

PubMed

Greco, Valentina; De Marco, Elvira Valeria; Rocca, Francesca Emanuela; Annesi, Ferdinanda; Civitelli, Donatella; Provenzano, Giovanni; Tarantino, Patrizia; Scornaienchi, Vittorio; Pucci, Franco; Salsone, Maria; Novellino, Fabiana; Morelli, Maurizio; Paglionico, Sandra; Gambardella, Antonio; Quattrone, Aldo; Annesi, Grazia

2011-06-01

Iron overload may lead to neurodegenerative disorders such as Parkinson's disease (PD) and alterations of iron-related genes might be involved in the pathogenesis of this disease. The gene of haemochromatosis (HFE) encodes the HFE protein which interacts with the transferrin receptor (TFR), lowering its affinity for iron-bound transferrin (TF). We examined four known polymorphisms, C282Y and H63D in the HFE gene, G258S in the TF gene and S82G in the TFR gene, in 181 sporadic PD patients and 180 controls from Southern Italy to investigate their possible role in susceptibility to PD. No significant differences were found in genotype and allele frequencies between PD and controls for all the polymorphisms studied, suggesting that these variants do not contribute significantly to the risk of PD.

Hemochromatosis Enhances Tumor Progression via Upregulation of Intracellular Iron in Head and Neck Cancer

PubMed Central

Lenarduzzi, Michelle; Hui, Angela B. Y.; Yue, Shijun; Ito, Emma; Shi, Wei; Williams, Justin; Bruce, Jeff; Sakemura-Nakatsugawa, Noriko; Xu, Wei; Schimmer, Aaron; Liu, Fei-Fei

2013-01-01

Introduction Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC. Experimental Design Expression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS), clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry. Results In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP) expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX), significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression. Conclusions Our data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management. PMID:23991213

Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection

PubMed Central

Nairz, Manfred; Schroll, Andrea; Haschka, David; Dichtl, Stefanie; Tymoszuk, Piotr; Demetz, Egon; Moser, Patrizia; Haas, Hubertus; Fang, Ferric C.; Theurl, Igor; Weiss, Günter

2017-01-01

Genetic and dietary forms of iron overload have distinctive clinical and pathophysiological features. HFE-associated hereditary hemochromatosis is characterized by overwhelming intestinal iron absorption, parenchymal iron deposition, and macrophage iron depletion. In contrast, excessive dietary iron intake results in iron deposition in macrophages. However, the functional consequences of genetic and dietary iron overload for the control of microbes are incompletely understood. Using Hfe+/+ and Hfe−/− mice in combination with oral iron overload in a model of Salmonella enterica serovar Typhimurium infection, we found animals of either genotype to induce hepcidin antimicrobial peptide expression and hypoferremia following systemic infection in an Hfe-independent manner. As predicted, Hfe−/− mice, a model of hereditary hemochromatosis, displayed reduced spleen iron content, which translated into improved control of Salmonella replication. Salmonella adapted to the iron-poor microenvironment in the spleens of Hfe−/− mice by inducing the expression of its siderophore iron-uptake machinery. Dietary iron loading resulted in higher bacterial numbers in both WT and Hfe−/− mice, although Hfe deficiency still resulted in better pathogen control and improved survival. This suggests that Hfe deficiency may exert protective effects in addition to the control of iron availability for intracellular bacteria. Our data show that a dynamic adaptation of iron metabolism in both immune cells and microbes shapes the host-pathogen interaction in the setting of systemic Salmonella infection. Moreover, Hfe-associated iron overload and dietary iron excess result in different outcomes in infection, indicating that tissue and cellular iron distribution determines the susceptibility to infection with specific pathogens. PMID:28443246

Iranian hereditary hemochromatosis patients: baseline characteristics, laboratory data and gene mutations.

PubMed

Zamani, Farhad; Bagheri, Zohreh; Bayat, Maryam; Fereshtehnejad, Seyed-Mohammad; Basi, Ali; Najmabadi, Hossein; Ajdarkosh, Hossein

2012-10-01

Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder in white people, characterized by highly abnormal uptake of iron from the gastrointestinal tracts. Recently, mutation studies have focused to detect the genes responsible for HH. In this cross-sectional study, 12 HH patients were recruited, who were referred to Firoozgar Hospital, Tehran, Iran. In addition to the clinical assessments, a complete laboratory evaluation, imaging modalities, histopathologic assessment, atomic absorption spectrophotometry and gene mutation study were performed. The genetic study for HFE gene mutation was examined for all of the patients since 2006, while non-HFE mutation was conducted since December 2010 (only for 1 of them). Twelve patients were evaluated consisting of 11 men and 1 woman, with the mean age of 39.58±12.68 yr. The average of atomic iron loads was 13.25±4.83-fold higher than normal standards. Four patients had heterozygotic mutation of H63D (33.3%). There was no significant difference in either the iron load of liver (P=0.927) and heart (P=0.164) or serum concentration of ferritin (P=0.907) and TIBC (P=0.937) between the HFE-mutant and without HFE mutation HH cases. In contrast to other studies, C282Y mutation was not detected in any of our Iranian HH patients. Heterozygotic mutations of H63D (HFE) and TFR2 (non-HFE) genes were found to be more common in these patients. Similar to previous reports, these mutations were not found to be significantly associated with severity of presentation in HH patients.

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

O'Hara, J.M.; W. Gunther, G. Martinez-Guridi

New and advanced reactors will use integrated digital instrumentation and control (I&C) systems to support operators in their monitoring and control functions. Even though digital systems are typically highly reliable, their potential for degradation or failure could significantly affect operator performance and, consequently, impact plant safety. The U.S. Nuclear Regulatory Commission (NRC) supported this research project to investigate the effects of degraded I&C systems on human performance and plant operations. The objective was to develop human factors engineering (HFE) review guidance addressing the detection and management of degraded digital I&C conditions by plant operators. We reviewed pertinent standards and guidelines,more » empirical studies, and plant operating experience. In addition, we conducted an evaluation of the potential effects of selected failure modes of the digital feedwater system on human-system interfaces (HSIs) and operator performance. The results indicated that I&C degradations are prevalent in plants employing digital systems and the overall effects on plant behavior can be significant, such as causing a reactor trip or causing equipment to operate unexpectedly. I&C degradations can impact the HSIs used by operators to monitor and control the plant. For example, sensor degradations can make displays difficult to interpret and can sometimes mislead operators by making it appear that a process disturbance has occurred. We used the information obtained as the technical basis upon which to develop HFE review guidance. The guidance addresses the treatment of degraded I&C conditions as part of the design process and the HSI features and functions that support operators to monitor I&C performance and manage I&C degradations when they occur. In addition, we identified topics for future research.« less

Crossing levels in systems ergonomics: a framework to support 'mesoergonomic' inquiry.

PubMed

Karsh, Ben-Tzion; Waterson, Patrick; Holden, Richard J

2014-01-01

In this paper we elaborate and articulate the need for what has been termed 'mesoergonomics'. In particular, we argue that the concept has the potential to bridge the gap between, and integrate, established work within the domains of micro- and macroergonomics. Mesoergonomics is defined as an open systems approach to human factors and ergonomics (HFE) theory and research whereby the relationship between variables in at least two different system levels or echelons is studied, and where the dependent variables are human factors and ergonomic constructs. We present a framework which can be used to structure a set of questions for future work and prompt further empirical and conceptual inquiry. The framework consists of four steps: (1) establishing the purpose of the mesoergonomic investigation; (2) selecting human factors and ergonomics variables; (3) selecting a specific type of mesoergonomic investigation; and (4) establishing relationships between system levels. In addition, we describe two case studies which illustrate the workings of the framework and the value of adopting a mesoergonomic perspective within HFE. The paper concludes with a set of issues which could form part of a future agenda for research within systems ergonomics. Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Association of HFE gene mutations with nonalcoholic fatty liver disease in the Iranian population.

PubMed

Saremi, L; Lotfipanah, S; Mohammadi, M; Hosseinzadeh, H; Sayad, A; Saltanatpour, Z

2016-10-31

To determine whether the HFE gene variants H63D and C282Y are associated with NAFLD in persons with type 2 diabetes, we conducted a case-control study including 145 case of NAFLD patients with a history of type 2 diabetes and 145 matching control. The genomic DNA was extracted from the peripheral venous blood and the genotyping of HFE gene mutations was analyzed using the PCR-RFLP technique. Statistical analysis was performed using SPSS 12.0 software by χ2 test, t test and ANOVA (P<0.05). Data showed no increased frequency of HFE mutations in persons with type 2 diabetes and no association between H63D mutation and NAFLD in the study population. Also, we analyzed index of physiological variables including FBS, lipid profile (TC, TG, LDL-C, and HDL-C), BMI, HbA1c, and micro albuminuria and Cr levels). Data showed there are no relationship between these indexes and HFE gene mutations and either NAFLD as a complication of diabetes. But our results showed a relationship between C282Y mutation and NAFLD in persons with type 2 diabetes. C282Y mutation might be a genetic marker of NAFLD in Iranian population.

Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes.

PubMed

Grosse, Scott D; Gurrin, Lyle C; Bertalli, Nadine A; Allen, Katrina J

2018-04-01

Iron overload (hemochromatosis) can cause serious, symptomatic disease that is preventable if detected early and managed appropriately. The leading cause of hemochromatosis in populations of predominantly European ancestry is homozygosity of the C282Y variant in the HFE gene. Screening of adults for iron overload or associated genotypes is controversial, largely because of a belief that severe phenotypes are uncommon, although cascade testing of first-degree relatives of patients is widely endorsed. We contend that severe liver disease (cirrhosis or hepatocellular cancer) is not at all uncommon among older males with hereditary hemochromatosis. Our review of the published data from a variety of empirical sources indicates that roughly 1 in 10 male HFE C282Y homozygotes is likely to develop severe liver disease during his lifetime unless iron overload is detected early and treated. New evidence from a randomized controlled trial of treatment allows for evidence-based management of presymptomatic patients. Although population screening for HFE C282Y homozygosity faces multiple barriers, a potentially effective strategy for increasing the early detection and prevention of clinical iron overload and severe disease is to include HFE C282Y homozygosity in lists of medically actionable gene variants when reporting the results of genome or exome sequencing.

A HUMAN FACTORS ENGINEERING PROCESS TO SUPPORT HUMAN-SYSTEM INTERFACE DESIGN IN CONTROL ROOM MODERNIZATION

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

Kovesdi, C.; Joe, J.; Boring, R.

The primary objective of the United States (U.S.) Department of Energy (DOE) Light Water Reactor Sustainability (LWRS) program is to sustain operation of the existing commercial nuclear power plants (NPPs) through a multi-pathway approach in conducting research and development (R&D). The Advanced Instrumentation, Information, and Control (II&C) System Technologies pathway conducts targeted R&D to address aging and reliability concerns with legacy instrumentation and control (I&C) and other information systems in existing U.S. NPPs. Control room modernization is an important part following this pathway, and human factors experts at Idaho National Laboratory (INL) have been involved in conducting R&D to supportmore » migration of new digital main control room (MCR) technologies from legacy analog and legacy digital I&C. This paper describes a human factors engineering (HFE) process that supports human-system interface (HSI) design in MCR modernization activities, particularly with migration of old digital to new digital I&C. The process described in this work is an expansion from the LWRS Report INL/EXT-16-38576, and is a requirements-driven approach that aligns with NUREG-0711 requirements. The work described builds upon the existing literature by adding more detail around key tasks and decisions to make when transitioning from HSI Design into Verification and Validation (V&V). The overall objective of this process is to inform HSI design and elicit specific, measurable, and achievable human factors criteria for new digital technologies. Upon following this process, utilities should have greater confidence with transitioning from HSI design into V&V.« less

Reducing Hazardous Emissions at Anniston Army Depot

DTIC Science & Technology

2012-05-01

alkaline detergent DuPont Vertrel SDG Hydrofluorocarbon (HFC)-based immersion vapor degreaser with ultrasonics 3M HFE-72DE Hydrofluoroether (HFE... SDG provided the best results for degreasing (Building 409)  Both systems/products were effective at degreasing the various vehicle components and

Hydrodynamics and PIV study in the impingement zone formed by a droplet train

NASA Astrophysics Data System (ADS)

Kanjirakat, Anoop; Sadr, Reza; Zhang, Taolue; Muthusamy, Jayaveera; Alvarado, Jorge; Texas A; M University at Qatar Collaboration; Texas A; M University College Station Collaboration

2016-11-01

Droplet impingement is encountered in numerous technical applications, such as ink jet printing, spray cooling, and fuel injection in internal combustion engines. Even though many studies in droplet impingement were conducted in past, not many have measured the near-wall velocities in the droplet impingement zone. With the goal of gaining a better understanding of the hydrodynamics in the impingement zone, well-controlled experiments are performed in combination with micro-PIV measurements and numerical simulations. Hydrodynamics of HFE-7100 droplets generated using a piezoelectric droplet generator, impinging on a pre-wetted surface is investigated. Micro-PIV studies in the high-velocity impingement zone are performed using one-micron meter fluorescent particles dispersed in HFE-7100 along with the double exposed images. Three-dimensional and 2D-axisymmetric numerical modeling for a transient droplet crown development is performed. The interface between the gas and the liquid is modeled using a Volume of Fluid (VOF) method. Numerical simulation results obtained are observed to be in good agreement with that of the experimental observations. Supported by National Priority Research Program (NPRP) of Qatar National Research Fund (QNRF), Grant No.: NPRP 6-1304-2-525.

With eloquence and humanity? Human factors/ergonomics in sustainable human development.

PubMed

Moore, Dave; Barnard, Tim

2012-12-01

This article is based on a keynote presentation given at the 18th Congress of the International Ergonomics Association in Recife, Brazil, February 2012. It considers new, and not so new, approaches and practical roles for the emerging field of human factors/ergonomics (HFE) in sustainable development (SD).The material for this article was largely drawn from the literature in the fields of human development, sustainability, climate change mitigation and adaptation, and social/environmental impact assessment. Identifying the role of HFE in SD is not a simple one and from the outset is complicated by the widely differing ideas in the sustainability literature about what exactly it is we are hoping to sustain. Is it individual companies, business models, cultures, or the carrying capacity of our planet? Or combinations of these? For the purposes of this article, certain assumptions are made, and various emerging opportunities and responsibilities associated with our changing world of work are introduced. First, there are new versions of traditional tasks for us, such as working with the people and companies in the renewable energy sectors. Beyond this, however, it is suggested that there are emerging roles for HFE professionals in transdisciplinary work where we might play our part, for example, in tackling the twinned issues of climate change and human development in areas of significant poverty. In particular we have the tools and capabilities to help define and measure what groups have reason to value, and wish to sustain. It is suggested, that to do this effectively, however, will require a philosophical shift, or perhaps just a philosophical restatement at a collective level, regarding who and what we ultimately serve.

Diabetes in first-degree family members: a predictor of type 2 diabetes in 159 nonscreening Alabama hemochromatosis probands with HFE C282Y homozygosity.

PubMed

Barton, James C; Barton, J Clayborn; Acton, Ronald T

2014-01-01

OBJECTIVE We sought to identify predictors of diabetes diagnosed before hemochromatosis. RESEARCH DESIGN AND METHODS We studied these 16 variables in 159 nonscreening hemochromatosis probands with HFE C282Y homozygosity: age; sex; BMI; diabetes reports in first-degree family members (dichotomous); heavy ethanol consumption; cigarette smoking; elevated serum alanine aminotransferase/aspartate aminotransferase levels; nonalcoholic fatty liver; chronic viral hepatitis; cirrhosis; hand arthropathy; iron removed by phlebotomy; and positivity for HLA-A*01, B*08; A*03, B*07; and A*03, B*14 haplotypes. We performed univariable and multivariable analyses. RESULTS Twenty-three probands (14.5%) had diabetes; 19 were men. Each of the 23 probands had type 2 diabetes. Mean BMI was greater in probands with diabetes (31.7 ± 8.5 [SD] kg/m(2) vs. 27.6 ± 5.1 kg/m(2); P = 0.032). Reports of any first-degree family member with diabetes were more prevalent in probands with than in probands without diabetes (69.6 vs. 17.6%; P < 0.0001). In probands with diabetes, the odds ratio (OR) of maternal diabetes was 6.7 (95% CI 2.3-19.7; P = 0.0005) and of sibling diabetes was 11.7 (3.0-45.5; P = 0.0004). In a logistic regression model, predictors of diabetes at hemochromatosis diagnosis in 159 probands were diabetes reports in family members (OR 8.5 [95% CI 2.9-24.8]; P < 0.0001) and BMI (1.1 [1.0-1.2]; P = 0.049). This model explained 26.0% of total deviance contributing to diabetes. CONCLUSIONS In nonscreening hemochromatosis probands with HFE C282Y homozygosity, a heritable factor(s) increases the risk of diabetes diagnosed before hemochromatosis.

Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice.

PubMed

Meadowcroft, Mark D; Wang, Jianli; Purnell, Carson J; Peters, Douglas G; Eslinger, Paul J; Neely, Elizabeth B; Gill, David J; Vasavada, Megha; Ali-Rahmani, Fatima; Yang, Qing X; Connor, James R

2016-12-01

Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R 2 ) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R 2 compared to non-carriers within white matter association fibers in the brain. Similar R 2 decreases within white matter tracts were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R 2 decrease is found in the H67D animal model in white matter regions of interest. The decrease in R 2 within white matter tracts of both species is speculated to be multifaceted. The R 2 changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R 2 changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.

Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin.

PubMed

Coelho-Borges, Silvia; Cheinquer, Hugo; Wolff, Fernando Herz; Cheinquer, Nelson; Krug, Luciano; Ashton-Prolla, Patricia

2012-01-01

Abnormal serum ferritin levels are found in approximately 20%-30% of the patients with chronic hepatitis C and are associated with a lower response rate to interferon therapy. To determine if the presence of HFE gene mutations had any effect on the sustained virological response rate to interferon based therapy in chronic hepatitis C patients with elevated serum ferritin. A total of 44 treatment naÏve patients with histologically demonstrated chronic hepatitis C, all infected with hepatitis C virus genotype non-1 (38 genotype 3; 6 genotype 2) and serum ferritin above 500 ng/mL were treated with interferon (3 MU, 3 times a week) and ribavirin (1.000 mg, daily) for 24 weeks. Sustained virological response was defined as negative qualitative HCV-RNA more than 24 weeks after the end of treatment. Serum HCV-RNA was measured by qualitative in house polymerase chain reaction with a limit of detection of 200 IU/mL. HFE gene mutation was detected using restriction-enzyme digestion with RsaI (C282Y mutation analysis) and BclI (H63D mutation analysis) in 16 (37%) patients, all heterozygous (11 H63D, 2 C282Y and 3 both). Sustained virological response was achieved in 0 of 16 patients with HFE gene mutations and 11 (41%) of 27 patients without HFE gene mutations (P = 0.002; exact Fisher test). Heterozigozity for H63D and/or C282Y HFE gene mutation predicts absence of sustained virological response to combination treatment with interferon and ribavirin in patients with chronic hepatitis C, non-1 genotype and serum ferritin levels above 500 ng/mL.

The role of HFE genotype in macrophage phenotype.

PubMed

Nixon, Anne M; Neely, Elizabeth; Simpson, Ian A; Connor, James R

2018-02-01

Iron regulation is essential for cellular energy production. Loss of cellular iron homeostasis has critical implications for both normal function and disease progression. The H63D variant of the HFE gene is the most common gene variant in Caucasians. The resulting mutant protein alters cellular iron homeostasis and is associated with a number of neurological diseases and cancer. In the brain, microglial and infiltrating macrophages are critical to maintaining iron homeostasis and modulating inflammation associated with the pathogenic process in multiple diseases. This study addresses whether HFE genotype affects macrophage function and the implications of these findings for disease processes. Bone marrow macrophages were isolated from wildtype and H67D HFE knock-in mice. The H67D gene variant in mice is the human equivalent of the H63D variant. Upon differentiation, the macrophages were used to analyze iron regulatory proteins, cellular iron release, migration, phagocytosis, and cytokine expression. The results of this study demonstrate that the H67D HFE genotype significantly impacts a number of critical macrophage functions. Specifically, fundamental activities such as proliferation in response to iron exposure, L-ferritin expression in response to iron loading, secretion of BMP6 and cytokines, and migration and phagocytic activity were all found to be impacted by genotype. Furthermore, we demonstrated that exposure to apo-Tf (iron-poor transferrin) can increase the release of iron from macrophages. In normal conditions, 70% of circulating transferrin is unsaturated. Therefore, the ability of apo-Tf to induce iron release could be a major regulatory mechanism for iron release from macrophages. These studies demonstrate that the HFE genotype impacts fundamental components of macrophage phenotype that could alter their role in degenerative and reparative processes in neurodegenerative disorders.

Brain transcriptome perturbations in the Hfe(-/-) mouse model of genetic iron loading.

PubMed

Johnstone, Daniel; Graham, Ross M; Trinder, Debbie; Delima, Roheeth D; Riveros, Carlos; Olynyk, John K; Scott, Rodney J; Moscato, Pablo; Milward, Elizabeth A

2012-04-11

Severe disruption of brain iron homeostasis can cause fatal neurodegenerative disease, however debate surrounds the neurologic effects of milder, more common iron loading disorders such as hereditary hemochromatosis, which is usually caused by loss-of-function polymorphisms in the HFE gene. There is evidence from both human and animal studies that HFE gene variants may affect brain function and modify risks of brain disease. To investigate how disruption of HFE influences brain transcript levels, we used microarray and real-time reverse transcription polymerase chain reaction to assess the brain transcriptome in Hfe(-/-) mice relative to wildtype AKR controls (age 10 weeks, n≥4/group). The Hfe(-/-) mouse brain showed numerous significant changes in transcript levels (p<0.05) although few of these related to proteins directly involved in iron homeostasis. There were robust changes of at least 2-fold in levels of transcripts for prominent genes relating to transcriptional regulation (FBJ osteosarcoma oncogene Fos, early growth response genes), neurotransmission (glutamate NMDA receptor Grin1, GABA receptor Gabbr1) and synaptic plasticity and memory (calcium/calmodulin-dependent protein kinase IIα Camk2a). As previously reported for dietary iron-supplemented mice, there were altered levels of transcripts for genes linked to neuronal ceroid lipofuscinosis, a disease characterized by excessive lipofuscin deposition. Labile iron is known to enhance lipofuscin generation which may accelerate brain aging. The findings provide evidence that iron loading disorders can considerably perturb levels of transcripts for genes essential for normal brain function and may help explain some of the neurologic signs and symptoms reported in hemochromatosis patients. Copyright © 2012 Elsevier B.V. All rights reserved.

The relationship between selected VDR, HFE and ALAD gene polymorphisms and several basic toxicological parameters among persons occupationally exposed to lead.

PubMed

Szymańska-Chabowska, Anna; Łaczmański, Łukasz; Jędrychowska, Iwona; Chabowski, Mariusz; Gać, Paweł; Janus, Agnieszka; Gosławska, Katarzyna; Smyk, Beata; Solska, Urszula; Mazur, Grzegorz; Poręba, Rafał

2015-08-06

The aim of this study was to find a relationship between polymorphisms of ALAD rs1805313, rs222808, rs1139488, VDR FokI and HFE C282Y and H63D and basic toxicological parameters (lead and ZnPP blood concentration) in people occupationally exposed to lead. We collected data of 101 workers (age 25-63 years) directly exposed to lead. The toxicological lab tests included blood lead, cadmium and ZnPP concentration measurement and arsenic urine concentration measurement. Workers were genotyped for ALAD (rs1805313, rs222808, rs1139488), HFE (C282Y, H63D) and VDR (FokI). Individuals with the lead exposure and coexisting F allel in the locus Fok-I of VDR gene are suspected of higher zinc protoporphyrins concentrations. Workers exposed to the lead with the Y allel in the locus C282Y of the HFE gene are predisposed to lower ZnPP levels and individuals with coexisting H allel in the locus H63D HFE gene are predisposed to lower Pb-B levels. The T allel in the locus rs1805313 of the ALAD gene determines lower Pb-B and ZnPP levels in lead-exposed individuals. The heterozigosity of the locus rs2228083 of the ALAD gene has a strong predilection to higher Pb-B levels. The carriage of the C allel in the locus rs1139488 of the ALAD gene might determine higher Pb-B levels and the heterozigosity of the locus rs1139488 of the ALAD gene might result in higher ZnPP levels. The study revealed relationship between VDR, HFE and ALAD genes polymorphism and basic toxicological parameters in occupationally exposed workers. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Serum hepcidin levels, iron status, and HFE gene alterations during the first year of life in healthy Spanish infants.

PubMed

Aranda, Nuria; Bedmar, Cristina; Arija, Victoria; Jardí, Cristina; Jimenez-Feijoo, Rosa; Ferré, Natalia; Tous, Monica

2018-06-01

The aims of this study were to describe hepcidin levels and to assess their associations with iron status and the main variants in the HFE gene in healthy and full-term newborns during the first year of life, as a longitudinal study conducted on 140 infants. Anthropometric and biochemical parameters, hepcidin, hemoglobin (Hb), serum ferritin (SF), transferrin saturation (TS), mean corpuscular volume (MCV), and C-reactive protein (CRP), were assessed in 6- and 12-month-olds. Infants were genotyped for the three main HFE variants: C282Y, H63D, and S65C. Hepcidin levels increased from 6 to 12 months of age (43.7 ± 1.5 to 52.0 ± 1.5 ng/mL; p < 0.001), showing higher levels in infants with better iron status compared to those with iron deficiency (ID) (44.8 ± 1.5 vs 37.9 ± 1.3 ng/mL, p < 0.018, and 54.3 ± 1.5 vs 44.0 ± 1.4 ng/mL, p < 0.038, in 6- and 12-month-olds, respectively). In multivariate linear regression models, iron status was found to be associated with hepcidin levels in infants with wild-type HFE gene (p = 0.046 and p = 0.048 in 6- and 12-month-olds, respectively). However, this association was not found in HFE-alteration-carrying infants. Hepcidin levels increased in healthy infants during the first year of life and were positively associated with iron levels only in infants with wild-type HFE gene, a situation that requires further investigation.

The performance of H2O, R134a, SES36, ethanol, and HFE7100 two-phase closed thermosyphons for varying operating parameters and geometry

NASA Astrophysics Data System (ADS)

Andrzejczyk, Rafał; Muszyński, Tomasz

2017-09-01

In this study, the influences of different parameters at performance two-phase closed thermosiphon (TPCT) was presented. It has been confirmed that the working fluid, as well as operating parameters and fill ratio, are very important factors in the performance of TPCT. The article shows characteristics of gravitational tube geometries, as well as the technical characteristic of the most important system components, i.e., the evaporator/condenser. The experiment's plan and the results of it for the two-phase thermosiphon for both evaluated geometries with varying thermal and fluid flow parameters are presented. Experiments were performed for the most perspective working fluids, namely: water, R134a, SES36, ethanol and HFE7100. Obtained research proves the possibility to use TPCT for heat recovery from the industrial waste water.

HFE gene in primary and secondary hepatic iron overload

PubMed Central

Sebastiani, Giada; Walker, Ann P

2007-01-01

Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non-alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis. PMID:17729389

Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis

PubMed Central

Ye, Qi; Kim, Jonghan

2015-01-01

Manganese in excess promotes unstable emotional behavior. Our previous study showed that olfactory manganese uptake into the brain is altered in Hfe−/− mice, a model of iron overload hemochromatosis, suggesting that Hfe deficiency could modify the neurotoxicity of airborne manganese. We determined anxiety-related behavior and monoaminergic protein expression after repeated intranasal instillation of MnCl2 to Hfe−/− mice. Compared with manganese-instilled wild-type mice, Hfe−/− mice showed decreased manganese accumulation in the cerebellum. Hfe−/− mice also exhibited increased anxiety with decreased exploratory activity and elevated dopamine D1 receptor and norepinephrine transporter in the striatum. Moreover, Hfe deficiency attenuated manganese-associated impulsivity and modified the effect of manganese on the expression of tyrosine hydroxylase, vesicular monoamine transporter and serotonin transporter. Together, our data indicate that loss of HFE function alters manganese-associated emotional behavior and further suggest that HFE could be a potential molecular target to alleviate affective disorders induced by manganese inhalation. PMID:26189056

Restoration of the Apollo 15 Heat Flow Experiment Data from 1975 to 1977

NASA Technical Reports Server (NTRS)

Nagihara, S.; Nakamura, Y.; Taylor, P. T.; Williams, D. R.; Kiefer, W. S.

2017-01-01

The Apollo 15 Heat Flow Experiment (HFE) was conducted from July 1971 through January 1977. Two heat flow probes were deployed roughly 8.5 meters apart. Probe 1 and Probe 2 penetrated to 1.4-meters and 1-meter depths into the lunar regolith, respectively. Temperatures at different depths and the surface were logged with 7.25-minute intervals and transmitted to Earth. At the conclusion of the experiment, only data obtained from July 1971 through December 1974 were processed and archived at the National Space Science Data Center (NSSDC) by the principal investigator of the experiment, Marcus Langseth of Columbia University. Langseth died in 1997. It is not known what happened to the HFE data tapes he used. Current researchers have strong interests in re-examining the HFE data for the full duration of the experiment. We have recovered and processed large portions of the Apollo 15 HFE data from 1975 through 1977 by assembling data and metadata from various sources.

Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin.

PubMed

Latour, Chloé; Besson-Fournier, Céline; Meynard, Delphine; Silvestri, Laura; Gourbeyre, Ophélie; Aguilar-Martinez, Patricia; Schmidt, Paul J; Fleming, Mark D; Roth, Marie-Paule; Coppin, Hélène

2016-01-01

Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and β2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice. © 2015 by the American Association for the Study of Liver Diseases.

Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE)

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

Yaouanq, J.; Perichon, M.; Treut, A.L.

1994-02-01

The hemochromatosis gene (HFE) maps to 6p21.3 and is less than 1 cM from the HLA class I gene; however, the precise physical location of the gene has remained elusive and controversial. The unambiguous identification of a crossover event within hemochromatosis families is very difficult; it is particularly hampered by the variability of the phenotypic expression as well as by the sex- and age-related penetrance of the disease. For these considerations, traditional linkage analysis could prove of limited value in further refining the extrapolated physical position of HFE. The authors therefore embarked upon a linkage-disequilibrium analysis of HFE and normalmore » chromosomes for the Brittany population. In this report, 66 hemochromatosis families yielding 151 hemochromatosis chromosomes and 182 normal chromosomes were RFLP-typed with a battery of probes, including two newly derived polymorphic markers from the 6.7 and HLA-F loci located 150 and 250 kb telomeric to HLA-A, respectively. The results suggest a strong peak of existing linkage disequilibrium focused within the i82-to-6.7 interval (approximately 250 kb). The zone of linkage disequilibrium is flanked by the i97 locus, positioned 30 kb proximal to i82, and the HLA-F gene, found 250 kb distal to HLA-A, markers of which display no significant association with HFE. These data support the possibility that HFE resides within the 400-kb expanse of DNA between i97 and HLA-F. Alternatively, the very tight association of HLA-A3 and allele 1 of the 6.7 locus, both of which are comprised by the major ancestral or founder HFE haplotype in Brittany, supports the possibility that the disease gene may reside immediately telomeric to the 6.7 locus within the linkage-disequilibrium zone. Additionally, hemochromatosis haplotypes possessing HLA-A11 and the low-frequency HLA-F polymorphism (allele 2) are supportive of a separate founder chromosome containing a second, independently arising mutant allele. 69 refs., 1 fig., 5 tabs.« less

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

PubMed Central

Di Martino, Julie; Ruiz, Mathias; Garin, Roman; Restier, Lioara; Belmalih, Abdelouahed; Marchal, Christelle; Cullin, Christophe; Arveiler, Benoit; Fergelot, Patricia; Gitler, Aaron D.; Lachaux, Alain; Couthouis, Julien

2017-01-01

Background The most common and severe disease causing allele of Alpha 1-Antitrypsin Deficiency (1ATD) is Z-1AT. This protein aggregates in the endoplasmic reticulum, which is the main cause of liver disease in childhood. Based on recent evidences and on the frequency of liver disease occurrence in Z-1AT patients, it seems that liver disease progression is linked to still unknown genetic factors. Methods We used an innovative approach combining yeast genetic screens with next generation exome sequencing to identify and functionally characterize the genes involved in 1ATD associated liver disease. Results Using yeast genetic screens, we identified HRD1, an Endoplasmic Reticulum Associated Degradation (ERAD) associated protein, as an inducer of Z-mediated toxicity. Whole exome sequencing of 1ATD patients resulted in the identification of two variants associated with liver damages in Z-1AT homozygous cases: HFE H63D and HERPUD1 R50H. Functional characterization in Z-1AT model cell lines demonstrated that impairment of the ERAD machinery combined with the HFE H63D variant expression decreased both cell proliferation and cell viability, while Unfolded Protein Response (UPR)-mediated cell death was hyperstimulated. Conclusion This powerful experimental pipeline allowed us to identify and functionally validate two genes involved in Z-1AT-mediated severe liver toxicity. This pilot study moves forward our understanding on genetic modifiers involved in 1ATD and highlights the UPR pathway as a target for the treatment of liver diseases associated with 1ATD. Finally, these findings support a larger scale screening for HERPUD1 R50H and HFE H63D variants in the sub-group of 1ATD patients developing significant chronic hepatic injuries (hepatomegaly, chronic cholestasis, elevated liver enzymes) and at risk developing liver cirrhosis. PMID:28617828

Potential nonresponse bias in a clinical examination after initial screening using iron phenotyping and HFE genotyping in the hemochromatosis and iron overload screening study.

PubMed

Speechley, Mark; Barton, James C; Passmore, Leah; Harrison, Helen; Reboussin, David M; Harris, Emily L; Rivers, Charles A; Fadojutimi-Akinsiku, Margaret; Wenzel, Lari; Diaz, Sharmin

2009-12-01

Little is known about the factors affecting participation in clinical assessments after HEmochromatosis and IRon Overload Screening. Initial screening of 101,168 primary care patients in the HEmochromatosis and IRon Overload Screening study was performed using serum iron measures and hemochromatosis gene (HFE) genotyping. Using iron phenotypes and HFE genotypes, we identified 2256 cases and 1232 controls eligible to participate in a clinical examination. To assess the potential for nonresponse bias, we compared the sociodemographic, health status, and attitudinal characteristics of participants and nonparticipants using adjusted odds ratios (ORs) and 95% confidence interval (CI). Overall participation was 74% in cases and 52% in controls; in both groups, participation was highest at a health maintenance organization and lowest among those under 45 years of age (cases: OR = 0.68; 95% CI 0.53, 0.87; controls: OR = 0.59; 95% CI 0.44, 0.78). In controls only, participation was also lower among those over 65 years of age than the reference group aged 46-64 (OR = 0.64; 95% CI 0.47, 0.88). Among cases, participation was higher in HFE C282Y homozygotes (OR = 3.98; 95% CI 2.60, 6.09), H63D homozygotes (OR = 2.79; 95% CI 1.23, 6.32), and C282Y/H63D compound heterozygotes (OR = 1.82; 95% CI 1.03, 3.22) than in other genotypes, and lower among non-Caucasians and those who preferred a non-English language than in Caucasians and those who preferred English (p < 0.0001). Subjects with greatest risk to have iron overload (C282Y homozygotes; cases > or =45 years; Caucasians) were more likely to participate in a postscreening clinical examination than other subjects. We detected no evidence of strong selection bias.

Coinheritance of hereditary spherocytosis and reversibility of cirrhosis in a young female patient with hereditary hemochromatosis.

PubMed

Höblinger, A; Erdmann, C; Strassburg, C P; Sauerbruch, T; Lammert, F

2009-04-16

Here we report a 33-years-old woman with hereditary spherocytosis and hemochromatosis due to homozygosity for the C282Y mutation of the HFE gene. The coinheritance of both conditions led to severe iron overload and liver cirrhosis at young age. The patient was treated by repeated phlebotomy, and reversibility of cirrhosis was documented by transient elastography. This report discusses the pathophysiology of iron accumulation in patients with hemolytic anemia combined with HFE C282Y homozygosity. The case indicates that patients with hematological disorders characterized by increased erythropoetic activity should be screened for HFE mutations.

Association of Transition Readiness to Intentional Self-Regulation and Hopeful Future Expectations in Youth With Illness.

PubMed

Hart, Laura C; Pollock, McLean; Hill, Sherika; Maslow, Gary

Little is known about how transition readiness relates to other developmental skills of adolescence in youth with chronic illness. Better understanding of how transition readiness relates to these other developmental skills could lead to a broader array of tools to improve transition readiness. Intentional self-regulation (ISR) and hopeful future expectations (HFE) are 2 developmental skills of adolescence that improve with participation in developmental programming and thus are modifiable. We explored associations between transition readiness, as measured by the Transition Readiness Assessment Questionnaire 29 (TRAQ-29) and ISR and HFE in youth with chronic illness recruited from a variety of subspecialty clinics from a major southeast medical center. A total of 71 adolescents with chronic illness were included in the analysis. The TRAQ-29 Self-Advocacy domain showed positive associations to both ISR (P = .03) and HFE (P = .009). In addition, the TRAQ-29 overall had positive associations to HFE (P = .04). The significant associations between TRAQ-29 Self-Advocacy domain scores and ISR and HFE suggest that transition readiness is developing within the context of other developmental areas in adolescence. More work is needed to see if the programming that improves these other developmental skills might also improve transition readiness. Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Influence of growing phase feed efficiency classification on finishing phase growth performance and carcass characteristics of beef steers fed different diet types.

PubMed

Russell, J R; Lundy, E L; Minton, N O; Sexten, W J; Kerley, M S; Hansen, S L

2016-07-01

A 5-yr study was conducted using 985 crossbred steers (464 kg [SD 32]) fed in 6 separate, replicated groups to determine the influence of growing phase (GP) feed efficiency (FE) classification and diet type on finishing phase (FP) FE of steers. During the GP at the University of Missouri, steers were fed either a whole shell corn-based diet (G-Corn; 528 steers) or a roughage-based diet (G-Rough; 457 steers) using GrowSafe feed bunks to measure DMI for 69 to 89 d. At the end of the GP, steers were ranked by residual feed intake (RFI) within diet, shipped to Iowa State University, and blocked into FP pens (5 to 6 steers/pen) by GP diet and RFI rank (upper, middle, or lower one-third). Steers were transitioned to either FP cracked corn- or byproduct-based diets and fed until 1.27 cm backfat was reached. After completion of the sixth group, average GP G:F within GP diet was calculated for each FP pen (168 total pens) using GP initial BW as a covariate (G-Corn: 0.207 [SD 0.038]; G-Rough: 0.185 [SD 0.036]). Pens were classified as highly feed efficient (HFE; >0.5 SD from the G:F mean; 58 pens), mid feed efficient (MFE; ±0.5 SD from the G:F mean; 60 pens), or lowly feed efficient (LFE; <0.5 SD from the G:F mean; 50 pens). Data were analyzed using PROC MIXED of SAS. Experimental unit was FP pen and the model included the fixed effects of GP diet, FE classification, FP diet, and the interactions. Group (1 to 6) was included as a fixed effect. There were no 3-way interactions ( ≥ 0.2) for any measured traits. Finishing phase G:F was not affected by any interactions ( ≥ 0.5) but was greater ( ≤ 0.03) for HFE versus MFE and LFE and greater ( = 0.02) for MFE versus LFE. Growing phase diet × FE classification effects were detected ( ≤ 0.01) for FP final BW (FBW), ADG, and DMI. Among G-Rough steers, HFE and MFE had greater ( ≤ 0.04) FBW and ADG than LFE, but among G-Corn steers, LFE had heavier ( = 0.03) FBW than HFE whereas ADG was unaffected ( ≥ 0.2) by FE classification. Dry matter intake was unaffected ( ≥ 0.3) by FE classification among G-Rough steers, but among G-Corn steers, LFE had greater ( ≤ 0.003) DMI than MFE and HFE. Overall, differences in FP G:F between FE classifications were driven by different factors depending on diet; ADG differed among roughage-grown steers and DMI differed among corn-grown steers. Ultimately, steers classified as HFE during the GP still had superior FE during the FP.

Evidence-based ergonomics: a model and conceptual structure proposal.

PubMed

Silveira, Dierci Marcio

2012-01-01

In Human Factors and Ergonomics Science (HFES), it is difficult to identify what is the best approach to tackle the workplace and systems design problems which needs to be solved, and it has been also advocated as transdisciplinary and multidisciplinary the issue of "How to solve the human factors and ergonomics problems that are identified?". The proposition on this study is to combine the theoretical approach for Sustainability Science, the Taxonomy of the Human Factors and Ergonomics (HFE) discipline and the framework for Evidence-Based Medicine in an attempt to be applied in Human Factors and Ergonomics. Applications of ontologies are known in the field of medical research and computer science. By scrutinizing the key requirements for the HFES structuring of knowledge, it was designed a reference model, First, it was identified the important requirements for HFES Concept structuring, as regarded by Meister. Second, it was developed an evidence-based ergonomics framework as a reference model composed of six levels based on these requirements. Third, it was devised a mapping tool using linguistic resources to translate human work, systems environment and the complexities inherent to their hierarchical relationships to support future development at Level 2 of the reference model and for meeting the two major challenges for HFES, namely, identifying what problems should be addressed in HFE as an Autonomous Science itself and proposing solutions by integrating concepts and methods applied in HFES for those problems.

Mutations in the hereditary haemochromatosis gene HFE in professional endurance athletes

PubMed Central

Chicharro, J; Hoyos, J; Gomez-Gallego, F; Villa, J; Bandres, F; Celaya, P; Jimenez, F; Alonso, J; Cordova, A; Lucia, A

2004-01-01

Background: Hereditary haemochromatosis, a disease that affects iron metabolism, progresses with a greater or lesser tendency to induce iron overload, possibly leading to severe organ dysfunction. Most elite endurance athletes take iron supplements during their active sporting life, which could aggravate this condition. Objective: To determine the prevalence and discuss potential clinical implications of mutations of HFE (the gene responsible for hereditary haemochromatosis) in endurance athletes. Methods: Basal concentrations of iron, ferritin, and transferrin and transferrin saturation were determined in the period before competition in 65 highly trained athletes. Possible mutations in the HFE gene were evaluated in each subject by extracting genomic DNA from peripheral blood. The restriction enzymes SnaBI and BclI were used to detect the mutations 845G→A (C282Y) and 187C→G (H63D). Results: Our findings indicate a high prevalence of HFE gene mutations in this population (49.2%) compared with sedentary controls (33.5%). No association was detected in the athletes between mutations and blood iron markers. Conclusions: The findings support the need to assess regularly iron stores in elite endurance athletes. PMID:15273174

Experimental study on pool boiling of distilled water and HFE7500 fluid under microgravity

NASA Astrophysics Data System (ADS)

Yang, Yan-jie; Chen, Xiao-qian; Huang, Yi-yong; Li, Guang-yu

2018-02-01

The experimental study on bubble behavior and heat transfer of pool boiling for distilled water and HFE7500 fluid under microgravity has been conducted by using drop tower in the National Microgravity Laboratory of China (NMLC). Two MCH ceramic plates of 20 mm(L) × 10 mm(W) × 1.2 mm(H) were used as the heaters. The nucleate boiling evolution under microgravity was observed during the experiment. It has been found that at the same heat flux, the bubbles of HFE7500 (which has smaller contact angle) grew faster and bigger, moved quickly on the heater surface, and were easier to merge into a central big bubble with other bubbles than that of distilled water. The whole process of bubbles coalescence from seven to one was recorded by using video camera. For distilled water (with bigger contact angle), the bubbles tended to keep at the nucleate location on heater surface, and the central big bubble evolved at its nucleate cite by absorbing smaller bubbles nearby. Compared with the bubbles under normal gravity, bubble radius of distilled water under microgravity was about 1.4 times bigger and of HFE7500 was about more than 6 times bigger till the end of experiment. At the beginning, pool boiling heat transfer of distilled water was advanced and then impeded under microgravity. As to HFE7500, the pool boiling impedes the heat transfer from heater to liquid under microgravity throughout the experiment.

Iron overload in a murine model of hereditary hemochromatosis is associated with accelerated progression of osteoarthritis under mechanical stress.

PubMed

Camacho, A; Simão, M; Ea, H-K; Cohen-Solal, M; Richette, P; Branco, J; Cancela, M L

2016-03-01

Hereditary hemochromatosis (HH) is a disease caused by mutations in the Hfe gene characterised by systemic iron overload and associated with an increased prevalence of osteoarthritis (OA) but the role of iron overload in the development of OA is still undefined. To further understand the molecular mechanisms involved we have used a murine model of HH and studied the progression of experimental OA under mechanical stress. OA was surgically induced in the knee joints of 10-week-old C57BL6 (wild-type) mice and Hfe-KO mice. OA progression was assessed using histology, micro CT, gene expression and immunohistochemistry at 8 weeks after surgery. Hfe-KO mice showed a systemic iron overload and an increased iron accumulation in the knee synovial membrane following surgery. The histological OA score was significantly higher in the Hfe-KO mice at 8 weeks after surgery. Micro CT study of the proximal tibia revealed increased subchondral bone volume and increased trabecular thickness. Gene expression and immunohistochemical analysis showed a significant increase in the expression of matrix metallopeptidase 3 (MMP-3) in the joints of Hfe-KO mice compared with control mice at 8 weeks after surgery. HH was associated with an accelerated development of OA in mice. Our findings suggest that synovial iron overload has a definite role in the progression of HH-related OA. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Correlation between HFE gene polymorphisms and increased risk of coronary artery disease among patients with type 2 diabetes in Iran.

PubMed

Saremi, Leila; Saremi, Marzieh; Lotfipanah, Shirin; İmani, Saber; Fu, Junjiang; Zhang, Tianyu

2016-04-19

Diabetes mellitus is a risk factor for cardiovascular diseases (CVDs), which are among the major causes of deaths in type 2 diabetes (T2D). The purpose of the present study was to determine the association of C282Y and H63D mutations in the HFE gene with increased risk of coronary artery disease (CAD) in T2D patients. Two hundred and ninety individuals were divided into two groups: a case group and a control group. Genomic DNA of peripheral venous blood cells was extracted and the HFE gene mutations were analyzed using the PCR-RFLP technique. Data analysis revealed a significant difference between the allele frequencies of H63D and C282Y mutations between the case group and the controls (P < 0.05). The relationships between the GA and GG genotypes in C282Y and H63D mutations in terms of fasting blood sugar (FBS), lipid profile (total cholesterol, triglycerides, high-density lipoproteins (HDL), low-density lipoproteins), body mass index (BMI), HbA1c, micro albuminuria, and creatine levels did not show a significant differences between the two groups (P > 0.05). Using a logistic regression model, BMI, FBS, HDL, and total cholesterol levels were significantly different with independent predictors of CVD (P < 0.05). Our results revealed a significant correlation between C282Y and H63D mutations and the development of CAD in T2D patients.

Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations

PubMed Central

Nelson, James E.; Brunt, Elizabeth M.; Kowdley, Kris V.

2012-01-01

Hepcidin regulation is linked to both iron and inflammatory signals and may influence iron loading in nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the relationships among HFE genotype, serum hepcidin level, hepatic iron deposition and histology in nonalcoholic fatty liver disease (NAFLD). SNP genotyping for C282Y (rs1800562) and H63D (rs1799945) HFE mutations was performed in 786 adult subjects in the NASH Clinical Research Network (CRN). Clinical, histologic, and laboratory data were compared using nonparametric statistics and multivariate logistic regression. NAFLD patients with C282Y, but not H63D mutations, had lower median serum hepcidin levels (57 vs 65 ng/ml, p=0.01) and higher mean hepatocellular (HC) iron grades (0.59 vs 0.28, p<0.001), compared to wild type (WT) subjects. Subjects with hepatic iron deposition had higher serum hepcidin levels than subjects without iron for all HFE genotypes (p<0.0001). Hepcidin levels were highest among patients with mixed HC/reticuloendothelial system cell (RES) iron deposition. H63D mutations were associated with higher steatosis grades and NAFLD activity scores (OR≥1.4, CI >1.0≤2.5, p≤0.041), compared to WT, but not with either HC or RES iron. NAFLD patients with C282Y mutations had less ballooning or NASH (OR ≤0.62, 95% CI >0.39<0.94, p≤0.024) compared to WT subjects. Conclusions Presence of C282Y mutations in patients with NAFLD is associated with greater HC iron deposition and decreased serum hepcidin levels and there is a positive relationship between hepatic iron stores and serum hepcidin level across all HFE genotypes. These data suggest that body iron stores are the major determinant of hepcidin regulation in NAFLD regardless of HFE genotype. A potential role for H63D mutations in NAFLD pathogenesis is possible through iron-independent mechanisms. PMID:22611049

Association between the HFE C282Y, H63D Polymorphisms and the Risks of Non-Alcoholic Fatty Liver Disease, Liver Cirrhosis and Hepatocellular Carcinoma: An Updated Systematic Review and Meta-Analysis of 5,758 Cases and 14,741 Controls

PubMed Central

Yin, Wei-Li; Wang, Feng-Mei; Han, Tao

2016-01-01

Background Conflicting results have been obtained for the association between two common polymorphisms (C282Y, H63D) of human HFE (hereditary hemochromatosis) gene and the risks of the liver diseases, including non-alcoholic fatty liver disease (NAFLD), liver cirrhosis and hepatocellular carcinoma (HCC). Methods An updated systematic review and meta-analysis was conducted to evaluate the potential role of HFE polymorphisms in the susceptibility to NAFLD, liver cirrhosis and HCC. After retrieving articles from online databases, eligible studies were enrolled according to the selection criteria. Stata/SE 12.0 software was utilized to perform the statistical analysis. Results In total, 43 articles with 5,758 cases and 14,741 controls were selected. Compared with the control group, a significantly increased risk of NAFLD was observed for the C282Y polymorphism in the Caucasian population under all genetic models and for the H63D polymorphism under the allele, heterozygote and dominant models (all OR>1, Passociation<0.05). However, no significant difference between liver cirrhosis cases and the control group was observed for HFE C282Y and H63D (all Passociation>0.05). In addition, we found that HFE C282Y was statistically associated with increased HCC susceptibility in the overall population, while H63D increased the odds of developing non-cirrhotic HCC in the African population (all OR>1, Passociation<0.05). Moreover, a positive association between compound heterozygosity for C282Y/H63D and the risk of NAFLD and HCC, but not liver cirrhosis, was observed. Conclusion Our meta-analysis provides evidence that the HFE C282Y and H63D polymorphisms confer increased genetic susceptibility to NAFLD and HCC but not liver cirrhosis. Additional well-powered studies are required to confirm our conclusion. PMID:27657935

Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.

PubMed

Ye, Qi; Kim, Jonghan

2016-06-01

Increased accumulation of manganese (Mn) in the brain is significantly associated with neurobehavioral deficits and impaired brain function. Airborne Mn has a high systemic bioavailability and can be directly taken up into the brain, making it highly neurotoxic. While Mn transport is in part mediated by several iron transporters, the expression of these transporters is altered by the iron regulatory gene, HFE. Mutations in the HFE gene are the major cause of the iron overload disorder, hereditary hemochromatosis, one of the prevalent genetic diseases in humans. However, whether or not HFE mutation modifies Mn-induced neurotoxicity has not been evaluated. Therefore, our goal was to define the role of HFE mutation in Mn deposition in the brain and the resultant neurotoxic effects after olfactory Mn exposure. Mice carrying the H67D HFE mutation, which is homologous to the H63D mutation in humans, and their control, wild-type mice, were intranasally instilled with MnCl2 with different doses (0, 0.2, 1.0 and 5.0 mg kg(-1)) daily for 3 days. Mn levels in the blood, liver and brain were determined using inductively-coupled plasma mass spectrometry (ICP-MS). H67D mutant mice showed significantly lower Mn levels in the blood, liver, and most brain regions, especially in the striatum, while mice fed an iron-overload diet did not. Moreover, mRNA expression of ferroportin, an essential exporter of iron and Mn, was up-regulated in the striatum. In addition, the levels of isoprostane, a marker of lipid peroxidation, were increased in the striatum after Mn exposure in wild-type mice, but were unchanged in H67D mice. Together, our results suggest that the H67D mutation provides decreased susceptibility to Mn accumulation in the brain and neurotoxicity induced by inhaled Mn.

Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload.

PubMed

Meroño, Tomás; Brites, Fernando; Dauteuille, Carolane; Lhomme, Marie; Menafra, Martín; Arteaga, Alejandra; Castro, Marcelo; Saez, María Soledad; Ballerga, Esteban González; Sorroche, Patricia; Rey, Jorge; Lesnik, Philippe; Sordá, Juan Andrés; Chapman, M John; Kontush, Anatol; Daruich, Jorge

2015-05-01

Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex- and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93%, P< 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n=7) presented a reduced β-cell function and insulin secretion compared with non-C282Y patients (n=11) (-58% and -73%, respectively, P< 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43±5; non-C282Y: 25±8; controls: 32±7%; P< 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23±5; non-C282Y: 39±10; controls: 26±4%; P< 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined.

HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity.

PubMed

Gurrin, Lyle C; Bertalli, Nadine A; Dalton, Gregory W; Osborne, Nicholas J; Constantine, Clare C; McLaren, Christine E; English, Dallas R; Gertig, Dorota M; Delatycki, Martin B; Nicoll, Amanda J; Southey, Melissa C; Hopper, John L; Giles, Graham G; Anderson, Gregory J; Olynyk, John K; Powell, Lawrie W; Allen, Katrina J

2009-07-01

The risk of hemochromatosis-related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population-based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis-related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE-genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild-types at baseline and follow-up (all P < 0.02) except for females who were premenopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow-up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 microg/L for compound heterozygotes and from 35 to 64 microg/L for wild-types (both P < 0.001). Male and female compound heterozygotes had a similar prevalence of hemochromatosis-related morbidity to wild-types. One of 82 males and zero of 95 females had documented iron overload-related disease. For male compound heterozygotes, mean iron indices do not change during middle age but for female compound heterozygotes menopause results in increased mean SF. Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload-related disease is rare.

Lymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivo.

PubMed

Costa, Mónica; Cruz, Eugénia; Oliveira, Susana; Benes, Vladimir; Ivacevic, Tomi; Silva, Maria João; Vieira, Inês; Dias, Francisco; Fonseca, Sónia; Gonçalves, Marta; Lima, Margarida; Leitão, Catarina; Muckenthaler, Martina U; Pinto, Jorge; Porto, Graça

2015-01-01

Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe-/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe-/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH.

Lymphocyte Gene Expression Signatures from Patients and Mouse Models of Hereditary Hemochromatosis Reveal a Function of HFE as a Negative Regulator of CD8+ T-Lymphocyte Activation and Differentiation In Vivo

PubMed Central

Costa, Mónica; Cruz, Eugénia; Oliveira, Susana; Benes, Vladimir; Ivacevic, Tomi; Silva, Maria João; Vieira, Inês; Dias, Francisco; Fonseca, Sónia; Gonçalves, Marta; Lima, Margarida; Leitão, Catarina; Muckenthaler, Martina U.; Pinto, Jorge; Porto, Graça

2015-01-01

Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe -/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe -/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe -/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH. PMID:25880808

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

Hugo, Jacques

The software application is called "HFE-Trace". This is an integrated method and tool for the management of Human Factors Engineering analyses and related data. Its primary purpose is to support the coherent and consistent application of the nuclear industry's best practices for human factors engineering work. The software is a custom Microsoft® Access® application. The application is used (in conjunction with other tools such as spreadsheets, checklists and normal documents where necessary) to collect data on the design of a new nuclear power plant from subject matter experts and other sources. This information is then used to identify potential systemmore » and functional breakdowns of the intended power plant design. This information is expanded by developing extensive descriptions of all functions, as well as system performance parameters, operating limits and constraints, and operational conditions. Once these have been verified, the human factors elements are added to each function, including intended operator role, function allocation considerations, prohibited actions, primary task categories, and primary work station. In addition, the application includes a computational method to assess a number of factors such as system and process complexity, workload, environmental conditions, procedures, regulations, etc.) that may shape operator performance. This is a unique methodology based upon principles described in NUREG/CR-3331 ("A methodology for allocating nuclear power plant control functions to human or automatic control") and it results in a semi-quantified allocation of functions to three or more levels of automation for a conceptual automation system. The aggregate of all this information is then linked to the Task Analysis section of the application where the existing information on all operator functions is transformed into task information and ultimately into design requirements for Human-System Interfaces and Control Rooms. This final step includes assessment of methods to prevent potential operator errors.« less

Riparian Vegetation Response to the March 2008 Short-Duration, High-Flow Experiment-Implications of Timing and Frequency of Flood Disturbance on Nonnative Plant Establishment Along the Colorado River Below Glen Canyon Dam

USGS Publications Warehouse

Ralston, Barbara E.

2010-01-01

Riparian plant communities exhibit various levels of diversity and richness. These communities are affected by flooding and are vulnerable to colonization by nonnative species. Since 1996, a series of three high-flow experiments (HFE), or water releases designed to mimic natural seasonal flooding, have been conducted at Glen Canyon Dam, Ariz., primarily to determine the effectiveness of using high flows to conserve sediment, a limited resource. These experiments also provide opportunities to examine the susceptibility of riparian plant communities to nonnative species invasions. The third and most recent HFE was conducted from March 5 to 9, 2008, and scientists with the U.S. Geological Survey's Grand Canyon Monitoring and Research Center examined the effects of high flows on riparian vegetation as part of the overall experiment. Total plant species richness, nonnative species richness, percent plant cover, percent organic matter, and total carbon measured from sediment samples were compared for Grand Canyon riparian vegetation zones immediately following the HFE and 6 months later. These comparisons were used to determine if susceptibility to nonnative species establishment varied among riparian vegetation zones and if the timing of the HFE affected nonnative plant establishment success. The 2008 HFE primarily buried vegetation rather than scouring it. Percent nonnative cover did not differ among riparian vegetation zones; however, in the river corridor affected by Glen Canyon Dam operations, nonnative species richness showed significant variation. For example, species richness was significantly greater immediately after and 6 months following the HFE in the hydrologic zone farthest away from the shoreline, the area that represents the oldest riparian zone within the post-dam riparian area. In areas closer to the river channel, tamarisk (Tamarix ramosissima X chinensis) seedling establishment occurred (<2 percent cover) in 2008 but not to the extent reported in either 2000, a year when experimental summer flows coincided with tamarisk seed production, or in 1986, a year following several years of sustained flooding. The results from the 2008 HFE suggest that riparian vegetation zones subject to intermittent disturbance and near the river under normal dam operations are more susceptible to nonnative species introductions following a disturbance. This study also finds that the timing of an HFE affects the types of species that can become established. For example, HFEs conducted in March are associated with reduced tamarisk seedling establishment compared to disturbances later in the season. Additionally, early season, short-duration flooding that results in vegetation burial may favor clonal species. Along the Colorado River many of these clonal species are native; these species include arrowweed (Pluchea sericea), coyote willow (Salix exigua), and rivercane (Phragmites australis).

Social and personal normative influences on healthcare professionals to use information technology: Towards a more robust social ergonomics

PubMed Central

Holden, Richard J

2011-01-01

Social structures and processes are increasingly acknowledged and studied within the human factors/ergonomics (HFE) discipline. At the same time, social phenomena are rarely the focus of HFE work, leaving a knowledge gap. The present study directly addresses social and personal normative forces that influence technology use and performance. Social and personal normative influence to use electronic health records (EHR) were investigated using semi-structured qualitative interviews with 20 attending physicians at two US hospitals. Analyses used a comprehensive framework based on leading social scientific theories and revealed numerous sources of influence, including hospital administration, colleagues, patients, clinical and professional groups, government, and one’s self. Influence was achieved through different means and invoked different psychological processes. Findings motivate a new view of professionals’ technology use as a highly social process occurring in a social context, with implications for research, policy, design, and in general the development of a robust social ergonomics. PMID:23066349

Application of participatory ergonomics to the redesign of the family-centred rounds process.

PubMed

Xie, Anping; Carayon, Pascale; Cox, Elizabeth D; Cartmill, Randi; Li, Yaqiong; Wetterneck, Tosha B; Kelly, Michelle M

2015-01-01

Participatory ergonomics (PE) can promote the application of human factors and ergonomics (HFE) principles to healthcare system redesign. This study applied a PE approach to redesigning the family-centred rounds (FCR) process to improve family engagement. Various FCR stakeholders (e.g. patients and families, physicians, nurses, hospital management) were involved in different stages of the PE process. HFE principles were integrated in both the content (e.g. shared mental model, usability, workload consideration, systems approach) and process (e.g. top management commitment, stakeholder participation, communication and feedback, learning and training, project management) of FCR redesign. We describe activities of the PE process (e.g. formation and meetings of the redesign team, data collection activities, intervention development, intervention implementation) and present data on PE process evaluation. To demonstrate the value of PE-based FCR redesign, future research should document its impact on FCR process measures (e.g. family engagement, round efficiency) and patient outcome measures (e.g. patient satisfaction).

Application of participatory ergonomics to the redesign of the family-centered rounds process

PubMed Central

Xie, Anping; Carayon, Pascale; Cox, Elizabeth D.; Cartmill, Randi; Li, Yaqiong; Wetterneck, Tosha B.; Kelly, Michelle M.

2015-01-01

Participatory ergonomics (PE) can promote the application of human factors and ergonomics (HFE) principles to healthcare system redesign. This study applied a PE approach to redesigning the family-centered rounds (FCR) process to improve family engagement. Various FCR stakeholders (e.g., patients and families, physicians, nurses, hospital management) were involved in different stages of the PE process. HFE principles were integrated in both the content (e.g., shared mental model, usability, workload consideration, systems approach) and process (e.g., top management commitment, stakeholder participation, communication and feedback, learning and training, project management) of FCR redesign. We describe activities of the PE process (e.g., formation and meetings of the redesign team, data collection activities, intervention development, intervention implementation) and present data on PE process evaluation. To demonstrate the value of PE-based FCR redesign, future research should document its impact on FCR process measures (e.g., family engagement, round efficiency) and patient outcome measures (e.g., patient satisfaction). PMID:25777042

Social and personal normative influences on healthcare professionals to use information technology: Towards a more robust social ergonomics.

PubMed

Holden, Richard J

2012-09-01

Social structures and processes are increasingly acknowledged and studied within the human factors/ergonomics (HFE) discipline. At the same time, social phenomena are rarely the focus of HFE work, leaving a knowledge gap. The present study directly addresses social and personal normative forces that influence technology use and performance. Social and personal normative influence to use electronic health records (EHR) were investigated using semi-structured qualitative interviews with 20 attending physicians at two US hospitals. Analyses used a comprehensive framework based on leading social scientific theories and revealed numerous sources of influence, including hospital administration, colleagues, patients, clinical and professional groups, government, and one's self. Influence was achieved through different means and invoked different psychological processes. Findings motivate a new view of professionals' technology use as a highly social process occurring in a social context, with implications for research, policy, design, and in general the development of a robust social ergonomics.

Implicating the H63D polymorphism in the HFE gene in increased incidence of solid cancers: a meta-analysis.

PubMed

Shen, L L; Gu, D Y; Zhao, T T; Tang, C J; Xu, Y; Chen, J F

2015-10-29

A number of previous studies have demonstrated that the HFE H63D polymorphism is associated with increased risk of incidence multiple types of cancer, including colorectal cancer, breast cancer, liver cancer, pancreatic cancer, and gynecological malignant tumors. However, the clinical outcomes were inconsistent. Therefore, this meta-analysis was conducted to summarize the effect of the H63D variant on the incidence of solid tumor. PubMed and EMBASE databases were searched for articles associating the HFE H63D polymorphism with cancer risk. The relationships were evaluated by calculating the pooled odds ratios (ORs) with 95% confidence intervals (CIs). A total of 28 studies, including 7728 cancer cases and 11,895 controls, were identified. Statistically significant associations were identified between the HFE H63D polymorphism and solid cancer risk (CG vs CC, OR = 1.14, 95%CI = 1.07-1.23, P < 0.001; GG vs CC, OR = 1.28, 95%CI = 1.06-1.55, P = 0.010; CG/GG vs CC, OR = 1.16, 95%CI = 1.08-1.24, P < 0.001; GG vs CC/CG, OR = 1.24, 95%CI = 1.02-1.49, P = 0.027). In the subgroup analysis, we illustrated the effect of the H63D polymorphism on hepatocellular carcinoma and pancreatic cancer risk, particularly in the Asian and African subgroups; however, this was not observed in gynecological malignant tumors. In summary, this analysis provided strong evidence that the HFE H63D polymorphism may play a critical role in the increased aggressiveness of hepatocellular carcinoma and pancreatic cancer.

Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal).

PubMed

Spínola, Carla; Brehm, António; Spínola, Hélder

2011-01-01

Hereditary HFE Hemochromatosis is an inherited disorder of iron metabolism that results from mutations in the HFE gene. Almost all patients with hereditary hemochromatosis show a C282Y mutation in homozygosity or in compound heterozygosity with H63D. Also, the mutation S65C has been shown to be associated to a milder iron overload. Since allele and genotype frequencies of these three variants of the HFE gene vary between populations, the determination of their prevalence in Madeira Island will clarify the population susceptibility to hereditary hemochromatosis. One hundred and fifty-four samples from Madeira Island were genotyped for the three most common HFE gene mutations, H63D, C282Y, and S65C, by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results have shown a prevalence of 20.5%, 0.33%, and 1% for H63D, C282Y, and S65C, respectively. Accordingly to our estimates, both genotypes associated to hereditary hemochromatosis, C282Y homozygotes and C282/H63D compound heterozygotes, could be present in Madeira Island population in 1,648 individuals, which represents 0.65% of the total population.

Cross Sections for Electron-Impact Dissociation of Alternative Etching Gas, C3HF7O

NASA Astrophysics Data System (ADS)

Tanaka, Hideyuki; Toyoda, Hirotaka; Sugai, Hideo

1998-09-01

The search for alternative for perfluorocarbon gases from the environmental point of view has resulted in a new etching gas, C3HF7O (1,2,2,2-tetrafluoroethyl-trifluoromethyl ether, abbreviated as HFE-227). In this paper, the first measurement of the absolute cross sections for the dissociation of HFE-227, is reported.The neutral dissociation is measured from the threshold to 250 eV by appearance mass spectrometry in a dual electron beam device.The threshold energies for the neutral dissociation into CF, CF2 and CF3 are 14.7, 12.5 and 11.2 eV, respectively.The cross sections for the dissociation from HFE-227 into CF3 and CF are larger than those from c-C4F8 (octafluorocyclobutane), but not for the dissociation into CF2.Besides the neutral dissociation, the cross sections for the dissociative ionization of HFE-227 are extensively measured for the formation of twelve ionic species, i.e., CO+, CHO+, CF+, CHF+, CFO+, CF2+, CHF2+, CF3+, CHF3+, C2HF2O+, C2HF4+ and C2HF4O+.

The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model

PubMed Central

Sumizono, Megumi; Otsuka, Shotaro; Terashi, Takuto; Nakanishi, Kazuki; Ueda, Koki; Takada, Seiya; Kikuchi, Kiyoshi

2018-01-01

Background Exercise regimens are established methods that can relieve neuropathic pain. However, the relationship between frequency and intensity of exercise and multiple cellular responses of exercise-induced alleviation of neuropathic pain is still unclear. We examined the influence of exercise frequency on neuropathic pain and the intracellular responses in a sciatic nerve chronic constriction injury (CCI) model. Materials and methods Rats were assigned to four groups as follows: CCI and high-frequency exercise (HFE group), CCI and low-frequency exercise (LFE group), CCI and no exercise (No-Ex group), and naive animals (control group). Rats ran on a treadmill, at a speed of 20 m/min, for 30 min, for 5 (HFE) or 3 (LFE) days a week, for a total of 5 weeks. The 50% withdrawal threshold was evaluated for mechanical sensitivity. The activation of glial cells (microglia and astrocytes), expression of brain-derived neurotrophic factor (BDNF) and μ-opioid receptor in the spinal dorsal horn and endogenous opioid in the midbrain were examined using immunohistochemistry. Opioid receptor antagonists (naloxone) were administered using intraperitoneal injection. Results The development of neuropathic pain was related to the activation of glial cells, increased BDNF expression, and downregulation of the μ-opioid receptor in the ipsilateral spinal dorsal horn. In the No-Ex group, neuropathic pain showed the highest level of mechanical hypersensitivity at 2 weeks, which improved slightly until 5 weeks after CCI. In both exercise groups, the alleviation of neuropathic pain was accelerated through the regulation of glial activation, BDNF expression, and the endogenous opioid system. The expression of BDNF and endogenous opioid in relation to exercise-induced alleviation of neuropathic pain differed in the HFE and LFE groups. The effects of exercise-induced alleviation of mechanical hypersensitivity were reversed by the administration of naloxone. Conclusion The LFE and HFE program reduced neuropathic pain. Our findings indicated that aerobic exercise-induced alleviated neuropathic pain through the regulation of glial cell activation, expression of BDNF in the ipsilateral spinal dorsal horn, and the endogenous opioid system. PMID:29445295

Influence of diet, menstruation and genetic factors on iron status: a cross-sectional study in Spanish women of childbearing age.

PubMed

Blanco-Rojo, Ruth; Toxqui, Laura; López-Parra, Ana M; Baeza-Richer, Carlos; Pérez-Granados, Ana M; Arroyo-Pardo, Eduardo; Vaquero, M Pilar

2014-03-06

The aim of this study was to investigate the combined influence of diet, menstruation and genetic factors on iron status in Spanish menstruating women (n = 142). Dietary intake was assessed by a 72-h detailed dietary report and menstrual blood loss by a questionnaire, to determine a Menstrual Blood Loss Coefficient (MBLC). Five selected SNPs were genotyped: rs3811647, rs1799852 (Tf gene); rs1375515 (CACNA2D3 gene); and rs1800562 and rs1799945 (HFE gene, mutations C282Y and H63D, respectively). Iron biomarkers were determined and cluster analysis was performed. Differences among clusters in dietary intake, menstrual blood loss parameters and genotype frequencies distribution were studied. A categorical regression was performed to identify factors associated with cluster belonging. Three clusters were identified: women with poor iron status close to developing iron deficiency anemia (Cluster 1, n = 26); women with mild iron deficiency (Cluster 2, n = 59) and women with normal iron status (Cluster 3, n = 57). Three independent factors, red meat consumption, MBLC and mutation C282Y, were included in the model that better explained cluster belonging (R2 = 0.142, p < 0.001). In conclusion, the combination of high red meat consumption, low menstrual blood loss and the HFE C282Y mutation may protect from iron deficiency in women of childbearing age. These findings could be useful to implement adequate strategies to prevent iron deficiency anemia.

Normal accidents: human error and medical equipment design.

PubMed

Dain, Steven

2002-01-01

High-risk systems, which are typical of our technologically complex era, include not just nuclear power plants but also hospitals, anesthesia systems, and the practice of medicine and perfusion. In high-risk systems, no matter how effective safety devices are, some types of accidents are inevitable because the system's complexity leads to multiple and unexpected interactions. It is important for healthcare providers to apply a risk assessment and management process to decisions involving new equipment and procedures or staffing matters in order to minimize the residual risks of latent errors, which are amenable to correction because of the large window of opportunity for their detection. This article provides an introduction to basic risk management and error theory principles and examines ways in which they can be applied to reduce and mitigate the inevitable human errors that accompany high-risk systems. The article also discusses "human factor engineering" (HFE), the process which is used to design equipment/ human interfaces in order to mitigate design errors. The HFE process involves interaction between designers and endusers to produce a series of continuous refinements that are incorporated into the final product. The article also examines common design problems encountered in the operating room that may predispose operators to commit errors resulting in harm to the patient. While recognizing that errors and accidents are unavoidable, organizations that function within a high-risk system must adopt a "safety culture" that anticipates problems and acts aggressively through an anonymous, "blameless" reporting mechanism to resolve them. We must continuously examine and improve the design of equipment and procedures, personnel, supplies and materials, and the environment in which we work to reduce error and minimize its effects. Healthcare providers must take a leading role in the day-to-day management of the "Perioperative System" and be a role model in promoting a culture of safety in their organizations.

Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations.

PubMed

Nelson, James E; Brunt, Elizabeth M; Kowdley, Kris V

2012-11-01

Hepcidin regulation is linked to both iron and inflammatory signals and may influence iron loading in nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the relationships among HFE genotype, serum hepcidin level, hepatic iron deposition, and histology in nonalcoholic fatty liver disease (NAFLD). Single-nucleotide polymorphism genotyping for C282Y (rs1800562) and H63D (rs1799945) HFE mutations was performed in 786 adult subjects in the NASH Clinical Research Network (CRN). Clinical, histologic, and laboratory data were compared using nonparametric statistics and multivariate logistic regression. NAFLD patients with C282Y, but not H63D mutations, had lower median serum hepcidin levels (57 versus 65 ng/mL; P = 0.01) and higher mean hepatocellular (HC) iron grades (0.59 versus 0.28; P < 0.001), compared to wild-type (WT) subjects. Subjects with hepatic iron deposition had higher serum hepcidin levels than subjects without iron for all HFE genotypes (P < 0.0001). Hepcidin levels were highest among patients with mixed HC/reticuloendothelial system cell (RES) iron deposition. H63D mutations were associated with higher steatosis grades and NAFLD activity scores (odds ratio [OR], ≥1.4; 95% confidence interval [CI]: >1.0, ≤2.5; P ≤ 0.041), compared to WT, but not with either HC or RES iron. NAFLD patients with C282Y mutations had less ballooning or NASH (OR, ≤0.62; 95% CI: >0.39, <0.94; P ≤ 0.024), compared to WT subjects. The presence of C282Y mutations in patients with NAFLD is associated with greater HC iron deposition and decreased serum hepcidin levels, and there is a positive relationship between hepatic iron stores and serum hepcidin level across all HFE genotypes. These data suggest that body iron stores are the major determinant of hepcidin regulation in NAFLD, regardless of HFE genotype. A potential role for H63D mutations in NAFLD pathogenesis is possible through iron-independent mechanisms. Copyright © 2012 American Association for the Study of Liver Diseases.

Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes.

PubMed

Kennedy, Amy E; Kamdar, Kala Y; Lupo, Philip J; Okcu, M Fatih; Scheurer, Michael E; Baum, Marianna K; Dorak, M Tevfik

2014-09-01

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI=0.83-2.35), which increased to 2.96 (95% CI=1.29-6.80) in the presence of a particular TFRC genotype for rs3817672 (P interaction=0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR=2.54, 95% CI=1.05-6.12; P interaction with ethnicity=0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR=1.52-2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR=2.0 per incremental change, 95% CI=1.29-3.12; P=0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

Liver steatosis correlates with iron overload but not with HFE gene mutations in chronic hepatitis C.

PubMed

Sikorska, Katarzyna; Stalke, Piotr; Romanowski, Tomasz; Rzepko, Robert; Bielawski, Krzysztof Piotr

2013-08-01

Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non-alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serum markers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations.

HFE gene C282Y, H63D and S65C mutations frequency in the Transylvania region, Romania.

PubMed

Trifa, Adrian P; Popp, Radu A; Militaru, Mariela S; Farcaş, Marius F; Crişan, Tania O; Gana, Ionuţ; Cucuianu, Andrei; Pop, Ioan V

2012-06-01

HFE-associated haemochromatosis is one of the most frequent autosomal recessive disorders in the Caucasian population. Although most of the cases are homozygous individuals for the C282Y mutation, another two mutations, H63D and S65C, have been reported to be associated with milder forms of the disease. This study was a first attempt to evaluate the distribution of these HFE gene mutations in the Transylvania region. Two-hundred and twenty-five healthy, unrelated volunteers originating from the Transylvania region, Romania, were screened for the HFE gene C282Y, H63D and S65C mutations, using molecular genetics assays (Polymerase Chain Reaction-Restriction Fragments Length Polymorphism). For the C282Y mutation, 7 heterozygotes (3.1%) were found, but no homozygous individual. In the case of the H63D mutation, 40 heterozygotes (17.8%) and 4 homozygotes (1.75%) for the mutant allele were evidenced. We found a compound heterozygous genotype (C282Y/H63D) in one individual (0.45%). Thus, the allele frequencies of the C282Y and H63D were 1.75% and 10.9%, respectively. Three individuals (1.3%) were found to harbour the S65C mutation in a heterozygous state, but none in a homozygous state: the allele frequency of the mutant allele was 0.75%. The distribution of the HFE gene C282Y, H63D and S65C mutations found in our group matches the tendencies observed in other European countries: a decreasing gradient from Northern to Southern Europe for the C282Y mutation; high frequency for the H63D mutation, and low frequency for the S65C mutation in most of the countries.

Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients.

PubMed

van der Schoot, Gabriela G F; Westerink, Nico-Derk L; Lubberts, Sjoukje; Nuver, Janine; Zwart, Nynke; Walenkamp, Annemiek M E; Wempe, Johan B; Meijer, Coby; Gietema, Jourik A

2016-05-01

Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic variants of the HFE gene induces altered iron metabolism and may contribute to toxicity. We investigated the association between two common allelic variants of the HFE gene, H63D and C282Y, with development of pulmonary and renal toxicity during and after treatment with bleomycin- and cisplatin-containing chemotherapy. In 369 testicular cancer patients treated with bleomycin and cisplatin at the University Medical Center Groningen between 1978 and 2006, H63D and/or C282Y genotypes were determined with an allelic discrimination assay. Data were collected on development of BIP, pulmonary function parameters, renal function, and survival. BIP developed more frequently in patients who were heterozygote (16 in 75, 21%) and homozygote (2 in 4, 50%) for the H63D variant, compared with those who had the HFE wild-type gene (31 in 278, 11%) (p = 0.012). Overall survival, testicular cancer-related survival, and change in renal function were not associated with the H63D variant. We observed an association between presence of one or both H63D alleles and development of BIP in testicular cancer patients treated with bleomycin combination chemotherapy. In patients heterozygote and homozygote for the H63D variant, BIP occurred more frequently compared with wild-type patients. When validated and confirmed, HFE H63D genotyping may be used to identify patients with increased risk for pulmonary bleomycin toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

White blood cells and subtypes in HFE p.C282Y and wild-type homozygotes in the Hemochromatosis and Iron Overload Screening Study.

PubMed

Barton, James C; Barton, J Clayborn; Acton, Ronald T

2017-03-01

The major histocompatibility complex is linked to white blood cell (WBC) and lymphocyte counts in subjects unselected for HFE genotypes. We compared age, sex, body mass index, total WBC and subtypes (neutrophils, lymphocytes, monocytes, eosinophils, basophils) (Beckman Coulter® Gen-S), transferrin saturation, and serum ferritin of HFE p.C282Y and wild-type (p.C282Y, p.H63D negative) homozygotes without acquired conditions that influence WBC counts. We performed regressions on WBC and subtypes. There were 161 p.C282Y homozygotes (45.3% men) and 221 wild-type homozygotes (40.3% men). Mean WBC of men and women and between HFE genotypes were similar. Mean lymphocytes were higher in male p.C282Y homozygotes: 1.6×10 9 /L [95% confidence interval: 1.5,1.7] vs. 1.4 [1.3,1.5], p=0.0002. Mean lymphocytes and basophils were higher in female p.C282Y homozygotes: 1.6 [1.5,1.7] vs. 1.4 [1.3,1.5], p=0.0002; and 0.065 [0.059,0.071] vs. 0.052 [0.051,0.054], p=0.0001, respectively. Transferrin saturation was associated with neutrophils (negative; p=0.0163). Age was associated with lymphocytes (negative; p=0.0003) and monocytes (positive; p<0.0001). Regressions on lymphocytes and basophils revealed positive associations with p.C282Y homozygosity (p=0.0043 and 0.0003, respectively). There were significant positive associations of neutrophils, lymphocytes, monocytes, and eosinophils. We conclude that HFE p.C282Y homozygosity is significantly associated with lymphocyte and basophil counts. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical expression of C282Y homozygous HFE haemochromatosis at 14 years of age.

PubMed

Rossi, Enrico; Wallace, Daniel F; Subramaniam, V Nathan; St Pierre, Timothy G; Mews, Catherine; Jeffrey, Gary P

2006-05-01

A 14-year-old boy who presented with debilitating lethargy was shown to have an elevated serum ferritin of 572 microg/L and a C282Y homozygous HFE genotype. Liver iron concentration was measured non-invasively by magnetic resonance imaging, which revealed a liver iron concentration of 59 micromol/g dry weight (children's reference range < 14). The early phenotypic expression was further investigated by screening genomic DNA for the presence of co-inherited mutations in genes responsible for non-HFE haemochromatosis. Coding regions and splice sites in genes encoding hepcidin and haemojuvelin were sequenced and previously described mutations in ferroportin 1 and transferrin receptor 2 genes were screened. Although no mutations were found, the most likely cause for the early expression is the presence of novel mutations or gene(s).

Ergonomic Evaluation of the Foot Restraint Equipment Device (FRED)

NASA Technical Reports Server (NTRS)

Whitmore, Mihriban; Chmielewski, Cindy; Qazi, A. S.; Mount, Francis

1999-01-01

Within the scope of the Microgravity Workstation and Restraint Evaluation project, funded by the NASA Headquarters Life Sciences Division, evaluations were proposed to be conducted in ground, KC-135, and/or Shuttle environments to investigate the human factors engineering (HFE) issues concerning confined/unique workstations, including crew restraint requirements. As part of these evaluations, KC-135 flights were conducted to investigate user/ workstation/ restraint integration for microgravity use of the FRED with the RMS workstation. This evaluation was a pre-cursor to Detailed Supplementary Objective (DSO) - 904 on STS-88. On that mission, a small-statured astronaut will be using the FRED restraint while working at the Aft RMS workstation. The DSO will collect video for later posture analyses, as well as subjective data in the form of an electronic questionnaire. This report describes the current FRED KC-135 evaluations. The primary objectives were to evaluate the usability of the FRED and to verify the DSO in-flight setup. The restraint interface evaluation consisted of four basic areas of restraint use: 1) adjustability; 2) general usability and comfort; 3) usability at the RMS workstation; and 4) assembly and disassembly.

Recognizing nurse stakeholder dissonance as a critical determinant of patient safety in new healthcare information technologies.

PubMed

Samaras, Elizabeth A; Real, Sara D; Curtis, Amber M; Meunier, Tessa S

2012-01-01

Proper identification of all stakeholders and the comprehensive assessment of their evolving and often conflicting Needs, Wants, and Desires (NWDs) is a fundamental principle of human factors science and human-centered systems engineering; it is not yet a consistent element in development and deployment of new health information technologies (HIT). As the single largest group of healthcare professionals, nurses are critical stakeholders for these new technologies. Careful analysis can reveal nurse stakeholder dissonance (NSD) when integrating new technologies into the healthcare environment. Stakeholder dissonance is a term that describes the conflict between the NWDs of different stakeholders which, if left unresolved, can result in dissatisfaction, workarounds, errors, and threats to patient safety. Three case studies drawn from the authors' experience in a variety of acute-care settings where new HITs have been recently deployed are examined to illustrate the concept of NSD. Conflicting NWDs, other stakeholders, and possible root causes of the NSD are analyzed and mapped to threats to patient safety. Lessons learned, practical guidance for anticipating, identifying, and mitigating NSD, future research and implications for HFE and nursing practice are discussed.

Iron Overload Accelerates the Progression of Diabetic Retinopathy in Association with Increased Retinal Renin Expression.

PubMed

Chaudhary, Kapil; Promsote, Wanwisa; Ananth, Sudha; Veeranan-Karmegam, Rajalakshmi; Tawfik, Amany; Arjunan, Pachiappan; Martin, Pamela; Smith, Sylvia B; Thangaraju, Muthusamy; Kisselev, Oleg; Ganapathy, Vadivel; Gnana-Prakasam, Jaya P

2018-02-14

Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Increased iron accumulation is associated with several degenerative diseases. However, there are no reports on the status of retinal iron or its implications in the pathogenesis of DR. In the present study, we found that retinas of type-1 and type-2 mouse models of diabetes have increased iron accumulation compared to non-diabetic retinas. We found similar iron accumulation in postmortem retinal samples from human diabetic patients. Further, we induced diabetes in HFE knockout (KO) mice model of genetic iron overload to understand the role of iron in the pathogenesis of DR. We found increased neuronal cell death, vascular alterations and loss of retinal barrier integrity in diabetic HFE KO mice compared to diabetic wildtype mice. Diabetic HFE KO mouse retinas also exhibited increased expression of inflammation and oxidative stress markers. Severity in the pathogenesis of DR in HFE KO mice was accompanied by increase in retinal renin expression mediated by G-protein-coupled succinate receptor GPR91. In light of previous reports implicating retinal renin-angiotensin system in DR pathogenesis, our results reveal a novel relationship between diabetes, iron and renin-angiotensin system, thereby unraveling new therapeutic targets for the treatment of DR.

Molecular epidemiology of HFE gene polymorphic variants (C282Y, H63D and S65C) in the population of Espírito Santo, Brazil.

PubMed

Alves, L N R; Santos, E V W; Stur, E; Silva Conforti, A M A; Louro, I D

2016-04-27

Hereditary hemochromatosis (HH) is an autosomal recessive disorder that leads to progressive iron accumulation and may cause cirrhosis, hepatocellular carcinoma, diabetes, and heart failure. Most cases of HH have been linked to mutations in genes associated with iron homeostasis. There have been three major variants in the high Fe (HFE) gene associated with the disease: C282Y, H63D and S65C. In this context, we aimed to evaluate the prevalence of the polymorphic variants (C282Y, H63D and S65C) of the HFE gene in the population of the Espírito Santo State (ES), Brazil by analyzing three different groups: general population (N = 120), Pomeranian descendants (N = 59), and patients with HH (N = 20). Using genomic DNA extracted from peripheral blood, polymorphic variant identification was performed by polymerase chain reaction-restriction fragment length polymorphism. Statistically significant differences were observed for genotype distribution of C282Y (P < 0.001) and H63D (P = 0.013) between the general population and the patients diagnosed with HH. This is the first study to analyze HFE gene allele frequencies for the general population, Pomeranian subpopulation, and patients with HH of ES, Brazil.

High resolution melting analysis to genotype the most common variants in the HFE gene.

PubMed

Marotta, Roberta V; Turri, Olivia; Morandi, Antonella; Murano, Manuela; d'Eril, Gianlodovico Melzi; Biondi, Maria Luisa

2011-09-01

High resolution melting (HRM) analysis of PCR amplicons was recently introduced as a closed-tube, rapid, and inexpensive method of genotyping. This study evaluated this system as an option for detecting the three most common mutations in the HFE gene (C282Y, H63D, S65C), accounting for the main form of hereditary haemochromatosis. Ninety samples, previously screened by direct sequencing, and 27 controls were used. The analysis were performed on the Rotor Gene Q, using the commercial HRM mix containing the Eva Green dye (Qiagen). Specific primers allowed the amplification of the regions of interest in the HFE gene. Following amplification, a HRM analysis was conducted to detect DNA variants. The thermal denaturation profiles of the samples were compared with those of the controls. One hundred percent of heterozygous and homozygous samples were readily identified. Heterozygotes were easily identified because heteroduplexes altered the shape of the melting curves, but significant differences were also present in the melting curves of the homozygous carries compared with those of the wild-type subjects. HRM analysis is an appealing technology for HFE gene screening. It is a robust technique that can be widely adopted in diagnostic laboratories to facilitate gene mutation screening.

Common founder effects of hereditary hemochromatosis, Wilson´s disease, the long QT syndrome and autosomal recessive deafness caused by two novel mutations in the WHRN and TMC1 genes.

PubMed

Olsson, K Sigvard; Wålinder, Olof; Jansson, Ulf; Wilbe, Maria; Bondeson, Marie-Louise; Stattin, Eva-Lena; Raha-Chowdhury, Ruma; Williams, Roger

2017-01-01

Genealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p. C282Y mutation is inherited with other recessive disorders such as Wilson´s disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation ( KCNQ1 /p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL).Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree. LQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing. Of nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder ( b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjällsjö river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of the late 16 th century. One was of Swedish origin carrying the WHRN, c.1977delC, (p.S660Afs*30) mutation, the other was a TMC1 (NM_138691),c.1814T>C,(p.L605P) mutation, possibly of Finnish origin. Deep human HFE genealogies show HFE to be associated with other genetic disorders like Wilson´s disease, LQTS, JLNS, and autosomal recessive hearing loss. Two new homozygous HL mutations in WHRN /p.S660Afs*30 and TMC1/ p.L605P were identified,none of them previously reported from Scandinavia. The rarity of JLNS was possibly caused by miscarriage or intrauterine death. Most hearing loss (81.7%) was seen after 1844 when first cousin marriages were permitted. However, only 10 (10.3%) came from 1 st cousin unions and only 2 (2.0 %) was born out of wedlock.

[Analysis of H63D mutation in hemochromatosis (HFE) gene in populations of central Eurasia].

PubMed

Khusainova, R I; Khusnutdinova, N N; Litvinov, S S; Khusnutdinova, E K

2013-02-01

An analysis of the frequency of H63D (c. 187C>G) mutations in the HFEgene in 19 populations from Central Eurasia demonstrated that the distribution of the mutation in the region of interest was not uniform and that there were the areas of H63D accumulation. The investigation of three polymorphic variants, c.340+4T>C (rs2071303, IVS2(+4)T>C), c.893-44T>C (rs1800708, IVS4(-44)T>C), and c.1007-47G>A (rs1572982, IVS5(-47)A>G), in the HFE gene in individuals homozygous for H63D mutations in the HFE gene revealed the linkage of H63D with three haplotypes, *CTA, *TG, and *TTA. These findings indicated the partial spread of the mutation in Central Eurasia from Western Europe, as well as the possible repeated appearance of the mutation on the territory on interest.

Effects of the 2008 high-flow experiment on water quality in Lake Powell and Glen Canyon Dam releases, Utah-Arizona

USGS Publications Warehouse

Vernieu, William S.

2010-01-01

Under the direction of the Secretary of the Interior, the U.S. Geological Survey`s Grand Canyon Monitoring and Research Center (GCMRC) conducted a high-flow experiment (HFE) at Glen Canyon Dam (GCD) from March 4 through March 9, 2008. This experiment was conducted under enriched sediment conditions in the Colorado River within Grand Canyon and was designed to rebuild sandbars, aid endangered humpback chub (Gila cypha), and benefit various downstream resources, including rainbow trout (Oncorhynchus mykiss), the aquatic food base, riparian vegetation, and archaeological sites. During the experiment, GCD discharge increased to a maximum of 1,160 m3/s and remained at that rate for 2.5 days by near-capacity operation of the hydroelectric powerplant at 736 m3/s, augmented by discharge from the river outlet works (ROW) at 424 m3/s. The ROW releases water from Lake Powell approximately 30 m below the powerplant penstock elevation and bypasses the powerplant turbines. During the HFE, the surface elevation of Lake Powell was reduced by 0.8 m. This report describes studies that were conducted before and after the experiment to determine the effects of the HFE on (1) the stratification in Lake Powell in the forebay immediately upstream of GCD and (2) the water quality of combined GCD releases and changes that occurred through the tailwater below the dam. The effects of the HFE to the water quality and stratigraphy in the water column of the GCD forebay and upstream locations in Lake Powell were minimal, compared to those during the beach/habitat-building flow experiment conducted in 1996, in which high releases of 1,273 m3/s were sustained for a 9-day period. However, during the 2008 HFE, there was evidence of increased advective transport of reservoir water at the penstock withdrawal depth and subsequent mixing of this withdrawal current with water above and below this depth. Reservoir hydrodynamics during the HFE period were largely being controlled by a winter inflow density current, which was moving through the deepest portion of the reservoir and approaching GCD near the end of the experiment. Compared to the beach/habitat-building flow experiment of 1996, the 2008 HFE had less affect on the reservoir because of the decreased volume of discharge from the dam and the different behavior of the winter inflow density current. The operation of the ROW increased the dissolved oxygen (DO) concentration of GCD releases and resulted in DO supersaturation at higher release volumes. The jets of water discharged from the ROW caused these increases. Elevated DO concentrations persisted through the tailwater of the dam to Lees Ferry. At maximum ROW operation, downstream DO concentrations increased to approximately 120 percent of saturation.

HFE gene mutation and oxidative damage biomarkers in patients with myelodysplastic syndromes and its relation to transfusional iron overload: an observational cross-sectional study.

PubMed

De Souza, Geane Felix; Ribeiro, Howard Lopes; De Sousa, Juliana Cordeiro; Heredia, Fabíola Fernandes; De Freitas, Rivelilson Mendes; Martins, Manoel Ricardo Alves; Gonçalves, Romélia Pinheiro; Pinheiro, Ronald Feitosa; Magalhães, Silvia Maria Meira

2015-04-03

A relation between transfusional IOL (iron overload), HFE status and oxidative damage was evaluated. An observational cross-sectional study involving 87 healthy individuals and 78 patients with myelodysplastic syndromes (MDS) with and without IOL, seen at University Hospital of the Federal University of Ceará, Brazil, between May 2010 and September 2011. IOL was defined using repeated measures of serum ferritin ≥1000 ng/mL. Variations in the HFE gene were investigated using PCR/restriction fragment length polymorphism (RFLP). The biomarkers of oxidative stress (plasmatic malonaldehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD)) were determined by spectrophotometry. The HFE gene variations were identified in 24 patients (30.77%) and 5 volunteers (5.74%). The H63D variant was observed in 35% and the C282Y variant as heterozygous in 5% of patients with MDS with IOL. One patient showed double heterozygous variant (C282Y/H63D) and serum ferritin of 11,649 ng/mL. In patients without IOL, the H63D variant was detected in 29.34%. Serum MDA levels were highest in patients with MDS with IOL, with a significant difference when compared with patients without IOL and healthy volunteers, pointing to the relationship between IOL and oxidative stress. The GPx and SOD were also significantly higher in these patients, indicating that lipid peroxidation increase was followed by an increase in antioxidant capacity. Higher ferritin levels were observed in patients with HFE gene variation. 95.7% of patients with MDS with the presence of HFE gene variations had received more of 20 transfusions. We observed a significant increase in MDA levels in patients with MDS and IOL, suggesting an increased lipid peroxidation in these patients. The accumulation of MDA alters the organisation of membrane phospholipids, contributing to the process of cellular degeneration. Results show that excess iron intensifies the process of cell damage through oxidative stress. Local Ethics Committee (licence 150/2009). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene.

PubMed

Altès, Albert; Bach, Vanessa; Ruiz, Angels; Esteve, Anna; Felez, Jordi; Remacha, Angel F; Sardà, M Pilar; Baiget, Montserrat

2009-10-01

Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype-genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.

Self-assembly synthesis of 3D graphene-encapsulated hierarchical Fe3O4 nano-flower architecture with high lithium storage capacity and excellent rate capability

NASA Astrophysics Data System (ADS)

Ma, Yating; Huang, Jian; Lin, Liang; Xie, Qingshui; Yan, Mengyu; Qu, Baihua; Wang, Laisen; Mai, Liqiang; Peng, Dong-Liang

2017-10-01

Graphene-encapsulated hierarchical metal oxides architectures can efficiently combine the merits of graphene and hierarchical metal oxides, which are deemed as the potential anode material candidates for the next-generation lithium-ion batteries due to the synergistic effect between them. Herein, a cationic surfactant induced self-assembly method is developed to construct 3D Fe3O4@reduction graphene oxide (H-Fe3O4@RGO) hybrid architecture in which hierarchical Fe3O4 nano-flowers (H-Fe3O4) are intimately encapsulated by 3D graphene network. Each H-Fe3O4 particle is constituted of rod-shaped skeletons surrounded by petal-like nano-flakes that are made up of enormous nanoparticles. When tested as the anode material in lithium-ion batteries, a high reversible capacity of 2270 mA h g-1 after 460 cycles is achieved under a current density of 0.5 A g-1. More impressively, even tested at a large current density of 10 A g-1, a decent reversible capacity of 490 mA h g-1 can be retained, which is still higher than the theoretical capacity of traditional graphite anode, demonstrating the remarkable lithium storage properties. The reasons for the excellent electrochemical performance of H-Fe3O4@RGO electrode have been discussed in detail.

A Novel Approach to Improving Utilization of Laboratory Testing.

PubMed

Zhou, Yaolin; Procop, Gary W; Riley, Jacquelyn D

2018-02-01

- The incorporation of best practice guidelines into one's institution is a challenging goal of utilization management, and the successful adoption of such guidelines depends on institutional context. Laboratorians who have access to key clinical data are well positioned to understand existing local practices and promote more appropriate laboratory testing. - To apply a novel approach to utilization management by reviewing international clinical guidelines and current institutional practices to create a reliable mechanism to improve detection and reduce unnecessary tests in our patient population. - We targeted a frequently ordered genetic test for HFE-related hereditary hemochromatosis, a disorder of low penetrance. After reviewing international practice guidelines, we evaluated 918 HFE tests and found that all patients with new diagnoses had transferrin saturation levels that were significantly higher than those of patients with nonrisk genotypes (72% versus 42%; P < .001). - Our "one-button" order that restricts HFE genetic tests to patients with transferrin saturation greater than 45% is consistent with published practice guidelines and detected 100% of new patients with HFE-related hereditary hemochromatosis. - Our proposed algorithm differs from previously published approaches in that it incorporates both clinical practice guidelines and local physician practices, yet requires no additional hands-on effort from pathologists or clinicians. This novel approach to utilization management embraces the role of pathologists as leaders in promoting high-quality patient care in local health care systems.

Genome-wide association study identifies TF as a significant modifier gene of iron metabolism in HFE hemochromatosis.

PubMed

de Tayrac, Marie; Roth, Marie-Paule; Jouanolle, Anne-Marie; Coppin, Hélène; le Gac, Gérald; Piperno, Alberto; Férec, Claude; Pelucchi, Sara; Scotet, Virginie; Bardou-Jacquet, Edouard; Ropert, Martine; Bouvet, Régis; Génin, Emmanuelle; Mosser, Jean; Deugnier, Yves

2015-03-01

Hereditary hemochromatosis (HH) is the most common form of genetic iron loading disease. It is mainly related to the homozygous C282Y/C282Y mutation in the HFE gene that is, however, a necessary but not a sufficient condition to develop clinical and even biochemical HH. This suggests that modifier genes are likely involved in the expressivity of the disease. Our aim was to identify such modifier genes. We performed a genome-wide association study (GWAS) using DNA collected from 474 unrelated C282Y homozygotes. Associations were examined for both quantitative iron burden indices and clinical outcomes with 534,213 single nucleotide polymorphisms (SNP) genotypes, with replication analyses in an independent sample of 748 C282Y homozygotes from four different European centres. One SNP met genome-wide statistical significance for association with transferrin concentration (rs3811647, GWAS p value of 7×10(-9) and replication p value of 5×10(-13)). This SNP, located within intron 11 of the TF gene, had a pleiotropic effect on serum iron (GWAS p value of 4.9×10(-6) and replication p value of 3.2×10(-6)). Both serum transferrin and iron levels were associated with serum ferritin levels, amount of iron removed and global clinical stage (p<0.01). Serum iron levels were also associated with fibrosis stage (p<0.0001). This GWAS, the largest one performed so far in unselected HFE-associated HH (HFE-HH) patients, identified the rs3811647 polymorphism in the TF gene as the only SNP significantly associated with iron metabolism through serum transferrin and iron levels. Because these two outcomes were clearly associated with the biochemical and clinical expression of the disease, an indirect link between the rs3811647 polymorphism and the phenotypic presentation of HFE-HH is likely. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients.

PubMed

Pelucchi, Sara; Mariani, Raffaella; Calza, Stefano; Fracanzani, Anna Ludovica; Modignani, Giulia Litta; Bertola, Francesca; Busti, Fabiana; Trombini, Paola; Fraquelli, Mirella; Forni, Gian Luca; Girelli, Domenico; Fargion, Silvia; Specchia, Claudia; Piperno, Alberto

2012-12-01

Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis.

CYBRD1 as a modifier gene that modulates iron phenotype in HFE p.C282Y homozygous patients

PubMed Central

Pelucchi, Sara; Mariani, Raffaella; Calza, Stefano; Fracanzani, Anna Ludovica; Modignani, Giulia Litta; Bertola, Francesca; Busti, Fabiana; Trombini, Paola; Fraquelli, Mirella; Forni, Gian Luca; Girelli, Domenico; Fargion, Silvia; Specchia, Claudia; Piperno, Alberto

2012-01-01

Background Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. Design and Methods: In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. Results We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. Conclusions While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis. PMID:22773607

Relationship between antioxidant capacity, oxidative stress, and feed efficiency in beef steers.

PubMed

Russell, J R; Sexten, W J; Kerley, M S; Hansen, S L

2016-07-01

Feed efficiency (FE) can vary between individuals but sources of variation are not well characterized. Oxidative stress is among the biological mechanisms believed to contribute to variation. The objective of this study was to evaluate the relationship between FE, antioxidant activity, and oxidative stress in feedlot steers representing phenotypic extremes for FE. Crossbred beef steers ( = 181) fed 70-d growing phase (GP) whole-shell corn-based (G-Corn) or rye baleage and soybean hull-based (G-Rough) diets in GrowSafe bunks at the University of Missouri were shipped to Iowa State University where the 12 most feed efficient (HFE) and 12 least feed efficient (LFE) steers from each diet (n = 48; 467 kg [SD 51]) were selected for evaluation. Steers received diets similar to GP diets, and 3 d after arrival, blood was sampled to evaluate antioxidant activity and oxidative stress markers for the GP following transit. Steers were transitioned to finishing phase (FP) cracked corn-based (F-Corn) or dried distillers' grains and soybean hull-based (F-Byp) diets, and on FP d 97, blood samples for the FP were collected. Data for the GP were analyzed as a 2 × 2 factorial, and data for the FP were analyzed as a 2 × 2 × 2 factorial using PROC MIXED of SAS. No GP diet × FP diet, FP diet × FE group, or 3-way interactions were noted ( ≥ 0.11) for FP measures. Steers fed the G-Rough diet had greater ( = 0.04) GP plasma protein carbonyl concentrations. During the GP, HFE steers had greater ( ≤ 0.04) protein carbonyl and ratio of oxidized:reduced blood lysate glutathione concentrations than LFE steers. There were GP diet × FE group interactions ( ≤ 0.03) during the GP and FP. During the GP, total blood lysate superoxide dismutase (SOD) activity was greater ( ≤ 0.03) in G-Rough/LFE steers than in G-Rough/HFE and G-Corn/LFE steers; G-Corn/HFE steers were intermediate. The G-Rough/LFE steers had greater ( < 0.04) glutathione peroxidase (GPX) activity than other groups and greater ( = 0.03) plasma malondialdehyde concentrations than G-Corn/LFE steers. During the FP, the G-Rough/LFE steers had greater ( ≤ 0.04) GPX activity than G-Rough/HFE and G-Corn/LFE steers; G-Corn/HFE steers were intermediate. The F-Byp diet had greater ( < 0.01) protein carbonyl than the F-Corn diet, and no other FP diet effects were noted ( ≥ 0.3) for any FP measures. The GP diet and FE groups had stronger relationships with antioxidant activity and oxidative stress markers measured for the GP than for the FP. Overall, antioxidant activity may play a role in FE as LFE steers, driven largely by G-Rough/LFE steers, had greater SOD activity and GPX activity than HFE steers, potentially using a greater proportion of energy otherwise available for tissue accretion.

EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH).

PubMed

Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

2016-04-01

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines.

Gully monitoring at two locations in the Grand Canyon National Park, Arizona, 1996-2010, with emphasis on documenting effects of the March 2008 high-flow experiment

USGS Publications Warehouse

Schott, Nathan D.; Hazel, Joseph E.; Fairley, Helen C.; Kaplinski, Matt; Parnell, Roderic A.

2014-01-01

Many archeological sites in the Grand Canyon are being impacted by gully incision. In March 2008, a high-flow experiment (2008 HFE) was conducted with the intention of redistributing fine sediment (sand, silt, and clay) from the bed of the Colorado River to higher elevations along the channel margin. Deposition of fine sediment in gully mouths has been hypothesized to slow gully erosion rates and lessen impacts to archeological sites. The effects of the 2008 HFE on gullies were evaluated by comparing the topographic changes of three gullies at two study sites before and after the 2008 HFE. Comparison results indicated that sediment was deposited in gully mouths during the 2008 HFE, and that the inundated areas nearest to the river can be extensively altered by mainstream flow during high-flow events. Additionally, the history of gully evolution at the two study sites was examined between 1996 and 2010 and indicated that gullies have been subjected to thalweg incision and gully widening processes over a decadal timescale. Although the small sample size precludes extrapolating the results to other gullies, the findings contribute to the understanding of gully erosion in archeologically significant areas and have implications for future monitoring of gully erosion and evaluating the effectiveness of check dams intended to mitigate that erosion at archaeological sites in the Grand Canyon National Park.

Frequency of the HFE C282Y and H63D mutations in Danish patients with clinical haemochromatosis initially diagnosed by phenotypic methods.

PubMed

Milman, Nils; Koefoed, Pernille; Pedersen, Palle; Nielsen, Finn Cilius; Eiberg, Hans

2003-12-01

To assess the frequency of the C282Y and H63D mutations on the HFE gene in Danish patients with clinical hereditary haemochromatosis initially diagnosed by phenotypic methods. In the period 1950-1985, an epidemiological survey in Denmark identified 179 patients with clinical idiopathic haemochromatosis diagnosed by phenotypic methods (serum transferrin saturation, serum ferritin, liver biopsy and mobilisable body iron stores). In 32 unrelated patients, frozen blood samples were available for genetic analysis. In a subsequent series of 26 unrelated Danish patients, a phenotypic diagnosis of clinical idiopathic haemochromatosis was made before blood samples were taken for HFE genotyping. The total series consisted of 58 patients (40 men and 18 women) with a median age of 60 yrs (range 18-74). HFE genotyping was performed by the polymerase chain reaction (PCR) technique. Among the patients, 55 of 58 (94.8%) were C282Y/C282Y homozygous. One 63-year-old woman (1.7%) was compound C282Y/H63D heterozygous. Two women (3.4%), aged 42 and 43 yrs were negative for both the C282Y and the H63D mutation. In the Danish population, homozygosity for the C282Y mutation appears to be the prevailing cause of clinically overt genetic haemochromatosis. This finding has implications both for the evaluation of patients with iron overload disorders and for the strategy in future population screening surveys.

EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH)

PubMed Central

Porto, Graça; Brissot, Pierre; Swinkels, Dorine W; Zoller, Heinz; Kamarainen, Outi; Patton, Simon; Alonso, Isabel; Morris, Michael; Keeney, Steve

2016-01-01

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE gene, referred to as HFE-related HH. Since 1996, HFE genotyping was implemented in diagnostic algorithms for suspected HH, allowing its early diagnosis and prevention. However, the penetrance of disease in p.C282Y homozygotes is incomplete. Hence, homozygosity for p.C282Y is not sufficient to diagnose HH. Neither is p.C282Y homozygosity required for diagnosis as other rare forms of HH exist, generally referred to as non-HFE-related HH. These pose significant challenges when defining criteria for referral, testing protocols, interpretation of test results and reporting practices. We present best practice guidelines for the molecular genetic diagnosis of HH where recommendations are classified, as far as possible, according to the level and strength of evidence. For clarification, the guidelines' recommendations are preceded by a detailed description of the methodology and results obtained with a series of actions taken in order to achieve a wide expert consensus, namely: (i) a survey on the current practices followed by laboratories offering molecular diagnosis of HH; (ii) a systematic literature search focused on some identified controversial topics; (iii) an expert Best Practice Workshop convened to achieve consensus on the practical recommendations included in the guidelines. PMID:26153218

Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis: the HEmochromatosis FAmily Study.

PubMed

Jacobs, Esther M G; Hendriks, Jan C M; van Deursen, Cees Th B M; Kreeftenberg, Herman G; de Vries, Richard A; Marx, Joannes J M; Stalenhoef, Anton F H; Verbeek, André L M; Swinkels, Dorine W

2009-01-01

In families of patients with clinically detected hereditary hemochromatosis (HH) early screening has been suggested to prevent morbidity and mortality. Here, we aim to identify determinants for iron overload in first-degree family members of C282Y homozygous probands with clinically detected HH. Data on HFE-genotype, iron parameters, demographics, lifestyle factors and health, were collected from 224 Dutch C282Y homozygous patients with clinically diagnosed HH and 735 of their first-degree family members (FDFM), all participating in the HEmochromatosis FAmily Study (HEFAS). The best predictive multivariable model forecasted 45% of variation of the serum ferritin levels. In this model severity of iron overload in the proband significantly predicted serum ferritin levels in FDFM. Other significant determinants in this model consisted of C282Y homozygosity, compound heterozygosity, age at testing for serum ferritin and supplemental iron intake, whereas a low body mass index showed a protective effect. This study provides a model to assess the risk of development of iron overload for relatives of probands with HH. These results might be instrumental in the development of an optimal strategy for future family screening programs.

A survey of anthropometry and physical accommodation in ergonomics curricula.

PubMed

Garneau, Christopher J; Parkinson, Matthew B

2016-01-01

The size and shape of users are an important consideration for many products and environments. Designers and engineers in many disciplines must often accommodate these attributes to meet objectives such as fit and safety. When practitioners have academic training in addressing these issues, it is typically through courses in Human Factors/Ergonomics (HF/E). This paper investigates education related to physical accommodation and offers suggestions for improvement. A survey was conducted wherein 21 instructors at 18 universities in the United States provided syllabi for 29 courses, which were analysed to determine topics related to anthropometry and resources used for the courses. The results show that within the U.S., anthropometry is covered in the majority of courses discussing physical ergonomics, but important related concepts were often omitted (e.g., digital human modelling, multivariate accommodation and variability across global populations). Curricula could be improved by incorporating more accurate anthropometry, multivariate problems and interactive online tools. This paper describes a study investigating collegiate ergonomics courses within the U.S. in the area of physical accommodation. Course schedules and texts were studied for their treatment of several topics related to accommodating the spatial requirements (anthropometry) of users. Recommendations are made for improving course curricula.

An experimental investigation of the effects of alarm processing and display on operator performance

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

O`Hara, J.; Brown, W.; Hallbert, B.

1998-03-01

This paper describes a research program sponsored by the US Nuclear Regulatory Commission to address the human factors engineering (HFE) aspects of nuclear power plant alarm systems. The overall objective of the program is to develop HFE review guidance for advanced alarm systems. As part of this program, guidance has been developed based on a broad base of technical and research literature. In the course of guidance development, aspects of alarm system design for which the technical basis was insufficient to support complete guidance development were identified. The primary purpose of the research reported in this paper was to evaluatemore » the effects of three of these alarm system design characteristics on operator performance in order to contribute to the understanding of potential safety issues and to provide data to support the development of design review guidance in these areas. Three alarm system design characteristics studied were (1) alarm processing (degree of alarm reduction), (2) alarm availability (dynamic prioritization and suppression), and (3) alarm display (a dedicated tile format, a mixed tile and message list format, and a format in which alarm information is integrated into the process displays). A secondary purpose was to provide confirmatory evidence of selected alarm system guidance developed in an earlier phase of the project. The alarm characteristics were combined into eight separate experimental conditions. Six, two-person crews of professional nuclear power plant operators participated in the study. Following training, each crew completed 16 test trials which consisted of two trials in each of the eight experimental conditions (one with a low-complexity scenario and one with a high-complexity scenario). Measures of process performance, operator task performance, situation awareness, and workload were obtained. In addition, operator opinions and evaluations of the alarm processing and display conditions were collected. No deficient performance was observed in any of the experimental conditions, providing confirmatory support for many design review guidelines. The operators identified numerous strengths and weaknesses associated with individual alarm design characteristics.« less

Hydrocyclone/Filter for Concentrating Biomarkers from Soil

NASA Technical Reports Server (NTRS)

Ponce, Adrian; Obenhuber, Donald

2008-01-01

The hydrocyclone-filtration extractor (HFE), now undergoing development, is a simple, robust apparatus for processing large amounts of soil to extract trace amounts of microorganisms, soluble organic compounds, and other biomarkers from soil and to concentrate the extracts in amounts sufficient to enable such traditional assays as cell culturing, deoxyribonucleic acid (DNA) analysis, and isotope analysis. Originally intended for incorporation into a suite of instruments for detecting signs of life on Mars, the HFE could also be used on Earth for similar purposes, including detecting trace amounts of biomarkers or chemical wastes in soils.

Variations in CCR5, but not HFE, ELMO1, or SLC12A3, are associated with susceptibility to kidney disease in north Indian individuals with type 2 diabetes.

PubMed

Yadav, Ashok K; Kumar, Vinod; Dutta, Pinaki; Bhansali, Anil; Jha, Vivekanand

2014-11-01

Diabetic nephropathy (DN), the leading cause of end-stage renal disease worldwide, may have a genetic component. In the present study, we investigated variations in a set of genes with susceptibility to DN in a north Indian population. Four genes (HFE, ELMO1, SLC12A3, and CCR5) were selected on the basis of reported association with type 2 diabetes and nephropathy. In all, 417 diabetic subjects (215 without kidney disease [DM] and 202 with DN) and 197 healthy controls (HC) were evaluated for variations in HFE (845 G>A and 187G>C), SLC12A3 (g.34372G>A), CCR5 (59029A>G), and ELMO1 (+9170 G>A). Polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphism and Taqman allele discrimination assays. Significant differences were found in genotype and allelic frequency in SLC12A3 (g.34372G>A) between diabetic subjects and HC (P < 0.03). There were no differences in the SLC12A3 g.34372G>A (AA+GA) genotype between diabetic subjects with and without nephropathy. However, the CCR5 59029AA genotype and A allele were significantly more frequent in diabetics compared with the HC (P = 0.01 and 0.03, respectively) and subjects with DN versus DM (P = 0.002 and 0.01, respectively). For ELMO1 (+9170 G>A), the GG genotype frequency was higher in the diabetic versus HC group. There were no differences in the frequency of HFE-845 G>A and HFE-187G>C among the groups. This study shows that the CCR5 AA genotype is over-represented in subjects with kidney disease due to type 2 diabetes. The CCR5 59029G>A and ELMO1 (+9170 G>A) loci are more frequent, and the SLC12A3 34372 AA genotype is associated with a reduced risk of diabetes. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

2008 Weather and Aeolian Sand-Transport Data from the Colorado River Corridor, Grand Canyon, Arizona

USGS Publications Warehouse

Draut, Amy E.; Sondossi, Hoda A.; Hazel, Joseph E.; Andrews, Timothy; Fairley, Helen C.; Brown, Christopher R.; Vanaman, Karen M.

2009-01-01

This report presents measurements of weather parameters and aeolian (windblown) sand transport made in 2008 near selected archaeological sites in the Colorado River corridor through Grand Canyon, Ariz. The quantitative methods and data discussed here form a basis for monitoring ecosystem processes that affect archeological-site stability. Combined with forthcoming work to evaluate landscape evolution at nearby archaeological sites, these data can be used to document the relationship between physical processes, including weather and aeolian sand transport, and their effects on the physical integrity of archaeological sites. Data collected in 2008 reveal event- and seasonal-scale variations in rainfall, wind, temperature, humidity, and barometric pressure. Broad seasonal changes in aeolian sediment flux are also apparent at most study sites. The continuation of monitoring that began in 2007, and installation of equipment at several new sites in early 2008, allowed evaluation of the effects of the March 2008 high-flow experiment (HFE) on aeolian sand transport. At two of the nine sites studied, spring and summer winds reworked 2008 HFE sandbars to form new aeolian dunes, at which sand moved inland toward larger, well-established dune fields. At the other seven study sites, neither dune formation nor enhanced sand transport after the HFE were observed. At several of those sites, dominant wind directions in spring 2008 were not oriented such that much HFE sand would have moved inland; at other sites, lack of increased inland sand flux is attributable to lack of sandbar enlargement near the study sites or to inhibition of sand movement by vegetation or local topography.

Hemojuvelin regulates the innate immune response to peritoneal bacterial infection in mice.

PubMed

Wu, Qian; Shen, Yuanyuan; Tao, Yunlong; Wei, Jiayu; Wang, Hao; An, Peng; Zhang, Zhuzhen; Gao, Hong; Zhou, Tianhua; Wang, Fudi; Min, Junxia

2017-01-01

Hereditary hemochromatosis and iron imbalance are associated with susceptibility to bacterial infection; however, the underlying mechanisms are poorly understood. Here, we performed in vivo bacterial infection screening using several mouse models of hemochromatosis, including Hfe ( Hfe -/- ), hemojuvelin ( Hjv -/- ), and macrophage-specific ferroportin-1 ( Fpn1 fl/fl ; LysM-Cre + ) knockout mice. We found that Hjv -/- mice, but not Hfe -/- or Fpn1 fl/fl ; LysM-Cre + mice, are highly susceptible to peritoneal infection by both Gram-negative and Gram-positive bacteria. Interestingly, phagocytic cells in the peritoneum of Hjv -/- mice have reduced bacterial clearance, IFN-γ secretion, and nitric oxide production; in contrast, both cell migration and phagocytosis are normal. Expressing Hjv in RAW264.7 cells increased the level of phosphorylated Stat1 and nitric oxide production. Moreover, macrophage-specific Hjv knockout mice are susceptible to bacterial infection. Finally, we found that Hjv facilitates the secretion of IFN-γ via the IL-12/Jak2/Stat4 signaling pathway. Together, these findings reveal a novel protective role of Hjv in the early stages of antimicrobial defense.

Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia

PubMed Central

Rodriguez, Libia M; Giraldo, Mabel C; Velasquez, Laura I; Alvarez, Cristiam M; Garcia, Luis F; Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

2015-01-01

A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis (“HH”) and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry. PMID:25983618

Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia.

PubMed

Rodriguez, Libia M; Giraldo, Mabel C; Velasquez, Laura I; Alvarez, Cristiam M; Garcia, Luis F; Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

2015-03-01

A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis ("HH") and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry.

Effect of the Hydrofluoroether Cosolvent Structure in Acetonitrile-Based Solvate Electrolytes on the Li+ Solvation Structure and Li-S Battery Performance.

PubMed

Shin, Minjeong; Wu, Heng-Liang; Narayanan, Badri; See, Kimberly A; Assary, Rajeev S; Zhu, Lingyang; Haasch, Richard T; Zhang, Shuo; Zhang, Zhengcheng; Curtiss, Larry A; Gewirth, Andrew A

2017-11-15

We evaluate hydrofluoroether (HFE) cosolvents with varying degrees of fluorination in the acetonitrile-based solvate electrolyte to determine the effect of the HFE structure on the electrochemical performance of the Li-S battery. Solvates or sparingly solvating electrolytes are an interesting electrolyte choice for the Li-S battery due to their low polysulfide solubility. The solvate electrolyte with a stoichiometric ratio of LiTFSI salt in acetonitrile, (MeCN) 2 -LiTFSI, exhibits limited polysulfide solubility due to the high concentration of LiTFSI. We demonstrate that the addition of highly fluorinated HFEs to the solvate yields better capacity retention compared to that of less fluorinated HFE cosolvents. Raman and NMR spectroscopy coupled with ab initio molecular dynamics simulations show that HFEs exhibiting a higher degree of fluorination coordinate to Li + at the expense of MeCN coordination, resulting in higher free MeCN content in solution. However, the polysulfide solubility remains low, and no crossover of polysulfides from the S cathode to the Li anode is observed.

Effect of the Hydrofluoroether Cosolvent Structure in Acetonitrile-Based Solvate Electrolytes on the Li+ Solvation Structure and Li-S Battery Performance.

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

Shin, Minjeong; Wu, Heng-Liang; Narayanan, Badri

We evaluate hydrofluoroether (HFE) cosolvents with varying degrees of fluorination in the acetonitrile-based solvate electrolyte to determine the effect of the HFE structure on the electrochemical performance of the Li-S battery. Solvates or sparingly solvating electrolytes are an interesting electrolyte choice for the Li-S battery due to their low polysulfide solubility. The solvate electrolyte with a stoichiometric ratio of LiTFSI salt in acetonitrile, (MeCN)(2)-LiTFSI, exhibits limited polysulfide solubility due to the high concentration of LiTFSI. We demonstrate that the addition of highly fluorinated HFEs to the solvate yields better capacity retention compared to that of less fluorinated HFE cosolvents. Ramanmore » and NMR spectroscopy coupled with ab initio molecular dynamics simulations show that HFEs exhibiting a higher degree of fluorination coordinate to Li+ at the expense of MeCN coordination, resulting in higher free MeCN content in solution. However, the polysulfide solubility remains low, and no crossover of polysulfides from the S cathode to the Li anode is observed.« less

Evaluation of AK-225(R), Vertrel(R) MCA and HFE A 7100 as Alternative Solvents for Precision Cleaning and Verification Technology

NASA Technical Reports Server (NTRS)

Melendez, Orlando; Trizzino, Mary; Fedderson, Bryan

1997-01-01

The National Aeronautics and Space Administration (NASA), Kennedy Space Center (KSC) Materials Science Division conducted a study to evaluate alternative solvents for CFC-113 in precision cleaning and verification on typical samples that are used in the KSC environment. The effects of AK-225(R), Vertrel(R), MCA, and HFE A 7100 on selected metal and polymer materials were studied over 1, 7 and 30 day test times. This report addresses a study on the compatibility aspects of replacement solvents for materials in aerospace applications.

Experimental investigation of the ORC system in a cogenerative domestic power plant with a scroll expanders

NASA Astrophysics Data System (ADS)

Kaczmarczyk, Tomasz Z.; Ihnatowicz, Eugeniusz; Żywica, Grzegorz; Kiciński, Jan

2015-11-01

The paper presents the results of experimental investigations of the ORC system with two scroll expanders which have been used as a source of electricity. Theworking fluidwas HFE7100 - a newly engineered fluid with a unique heat transfer and favourable environmental properties. In the ORC system three heat exchangers were used (evaporator, regenerator, condenser) and before expanders the droplet separator was installed. As a source of heat an innovative biomass boiler was used. Studies have been carried out for the expanders worked in series and in parallel. The paper presents the thermal and fluidflow properties of the ORC installation for the selected flow rates and different temperatures of the working medium. The characteristics of output electrical power, operating speed and vibrations for scroll expanders were also presented.

Using iron studies to predict HFE mutations in New Zealand: implications for laboratory testing.

PubMed

O'Toole, Rebecca; Romeril, Kenneth; Bromhead, Collette

2017-04-01

The diagnosis of hereditary haemochromatosis (HH) is not straightforward because symptoms are often absent or non-specific. Biochemical markers of iron-overloading may be affected by other conditions. To measure the correlation between iron studies and HFE genotype to inform evidence-based recommendations for laboratory testing in New Zealand. Results from 2388 patients genotyped for C282Y, H63D and S65C in Wellington, New Zealand from 2007 to 2013 were compared with their biochemical phenotype as quantified by serum ferritin (SF), transferrin saturation (TS), serum iron (SI) and serum transferrin (ST). The predictive power of these markers was evaluated by receiver operator characteristic (ROC) curve analysis, and if a statistically significant association for a variable was seen, sensitivity, specificity and predictive values were calculated. Test ordering patterns showed that 62% of HFE genotyping tests were ordered because of an elevated SF alone and only 11% of these had a C-reactive protein test to rule out an acute phase reaction. The association between SF and significant HFE genotypes SF was low. However, TS values ≥45% predicted HH mutations with the highest sensitivity and specificity. A SF of >1000 µg/L was found in one at-risk patient (C282Y homozygote) who had a TS <45%. Our analysis highlights the need for clear guidelines for investigation of hyperferritinaemia and HH in New Zealand. Using our findings, we developed an evidence-based laboratory testing algorithm based on a TS ≥45%, a SF ≥1000 µg/L and/or a family history of HH which identified all C282Y homozygotes in this study. © 2016 Royal Australasian College of Physicians.

- 174 G>C IL-6 polymorphism and primary iron overload in male patients.

PubMed

Tetzlaff, Walter F; Meroño, Tomás; Botta, Eliana E; Martín, Maximiliano E; Sorroche, Patricia B; Boero, Laura E; Castro, Marcelo; Frechtel, Gustavo D; Rey, Jorge; Daruich, Jorge; Cerrone, Gloria E; Brites, Fernando

2018-04-14

Primary iron overload (IO) is commonly associated with mutations in the hereditary hemochromatosis gene (HFE). Nonetheless, other genetic variants may influence the development of IO beyond HFE mutations. There is a single nucleotide polymorphism (SNP) at - 174 G>C of the interleukin (IL)-6 gene which might be associated with primary IO. Our aim was to study the association between the SNP - 174 G>C gene promoter of IL-6 and primary IO in middle-aged male patients. We studied 37 men with primary IO diagnosed by liver histology. Controls were age-matched male volunteers (n = 37). HFE mutations and the SNP - 174 G>C gene promoter of IL-6 were evaluated by PCR-RFLP. Logistic regression was used to evaluate the association between primary IO and SNP - 174 G>C gene promoter of IL-6. Patients and control subjects were in Hardy-Weinberg equilibrium for the SNP - 174 G>C gene promoter of IL-6 (p = 0.17). Significantly different genotype frequencies were observed between patients (43% CC, 43% CG, and 14% GG) and control subjects (10% CC, 41% CG, and 49% GG) (OR = 4.09, 95% CI = 2.06-8.13; p < 0.0001). The multiple logistic regression analysis showed that IO was significantly associated with CC homozygosis in the SNP - 174 G>C gene promoter of IL-6 (OR = 6.3, 95% CI = 1.9-21.4; p < 0.005) in a model adjusted by age and body mass index. In conclusion, CC homozygosis in the SNP - 174 G>C gene promoter of IL-6 can be proposed as one of the gene variants influencing iron accumulation in male adults with HFE mutations. Studies in larger cohorts are warranted.

Transferrin saturation phenotype and HFE genotype screening for hemochromatosis and primary iron overload: predictions from a model based on national, racial, and ethnic group composition in central Alabama.

PubMed

Barton, J C; Acton, R T

2000-01-01

There is interest in general population screening for hemochromatosis and other primary iron overload disorders, although not all persons are at equal risk. We developed a model to estimate the numbers of persons in national, racial, or ethnic population subgroups in Jefferson County, Alabama, who would be detected using transferrin saturation (phenotype) or HFE mutation analysis (genotype) screening. Approximately 62% are Caucasians, 37% are African Americans, and the remainder are Hispanics, Asians, or Native Americans. The predicted phenotype frequencies are greatest in a Caucasian subgroup, ethnicity unspecified, which consists predominantly of persons of Scotch and Irish descent (0.0065 men, 0.0046 women), and in African Americans (0.0089 men, 0.0085 women). Frequencies of the HFE genotype C282Y/C282Y > or = 0.0001 are predicted to occur only among Caucasians; the greatest frequency (0.0080) was predicted to occur in the ethnicity-unspecified Caucasian population. C282Y/C282Y frequency estimates were lower in Italian, Greek, and Jewish subgroups. There is excellent agreement in the numbers of the ethnicity-unspecified Caucasians who would be detected using phenotype and genotype criteria. Our model also indicates that phenotyping would identify more persons with primary iron overload than would genotyping in our Italian Caucasian, Hispanic, and African American subgroups. This is consistent with previous observations that indicate that primary iron overload disorders in persons of southern Italian descent and African Americans are largely attributable to non-HFE alleles. Because the proportions of population subgroups and their genetic constitution may differ significantly in other geographic regions, we suggest that models similar to the present one be constructed to predict optimal screening strategies for primary iron overload disorders.

High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats

PubMed Central

Ha, Jung-Heun; Doguer, Caglar; Wang, Xiaoyu; Flores, Shireen R.; Collins, James F.

2016-01-01

Iron-copper interactions were described decades ago; however, molecular mechanisms linking the two essential minerals remain largely undefined. Investigations in humans and other mammals noted that copper levels increase in the intestinal mucosa, liver and blood during iron deficiency, tissues all important for iron homeostasis. The current study was undertaken to test the hypothesis that dietary copper influences iron homeostasis during iron deficiency and iron overload. We thus fed weanling, male Sprague-Dawley rats (n = 6-11/group) AIN-93G-based diets containing high (~8800 ppm), adequate (~80) or low (~11) iron in combination with high (~183), adequate (~8) or low (~0.9) copper for 5 weeks. Subsequently, the iron- and copper-related phenotype of the rats was assessed. Rats fed the low-iron diets grew slower than controls, with changes in dietary copper not further influencing growth. Unexpectedly, however, high-iron (HFe) feeding also impaired growth. Furthermore, consumption of the HFe diet caused cardiac hypertrophy, anemia, low serum and tissue copper levels and decreased circulating ceruloplasmin activity. Intriguingly, these physiologic perturbations were prevented by adding extra copper to the HFe diet. Furthermore, higher copper levels in the HFe diet increased serum nonheme iron concentration and transferrin saturation, exacerbated hepatic nonheme iron loading and attenuated splenic nonheme iron accumulation. Moreover, serum erythropoietin levels, and splenic erythroferrone and hepatic hepcidin mRNA levels were altered by the dietary treatments in unanticipated ways, providing insight into how iron and copper influence expression of these hormones. We conclude that high-iron feeding of weanling rats causes systemic copper deficiency, and further, that copper influences the iron-overload phenotype. PMID:27537180

Iron Metabolism Genes, Low-Level Lead Exposure, and QT Interval

PubMed Central

Park, Sung Kyun; Hu, Howard; Wright, Robert O.; Schwartz, Joel; Cheng, Yawen; Sparrow, David; Vokonas, Pantel S.; Weisskopf, Marc G.

2009-01-01

Background Cumulative exposure to lead has been shown to be associated with depression of electrocardiographic conduction, such as QT interval (time from start of the Q wave to end of the T wave). Because iron can enhance the oxidative effects of lead, we examined whether polymorphisms in iron metabolism genes [hemochromatosis (HFE), transferrin (TF) C2, and heme oxygenase-1 (HMOX-1)] increase susceptibility to the effects of lead on QT interval in 613 community-dwelling older men. Methods We used standard 12-lead electrocardiograms, K-shell X-ray fluorescence, and graphite furnace atomic absorption spectrometry to measure QT interval, bone lead, and blood lead levels, respectively. Results A one-interquartile-range increase in tibia lead level (13 μg/g) was associated with a 11.35-msec [95% confidence interval (CI), 4.05–18.65 msec] and a 6.81-msec (95% CI, 1.67–11.95 msec) increase in the heart-rate–corrected QT interval among persons carrying long HMOX-1 alleles and at least one copy of an HFE variant, respectively, but had no effect in persons with short and middle HMOX-1 alleles and the wild-type HFE genotype. The lengthening of the heart-rate–corrected QT interval with higher tibia lead and blood lead became more pronounced as the total number (0 vs. 1 vs. ≥2) of gene variants increased (tibia, p-trend = 0.01; blood, p-trend = 0.04). This synergy seems to be driven by a joint effect between HFE variant and HMOX-1 L alleles. Conclusion We found evidence that gene variants related to iron metabolism increase the impacts of low-level lead exposure on the prolonged QT interval. This is the first such report, so these results should be interpreted cautiously and need to be independently verified. PMID:19165391

Non-HFE iron overload as a surrogate marker of disease severity in patients of liver cirrhosis.

PubMed

Noor, Mohd Talha; Tiwari, Manish; Kumar, Ravindra

2016-01-01

Decompensated liver cirrhosis is an important cause of mortality worldwide. Various modifiable and non-modifiable factors are involved in the pathogenesis of cirrhosis and its complications. This study was aimed to evaluate the association of iron overload and disease severity in patients of liver cirrhosis and its association with HFE gene mutation. Forty-nine patients with decompensated liver cirrhosis were recruited. Clinical and laboratory parameters were compared in patients with and without iron overload. C282Y and H63D gene mutation analysis was performed in all patients with iron overload. Iron overload was found in 20 (40.82%) patients. A significant positive correlation of transferrin saturation with Child-Turcotte-Pugh (CTP) score (r = 0.705, p < 0.001) and model for end-stage liver disease (MELD) score (r = 0.668, p < 0.001) was found. Transferrin saturation was also independently associated with high CTP and MELD score on multivariate analysis. Mortality over 3 months was significantly more common in iron-overloaded patients (p = 0.028). C282Y homozygosity or C282Y/H63D compound heterozygosity was not found in any of the patients with iron overload. Iron overload was significantly associated with disease severity and reduced survival in patients of decompensated liver cirrhosis.

MIDAS-FAST: Design and Validation of a Model-Based Tool to Predict Operator Performance with Robotic Arm Automation

NASA Technical Reports Server (NTRS)

Sebok, Angelia (Principal Investigator); Wickens, Christopher; Gacy, Marc; Brehon, Mark; Scott-Nash, Shelly; Sarter, Nadine; Li, Huiyang; Gore, Brian; Hooey, Becky

2017-01-01

The Coalition for Aerospace and Science (CAS) is hosting an exhibition on Capitol Hill on June 14, 2017, to highlight the contributions of CAS members to NASAs portfolio of activities. This exhibition represents an opportunity for an HFES members ground breaking work to be displayed and to build on support within Congress for NASAs human research program including in those areas that are of specific interest to the HFE community. The intent of this poster presentation is to demonstrate the positive outcome that comes from funding HFE related research on a project like the one exemplified by MIDAS-FAST.

Frequency of Hereditary Hemochromatosis (HFE) Gene Mutations in Egyptian Beta Thalassemia Patients and its Relation to Iron Overload.

PubMed

Enein, Azza Aboul; El Dessouky, Nermine A; Mohamed, Khalda S; Botros, Shahira K A; Abd El Gawad, Mona F; Hamdy, Mona; Dyaa, Nehal

2016-06-15

This study aimed to detect the most common HFE gene mutations (C282Y, H63D, and S56C) in Egyptian beta thalassemia major patients and its relation to their iron status. The study included 50 beta thalassemia major patients and 30 age and sex matched healthy persons as a control group. Serum ferritin, serum iron and TIBC level were measured. Detection of the three HFE gene mutations (C282Y, H63D and S65C) was done by PCR-RFLP analysis. Confirmation of positive cases for the mutations was done by sequencing. Neither homozygote nor carrier status for the C282Y or S65C alleles was found. The H63D heterozygous state was detected in 5/50 (10%) thalassemic patients and in 1/30 (3.3%) controls with no statistically significant difference between patients and control groups (p = 0.22). Significantly higher levels of the serum ferritin and serum iron in patients with this mutation (p = 001). Our results suggest that there is an association between H63D mutation and the severity of iron overload in thalassemic patients.

Hfe Deficiency Impairs Pulmonary Neutrophil Recruitment in Response to Inflammation

PubMed Central

Benesova, Karolina; Vujić Spasić, Maja; Schaefer, Sebastian M.; Stolte, Jens; Baehr-Ivacevic, Tomi; Waldow, Katharina; Zhou, Zhe; Klingmueller, Ursula; Benes, Vladimir; Mall, Marcus A.; Muckenthaler, Martina U.

2012-01-01

Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe−/− mice) affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe−/− and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS) and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe−/− mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe−/− and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis. PMID:22745741

Characterization of the Long-term Subsurface Warming Observed at the Apollo 15 and 17 Sites Utilizing the Newly Restored Heat Flow Experiment Data from 1975 to 1977

NASA Astrophysics Data System (ADS)

Nagihara, S.; Kiefer, W. S.; Taylor, P. T.; Williams, D. R.; Nakamura, Y.; Krell, J. W.

2017-12-01

The Apollo Heat Flow Experiment (HFE) was conducted at landing sites 15 and 17 as part of the Apollo Lunar Surface Experiment Package (ALSEP) program. At each site, the astronauts drilled 2 holes, 10-m apart, and installed a probe in each. The probes monitored surface and subsurface temperatures. The Apollo 15 probes operated from July 1971 to January 1977. The Apollo 17 probes operated from December 1972 to September 1977. For both sites, only data from the beginning to December 1974 were archived previously. We have restored major portions of the 1975-1977 HFE data for both sites from two sets of sources recently recovered. One was the original ALSEP archival data tapes, from which raw HFE data were extracted and processed according to the procedure and the calibration data specified by the original investigators. The other was the ALSEP Performance Summary Reports, which included weekly logs of temperature readings from the deepest sensor of each of the probes. The original HFE investigators noted that temperature of the regolith well below the thermal skin depth ( 1 m) rose gradually through December 1974 at both sites. Possible causes of the warming have been debated since. The restored 1975-1977 HFE data allow more detailed characterization of this phenomenon, especially for the Apollo 17 site, for which the duration of data availability has more than doubled. For both sites, the subsurface warming continued till the end of observations. Simultaneously, thermal gradient decreased. Such behavior is consistent with one of the hypotheses proposed by the original investigators; temperature of the lunar surface around the probe increased by 2 to 4 K at the time of deployment. Consequently, the subsurface thermal regime gradually adjusted to the new boundary condition. The Lunar Reconnaissance Orbiter Camera images taken over the Apollo landing sites suggest that astronaut-induced surface disturbance resulted in lower albedo, and that should have raised average surface temperature. Other explanations may also be possible. For example, at the Apollo 15 site, it is known that radiation down the hole affected the upper section of the probe. In contrast, the Apollo 17 probes were installed with radiation shields at the top of the hole and at 0.3-m depth. Therefore, warming there is more likely to be conductive in nature.

Modified Universal Design Survey: Enhancing Operability of Launch Vehicle Ground Crew Worksites

NASA Technical Reports Server (NTRS)

Blume, Jennifer L.

2010-01-01

Operability is a driving requirement for next generation space launch vehicles. Launch site ground operations include numerous operator tasks to prepare the vehicle for launch or to perform preflight maintenance. Ensuring that components requiring operator interaction at the launch site are designed for optimal human use is a high priority for operability. To promote operability, a Design Quality Evaluation Survey based on Universal Design framework was developed to support Human Factors Engineering (HFE) evaluation for NASA s launch vehicles. Universal Design per se is not a priority for launch vehicle processing however; applying principles of Universal Design will increase the probability of an error free and efficient design which promotes operability. The Design Quality Evaluation Survey incorporates and tailors the seven Universal Design Principles and adds new measures for Safety and Efficiency. Adapting an approach proven to measure Universal Design Performance in Product, each principle is associated with multiple performance measures which are rated with the degree to which the statement is true. The Design Quality Evaluation Survey was employed for several launch vehicle ground processing worksite analyses. The tool was found to be most useful for comparative judgments as opposed to an assessment of a single design option. It provided a useful piece of additional data when assessing possible operator interfaces or worksites for operability.

Adoption Space and the Idea-to-Market Process of Health Technologies.

PubMed

Saranummi, Niilo; Beuscart, Regis; Black, Norman; Maglaveras, Nicos; Strano, Chiara; Karavidopoulou, Youla

2016-01-01

Although Europe 'produces' excellent science, it has not been equally successful in translating scientific results into commercially successful companies in spite of European and national efforts invested in supporting the translation process. The Idea-to-Market process is highly complex due to the large number of actors and stakeholders. ITECH was launched to propose recommendations which would accelerate the Idea-to-Market process of health technologies leading to improvements in the competitiveness of the European health technology industry in the global markets. The project went through the following steps: defining the Idea-to-Market process model; collection and analysis of funding opportunities; identification of 12 gaps and barriers in the Idea-to-Market process; a detailed analysis of these supported by interviews; a prioritization process to select the most important issues; construction of roadmaps for the prioritized issues; and finally generating recommendations and associated action plans. Seven issues were classified as in need of actions. Three of these are part of the ongoing Medical Device Directive Reform (MDR), namely health technology assessment, post-market surveillance and regulatory process, and therefore not within the scope of ITECH. Recommendations were made for eHealth taxonomy; Education and training; Clinical trials and Adoption space and Human Factors Engineering (HFE).

Example of a Human Factors Engineering approach to a medication administration work system: potential impact on patient safety.

PubMed

Beuscart-Zéphir, Marie-Catherine; Pelayo, Sylvia; Bernonville, Stéphanie

2010-04-01

The objectives of this paper are: In this approach, the implementation of such a complex IT solution is considered a major redesign of the work system. The paper describes the Human Factor (HF) tasks embedded in the project lifecycle: (1) analysis and modelling of the current work system and usability assessment of the medication CPOE solution; (2) HF recommendations for work re-design and usability recommendations for IT system re-engineering both aiming at a safer and more efficient work situation. Standard ethnographic methods were used to support the analysis of the current work system and work situations, coupled with cognitive task analysis methods and documents review. Usability inspection (heuristic evaluation) and both in-lab (simulated tasks) and on-site (real tasks) usability tests were performed for the evaluation of the CPOE candidate. Adapted software engineering models were used in combination with usual textual descriptions, tasks models and mock-ups to support the recommendations for work and product re-design. The analysis of the work situations identified different work organisations and procedures across the hospital's departments. The most important differences concerned the doctor-nurse communications and cooperation modes and the procedures for preparing and administering the medications. The assessment of the medication CPOE functions uncovered a number of usability problems including severe ones leading to impossible to detect or to catch errors. Models of the actual and possible distribution of tasks and roles were used to support decision making in the work design process. The results of the usability assessment were translated into requirements to support the necessary re-engineering of the IT application. The HFE approach to medication CPOE efficiently identifies and distinguishes currently unsafe or uncomfortable work situations that could obviously benefit from an IT solution from other work situations incorporating efficient work procedures that might be impaired by the implementation of the CPOE. In this context, a careful redesign of the work situation and of the entire work system is necessary to actually benefit from the installation of the product in terms of patient safety and human performances. In parallel, a usability assessment of the product to be implemented is mandatory to identify potentially dangerous usability flaws and to fix them before the installation. (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Cochlear Dead Regions in Typical Hearing Aid Candidates: Prevalence and Implications for Use of High-Frequency Speech Cues

PubMed Central

Cox, Robyn M; Alexander, Genevieve C; Johnson, Jani; Rivera, Izel

2011-01-01

We investigated the prevalence of cochlear dead regions in listeners with hearing losses similar to those of many hearing aid wearers, and explored the impact of these dead regions on speech perception. Prevalence of dead regions was assessed using the Threshold Equalizing Noise test (TEN(HL)). Speech recognition was measured using high-frequency emphasis (HFE) Quick Speech In Noise (QSIN) test stimuli and low-pass filtered HFE QSIN stimuli. About one third of subjects tested positive for a dead region at one or more frequencies. Also, groups without and with dead regions both benefited from additional high-frequency speech cues. PMID:21522068

Serum Ferritin, Insulin Resistance, and Metabolic Syndrome: Clinical and Laboratory Associations in 769 Non-Hispanic Whites Without Diabetes Mellitus in the HEIRS Study

PubMed Central

Barton, J. Clayborn; Barton, James C.

2015-01-01

Abstract Background: In some reports, serum ferritin (SF) has been associated with insulin resistance and metabolic syndrome. Methods: We studied non-Hispanic whites without diabetes mellitus in a postscreening examination. Participants included cases [HFE C282Y homozygosity; and transferrin saturation (TS) >50% and SF >300 μg/L (males) and TS >45% and SF >200 μg/dL (females), regardless of HFE genotype] and controls [HFE wild-type (wt/wt) and TS/SF 25th–75th percentiles]. We excluded participants with overnight fasts <8 hr, cirrhosis, hepatitis B or C, pregnancy, or missing data. Observations were age, sex, C282Y homozygosity, body mass index (BMI), systolic and diastolic blood pressures (SBP, DBP), lymphocytes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-reactive protein (CRP), TS, SF, and glucose/insulin. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR) 4th quartile (≥2.70). Results: A total of 407 women and 362 men (mean age 54 years) included 188 C282Y homozygotes and 371 wt/wt. Significant trends across HOMA-IR quartiles included age, male sex, BMI, SBP, DBP, lymphocytes, ALT, CRP >0.5 mg/dL (positive), and TS (negative). Multiple regression on HOMA-IR revealed significant associations with male sex, BMI, SBP, lymphocytes, ALT, CRP>0.5 mg/dL (positive), and DBP and SF (negative). Logistic regression on HOMA-IR 4th quartile revealed significant positive associations with age, male sex, BMI, and lymphocytes. Metabolic syndrome occurred in 53 participants (6.9%). Logistic regression on metabolic syndrome revealed these odds ratios: HOMA-IR 4th quartile [9.1 (4.8, 17.3)] and CRP >0.5 mg/dL [2.9 (1.6, 5.4)]. Conclusions: Age, male sex, BMI, and lymphocytes were positively associated with HOMA-IR after correction for other factors. HOMA-IR 4th quartile and CRP >0.5 mg/dL predicted metabolic syndrome. PMID:25423072

Serum ferritin, insulin resistance, and metabolic syndrome: clinical and laboratory associations in 769 non-hispanic whites without diabetes mellitus in the HEIRS study.

PubMed

Acton, Ronald T; Barton, J Clayborn; Barton, James C

2015-03-01

In some reports, serum ferritin (SF) has been associated with insulin resistance and metabolic syndrome. We studied non-Hispanic whites without diabetes mellitus in a postscreening examination. Participants included cases [HFE C282Y homozygosity; and transferrin saturation (TS) >50% and SF >300 μg/L (males) and TS >45% and SF >200 μg/dL (females), regardless of HFE genotype] and controls [HFE wild-type (wt/wt) and TS/SF 25th-75th percentiles]. We excluded participants with overnight fasts <8 hr, cirrhosis, hepatitis B or C, pregnancy, or missing data. Observations were age, sex, C282Y homozygosity, body mass index (BMI), systolic and diastolic blood pressures (SBP, DBP), lymphocytes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), C-reactive protein (CRP), TS, SF, and glucose/insulin. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR) 4th quartile (≥2.70). A total of 407 women and 362 men (mean age 54 years) included 188 C282Y homozygotes and 371 wt/wt. Significant trends across HOMA-IR quartiles included age, male sex, BMI, SBP, DBP, lymphocytes, ALT, CRP >0.5 mg/dL (positive), and TS (negative). Multiple regression on HOMA-IR revealed significant associations with male sex, BMI, SBP, lymphocytes, ALT, CRP>0.5 mg/dL (positive), and DBP and SF (negative). Logistic regression on HOMA-IR 4th quartile revealed significant positive associations with age, male sex, BMI, and lymphocytes. Metabolic syndrome occurred in 53 participants (6.9%). Logistic regression on metabolic syndrome revealed these odds ratios: HOMA-IR 4th quartile [9.1 (4.8, 17.3)] and CRP >0.5 mg/dL [2.9 (1.6, 5.4)]. Age, male sex, BMI, and lymphocytes were positively associated with HOMA-IR after correction for other factors. HOMA-IR 4th quartile and CRP >0.5 mg/dL predicted metabolic syndrome.

The antidiabetic effects of an herbal formula composed of Alnus hirsuta, Rosa davurica, Acanthopanax senticosus and Panax schinseng in the streptozotocin-induced diabetic rats.

PubMed

Hu, Weicheng; Yeo, Jin-Hee; Jiang, Yunyao; Heo, Seong-Il; Wang, Myeong-Hyeon

2013-04-01

A folk prescription consisting of Alnus hirsuta, Rosa davurica, Acanthopanax senticosus and Panax schinseng has been used in the treatment of diabetes mellitus. The aim of the present investigation was to evaluate the antidiabetic effects of the herb formula extract (HFE) composed of Alnus hirsuta, Rosa davurica, Acanthopanax senticosus and Panax schinseng in the streptozotocin (STZ)-induced diabetic rats. The HFE was mixed in the food supply of the healthy and STZ-induced diabetic male Sprague-Dawley rats, and its effects on the body weight, water and food intake, hyperglycemia, hypolipidemic and islet structure were studied. The treatment of the rats with STZ for 6 weeks resulted in marasmus, polydipsia, polyphagia, hyperglycemia and hypoinsulinemia. In addition, the diabetic rats showed an apparent decrease in the insulin immunoreactivity and the number of β-cells in the pancreas. The addition of the HFE to the rats' food supply significantly lowered the serum glucose and the serum triglycerides level and preserved the normal histological appearance of the pancreatic islets. These results indicate that the HEF have a strong antidiabetic potential along with the significant hypoglycemic and hypolipidemic effects, which may be applicable in the pharmaceutical industry.

Screening for hemochromatosis by measuring ferritin levels: a more effective approach

PubMed Central

Waalen, Jill; Felitti, Vincent J.; Gelbart, Terri

2008-01-01

Because the penetrance of HFE hemochromatosis is low, traditional population screening measuring the transferrin saturation is unlikely to be cost-effective because the majority of subjects detected neither have clinical disease nor are likely to develop it. Three independent studies show that only patients with serum ferritin concentrations more than 1000 μg/L are at risk for cirrhosis, one of the main morbidities of hemochromatosis. Among 29 699 white subjects participating in the Scripps/Kaiser hemochromatosis study, only 59 had serum ferritin levels more than 1000 μg/L; 24 had homozygous mutant or compound heterozygous mutant HFE genotypes. In all but 5 of the other subjects, the causes of elevated ferritin were excessive alcohol intake, cancer, or liver disease. Screening for hemochromatosis with serum ferritin levels will detect the majority of patients who will be clinically affected and may detect other clinically significant disease in patients who do not have hemochromatosis genotypes. Because the ferritin level of the majority of adult homozygotes for HFE mutations does not rise over long periods of time, excluding subjects with serum ferritin levels less than or equal to 1000 μg/L should not result in missed opportunities for early treatment of patients who could benefit. PMID:18025154

A Mouse Model of Cardiomyopathy Induced by Mutations in the Hemochromatosis HFE Gene.

PubMed

Djemai, Haidar; Thomasson, Rémi; Trzaskus, Yvan; Mougenot, Nathalie; Meziani, Amira; Toussaint, Jean-François; Noirez, Philippe; Vitiello, Damien

2017-07-01

The heart is 1 of the organs most affected by hereditary hemochromatosis (HH). The clinical impact of cardiomyopathy in patients with HH requires a particular diagnosis and less invasive treatments. We developed a model of cardiomyopathy in knockout (KO) mice for the high-Fe (HFE) gene and assessed left ventricular (LV) function and structure from 7-20 months. Male wild-type (WT) heterozygous and KO SV129 mice for the HFE gene were used in this study. Twenty-four mice were used to assess LV function and structure by echocardiography at 7, 14, 18, and 20 months. Evaluations of LV function and structure and myocardial fibrosis were performed at 7 and 20 months. The percent decrease of LV thickness-to-radius ratio between 7 and 20 months was higher in KO mice compared with WT mice (-30.2% ± 5.3% vs -10.5% ± 4.9%; P < 0.01). The LV diameters were higher in old mice compared with young mice (+13% at end-diastole; +33% at end-systole; P < 0.001). The LV ejection fraction values were lower in KO mice compared with WT mice between 7 and 20 months. The highest difference was found at 14 months (60.0% ± 7.6% vs 78.1% ± 3.5%; P < 0.001). Myocardial fibrosis was higher in old KO mice compared with old WT mice (+55%; P < 0.001), and myocardial iron deposition was slightly increased in old KO mice compared with old WT mice (1.31% ± 0.33% vs 0.84% ± 0.22%; P = 0.056). The present mouse model has the potential to allow the determination of underlying mechanisms involved in the cardiomyopathy induced by HFE-related hemochromatosis. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

[ALLELES C282Y AND H63D HFE GENE, INSULIN RESISTANCE AND SUSCEPTIBILITY TO DISTURBANCE OF PORPHYRIN METABOLISM IN NON-ALCOHOLIC FATTY LIVER DISEASE].

PubMed

Krivosheev, A B; Maximov, V N; Voevoda, M I; Kuimov, A D; Kondratova, M A; Tuguleva, T A; Koval, O N; Bezrukova, A A; Bogorianova, P A; Rybina, O V

2015-01-01

The aim of the present work was to study the frequency of genotypes and alleles of C282Y and H63D HFE gene that may be associated with impaired porphyrin metabolism, as well as possible reasons for the formation of dysmetabolism porphyrins with NAFLD. The study involved 65 patients (52 men and 13 women) aged 21 to 69 years (mean age 48.5±1.5 years). Excretion uroporphyrin, coproporphyrin, 6-aminolevulinic acid of porphobilinogen in urine was determined by chromatography and spectrophotometry calculated total excretion of porphyrins. Allele frequencies C282Y and H63D were determined during the molecular genetic analysis of DNA using the polymerase chain reaction followed by analysis of length polymorphism restraktsionnyh fragments. Condition of carbohydrate metabolism was evaluated by the level of fasting blood glucose and standard glucose tolerance test. Diagnosis of insulin resistance was performed according to the criteria proposed by the European Group for the Study of insulin resistance (EGIR). Skill test for the C282Y mutation carriage and H63D in the HFE gene in 65 patients with non-alcoholic fatty liver disease. Disturbances in the metabolism of porphyrins were recorded in 43 (66.2%) patients. H63D and C282Y mutations were found in 18 (27.7%) patients, of whom 13 (72.2%) people with different options dismetabolism porphyrins and signs of insulin resistance. In 47 (72.3%) patients without mutations studied porphyrin metabolism disorders were detected in 30 (63.8 %), of which insulin resistance is registered only in 16 (34.0 %). Detection of mutations C282Y and H63D in the HFE gene in combination with disorders of porphyrin metabolism on the background of insulin resistance is likely to allow such patients considered as candidates for inclusion in the higher risk of formation of diabetes.

Thyroid-stimulating hormone and free thyroxine levels in persons with HFE C282Y homozygosity, a common hemochromatosis genotype: the HEIRS study.

PubMed

Barton, James C; Leiendecker-Foster, Catherine; Reboussin, David M; Adams, Paul C; Acton, Ronald T; Eckfeldt, John H

2008-08-01

Relationships of thyroid and iron measures in large cohorts are unreported. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (T4) in white participants of the primary care-based Hemochromatosis and Iron Overload Screening (HEIRS) Study. We measured serum TSH and free T4 in 176 HFE C282Y homozygotes without previous hemochromatosis diagnoses and in 312 controls without HFE C282Y or H63D who had normal serum iron measures and were matched to C282Y homozygotes for Field Center, age group, and initial screening date. We defined hypothyroidism as having TSH >5.00 mIU/L and free T4 <0.70 ng/dL, and hyperthyroidism as having TSH <0.400 mIU/L and free T4 >1.85 ng/dL. Multivariate analyses were performed using age, sex, Field Center, log(10) serum ferritin (SF), HFE genotype, log(10) TSH, and log(10) free T4. Prevalences of hypothyroidism in C282Y homozygotes and controls were 1.7% and 1.3%, respectively, and of hyperthyroidism 0% and 1.0%, respectively. Corresponding prevalences did not differ significantly. Correlations of log(10) SF with log(10) free T4 were positive (p = 0.2368, C282Y homozygotes; p = 0.0492, controls). Independent predictors of log(10) free T4 were log(10) TSH (negative association) and age (positive association); positive predictors of log(10) SF were age, male sex, and C282Y homozygosity. Proportions of C282Y homozygotes and controls who took medications to supplement or suppress thyroid function did not differ significantly. Prevalences of hypothyroidism and hyperthyroidism are similar in C282Y homozygotes without previous hemochromatosis diagnoses and controls. In controls, there is a significant positive association of SF with free T4. We conclude that there is no rationale for routine measurement of TSH or free T4 levels in hemochromatosis or iron overload screening programs.

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network

PubMed Central

Gallego, Carlos J.; Burt, Amber; Sundaresan, Agnes S.; Ye, Zi; Shaw, Christopher; Crosslin, David R.; Crane, Paul K.; Fullerton, S. Malia; Hansen, Kris; Carrell, David; Kuivaniemi, Helena; Derr, Kimberly; de Andrade, Mariza; McCarty, Catherine A.; Kitchner, Terrie E.; Ragon, Brittany K.; Stallings, Sarah C.; Papa, Gabriella; Bochenek, Joseph; Smith, Maureen E.; Aufox, Sharon A.; Pacheco, Jennifer A.; Patel, Vaibhav; Friesema, Elisha M.; Erwin, Angelika Ludtke; Gottesman, Omri; Gerhard, Glenn S.; Ritchie, Marylyn; Motulsky, Arno G.; Kullo, Iftikhar J.; Larson, Eric B.; Tromp, Gerard; Brilliant, Murray H.; Bottinger, Erwin; Denny, Joshua C.; Roden, Dan M.; Williams, Marc S.; Jarvik, Gail P.

2015-01-01

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data. PMID:26365338

Towards the isolation of the idiopathic hemochromatosis disease gene

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

Chorney, M.J.; Venditti, C.P.; Harris, J.M.

1994-09-01

Despite the existence of many useful reagents which exist to aid in the positional cloning of the idiopathic hermochromatosis disease gene (HFE), the nature and precise location of this common genetic disease has remained elusive. Our group has pursued an MHC-based positional cloning approach which has centered on the precise physical definition of HLA-A variant chromosomes. Using deletion breakpoint locations in combination with genetic data derived from the Brittany founder population, we have used cDNA selection techniques to isolate new members of distinct multigene families which reside in the HFE critical region (distal to the HLA-A9 breakpoint/proximal to HLA-F). Wemore » have also initiated an independent set of cytogenetic and physical mapping studies to position the marker D6S105 with respect to the telomeric end of the class I subregion. Toward this end, we have performed double labelling FISH experiments which have allowed the localization of D6S105-containing YACs with respect to the HLA-A subregion and to the major G-bands which contain these loci. We have also derived single-copy probes, cosmids and cDNA clones from the region which have been used to create a physical map around D6S105. The combination of the cytogenetic and physical mapping data indicate that D6S105 is at least 2 Mb from HLA-A and that the distal limit of the MHC class I region may extend much further into the the euchromatic region of 6p21.3 than previously expected. A mega-YAC walk is now in progress to link the two loci. Finally, we have identified and characterized a family which is segregating a balanced inversion in phase with HFE. The breakpoint locations of this mutant chromosome may be important in the precise positioning of the HFE gene and attempts to define coding sequences in the proximity of this rearrangement are underway.« less

Insulin Resistance and Metabolic Syndrome: Clinical and Laboratory Associations in African Americans Without Diabetes in the Hemochromatosis and Iron Overload Screening Study.

PubMed

Barton, James C; Barton, Jackson Clayborn; Acton, Ronald T

2018-05-31

We sought to determine associations with insulin resistance (IR) and metabolic syndrome (MetS) in African Americans. We studied African American adults without diabetes in a postscreening examination. Participants included Cases: transferrin saturation (TS) >50% and serum ferritin (SF) >300 μg/L (M), and TS >45% and SF >200 μg/L (F), regardless of HFE genotype; and Controls: TS/SF 25th to 75th percentiles and HFE wt/wt (wild type). We excluded participants with fasting <8 h; fasting glucose >126 mg/dL; hepatitis B or C; cirrhosis; pregnancy; or incomplete datasets. We analyzed age; sex; Case/Control; body mass index (BMI); systolic and diastolic blood pressures; neutrophils; lymphocytes; alanine aminotransferase; aspartate aminotransferase; elevated C-reactive protein (CRP >0.5 mg/L); TS; and SF. We computed homeostasis model assessment of insulin resistance (HOMA-IR) using fasting serum glucose and insulin, and defined IR as HOMA-IR fourth quartile (≥2.42). There were 312 Cases and 86 Controls (56.3% men). Ninety-one percent had HFE wt/wt. None had HFE p.C282Y. A significant increasing trend across HOMA-IR quartiles was observed for BMI only. Multivariable regression on HOMA-IR revealed significant positive associations: age; BMI; lymphocytes; SF; and CRP >0.5 mg/L; and significant negative associations: neutrophils and TS. Logistic regression on IR revealed BMI [odds ratio (OR) 1.3 (95% confidence interval 1.2-1.4)] and CRP >0.5 mg/L [OR 2.7 (1.2-6.3)]. Fourteen participants (3.5%) had MetS. Logistic regression on MetS revealed one association: IR [OR 7.4 (2.1-25.2)]. In African Americans without diabetes, IR was associated with BMI and CRP >0.5 mg/L, after adjustment for other variables. MetS was associated with IR alone.

Kinetic assessment of the potassium ferrate(VI) oxidation of antibacterial drug sulfamethoxazole.

PubMed

Sharma, Virender K; Mishra, Santosh K; Ray, Ajay K

2006-01-01

Sulfamethoxazole (SMX), a worldwide-applied antibacterial drug, was recently found in surface waters and in secondary wastewater effluents, which may result in ecotoxical effects in the environment. Herein, removal of SMX by environmentally-friendly oxidant, potassium ferrate(VI) (K(2)FeO(4)), is sought by studying the kinetics of the reaction between Fe(VI) and SMX as a function of pH (6.93-9.50) and temperature (15-45 degrees C). The rate law for the oxidation of SMX by Fe(VI) is first-order with respect to each reactant. The observed second-order rate constant decreased non-linearly from 1.33+/-0.08 x 10(3) M(-1)s(-1) to 1.33+/-0.10 x 10(0) M(-1)s(-1) with an increase of pH from 7.00 to 9.50. This is related to protonation of Fe(VI) (HFeO(4)(-) <==> H(+) + FeO(4)(2-); pK(a,HFeO(4)) = 7.23) and sulfamethoxazole (SH <==> H(+) + S(-); pK(a,SH)=5.7). The estimated rate constants were k(11)(HFeO(4)(-) + SH) = 3.0 x 10(4) M(-1)s(-1), k(12)(HFeO(4)(-) + S(-)) = 1.7 x 10(2) M(-1)s(-1), and k(13) (FeO(4)(2-) + SH) = 1.2 x 10(0) M(-1)s(-1). The energy of activation at pH 7.0 was found to be 1.86+/-0.04 kJ mol(-1). If excess potassium ferrate(VI) concentration (10 microM) is used than the SMX in water, the half-life of the reaction using a rate constant obtained in our study would be approximately 2 min at pH 7. The reaction rates are pH dependent; thus, so are the half-lives of the reactions. The results suggest that K(2)FeO(4) has the potential to serve as an oxidative treatment chemical for removing SMX in water.

Iron loading in HFE p.C282Y homozygotes found by population screening: relationships to HLA-type and T-lymphocyte subsets.

PubMed

Thorstensen, Ketil; Kvitland, Mona A; Irgens, Wenche Ø; Åsberg, Arne; Borch-Iohnsen, Berit; Moen, Torolf; Hveem, Kristian

2017-11-01

Iron loading in p.C282Y homozygous HFE hemochromatosis subjects is highly variable, and it is unclear what factors cause this variability. Finding such factors could aid in predicting which patients are at highest risk and require closest follow-up. The degree of iron loading has previously been associated with certain HLA-types and with abnormally low CD8 + cell counts in peripheral blood. In 183 Norwegian, p.C282Y homozygotes (104 men, 79 women) originally found through population screening we determined HLA type and measured total T-lymphocytes, CD4 + and CD8 + cells, and compared this with data on iron loading. In p.C282Y homozygous men, but not in homozygous women, we found that the presence of two HLA-A*03 alleles increased the iron load on average by approximately 2-fold compared to p.C282Y homozygous men carrying zero or one A*03 allele. On the other hand, the presence of two HLA-A*01 alleles, in male subjects, apparently reduced the iron loading. In p.C282Y homozygous individuals, the iron loading was increased if the CD8 + cell number was below the 25 percentile or if the CD4 + cell number was above the 75 percentile. This effect appeared to be additive to the effect of the number of HLA-A*03 alleles. Our data indicate that homozygosity for the HLA-A*03 allele significantly increases the risk of excessive iron loading in Norwegian p.C282Y homozygous male patients. In addition, low CD8 + cell number or high CD4 + cell number further increases the risk of excessive iron loading.

Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production.

PubMed

Desgrippes, Romain; Lainé, Fabrice; Morcet, Jeff; Perrin, Michèle; Manet, Ghislain; Jezequel, Caroline; Bardou-Jacquet, Edouard; Ropert, Martine; Deugnier, Yves

2013-05-01

An excess of visceral adipose tissue could be involved as a modulator of the penetrance of HFE hemochromatosis since fat mass is associated with overexpression of hepcidin and low transferrin saturation was found to be associated with being overweight in women. This study was aimed at assessing the relationship between body mass index (BMI), a surrogate marker of insulin resistance, and iron burden in HFE hemochromatosis. In all, 877 patients from a cohort of C282Y homozygotes were included in the study when BMI at diagnosis and amount of iron removed (AIR) by phlebotomy were available. No relationship between AIR and BMI was found in men, whereas 15.1% (52/345) of women with AIR <6 g had BMI ≥28 versus 3.9% (2/51) of women with AIR ≥6 g (P = 0.03). At multivariate analysis, BMI was an independent factor negatively associated with AIR (odds ratio: 0.13; 95% confidence interval [CI]: 0.03-0.71) together with serum ferritin, serum transferrin, transferrin saturation, hemoglobin, and alanine aminotransferase. In a control group of 30 C282Y homozygous women, serum hepcidin was significantly higher in overweight (14.3 mmoL/L ± 7.1) than in lean (7.9 mmoL/L ± 4.3) women (P = 0.0005). In C282Y homozygous women, BMI ≥28 kg/m(2) is independently associated with a lower amount of iron removed by phlebotomy. BMI is likely a modulator factor of the phenotypic expression of C282Y homozygosity, likely through an increase of circulating levels of hepcidin. Copyright © 2013 American Association for the Study of Liver Diseases.

Molecular Diagnostic and Pathogenesis of Hereditary Hemochromatosis

PubMed Central

Santos, Paulo C. J. L.; Krieger, Jose E.; Pereira, Alexandre C.

2012-01-01

Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by enhanced intestinal absorption of dietary iron. Without therapeutic intervention, iron overload leads to multiple organ damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism and skin pigmentation. Most HH patients carry HFE mutant genotypes: homozygosity for p.Cys282Tyr or p.Cys282Tyr/p.His63Asp compound heterozygosity. In addition to HFE gene, mutations in the genes that encode hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) have been associated with regulation of iron homeostasis and development of HH. The aim of this review was to identify the main gene mutations involved in the pathogenesis of type 1, 2, 3 and 4 HH and their genetic testing indication. HFE testing for the two main mutations (p.Cys282Tyr and p.His63Asp) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values. The evaluation of the HJV p.Gly320Val mutation must be the molecular test of choice in suspected patients with juvenile hemochromatosis with less than 30 years and cardiac or endocrine manifestations. In conclusion, HH is an example that genetic testing can, in addition to performing the differential diagnostic with secondary iron overload, lead to more adequate and faster treatment. PMID:22408404

Multi-unit Operations in Non-Nuclear Systems: Lessons Learned for Small Modular Reactors

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

OHara J. M.; Higgins, J.; DAgostino, A.

2012-01-17

The nuclear-power community has reached the stage of proposing advanced reactor designs to support power generation for decades to come. Small modular reactors (SMRs) are one approach to meet these energy needs. While the power output of individual reactor modules is relatively small, they can be grouped to produce reactor sites with different outputs. Also, they can be designed to generate hydrogen, or to process heat. Many characteristics of SMRs are quite different from those of current plants and may be operated quite differently. One difference is that multiple units may be operated by a single crew (or a singlemore » operator) from one control room. The U.S. Nuclear Regulatory Commission (NRC) is examining the human factors engineering (HFE) aspects of SMRs to support licensing reviews. While we reviewed information on SMR designs to obtain information, the designs are not completed and all of the design and operational information is not yet available. Nor is there information on multi-unit operations as envisioned for SMRs available in operating experience. Thus, to gain a better understanding of multi-unit operations we sought the lesson learned from non-nuclear systems that have experience in multi-unit operations, specifically refineries, unmanned aerial vehicles and tele-intensive care units. In this paper we report the lessons learned from these systems and the implications for SMRs.« less

Evaluation of HCFC AK 225 Alternatives for Precision Cleaning and Verification

NASA Technical Reports Server (NTRS)

Melton, D. M.

1998-01-01

Maintaining qualified cleaning and verification processes are essential in an production environment. Environmental regulations have and are continuing to impact cleaning and verification processing in component and large structures, both at the Michoud Assembly Facility and component suppliers. The goal of the effort was to assure that the cleaning and verification proceeds unimpeded and that qualified, environmentally compliant material and process replacements are implemented and perform to specifications. The approach consisted of (1) selection of a Supersonic Gas-Liquid Cleaning System; (2) selection and evaluation of three cleaning and verification solvents as candidate alternatives to HCFC 225 (Vertrel 423 (HCFC), Vertrel MCA (HFC/1,2-Dichloroethylene), and HFE 7100DE (HFE/1,2 Dichloroethylene)); and evaluation of an analytical instrumental post cleaning verification technique. This document is presented in viewgraph format.

Serum ferritin is a biomarker for liver mortality in the Hemochromatosis and Iron Overload Screening Study.

PubMed

Adams, Paul C; Barton, James C; Guo, Helen; Alter, David; Speechley, Mark

2015-01-01

We identified no reports of long-term follow-up of participants in hemochromatosis screening programs. We evaluated causes of death and survival in non-C282Y homozygous Canadian participants in the primary care-based hemochromatosis and iron overload screening (HEIRS) study. Initial screening (IS) included transferrin saturation (TS), serum ferritin (SF), HFE genotyping (C282Y, H63D), and health questionnaire responses. By definition, participants without C282Y or H63D had HFE wt/wt. We linked 20,306 Canadian participants to the Ontario Death Registry for dates and causes of death 9 y after IS. We computed Cox proportional hazards to identify factors with increased death risks and Kaplan-Meier curves to estimate survival of non-C282Y homozygous participants with SF ≤ 1,000 μg/L and > 1,000 μg/dL. There were 19,052 evaluable participants (IS mean age 49 y; 60% women; 93 C282Y homozygotes). There were 988 deaths. Significantly increased hazard ratios for all-cause mortality were positively associated with TS, SF, men, and C282Y homozygosity, and liver disease, diabetes, and heart failure reports. Non-C282Y homozygous participants with SF > 1,000 μg/L had lower survival than those with SF ≤ 1,000 μg/L (p < 0.0001). Nine years after initial screening, non-C282Y homozygous participants and SF > 1,000 μg/L was associated with decreased survival.

Morbidity and mortality in first-degree relatives of C282Y homozygous probands with clinically detected haemochromatosis compared with the general population: the HEmochromatosis FAmily Study (HEFAS).

PubMed

Jacobs, E M G; Hendriks, J C M; Marx, J J M; van Deursen, C Th B M; Kreeftenberg, H G; de Vries, R A; Stalenhoef, A F H; Verbeek, A L M; Swinkels, D W

2007-12-01

Family screening has been suggested as a sophisticated model for the early detection of HFE-related hereditary haemochromatosis (HH). However, until now, controlled studies on the morbidity and mortality in families with HH are lacking. Data on iron parameters, morbidity and mortality were collected from 224 dutch C282Y-homozygous probands with clinically overt HH and 735 of their first-degree family members, all participating in the HEmochromatosis fAmily study (HEfAs). These data were compared with results obtained from an age- and gender-matched normal population. HEfAs and controls filled in similar questionnaires on demographics, lifestyle factors, health, morbidity and mortality. A significantly higher proportion of the HEfAs first-degree family members reported to be diagnosed with haemochromatosis-related diseases: 45.7 vs 19.4% of the matched normal population (McNemar p<0.001). Mortality among siblings, children and parents in the HEFAS population was similar to that in the relatives of matched control. In this study we show that, morbidity among first-degree family members of C282Y-homozygous probands previously diagnosed with clinically proven HH is higher than that in an age- and gender-matched normal population. Further studies are needed to definitely connect these increase morbidity figures to increase prevalenc of the C282Y mutated HFE-gene and elevated serum iron indices.

Haplotype analysis of the HFE gene among populations of Northern Eurasia, in patients with metabolic disorders or stomach cancer, and in long-lived people.

PubMed

Mikhailova, S V; Babenko, V N; Ivanoshchuk, D E; Gubina, M A; Maksimov, V N; Solovjova, I G; Voevoda, M I

2016-06-17

Previously, it was shown that the HFE gene (associated with human hereditary hemochromatosis) has several haplotypes of intronic polymorphisms. Some haplotype frequencies are race specific and hence can be used in phylogenetic analysis. We assumed that analysis of Caucasoid patients-living now in Western Siberia and having diseases associated with dietary habits and metabolic rate-will allow us to understand the processes of possible selection during settling of the northern part of Asia. Haplotype analysis of Northern Eurasian native and recently settled ethnic groups was performed on polymorphisms rs1799945, rs1800730, rs1800562, rs2071303, rs1800708, rs1572982, rs2794719, rs807209, and rs2032451 of this gene. The CCA haplotype of the rs2071303, rs1800708, and rs1572982 was found to be associated with HLA-A2 (39 %) in Asian populations. Haplotype analysis for the rs1799945, rs1800730, rs1800562, rs2071303, rs1800708, and rs1572982 was performed on Russian patients with some metabolic disorders or stomach cancer and among long-lived people. Decreased frequencies of the TTA haplotype (T in rs2071303, T in rs1800708, and A in rs1572982) were observed in the groups of patients with diseases associated with overweight (fatty liver disease, type 2 diabetes mellitus, or metabolic syndrome + arterial hypertension) as compared with the control sample. We detected significant differences in this haplotype's frequency between the patients with type 2 diabetes mellitus and Russian adolescents, elderly citizens, and long-lived people (χ(2) P value = 0.003, 0.010, and 0.015, respectively). No significant differences in frequencies of the alleles with mutations in coding regions of the HFE gene (C282Y, H63D, and S65C) were detected between the analyzed patients (with stomach cancer, metabolic syndrome, fatty liver disease, or type 2 diabetes mellitus) and the control Caucasoid sample. Monophyletic origin of H63D (rs1799945) was confirmed in Caucasoids and Northern Asians. The reasons for a sharp increase in the frequency of CCA haplotype of HFE in the Asian race remain unclear.

Reverse cascade screening of newborns for hereditary haemochromatosis: a model for other late onset diseases?

PubMed

Cadet, E; Capron, D; Gallet, M; Omanga-Léké, M-L; Boutignon, H; Julier, C; Robson, K J H; Rochette, J

2005-05-01

Genetic testing can determine those at risk for hereditary haemochromatosis (HH) caused by HFE mutations before the onset of symptoms. However, there is no optimum screening strategy, mainly owing to the variable penetrance in those who are homozygous for the HFE Cys282Tyr (C282Y) mutation. The objective of this study was to identify the majority of individuals at serious risk of developing HFE haemochromatosis before they developed life threatening complications. We first estimated the therapeutic penetrance of the C282Y mutation in people living in la Somme, France, using genetic, demographic, biochemical, and follow up data. We examined the benefits of neonatal screening on the basis of increased risk to relatives of newborns carrying one or two copies of the C282Y mutation. Between 1999 and 2002, we screened 7038 newborns from two maternity hospitals in the north of France for the C282Y and His63Asp (H63D) mutations in the HFE gene, using bloodspots collected on Guthrie cards. Family studies and genetic counselling were undertaken, based on the results of the baby's genotype. In la Somme, we found that 24% of the adults homozygous for the C282Y mutation required at least 5 g iron to be removed to restore normal iron parameters (that is, the therapeutic penetrance). In the reverse cascade screening study, we identified 19 C282Y homozygotes (1/370), 491 heterozygotes (1/14) and 166 compound heterozygotes (1/42) in 7038 newborns tested. The reverse cascade screening strategy resulted in 80 adults being screened for both mutations. We identified 10 previously unknown C282Y homozygotes of whom six (four men and two women) required venesection. Acceptance of neonatal screening was high; parents understood the risks of having HH and the benefits of early detection, but a number of parents were reluctant to take the test themselves. Neonatal screening for HH is straightforward. Reverse cascade screening increased the efficiency of detecting affected adults with undiagnosed haemochromatosis. This strategy allows almost complete coverage for HH and could be a model for efficient screening for other late onset genetic diseases.

Longer survival associated with HLA-A*03, B*14 among 212 hemochromatosis probands with HFE C282Y homozygosity and HLA-A and -B typing and haplotyping.

PubMed

Barton, James C; Barton, J Clayborn; Acton, Ronald T

2010-11-01

Human leukocyte antigen (HLA) haplotypes may influence iron phenotypes in patients with HFE hemochromatosis and could affect survival. We tabulated general characteristics of HLA-A and -B types and haplotypes of HFE C282Y/C282Y probands diagnosed in medical care and analyzed these data to identify HLA survival modifiers. There were 212 probands (130 men, 82 women). Mean follow-up was 12.0 ± 6.4 yr (0.1-41.2 yr; 34 deaths). HLA-A*03 was more prevalent in men (76.9% vs. 61.0% women; P = 0.0129); 35.4% of men and 29.3% of women had A*03, B*07; and 7.7% of men and 8.5% of women had A*03, B*14. Twenty-three probands had cirrhosis; none had A*03, B*14. Positivity for A*03 or A*03, B*07 was not a significant predictor or modifier of survival. In multiple regression analyses, A*03, B*14 predicted longer survival (P = 0.0004). Kaplan-Meier analysis confirmed longer survival in probands with A*03, B*14 (P = 0.0199, log-rank test). After excluding the 23 non-A*03, B*14 probands with cirrhosis, survival of probands with A*03, B*14 was still greater than that of probands without A*03, B*14 (P = 0.0254; log-rank test). Twenty-four years after diagnosis, cumulative survival of probands with and without A*03, B*14 was 100% and 58%, respectively. The percentage of deaths due to iron overload was lower in probands with A*03, B*14 (0% vs. 21.9%; P = 0.0392). In hemochromatosis probands with HFE C282Y/C282Y, survival was longer in those with HLA-A*03, B*14. Earlier age at diagnosis and less severe iron overload in probands with A*03, B*14 could explain this difference. © 2010 John Wiley & Sons A/S.

Diagnosis of hepatic iron overload: a family study illustrating pitfalls in diagnosing hemochromatosis.

PubMed

Schranz, Melanie; Talasz, Heribert; Graziadei, Ivo; Winder, Thomas; Sergi, Consolato; Bogner, Klaus; Vogel, Wolfgang; Zoller, Heinz

2009-03-01

Recent identification of genetic variants in iron storage disease has changed the classification system and diagnostic algorithms for hemochromatosis. Clinical diagnosis of the disease requires phenotypic evidence of iron overload because the commonly disease-associated HFE genotypes have an incomplete penetrance. Furthermore, approximately 20% of patients with a clinical diagnosis of hemochromatosis have no disease-associated genotype, which underlines the importance of clear phenotypic criteria of hemochromatosis. A diagnosis of hemochromatosis cannot be made even in patients with liver cirrhosis simply on the basis of genetic testing that indicates that iron overload is the cause of the disease and not its consequence. Proper diagnosis requires integration of clinical presentation, family history, and the results of biochemical and histopathologic tests. Here we propose a rational diagnostic algorithm for hepatic iron overload syndromes and illustrate potential pitfalls by presenting a family study in a pedigree with rare HFE variants (H63D and E168Q), in cis on the same chromosome. Although the clinical suspicion of hemochromatosis was confirmed by histology, chemical analysis of liver tissue revealed a normal hepatic iron concentration, which is compatible with the genetic finding of 1 normal and 1 doubly mutated allele. In conclusion, clinical suspicion of hemochromatosis and elevated serum iron parameters should prompt HFE genotyping for C282Y and H63D. Should they be uninformative, further genetic tests should be recommended only if iron overload in liver tissue has been confirmed chemically.

HFE gene mutation and iron overload in Egyptian pediatric acute lymphoblastic leukemia survivors: a single-center study.

PubMed

El-Rashedi, Farida H; El-Hawy, Mahmoud A; El-Hefnawy, Sally M; Mohammed, Mona M

2017-08-01

Hereditary hemochromatosis gene (HFE) mutations have a role in iron overload in pediatric acute lymphoblastic leukemia (ALL) survivors. We aimed to evaluate the genotype frequency and allelic distribution of the two HFE gene mutations (C282Y and H63D) in a sample of Egyptian pediatric ALL survivors and to detect the impact of these two mutations on their iron profile. This study was performed on 35 ALL survivors during their follow-up visits to the Hematology and Oncology Unit, Pediatric Department, Menoufia University Hospitals. Thirty-five healthy children of matched age and sex were chosen as controls. After completing treatment course, ALL survivors were screened for the prevalence of these two mutations by polymerase chain reaction-restriction fragment length polymorphism. Serum ferritin levels were measured by an enzyme-linked immunosorbent assay technique (ELISA). C282Y mutation cannot be detected in any of the 35 survivors or the 35 controls. The H63D heterozygous state (CG) was detected in 28.6% of the survivors group and in 20% of controls, while the H63D homozygous (GG) state was detected in 17.1% of survivors. No compound heterozygosity (C282Y/H63D) was detected at both groups with high G allele frequency (31.4%) in survivors more than controls (10%). There were significant higher levels of iron parameters in homozygote survivors than heterozygotes and the controls. H63D mutation aggravates the iron overload status in pediatric ALL survivors.

Effect of hereditary haemochromatosis genotypes and iron overload on other trace elements.

PubMed

Beckett, Jeffrey M; Ball, Madeleine J

2013-02-01

Hereditary haemochromatosis is a common genetic disorder involving dysregulation of iron absorption. There is some evidence to suggest that abnormal iron absorption and metabolism may influence the status of other important trace elements. In this study, the effect of abnormal HFE genotypes and associated iron overload on the status of other trace elements was examined. Dietary data and blood samples were collected from 199 subjects (mean age = 55.4 years; range = 21-81 years). Dietary intakes, serum selenium, copper and zinc concentrations and related antioxidant enzymes (glutathione peroxidase and superoxide dismutase) in subjects with normal HFE genotype (n = 118) were compared to those with abnormal HFE genotype, with both normal iron status (n = 42) and iron overload (n = 39). For most dietary and biochemical variables measured, there were no significant differences between study groups. Red cell GPx was significantly higher in male subjects with normal genotypes and normal iron status compared to those with abnormal genotypes and normal iron status (P = 0.03) or iron overload (P = 0.001). Red cell GPx was also highest in normal women and significantly lower in the abnormal genotype and normal iron group (P = 0.016), but not in the iron overload group (P = 0.078). Although it may not be possible to exclude a small effect between the genotype groups on RBC GPx, overall, haemochromatosis genotypes or iron overload did not appear to have a significant effect on selenium, copper or zinc status.

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

PubMed Central

Wongjaikam, Suwakon; Kumfu, Sirinart; Khamseekaew, Juthamas; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

2017-01-01

Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca2+]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca2+]i homeostasis, only DFP + NAC restored cardiac [Ca2+]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca2+]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats. PMID:28287621

SPAR-H Step-by-Step Guidance

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

W. J. Galyean; A. M. Whaley; D. L. Kelly

This guide provides step-by-step guidance on the use of the SPAR-H method for quantifying Human Failure Events (HFEs). This guide is intended to be used with the worksheets provided in: 'The SPAR-H Human Reliability Analysis Method,' NUREG/CR-6883, dated August 2005. Each step in the process of producing a Human Error Probability (HEP) is discussed. These steps are: Step-1, Categorizing the HFE as Diagnosis and/or Action; Step-2, Rate the Performance Shaping Factors; Step-3, Calculate PSF-Modified HEP; Step-4, Accounting for Dependence, and; Step-5, Minimum Value Cutoff. The discussions on dependence are extensive and include an appendix that describes insights obtained from themore » psychology literature.« less

Renewable Formate from C-H Bond Formation with CO2: Using Iron Carbonyl Clusters as Electrocatalysts.

PubMed

Loewen, Natalia D; Neelakantan, Taruna V; Berben, Louise A

2017-09-19

As a society, we are heavily dependent on nonrenewable petroleum-derived fuels and chemical feedstocks. Rapid depletion of these resources and the increasingly evident negative effects of excess atmospheric CO 2 drive our efforts to discover ways of converting excess CO 2 into energy dense chemical fuels through selective C-H bond formation and using renewable energy sources to supply electrons. In this way, a carbon-neutral fuel economy might be realized. To develop a molecular or heterogeneous catalyst for C-H bond formation with CO 2 requires a fundamental understanding of how to generate metal hydrides that selectively donate H - to CO 2 , rather than recombining with H + to liberate H 2 . Our work with a unique series of water-soluble and -stable, low-valent iron electrocatalysts offers mechanistic and thermochemical insights into formate production from CO 2 . Of particular interest are the nitride- and carbide-containing clusters: [Fe 4 N(CO) 12 ] - and its derivatives and [Fe 4 C(CO) 12 ] 2- . In both aqueous and mixed solvent conditions, [Fe 4 N(CO) 12 ] - forms a reduced hydride intermediate, [H-Fe 4 N(CO) 12 ] - , through stepwise electron and proton transfers. This hydride selectively reacts with CO 2 and generates formate with >95% efficiency. The mechanism for this transformation is supported by crystallographic, cyclic voltammetry, and spectroelectrochemical (SEC) evidence. Furthermore, installation of a proton shuttle onto [Fe 4 N(CO) 12 ] - facilitates proton transfer to the active site, successfully intercepting the hydride intermediate before it reacts with CO 2 ; only H 2 is observed in this case. In contrast, isoelectronic [Fe 4 C(CO) 12 ] 2- features a concerted proton-electron transfer mechanism to form [H-Fe 4 C(CO) 12 ] 2- , which is selective for H 2 production even in the presence of CO 2 , in both aqueous and mixed solvent systems. Higher nuclearity clusters were also studied, and all are proton reduction electrocatalysts, but none promote C-H bond formation. Thermochemical insights into the disparate reactivities of these clusters were achieved through hydricity measurements using SEC. We found that only [H-Fe 4 N(CO) 12 ] - and its derivative [H-Fe 4 N(CO) 11 (PPh 3 )] - have hydricities modest enough to avoid H 2 production but strong enough to make formate. [H-Fe 4 C(CO) 12 ] 2- is a stronger hydride donor, theoretically capable of making formate, but due to an overwhelming thermodynamic driving force and the increased electrostatic attraction between the more negative cluster and H + , only H 2 is observed experimentally. This illustrates the fundamental importance of controlling thermochemistry when designing new catalysts selective for C-H bond formation and establishes a hydricity range of 15.5-24.1 or 44-49 kcal mol -1 where C-H bond formation may be favored in water or MeCN, respectively.

Proton Pump Inhibitors Decrease Phlebotomy Need in HFE Hemochromatosis: Double-Blind Randomized Placebo-Controlled Trial.

PubMed

Vanclooster, Annick; van Deursen, Cees; Jaspers, Reggy; Cassiman, David; Koek, Ger

2017-09-01

Phlebotomy constitutes the established treatment for HFE-related hemochromatosis. Retrospective studies have suggested proton pump inhibitors (PPIs) reduce the need for phlebotomy in this population. We conducted a randomized controlled trial to prove this. Thirty p.C282Y homozygous patients were randomly allocated to PPI (pantoprazole 40 mg/day) or placebo for 12 months. Phlebotomies were performed when serum ferritin was > 100 μg/L. Phlebotomy need turned out to be significantly lower in patients taking PPI (P = .0052). PPI treatment significantly reduces the need for phlebotomies in p.C282Y homozygous patients. In view of the known long-term safety profile of PPI, they can be a valuable addition to standard therapy. Clinicaltrials.gov: NCT01524757. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Comparison of effect of 5 MeV proton and Co-60 gamma irradiation on silicon NPN rf power transistors and N-channel depletion MOSFETs

NASA Astrophysics Data System (ADS)

Gnana Prakash, A. P.; Pradeep, T. M.; Hegde, Vinayakprasanna N.; Pushpa, N.; Bajpai, P. K.; Patel, S. P.; Trivedi, Tarkeshwar; Bhushan, K. G.

2017-12-01

NPN transistors and N-channel depletion metal oxide semiconductor field effect transistors (MOSFETs) were irradiated with 5 MeV protons and 60Co gamma radiation in the dose ranging from 1 Mrad(Si) to 100 Mrad(Si). The different electrical characteristics of the NPN transistor such as Gummel characteristics, excess base current (ΔIB), dc current gain (hFE), transconductance (gm), displacement damage factor (K) and output characteristics were studied as a function of total dose. The different electrical characteristics of N-channel MOSFETs such as threshold voltage (Vth), density of interface trapped charges (ΔNit), density of oxide trapped charges (ΔNot), transconductance (gm), mobility (µ) and drain saturation current (IDSat) were studied systematically before and after irradiation in the same dose ranges. A considerable increase in the base current (IB) and decrease in the hFE, gm and collector saturation current (ICSat) were observed after irradiation in the case of the NPN transistor. In the N-channel MOSFETs, the ΔNit and ΔNot were found to increase and Vth, gm, µ and IDSat were found to decrease with increase in the radiation dose. The 5 MeV proton irradiation results of both the NPN transistor and N-channel MOSFETs were compared with 60Co gamma-irradiated devices in the same dose ranges. It was observed that the degradation in 5 MeV proton-irradiated devices is more when compared with the 60Co gamma-irradiated devices at higher total doses.

Involvement of the major histocompatibility complex region in the genetic regulation of circulating CD8 T-cell numbers in humans.

PubMed

Cruz, E; Vieira, J; Gonçalves, R; Alves, H; Almeida, S; Rodrigues, P; Lacerda, R; Porto, G

2004-07-01

Variability in T-lymphocyte numbers is partially explained by a genetic regulation. From studies in animal models, it is known that the Major Histocompatibility Complex (MHC) is involved in this regulation. In humans, this has not been shown yet. The objective of the present study was to test the hypothesis that genes in the MHC region influence the regulation of T-lymphocyte numbers. Two approaches were used. Association studies between T-cell counts (CD4(+) and CD8(+)) or total lymphocyte counts and HLA class I alleles (A and B) or mutations in the HFE (C282Y and H63D), the hemochromatosis gene, in an unrelated population (n = 264). A second approach was a sibpair correlation analysis of the same T-cell counts in relation to HLA-HFE haplotypes in subjects belonging to 48 hemochromatosis families (n = 456 sibpairs). In the normal population, results showed a strong statistically significant association of the HLA-A*01 with high numbers of CD8(+) T cells and a less powerful association with the HLA-A*24 with low numbers of CD8(+) T cells. Sibpair correlations revealed the most significant correlation for CD8(+) T-cell numbers for sibpairs with HLA-HFE-identical haplotypes. This was not observed for CD4(+) T cells. These results show that the MHC region is involved in the genetic regulation of CD8(+) T-cell numbers in humans. Identification of genes responsible for this control may have important biological and clinical implications.

About the Barriers to Reaction of CCl4 with HFeOH and FeCl2

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

Ginovska-Pangovska, Bojana; Camaioni, Donald M.; Dupuis, Michel

2011-08-11

The reactivity of iron nanoparticles in aqueous environments has received considerable attention due to their potential utilization in environmental remediation technologies. As part of a broader program aiming at an improved understanding of the mechanisms involved in the degradation of harmful chlorocarbons, joint experimental and computational studies of model systems were initiated. We previously reported on the reaction of one and two Fe atoms reactions with carbon tetrachloride (CCl4) in direct mimic of “atom-dropping” experiments, with insights into the formation of novel iron-carbon-chlorine complexes, their structures and possible reaction mechanisms. Increasing the level of complexity, we report here on themore » modeling of the reaction of HFeOH and CCl4 as companion research of recent ultra high vacuum experiments of the reaction of Fe with water and CCl4. HFeOH is a stable molecular species formed in the reaction of Fe with H2O. Experimentally the (Fe, H2O, CCl4) system showed no reactivity up to the desorption temperature of CCl4. Electron correlated CCSD(T) calculations (at DFT(B3LYP) optimized structures) indicated an energy barrier to reactivity of 24.5 kcal/mol following the formation of a stable ( 7.5 kcal/mol) long-range precursor complex. This finding is consistent with the lack of experimentally detected reaction products. This work was supported by the US Department of Energy Basic Energy Sciences' Chemical Sciences, Geosciences & Biosciences Division. Pacific Northwest National Laboratory is operated by Battelle for the US Department of Energy.« less

Mild Hydroprocessing with Dispersed Catalyst of Highly Asphaltenic Pitch

NASA Astrophysics Data System (ADS)

Isquierdo, Fernanda

Asphaltene are known to have diverse negative impacts on heavy oil extraction and hydroprocessing. This research then, explores the optimal conditions to convert asphaltenes into lighter material using mild conditions of pressure and temperature, and investigates changes in asphaltene structure during hydroprocessing. Feedstock and products were characterized by Simulated Distillation, Microdeasphalting, Sulfur content, X-ray diffraction, X-ray photoelectron spectroscopy, and Nuclear magnetic resonance spectroscopy. Solid catalysts were analyzed by Themogravimetric analysis, X-ray diffraction, and Dynamic light scattering. Based on the results obtained from X-ray diffraction and Nuclear magnetic resonance spectroscopy analysis a mechanism for the asphaltene hydroprocessing at mild conditions is proposed in which the alky peripheric portion from the original asphaltenes is partially removed during the reaction. The consequence of that process being an increase in the stacking of the aromatics sheets in the remaining asphaltenes. Also, this study investigates different for ultradispersed catalyst compositions, where CoWS, CoMoS, NiWS, FeWS, NiMo/NaHFeSi 2O6 and NaHFeSi2O6 showed a high asphaltene conversion as determined by asphaltene microdeasphalting, FeMoS and NaHFeSi 2O6 presented a high Vacuum Residue as determined by distillation (SIMDIST) analysis conversion, and in terms of sulfur removal CoMoS gave the higher conversion. In addition, all the catalyst tested showed a coke production lower than 1%. Finally, a kinetic study for the pitch hydroprocessing using CoMoS as catalysts gave a global activation energy of 97.3 kJ/mol.

Highly sensitivity adhesion molecules detection in hereditary haemochromatosis patients reveals altered expression.

PubMed

Norris, S; White, M; Mankan, A K; Lawless, M W

2010-04-01

Several abnormalities in the immune status of patients with hereditary haemochromatosis (HH) have been reported, suggesting an imbalance in their immune function. This may include persistent production of, or exposure to, altered immune signalling contributing to the pathogenesis of this disorder. Adhesion molecules L-, E- and P-Selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) are some of the major regulators of the immune processes and altered levels of these proteins have been found in pathological states including cardiovascular diseases, arthritis and liver cancer. The aim of this study was to assess L-, E- and P-Selectin, ICAM-1 and VCAM-1 expression in patients with HH and correlate these results with HFE mutation status and iron indexes. A total of 139 subjects were diagnosed with HH (C282Y homozygotes = 87, C282Y/H63D = 26 heterozygotes, H63D homozygotes = 26), 27 healthy control subjects with no HFE mutation (N/N), 18 normal subjects heterozygous for the H63D mutation served as age-sex-matched controls. We observed a significant decrease in L-selectin (P = 0.0002) and increased E-selectin and ICAM-1 (P = 0.0006 and P = 0.0059) expression in HH patients compared with healthy controls. This study observes for the first time that an altered adhesion molecules profile occurs in patients with HH that is associated with specific HFE genetic component for iron overload, suggesting that differential expression of adhesion molecules may play a role in the pathogenesis of HH.

Increased risk of death from iron overload among 422 treated probands with HFE hemochromatosis and serum levels of ferritin greater than 1000 μg/L at diagnosis.

PubMed

Barton, James C; Barton, J Clayborn; Acton, Ronald T; So, Jeffrey; Chan, Susanne; Adams, Paul C

2012-04-01

We investigated the risk of death from iron overload among treated hemochromatosis probands who were homozygous for HFE C282Y and had serum levels of ferritin greater than 1000 μg/L at diagnosis. We compared serum levels of ferritin at diagnosis and other conditions with the rate of iron overload-associated death using data from 2 cohorts of probands with hemochromatosis who were homozygous for HFE C282Y (an Alabama cohort, n = 294, 63.9% men and an Ontario cohort, n = 128, 68.8% men). We defined iron overload-associated causes of death as cirrhosis (including hepatic failure and primary liver cancer) caused by iron deposition and cardiomyopathy caused by myocardial siderosis. All probands received phlebotomy and other appropriate therapy. The mean survival times after diagnosis were 13.2 ± 7.3 y and 12.5 ± 8.3 y in Alabama and Ontario probands, respectively. Serum levels of ferritin greater than 1000 μg/L at diagnosis were observed in 30.1% and 47.7% of Alabama and Ontario probands, respectively. In logistic regressions of serum ferritin greater than 1000 μg/L, there were significant positive associations with male sex and cirrhosis in Alabama probands and with age, male sex, increased levels of alanine and aspartate aminotransferases, and cirrhosis in Ontario probands. Of probands with serum levels of ferritin greater than 1000 μg/L at diagnosis, 17.9% of those from Alabama and 14.8% of those from Ontario died of iron overload. Among probands with serum levels of ferritin greater than 1000 μg/L, the relative risk of iron overload-associated death was 5.4 for the Alabama group (95% confidence interval [CI], 2.2-13.1; P = .0002) and 4.9 for the Ontario group (95% CI, 1.1-22.0; P = .0359). In hemochromatosis probands homozygous for HFE C282Y, serum levels of ferritin greater than 1000 μg/L at diagnosis were positively associated with male sex and cirrhosis. Even with treatment, the relative risk of death from iron overload was 5-fold greater in probands with serum levels of ferritin greater than 1000 μg/L. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

A Statistical Analysis of Langmuir Wave-Electron Correlations Observed by the CHARM II Auroral Sounding Rocket

NASA Astrophysics Data System (ADS)

Dombrowski, M. P.; Labelle, J. W.; Kletzing, C.; Bounds, S. R.; Kaeppler, S. R.

2014-12-01

Langmuir-mode electron plasma waves are frequently observed by spacecraft in active plasma environments such as the ionosphere. Ionospheric Langmuir waves may be excited by the bump-on-tail instability generated by impinging beams of electrons traveling parallel to the background magnetic field (B). The Correlation of High-frequencies and Auroral Roar Measurement (CHARM II) sounding rocket was launched into a substorm at 9:49 UT on 17 February 2010, from the Poker Flat Research Range in Alaska. The primary instruments included the University of Iowa Wave-Particle Correlator (WPC), the Dartmouth High-Frequency Experiment (HFE), several charged particle detectors, low-frequency wave instruments, and a magnetometer. The HFE is a receiver system which effectively yields continuous (100% duty cycle) electric-field waveform measurements from 100 kHz to 5 MHz, and which had its detection axis aligned nominally parallel to B. The HFE output was fed on-payload to the WPC, which uses a phase-locked loop to track the incoming wave frequency with the most power, then sorting incoming electrons at eight energy levels into sixteen wave-phase bins. CHARM II encountered several regions of strong Langmuir wave activity throughout its 15-minute flight, and the WPC showed wave-lock and statistically significant particle correlation distributions during several time periods. We show results of an in-depth analysis of the CHARM II WPC data for the entire flight, including statistical analysis of correlations which show evidence of direct interaction with the Langmuir waves, indicating (at various times) trapping of particles and both driving and damping of Langmuir waves by particles. In particular, the sign of the gradient in particle flux appears to correlate with the phase relation between the electrons and the wave field, with possible implications for the wave physics.

Modeling of "Stripe" Wave Phenomena Seen by the CHARM II and ACES Sounding Rockets

NASA Astrophysics Data System (ADS)

Dombrowski, M. P.; Labelle, J. W.

2010-12-01

Two recent sounding-rocket missions—CHARM II and ACES—have been launched from Poker Flat Research Range, carrying the Dartmouth High-Frequency Experiment (HFE) among their primary instruments. The HFE is a receiver system which effectively yields continuous (100% duty cycle) E-field waveform measurements up to 5 MHz. The CHARM II sounding rocket was launched 9:49 UT on 15 February 2010 into a substorm, while the ACES mission consisted of two rockets, launched into quiet aurora at 9:49 and 9:50 UT on 29 January 2009. At approximately 350 km on CHARM II and the ACES High-Flyer, the HFE detected short (~2s) bursts of broadband (200-500 kHz) noise with a 'stripe' pattern of nulls imposed on it. These nulls have 10 to 20 kHz width and spacing, and many show a regular, non-linear frequency-time relation. These events are different from the 'stripes' discussed by Samara and LaBelle [2006] and Colpitts et al. [2010], because of the density of the stripes, the non-linearity, and the appearance of being an absorptive rather than emissive phenomenon. These events are similar to 'stripe' features reported by Brittain et al. [1983] in the VLF range, explained as an interference pattern between a downward-traveling whistler-mode wave and its reflection off the bottom of the ionosphere. Following their analysis method, we modeled our stripes as higher-frequency interfering whistlers reflecting off of a density gradient. This model predicts the near-hyperbolic frequency-time curves and high density of the nulls, and therefore shows promise at explaining the new observations.

Gender and plasma iron biomarkers, but not HFE gene mutations, increase the risk of colorectal cancer and polyps.

PubMed

Castiella, Agustin; Múgica, Fernando; Zapata, Eva; Zubiaurre, Leire; Iribarren, Arantxa; de Juan, M Dolores; Alzate, Luis; Gil, Ines; Urdapilleta, Gregorio; Otazua, Pedro; Emparanza, José Ignacio

2015-09-01

A cohort study of patients included in the Basque Country colorectal cancer (CRC) screening programme was carried out to assess the risk of adenomatous polyps and CRC (P-CRC) associated with HFE gene mutations, with gender and with iron biomarkers (serum ferritin (SF), iron (Fe) and transferrin saturation index (TSI)). Among 432 included patients (mean age 59.8 years), 263 were men (60.9 %) and 169 women (39.1 %). P-CRC were identified in 221 patients (51.2 %) and no polyps (NP) in 211 patients (48.8 %). HFE mutations were identified in 43.8 % of the patients. C282Y/wt genotypic frequency was 6.8 % in the P-CRC group and 1.4 % in the NP group (p < 0.05). The allelic frequency was 3.8 versus 1.2 % (p < 0.05). For laboratory, all three iron biomarkers showed a statistically significant difference: mean Fe, 91.29 ± 34 for P-CRC and 80.81 ± 30.59 for NP group. Mean TSI for P-CRC was 24.95 ± 8.90 and 22.74 ± 8.79 for NP group. Mean SF 308.09 ± 536.32 for P-CRC and 177.55 ± 159.95 for NP group. In a multivariate logistic regression analysis, only male gender (odds ratio (OR) = 2.04, 1.29-3.22), SF (OR = 1.001, 1.0004-1.003) and Fe (OR = 1.01, 1.004-1.02) were related with the presence of CRC and adenoma. Men gender and raised serum iron biomarkers increase the risk of P-CRC.

Loss of Hfe Leads to Progression of Tumor Phenotype in Primary Retinal Pigment Epithelial Cells

PubMed Central

Gnana-Prakasam, Jaya P.; Veeranan-Karmegam, Rajalakshmi; Coothankandaswamy, Veena; Reddy, Sushma K.; Martin, Pamela M.; Thangaraju, Muthusamy; Smith, Sylvia B.; Ganapathy, Vadivel

2013-01-01

Purpose. Hemochromatosis is a disorder of iron overload arising mostly from mutations in HFE. HFE is expressed in retinal pigment epithelium (RPE), and Hfe−/− mice develop age-related iron accumulation and retinal degeneration associated with RPE hyperproliferation. Here, the mechanism underlying the hyperproliferative phenotype in RPE was investigated. Methods. Cellular senescence was monitored by β-galactosidase activity. Gene expression was monitored by real-time PCR. Survivin was analyzed by Western blot and immunofluorescence. Migration and invasion were monitored using appropriate kits. Glucose transporters (GLUTs) were monitored by 3-O-methyl-D-glucose uptake. Histone deacetylases (HDACs) were studied by monitoring catalytic activity and acetylation status of histones H3/H4. Results. Hfe−/− RPE cells exhibited slower senescence rate and higher survivin expression than wild type cells. Hfe−/− cells migrated faster and showed greater glucose uptake and increased expression of GLUTs. The expression of HDACs and DNA methyltransferase (DNMTs) also was increased. Similarly, RPE cells from hemojuvelin (Hjv)-knockout mice, another model of hemochromatosis, also had increased expression of GLUTs, HDACs, and DNMTs. The expression of Slc5a8 was decreased in Hfe−/− RPE cells, but treatment with a DNA methylation inhibitor restored the transporter expression, indicating involvement of DNA methylation in the silencing of Slc5a8 in Hfe−/− cells. Conclusions. RPE cells from iron-overloaded mice exhibit several features of tumor cells: decreased senescence, enhanced migration, increased glucose uptake, and elevated levels of HDACs and DNMTs. These features are seen in Hfe−/− RPE cells as well as in Hjv−/− RPE cells, providing a molecular basis for the hyperproliferative phenotype of Hfe−/− and Hjv−/− RPE cells. PMID:23169885

Comparison of oxidative stress and the frequency of polymorphisms in the HFE gene between hemoglobin S trait blood donors and sickle cell disease patients.

PubMed

Viana-Baracioli, L M S; Tukamoto Junior, N C; Ricci Junior, O; Mattos, L C; Ângulo, I L; Bonini-Domingos, C R

2011-12-08

It is well documented that Hb S and iron affect blood cells, and trigger oxidative processes and generation of free radicals with potential for lipid peroxidation. We evaluated the frequency of polymorphisms in the HFE gene in Hb AS blood donors and how these polymorphisms influenced lipid peroxidation and antioxidant capacity. Blood samples were collected from 211 Hb AS blood donors, 119 Hb AA blood donors as a control group, and 28 sickle cell disease patients (Hb SS). The H63D allele was found at a frequency of 10.5% in the Hb AS samples, and the C282Y allele frequency was 0.7%. In the control group, the frequencies of the H63D and C282Y alleles were 13.4 and 2.1%, respectively. In the sickle-cell disease patients, the H63D and the C282Y allele frequencies were 10.7 and 3.5%, respectively. The frequencies of the C282Y and H63D polymorphisms in Hb AS blood donors are similar to those reported for the Brazilian population. Serum malondialdehyde values, indicative of lipid peroxidation, were highest in sickle cell patients, independent of the polymorphisms in the HFE gene, with significant differences, showing the influence of Hb S allele in the levels of lipid peroxidation. However, the trolox equivalent antioxidant capacity average levels, indicative of the antioxidant capacity, were reduced with significant differences, indicating that in spite of a lipid peroxidation raise, this is not followed by the increased of the antioxidant capacity, leading to oxidative stress.

The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells.

PubMed Central

Halbert, C L; Demers, G W; Galloway, D A

1992-01-01

Previous studies have shown that the E7 gene of human papillomavirus (HPV) type 16 or 18 alone was sufficient for immortalization of human foreskin epithelial cells (HFE) and that the efficiency was increased in cooperation with the respective E6 gene, whereas the HPV6 E6 or E7 gene was not active in HFE. To detect weak immortalizing activities of the HPV6 genes, cells were infected with recombinant retroviruses containing HPV genes, alone and in homologous and heterologous combinations. The HPV6 genes, alone or together (HPV6 E6 plus HPV6 E7), were not able to immortalize cells. However the HPV6 E6 gene, in concert with HPV16 E7, increased the frequency of immortalization threefold over that obtained with HPV16 E7 alone. Interestingly, 6 of 20 clones containing the HPV16 E6 gene and the HPV6 E7 gene were immortalized, whereas neither gene alone was sufficient. Thus, the HPV6 E6 and E7 genes have weak immortalizing activities which can be detected in cooperation with the more active transforming genes of HPV16. Acute expression of the HPV6 and HPV16 E6 and E7 genes revealed that only HPV16 E7 was able to stimulate the proliferation of cells in organotypic culture, resulting in increased expression of the proliferative cell nuclear antigen and the formation of a disorganized epithelial layer. Additionally, combinations of genes that immortalized HFE cells (HPV16 E6 plus HPV16 E7, HPV16 E6 plus HPV6 E7, and HPV6 E6 plus HPV16 E7) also stimulated proliferation. Images PMID:1312623

Fluorescence resonance energy transfer-based real-time polymerase chain reaction method without DNA extraction for the genotyping of F5, F2, F12, MTHFR, and HFE.

PubMed

Martinez-Serra, Jordi; Robles, Juan; Nicolàs, Antoni; Gutierrez, Antonio; Ros, Teresa; Amat, Juan Carlos; Alemany, Regina; Vögler, Oliver; Abelló, Aina; Noguera, Aina; Besalduch, Joan

2014-01-01

Blood samples are extensively used for the molecular diagnosis of many hematological diseases. The daily practice in a clinical laboratory of molecular diagnosis in hematology involves using a variety of techniques, based on the amplification of nucleic acids. Current methods for polymerase chain reaction (PCR) use purified genomic DNA, mostly isolated from total peripheral blood cells or white blood cells (WBC). In this paper we describe a real-time fluorescence resonance energy transfer-based method for genotyping directly from blood cells. Our strategy is based on an initial isolation of the WBCs, allowing the removal of PCR inhibitors, such as the heme group, present in the erythrocytes. Once the erythrocytes have been lysed, in the LightCycler(®) 2.0 Instrument, we perform a real-time PCR followed by a melting curve analysis for different genes (Factors 2, 5, 12, MTHFR, and HFE). After testing 34 samples comparing the real-time crossing point (CP) values between WBC (5×10(6) WBC/mL) and purified DNA (20 ng/μL), the results for F5 Leiden were as follows: CP mean value for WBC was 29.26±0.566 versus purified DNA 24.79±0.56. Thus, when PCR was performed from WBC (5×10(6) WBC/mL) instead of DNA (20 ng/μL), we observed a delay of about 4 cycles. These small differences in CP values were similar for all genes tested and did not significantly affect the subsequent analysis by melting curves. In both cases the fluorescence values were high enough, allowing a robust genotyping of all these genes without a previous DNA purification/extraction.

Theoretical studies on atmospheric chemistry of HFE-245mc and perfluoro-ethyl formate: Reaction with OH radicals, atmospheric fate of alkoxy radical and global warming potential

NASA Astrophysics Data System (ADS)

Lily, Makroni; Baidya, Bidisha; Chandra, Asit K.

2017-02-01

Theoretical studies have been performed on the kinetics, mechanism and thermochemistry of the hydrogen abstraction reactions of CF3CF2OCH3 (HFE-245mc) and CF3CF2OCHO with OH radical using DFT based M06-2X method. IRC calculation shows that both hydrogen abstraction reactions proceed via weakly bound hydrogen-bonded complex preceding to the formation of transition state. The rate coefficients calculated by canonical transition state theory along with Eckart's tunnelling correction at 298 K: k1(CF3CF2OCH3 + OH) = 1.09 × 10-14 and k2(CF3CF2OCHO + OH) = 1.03 × 10-14 cm3 molecule-1 s-1 are in very good agreement with the experimental values. The atmospheric implications of CF3CF2OCH3 and CF3CF2OCHO are also discussed.

Hemojuvelin: a supposed role in iron metabolism one year after its discovery.

PubMed

Celec, Peter

2005-07-01

The discovery of hemojuvelin and its association with juvenile hemochromatosis are important not only for the diagnostics of this rare severe disease but also for the understanding of the complex mechanism of iron metabolism regulation. Currently, the physiological role of hemojuvelin is obscure. Recent experimental and clinical studies indicate that hemojuvelin will probably be a regulator of hepcidin, similar to HFE and transferrin receptor 2. However, in contrast to transferrin receptor 2, which is relevant in the hepcidin response to changes in transferrin saturation, HFE and especially hemojuvelin seem to be involved in the inflammation-induced hepcidin expression. Hepcidin, generally accepted as a hormone targeting enterocytes and macrophages, decreases iron absorption from the intestinal lumen and iron release from phagocytes. This mechanism explains the central role of hepcidin and, indirectly, its regulator, hemojuvelin, in the pathogenesis of hemochromatosis but also in anemia of chronic disease. Further basic and clinical research is needed to uncover the details of hemojuvelin pathophysiology required for potential pharmacological interventions.

How do abused elderly persons and their adult protective services caseworkers view law enforcement involvement and criminal prosecution, and what impact do these views have on case processing?

PubMed

Jackson, Shelly L; Hafemeister, Thomas L

2013-01-01

This study examined law enforcement and prosecution involvement in 71 cases of elder abuse where pure financial exploitation (PFE), physical abuse (PA), neglect (Neglect), or hybrid financial exploitation (HFE) (financial exploitation co-occurring with physical abuse and/or neglect) occurred in a domestic setting. Victims of elder abuse and assigned Adult Protective Services (APS) caseworkers were systematically interviewed. Law enforcement officials were involved in 54% of the cases, and 18% of the cases were prosecuted. PA was significantly more likely to trigger a law enforcement response and to be prosecuted than Neglect or PFE. HFE involved prosecution for assault rather than financial exploitation. Generally, the victims of elder abuse were not receptive to criminal justice involvement, which appears to have a significant impact upon the level of this involvement. The reasons for this reluctance are discussed, as well as the challenges and limitations of criminal justice system involvement and related implications for policy and practice.

How case characteristics differ across four types of elder maltreatment: implications for tailoring interventions to increase victim safety.

PubMed

Jackson, Shelly L; Hafemeister, Thomas L

2014-12-01

The purpose of this study was to determine whether case characteristics are differentially associated with four forms of elder maltreatment. Triangulated interviews were conducted with 71 APS caseworkers, 55 victims of substantiated abuse whose cases they managed, and 35 third party persons. Pure financial exploitation (PFE) was characterized by victim unawareness of financial exploitation and living alone. Physical abuse (PA) was characterized by victim's desire to protect the abusive individual. Neglect was characterized by isolation and victim's residing with the abusive individual. Hybrid financial exploitation (HFE) was characterized by mutual dependency. These differences indicate the need for tailoring interventions to increase victim safety. PFE requires victims to maintain financial security and independence. PA requires services to meet the needs of abusive individuals. Neglect requires greater monitoring when elderly persons reside with another person. HFE requires the provision of services to both members of the dyad. © The Author(s) 2012.

Gene-by-Psychosocial Factor Interactions Influence Diastolic Blood Pressure in European and African Ancestry Populations: Meta-Analysis of Four Cohort Studies.

PubMed

Smith, Jennifer A; Zhao, Wei; Yasutake, Kalyn; August, Carmella; Ratliff, Scott M; Faul, Jessica D; Boerwinkle, Eric; Chakravarti, Aravinda; Diez Roux, Ana V; Gao, Yan; Griswold, Michael E; Heiss, Gerardo; Kardia, Sharon L R; Morrison, Alanna C; Musani, Solomon K; Mwasongwe, Stanford; North, Kari E; Rose, Kathryn M; Sims, Mario; Sun, Yan V; Weir, David R; Needham, Belinda L

2017-12-18

Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene-Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region ( p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region ( p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors.

Elevated serum ferritin - what should GPs know?

PubMed

Goot, Katie; Hazeldine, Simon; Bentley, Peter; Olynyk, John; Crawford, Darrell

2012-12-01

Elevated serum ferritin is commonly encountered in general practice. Ninety percent of elevated serum ferritin is due to noniron overload conditions, where venesection therapy is not the treatment of choice. This article aims to outline the role of the Australian Red Cross Blood Service Therapeutic Venesection program, to clarify the interpretation of the HFE gene test and iron studies, and to describe the steps in evaluating a patient with elevated serum ferritin. After exclusion of hereditary haemochromatosis, investigation of elevated serum ferritin involves identifying alcohol consumption, metabolic syndrome, obesity, diabetes, liver disease, malignancy, infection or inflammation as causative factors. Referral to a gastroenterologist, haematologist or physician with an interest in iron overload is appropriate if serum ferritin is >1000 µg/L or if the cause of elevated serum ferritin is still unclear.

Population-based analysis of the frequency of HFE gene polymorphisms: Correlation with the susceptibility to develop hereditary hemochromatosis.

PubMed

Katsarou, Martha-Spyridoula; Latsi, Rosana; Papasavva, Maria; Demertzis, Nikolaos; Kalogridis, Thodoris; Tsatsakis, Aristides M; Spandidos, Demetrios A; Drakoulis, Nikolaos

2016-07-01

Hereditary hemochromatosis (HH) is an autosomal recessive genetic disease, characterized by increased dietary iron absorption. Due to the absence of an effective excretory mechanism, the excess iron in the body may accumulate resulting in toxic effects. The HFE gene also affects the activity of hepcidin, a hormone which acts as a negative regulator of iron metabolism. In this study, we performed a population-based analysis of the distribution of three hemochromatosis-related polymorphisms in the HFE gene (rs1800562, rs1799945 and rs1800730). DNA from 1,446 non‑related individuals of Greek ethnicity was collected and analyzed, either from whole blood or buccal swabs. The frequency distribution of these HFE gene polymorphisms was then determined. The results revealed that in our Greek population cohort (gr) the frequencies of each polymorphism were as follows: rs1800562: GG (wild‑type)=97.0%, GA=1.5%, AA=1.5%; rs1799945: CC (wild‑type)=74.4%, CG=23.4%, GG=2.2%; rs1800730: AA (wild‑type)=98.1%, AT=1.5% and TT=0.4%. No association between the HFE polymorphisms rs1800562, rs1799945 and rs1800730 and gender could be established. As regards the rs1800562 polymorphism, the A allele (mutant) was ~1.8‑fold more frequent in the European population (eur) than in the Greek population [(gr)=2,3%<(eur)=4%]. As for the rs1799945 polymorphism, the G allele (mutant) was 1.2‑fold more frequent in the European population than in the Greek population [(gr)=13,9%<(eur)=17%]. As regards the rs1800730 polymorphism, the T allele (mutant) was ~1.7‑fold more frequent in the European population than in the Greek population [(gr)=1.2%<(eur)=2%]. However, these pathogenic mutations were found more frequently in the Greek population compared to the global population (gl) [rs1800562: (gl)=1%<(gr)=2,3%; rs1799945: (gl)=7%<(gr)=13,9%; rs1800730: (gl)=<1%<(gr)=1.2%]. This suggests that the Greek population may differ genetically from the northern European population, due to influences from neighboring Asian and African populations. These findings also suggest that there is no gender-associated inheritance of these polymorphisms, and gender-specific symptoms appear as a result of independent biological processes. Thus, the early detection of the tendency towards iron accumulation may be achieved by the genotypic analysis of the polymorphisms that may contribute to the development of the hemochromatosis.

Hydrofluoroether electrolytes for lithium-ion batteries: Reduced gas decomposition and nonflammable

NASA Astrophysics Data System (ADS)

Nagasubramanian, Ganesan; Orendorff, Christopher J.

2011-10-01

The optimum combination of high energy density at the desired power sets lithium-ion battery technology apart from the other well known secondary battery chemistries. However, this is besieged by thermal instability of the electrolyte. This "Achilles heel" still remains a significant safety issue and unless this propensity is improved the promise of widespread adoption of Li-ion batteries for Transportation application may not be realized. With this in mind we launched a systematic study to evaluate fluoro solvents that are known to be nonflammable, for thermal and electrochemical performances. We investigated hydro-fluoro-ethers (HFE) (1) 2-trifluoromethyl-3-methoxyperfluoropentane {TMMP} and (2) 2-trifluoro-2-fluoro-3-difluoropropoxy-3-difluoro-4-fluoro-5-trifluoropentane {TPTP} in Sandia-built cells. Thermal properties under near abuse conditions that exist in thermal runaway environment and the electrochemical characteristics for these electrolytes were measured. In the thermal ramp (TR) measurement, EC:DEC:TPTP-1 M LiBETI (or TFSI or LiPF6) electrolytes exhibited no ignition/fire. Similar behavior was observed for the EC:DEC:TMMP-1 M LiBETI. Further, in ARC studies the HFE electrolytes generated less gas by 50% compared to the EC:EMC-1.2 M LiPF6 {CAR-1} electrolyte. Although in all cases the HFEs generated less gas, the onset of gas generation appears to depend on the salt. For the LiBETI and TFSI containing HFEs the onset is pushed out by ∼80 °C and for the LiPF6 the onset is comparable to that of the CAR-1. The solution ionic conductivity of these HFE electrolytes was lower (4-5 times) than that of the CAR-1 electrolyte however, the electrochemical performance was comparable. For example, full cells in 2032 type coin cells containing LiMN0.33Ni0.33Co0.33O2 cathode and carbon anode showed around 5 mA h capacity and the computed specific capacity was ∼154 mA h for all the electrolytes. In half-cells against lithium the cathode and anode gave specific capacity on the order of 170 mA h and 340 mA h respectively. These electrolytes when tested in 18,650 cells containing the above cathode and anode also showed comparable capacity. Further, the voltage stability window was not compromised by the HFEs. ARC measurements on 18,650 full cells showed less gas generation for the HFE electrolytes compared to CAR-1 electrolyte.

Human factors for a sustainable future.

PubMed

Thatcher, Andrew; Yeow, Paul H P

2016-11-01

Current human activities are seriously eroding the ability of natural and social systems to cope. Clearly we cannot continue along our current path without seriously damaging our own ability to survive as a species. This problem is usually framed as one of sustainability. As concerned professionals, citizens, and humans there is a strong collective will to address what we see as a failure to protect the natural and social environments that supports us. While acknowledging that we cannot do this alone, human factors and ergonomics needs to apply its relevant skills and knowledge to assist where it can in addressing the commonly identified problem areas. These problems include pollution, climate change, renewable energy, land transformation, and social unrest amongst numerous other emerging global problems. The issue of sustainability raises two fundamental questions for human factors and ergonomics: which system requires sustaining and what length of time is considered sustainable? In this paper we apply Wilson (2014) parent-sibling-child model to understanding what is required of an HFE sustainability response. This model is used to frame the papers that appear in this Special Issue. Copyright © 2016 Elsevier Ltd. All rights reserved.

Real-World Physics: A Portable MBL for Field Measurements.

ERIC Educational Resources Information Center

Albergotti, Clifton

1994-01-01

Uses a moderately priced digital multimeter that has output and software compatible with personal computers to make a portable, computer-based data-acquisition system. The system can measure voltage, current, frequency, capacitance, transistor hFE, and temperature. Describes field measures of velocity, acceleration, and temperature as function of…

Hypoglycemic activity evaluation and chemical study on hollyhock flowers.

PubMed

Zhang, Yi; Jin, Lijun; Chen, Qiu; Wu, Zhizhen; Dong, Yongzhe; Han, Lifeng; Wang, Tao

2015-04-01

Hollyhock (Althaea rosea (Linn.) Cavan) belongs to Althaea genus, Malvaceae family, is a perennial garden plant distributed throughout the world in warm temperate and tropical regions, which was used as anti-diabetes ingredient in traditional Chinese medicine. In the process of our research, ethanolic extract of hollyhock flower (HFE) was found to decrease serum triglyceride and glucose levels significantly in KK-A(y) mice after oral administration for 8weeks. Meanwhile, gene expressions on AMPK, IRS2, PI3K, AKT and GLUT4 in liver were remarkably up-regulated. Three new dihydroflavonol glycosides, named as roseaflavanonolosides A (1), B (2), and C (3), together with two known ones were obtained from HFE. Their structures were elucidated by chemical and spectroscopic methods. Hepatic cell glucose uptake experiment was performed using 2-NBDG as a glucose uptake indicator. At the dosage of 20μg/mL for 1-5, the glucose uptake increasing level was nearly 30%-40% in HepG2 cells. We partly revealed the glucose metabolism regulation effect may relate to dihydroflavonols in hollyhock flower. Copyright © 2015 Elsevier B.V. All rights reserved.

Revisiting the polytopal rearrangements in penta-coordinate d7-metallocomplexes: modified Berry pseudorotation, octahedral switch, and butterfly isomerization.

PubMed

Asatryan, Rubik; Ruckenstein, Eli; Hachmann, Johannes

2017-08-01

This paper provides a first-principles theoretical investigation of the polytopal rearrangements and fluxional behavior of five-coordinate d 7 -transition metal complexes. Our work is primarily based on a potential energy surface analysis of the iron tetracarbonyl hydride radical HFe˙(CO) 4 . We demonstrate the existence of distorted coordination geometries in this prototypical system and, for the first time, introduce three general rearrangement mechanisms, which account for the non-ideal coordination. The first of these mechanisms constitutes a modified version of the Berry pseudorotation via a square-based pyramidal C 4v transition state that connects two chemically identical edge-bridged tetrahedral stereoisomers of C 2v symmetry. It differs from the classical Berry mechanism, which involves two regular D 3h equilibrium structures and a C 4v transition state. The second mechanism is related to the famous "tetrahedral jump" hypothesis, postulated by Muetterties for a number of d 6 HML 4 and H 2 ML 4 complexes. Here, our study suggests two fluxional rearrangement pathways via distinct types of C 2v transition states. Both pathways of this mechanism can be described as a single-ligand migration to a vacant position of an "octahedron", thus interchanging (switching) the apical and basal ligands of the initial quasi-square pyramidal isomer, which is considered as an idealized octahedron with a vacancy. Accordingly, we call this mechanism "octahedral switch". The third mechanism follows a butterfly-type isomerization featuring a key-angle deformation, and we thus call it "butterfly isomerization". It connects the quasi-square pyramidal and edge-bridged tetrahedral isomers of HFe˙(CO) 4 through a distorted edge-bridged tetrahedral transition state of C s symmetry. Our paper discusses the overall features of the isomers and rearrangement mechanisms as well as their implications. We rationalize the existence of each stationary point through an electronic structure analysis and argue their relevance for isolobal analogues of HFe˙(CO) 4 .

Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening.

PubMed

McLaren, Gordon D; McLaren, Christine E; Adams, Paul C; Barton, James C; Reboussin, David M; Gordeuk, Victor R; Acton, Ronald T; Harris, Emily L; Speechley, Mark R; Sholinsky, Phyliss; Dawkins, Fitzroy W; Snively, Beverly M; Vogt, Thomas M; Eckfeldt, John H

2008-11-01

Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences. To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening. Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364). Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects. Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study.

Expansions of CD8+CD28- and CD8+TcRVbeta5.2+ T cells in peripheral blood of heavy alcohol drinkers.

PubMed

Arosa, F A; Porto, G; Cabeda, J M; Lacerda, R; Resende, D; Cruz, E; Cardoso, C; Fonseca, M; Simões, C; Rodrigues, P; Bravo, F; Oliveira, J C; Alves, H; Fraga, J; Justiça, B; de Sousa, M

2000-04-01

Despite heavy alcohol consumption, only a low percentage of heavy drinkers develop liver disease. Imbalances in T-cell subsets and iron metabolism parameters are common findings in heavy drinkers, yet the possible role played by discrete T-lymphocyte subsets under heavy alcohol consumption remains unclear. To gain new insights into the possible role played by T lymphocytes during alcohol consumption, characterization of CD28 expression and TcR repertoire in peripheral blood CD4+ and CD8+ T cells by two and three-color flow cytometry was performed. A group of heavy alcohol drinkers (AHD, n = 71) and a group of age-matched controls (n = 81), both HLA-phenotyped and HFE-genotyped, constituted the groups under study. Marked expansions of CD28- T cells within the CD8+ but not the CD4+ T-cell pool were observed in AHD compared with controls. These CD8+CD28- expansions were paralleled by expansions of CD8+ T cells bearing specific TcR Valpha/beta chains, namely VP5.2. Moreover, AHD, but not controls, carrying the H63D mutation in the HFE gene showed significantly higher percentages of CD28- T cells within the CD8+ T-cell pool than AHD carrying the normal HFE gene. Finally, high numbers of CD8+CD28- T cells in AHD were associated with lower levels of the liver-related enzymes ALT and GGT. This study showed that under active ethanol consumption, expansions of discrete CD8+ T-cell subsets occur within the CD8+ T-cell pool, that molecules of the MHC-class I locus seem to influence the extent of the expansions, and that high numbers of CD8+CD28- T cells are associated with low levels of liver enzymes in AHD.

Effect of Native American ancestry on iron-related phenotypes of Alabama hemochromatosis probands with HFE C282Y homozygosity

PubMed Central

Barton, James C; Barton, Ellen H; Acton, Ronald T

2006-01-01

Background In age-matched cohorts of screening study participants recruited from primary care clinics, mean serum transferrin saturation values were significantly lower and mean serum ferritin concentrations were significantly higher in Native Americans than in whites. Twenty-eight percent of 80 Alabama white hemochromatosis probands with HFE C282Y homozygosity previously reported having Native American ancestry, but the possible effect of this ancestry on hemochromatosis phenotypes was unknown. Methods We compiled observations in these 80 probands and used univariate and multivariate methods to analyze associations of age, sex, Native American ancestry (as a dichotomous variable), report of ethanol consumption (as a dichotomous variable), percentage transferrin saturation and loge serum ferritin concentration at diagnosis, quantities of iron removed by phlebotomy to achieve iron depletion, and quantities of excess iron removed by phlebotomy. Results In a univariate analysis in which probands were grouped by sex, there were no significant differences in reports of ethanol consumption, transferrin saturation, loge serum ferritin concentration, quantities of iron removed to achieve iron depletion, and quantities of excess iron removed by phlebotomy in probands who reported Native American ancestry than in those who did not. In multivariate analyses, transferrin saturation (as a dependent variable) was not significantly associated with any of the available variables, including reports of Native American ancestry and ethanol consumption. The independent variable quantities of excess iron removed by phlebotomy was significantly associated with loge serum ferritin used as a dependent variable (p < 0.0001), but not with reports of Native American ancestry or reports of ethanol consumption. Loge serum ferritin was the only independent variable significantly associated with quantities of excess iron removed by phlebotomy used as a dependent variable (p < 0.0001) (p < 0.0001; ANOVA of regression). Conclusion We conclude that the iron-related phenotypes of hemochromatosis probands with HFE C282Y homozygosity are similar in those with and without Native American ancestry reports. PMID:16533407

Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening

PubMed Central

McLaren, Gordon D; McLaren, Christine E; Adams, Paul C; Barton, James C; Reboussin, David M; Gordeuk, Victor R; Acton, Ronald T; Harris, Emily L; Speechley, Mark R; Sholinsky, Phyliss; Dawkins, Fitzroy W; Snively, Beverly M; Vogt, Thomas M; Eckfeldt, John H

2008-01-01

BACKGROUND: Patients with hemochromatosis may suffer organ damage from iron overload, often with serious clinical consequences. OBJECTIVE: To assess prevalences of self-reported symptoms and clinical signs and conditions in persons homozygous for the hemochromatosis gene (HFE) mutation (C282Y) identified by screening. METHODS: Participants were adults 25 years of age or older enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. C282Y homozygotes (n=282) were compared with control participants without the HFE C282Y or H63D alleles (ie, wild type/wild type; n=364). RESULTS: Previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels had higher prevalences of certain symptoms such as chronic fatigue (OR 2.8; 95% CI 1.34 to 5.95, and OR 2.0; 95% CI 1.07 to 3.75, respectively), and had more hyperpigmentation on physical examination (OR 4.7; 95% CI 1.50 to 15.06, and OR 3.7; 95% CI 1.10 to 12.16, respectively) and swelling or tenderness of the second and third metacarpophalangeal joints (OR 4.2; 95% CI 1.37 to 13.03, and OR 3.3; 95% CI 1.17 to 9.49, respectively) than control subjects. Joint stiffness was also more common among newly diagnosed C282Y homozygotes with elevated serum ferritin than among control subjects (OR 2.7; 95% CI 1.38 to 5.30). However, the sex- and age-adjusted prevalences of self-reported symptoms and signs of liver disease, heart disease, diabetes and most other major clinical manifestations of hemochromatosis were similar in C282Y homozygotes and control subjects. CONCLUSIONS: Some symptoms and conditions associated with hemochromatosis were more prevalent among C282Y homozygotes identified by screening than among control subjects, but prevalences of most outcomes were similar in C282Y homozygotes and controls in this primary care-based study. PMID:19018338

Use of Composite Fingerprinting Technique to Determine Contribution of Paria River Sediments to Dam-Release Flood Deposits in Marble Canyon, Grand Canyon, Az

NASA Astrophysics Data System (ADS)

Chapman, K.; Parnell, R. A.; Smith, M. E.; Grams, P. E.; Mueller, E. R.

2015-12-01

The 1963 closure of Glen Canyon Dam drastically reduced the downstream sediment supply and altered daily flow regimes of the Colorado River through Grand Canyon, resulting in significant sandbar erosion downstream of the dam. Dam-release floods, known as High Flow Experiments (HFEs), have occurred six times since 1996 and are intended to rebuild Grand Canyon sandbars using tributary-supplied sediment. In Marble Canyon (first 100 km of Grand Canyon) the targeted tributary is the Paria River which supplies approximately 90% of the annual suspended sediment flux through Marble Canyon; the same input contributed less than 6% prior to the dam. Annual topographic surveys have established that HFEs are effective at rebuilding sandbars. However, the long-term viability of using HFEs for sandbar maintenance is dependent on a sustainable source of sediments comprising HFE deposits. Significant use of non-tributary, main-stem sediments (i.e. pre-dam sand stored in eddies or the channel bed) in HFE deposits would indicate reliance on a limited resource, and diminishing returns in the ability of HFEs to rebuild sandbars. In this study, we sampled vertically throughout 12 bars in Marble Canyon to document temporal and downstream changes in the proportion of sediment sourced from the Paria River during the 2013 and 2014 HFEs. Preliminary data suggest that heavy mineral compositions and concentrations of Ti, S, Cr and Rb, all of which are influenced by grainsize, could be sufficiently capable of differentiating Paria-derived and main-stem sediments when combined into a composite fingerprint (CF). A multivariate mixing model using these CFs quantitatively determines the contribution of Paria-derived sediment in each HFE deposit sample. Mixing model endmembers for non-Paria sand include pre-dam flood deposits in Glen and Marble Canyons, and Marble Canyon dredge samples. These results elucidate the role of contemporary versus legacy sediment in long-term sandbar maintenance.

Sandbar Response in Marble and Grand Canyons, Arizona, Following the 2008 High-Flow Experiment on the Colorado River

USGS Publications Warehouse

Hazel, Joseph E.; Grams, Paul E.; Schmidt, John C.; Kaplinski, Matt

2010-01-01

A 60-hour release of water at 1,203 cubic meters per second (m3/s) from Glen Canyon Dam in March 2008 provided an opportunity to analyze channel-margin response at discharge levels above the normal, diurnally fluctuating releases for hydropower plant operations. We compare measurements at sandbars and associated campsites along the mainstem Colorado River, downstream from Glen Canyon Dam, at 57 locations in Marble and Grand Canyons. Sandbar and main-channel response to the 2008 high-flow experiment (2008 HFE) was documented by measuring bar and bed topography at the study sites before and after the controlled flood and twice more in the following 6 months to examine the persistence of flood-formed deposits. The 2008 HFE caused widespread deposition at elevations above the stage equivalent to a flow rate of 227 m3/s and caused an increase in the area and volume of the high-elevation parts of sandbars, thereby increasing the size of campsite areas. In this study, we differentiate between four response styles, depending on how sediment was distributed throughout each study site. Then, we present the longitudinal pattern relevant to the different response styles and place the site responses in context with two previous high-release experiments conducted in 1996 and 2004. We find that (1) nearly every measured sandbar aggraded above the 227-m3/s water-surface elevation, resulting in sandbars as large or larger than occurred following previous high flows; (2) reaches closest to Glen Canyon Dam were characterized by a greater percentage of sites that incurred net erosion, although the total sand volume in all sediment-flux monitoring reaches was greater following the 2008 HFE than following previous high flows; and (3) longitudinal differences in topographic response in eddies and in the channel suggest a greater and more evenly distributed sediment supply than existed during previous controlled floods from Glen Canyon Dam.

Cold Regions - Environmental Testing of Individual Soldier Equipment

DTIC Science & Technology

2011-10-17

REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188 The public reporting burden for this collection of information is estimated to average 1 ...currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1 . REPORT DATE (DD-MM-YYYY) 17-10-2011 2. REPORT...TOP. 15. SUBJECT TERMS Soldier equipment HFE MANPRINT cold region environment CRTC 16. SECURITY

Effectiveness of T. harzianum and Humate Amendment in Soil Salinity Restoration

NASA Astrophysics Data System (ADS)

Apostolakis, Antonios; Daliakopoulos, Ioannis; Tsanis, Ioannis

2017-04-01

Soil salinity is a major soil degradation threat, especially for the water stressed parts of the Mediterranean region, where it hinders soil fertility and thus agricultural productivity. Soil salinity management can be complex and expensive, often resorting to the use of chemical amendments thus risking soil and aquifer pollution. This study quantifies the beneficial effects of (a) a commercial strain of the beneficial fungus Trichoderma harzianum (TH), and (b) a commercial humate fertilizer enhancer (HFE) approved for organic farming, against soil salinization. The treatments are tested in the context of a Solanum lycopersicum (tomato) greenhouse simulation of the cultivation conditions typical for the semi-arid coastal Timpaki basin in south-central Crete. 20 vigorous 20-day-old Solanum lycopersicum L. cv Elpida seedlings are treated either with TH or HFE, using soil substrates and irrigation treatments of two degradation states. 20 additional plants serve either as controls or guard rows. All plants are transplanted into 35 L pots under greenhouse conditions. Preliminary analysis of soil salinity and crop yield indicators suggest that both treatments are beneficial for the soil-plant system, each to a different extent depending on initial soil conditions.

Iron overload secondary to cirrhosis: a mimic of hereditary haemochromatosis?

PubMed

Abu Rajab, Murad; Guerin, Leana; Lee, Pauline; Brown, Kyle E

2014-10-01

Hepatic iron deposition unrelated to hereditary haemochromatosis is common in cirrhosis. The aim of this study was to determine whether hepatic haemosiderosis secondary to cirrhosis is associated with iron deposition in extrahepatic organs. Records of consecutive adult patients with cirrhosis who underwent autopsy were reviewed. Storage iron was assessed by histochemical staining of sections of liver, heart, pancreas and spleen. HFE genotyping was performed on subjects with significant liver, cardiac and/or pancreatic iron. The 104 individuals were predominantly male (63%), with a mean age of 55 years. About half (46%) had stainable hepatocyte iron, 2+ or less in most cases. In six subjects, there was heavy iron deposition (4+) in hepatocytes and biliary epithelium. All six of these cases had pancreatic iron and five also had cardiac iron. None of these subjects had an explanatory HFE genotype. In this series, heavy hepatocyte iron deposition secondary to cirrhosis was commonly associated with pancreatic and cardiac iron. Although this phenomenon appears to be relatively uncommon, the resulting pattern of iron deposition is similar to haemochromatosis. Patients with marked hepatic haemosiderosis secondary to cirrhosis may be at risk of developing extrahepatic complications of iron overload. © 2014 John Wiley & Sons Ltd.

Gender and vocal production mode discrimination using the high frequencies for speech and singing

PubMed Central

Monson, Brian B.; Lotto, Andrew J.; Story, Brad H.

2014-01-01

Humans routinely produce acoustical energy at frequencies above 6 kHz during vocalization, but this frequency range is often not represented in communication devices and speech perception research. Recent advancements toward high-definition (HD) voice and extended bandwidth hearing aids have increased the interest in the high frequencies. The potential perceptual information provided by high-frequency energy (HFE) is not well characterized. We found that humans can accomplish tasks of gender discrimination and vocal production mode discrimination (speech vs. singing) when presented with acoustic stimuli containing only HFE at both amplified and normal levels. Performance in these tasks was robust in the presence of low-frequency masking noise. No substantial learning effect was observed. Listeners also were able to identify the sung and spoken text (excerpts from “The Star-Spangled Banner”) with very few exposures. These results add to the increasing evidence that the high frequencies provide at least redundant information about the vocal signal, suggesting that its representation in communication devices (e.g., cell phones, hearing aids, and cochlear implants) and speech/voice synthesizers could improve these devices and benefit normal-hearing and hearing-impaired listeners. PMID:25400613

2009 weather and aeolian sand-transport data from the Colorado River corridor, Grand Canyon, Arizona

USGS Publications Warehouse

Draut, Amy E.; Sondossi, Hoda A.; Dealy, Timothy P.; Hazel, Joseph E.; Fairley, Helen C.; Brown, Christopher R.

2010-01-01

This report presents measurements of weather parameters and aeolian sand transport made in 2009 near selected archeological sites in the Colorado River corridor through Grand Canyon, Ariz. The quantitative methods and data discussed here form a basis for monitoring ecosystem processes that affect archeological-site stability. Combined with forthcoming work to evaluate landscape evolution at nearby archeological sites, these data can be used to document the relation between physical processes, including weather and aeolian sand transport, and their effects on the physical integrity of archeological sites. Data collected in 2009 reveal event- and seasonal-scale variations in rainfall, wind, temperature, humidity, and barometric pressure. Broad seasonal changes in aeolian sediment flux are also apparent at most study sites. Differences in weather patterns between 2008 and 2009 included an earlier spring windy season, greater spring precipitation even though 2009 annual rainfall totals were in general substantially lower than in 2008, and earlier onset of the reduced diurnal barometric-pressure fluctuations commonly associated with summer monsoon conditions. Weather patterns in middle to late 2009 were apparently affected by a transition of the ENSO cycle from a neutral phase to the El Ni?o phase. The continuation of monitoring that began in 2007, and installation of additional equipment at several new sites in early 2008, allowed evaluation of the effects of the March 2008 high-flow experiment (HFE) on aeolian sand transport. As reported earlier, at 2 of the 9 sites studied, spring and summer winds in 2008 reworked the HFE sandbars to form new aeolian dunes, where sand moved inland toward larger, well-established dune fields. Observations in 2009 showed that farther inland migration of the dune at one of those two sites is likely inhibited by vegetation. At the other location, the new aeolian dune form was found to have moved 10 m inland toward older, well-established dunes during 2009, resulting in landward transport of several hundred cubic meters of new sand upslope and above the elevation reached by the peak HFE water level.

Polysaccharides of Dendrobium officinale Kimura & Migo protect gastric mucosal cell against oxidative damage-induced apoptosis in vitro and in vivo.

PubMed

Zeng, Qiang; Ko, Chun-Hay; Siu, Wing-Sum; Li, Long-Fei; Han, Xiao-Qiang; Yang, Liu; Bik-San Lau, Clara; Hu, Jiang-Miao; Leung, Ping-Chung

2017-08-17

Dendrobium officinale Kimura & Migo (DO) is a valuable Traditional Chinese Medicine to nourish stomach, in which polysaccharides are identified as active ingredients. However, limited scientific evidences have been reported on the gastroprotective efficacy of DO. The aim of the current study was to investigate the protective effects and underlying mechanism of polysaccharides from DO(DOP) on gastric mucosal injury. For in vitro study, HFE145 cells were pretreated with DOP before induction of cell apoptosis by H 2 O 2 . Cell apoptosis and related proteins expression were detected. In the in vivo study, absolute ethanol was administered orally to induce gastric mucosal injury in rat. The gastric mucosal injury area and histological examination were used to evaluate the effects of DOP treatment on the recovery of the gastric mucosal injury. H 2 O 2 treatment for 6h significantly induced cell apoptosis in HFE145 cells. However, the destructive effects of H 2 O 2 on HFE 145 cells could be reversed by the pretreatment with DOP. The increased ROS level induced by H 2 O 2 for 4h was reduced after DOP pretreatment. The number of apoptotic cells in both early and late apoptosis stages decreased significantly and the nuclei morphology changes were improved with DOP pretreatment. Furthermore, DOP inhibited caspase 3 activation and PARP cleavage, downregulated Bax expression and upregulated Bcl2 expression in cell model. Further study revealed that pretreatment of DOP inhibited p -NF-κBp65/NF-κBp65 level, indicating DOP inhibited H 2 O 2 -mediated apoptosis via suppression of NF-κB activation. In addition, DOP treatment could ameliorate gastric mucosal injury and inhibit mucin loss induced by ethanol in animal model. DOP treatment also interfered with ethanol-induced apoptosis process by downregulating Bax/Bcl2 ratio in gastric mucosa. The present study was the first one to demonstrate the gastroprotective effect of DOP through inhibiting oxidative stress-induced apoptosis. This study provided a solid evidence for the potential use of DO as a therapy or health supplement for gastric mucosal diseases. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Equations Governing the Propagation of Second-Order Correlations in Non-Stationary Electromagnetic Fields

DTIC Science & Technology

1961-09-25

eqlwatwnis vanish and t hese equations are- then gene - rali/Mit ions to a non-statiiona ry free field of eils. (1.3.1 Jl) and (1.3.11b). Thie remiainingi...correlation eqluations may hfe derived from eql. (3.1), which is tlite- snime as for the free field. Or’ 2 obtains :i~:•a •,,;l ,. X .. TI. T,, 2) -_ TI

An investigation into the mechanism for enhanced mechanical properties in friction stir welded AA2024-T3 joints coated with cold spraying

NASA Astrophysics Data System (ADS)

Li, N.; Li, W. Y.; Yang, X. W.; Feng, Y.; Vairis, A.

2018-05-01

Using cold spraying (CS), a surface layer with a modified microstructure and enhanced mechanical properties was formed on a 3.2 mm thick friction stir welded (FSWed) AA2024-T3 joint. The combined effect of "shot peening effect (SPE)" and "heat flow effect (HFE)" during CS were used to enhance joint mechanical properties. The microstructure evolution of the FSWed AA2024-T3 joints in the surface layer following CS coatings and their effect on mechanical properties were systematically characterized with electron back-scattered diffraction, transmission electron microscopy, differential scanning calorimetry and mechanical tests. Based on these experiments, a grain refinement, finer and more S phases, and improved amount of Guinier-Preston-Bagaryatsky (GPB) zones produced by CS treatments are proposed. The deposition of aluminum coating on the joint, lead to hardness recovery in the stir zone and the development of two low hardness zones as the density of GPB increased. The tensile properties of FSWed AA2024-T3 joints improved with the application of the aluminum coatings. Experiments and analysis of the enhanced mechanical properties mechanism indicate that SPE with a high plastic deformation and HFE with an intensive heat flow are necessary for the production of refined grains and increased numbers of GPB zones.

Evaluation and Comparison of Three Types of Spray Dried Coprocessed Excipient Avicel® for Direct Compression

PubMed Central

Solný, Tomaš

2018-01-01

As coprocessed excipients (CPE) gain a lot of focus recently, this article compares three commercially available CPE of Avicel brand, namely, CE 15, DG, and HFE 102. Comparison is based on measured physical properties of coprocessed mixtures, respectively, flow properties, pycnometric density, mean particle size, specific surface area, moisture content, hygroscopicity, solubility, pH leaching, electrostatic charge, SEM images, and DSC. Tablets were made employing three pressure sets. Viscoelastic properties and ejection force were assessed during compression, as well as pycnometric density, mass uniformity, height, tensile strength, friability, disintegration, and wetting times. Avicel CE 15 is of mid-range flow properties, contains mid-size and nonspherical particles, and has high hygroscopicity, growing negative charge, best lubricity, lowest tensile strength, and mid-long disintegration times. Avicel DG possesses the worst flow properties, small asymmetrical particles, lowest hygroscopicity, stable charge, intermediate lubricity, and tensile strength and exhibits fast disintegration of tablets. Finally, Avicel HFE 102 has the best flow properties, large symmetrical particles, and middle hygroscopicity and its charge fluctuates throughout blending. It also exhibits inferior lubricity, the highest tensile strength, and slow disintegration of tablets. Generally, it is impossible to select the best CPE, as their different properties fit versatile needs of countless manufacturers and final products. PMID:29850496

Hereditary hemochromatosis of tongue.

PubMed

Al Wayli, Hessa; Rastogi, Sanjay; Verma, Neha

2011-01-01

Hereditary hemochromatosis (HH) refers to several inherited disorders of iron metabolism leading to tissue iron overload. Classical HH is associated with mutations in HFE (C282Y homozygotes or C282Y/H63D compound heterozygotes) and is almost exclusively found in populations of northern European descent. Non-HFE-associated HH is caused by mutations in other recently identified genes involved in iron metabolism. Hepcidin is an iron regulatory hormone that inhibits ferroportin-mediated iron export from enterocytes and macrophages. Defective hepcidin gene expression or function may underlie most forms of HH. Target organs and tissues affected by HH include the liver, heart, pancreas, joints, and skin, with cirrhosis and diabetes mellitus representing late signs of disease in patients with markedly elevated liver iron concentration. Recently, we have encountered the rare representation of this disease of the oral cavity associated with generalized burning sensation of the tongue. The diagnosis was established accidently, from the lab investigations, otherwise the patient was healthy and free from classical signs and symptoms of the disease. The patient was adequately treated by phlebotomy. To conclude, all patients with a chief complaint of burning sensation of the oral cavity and tongue should be adequately screened for hereditary hemochromatosis to prevent the associated mortality and morbidity with the hemochromatosis. Copyright © 2011 Mosby, Inc. All rights reserved.

Vapor-based interferometric measurement of local evaporation rate and interfacial temperature of evaporating droplets.

PubMed

Dehaeck, Sam; Rednikov, Alexey; Colinet, Pierre

2014-03-04

The local evaporation rate and interfacial temperature are two quintessential characteristics for the study of evaporating droplets. Here, it is shown how one can extract these quantities by measuring the vapor concentration field around the droplet with digital holographic interferometry. As a concrete example, an evaporating freely receding pending droplet of 3M Novec HFE-7000 is analyzed at ambient conditions. The measured vapor cloud is shown to deviate significantly from a pure-diffusion regime calculation, but it compares favorably to a new boundary-layer theory accounting for a buoyancy-induced convection in the gas and the influence upon it of a thermal Marangoni flow. By integration of the measured local evaporation rate over the interface, the global evaporation rate is obtained and validated by a side-view measurement of the droplet shape. Advective effects are found to boost the global evaporation rate by a factor of 4 as compared to the diffusion-limited theory.

Electron interactions with the heteronuclear carbonyl precursor H2FeRu3(CO)13 and comparison with HFeCo3(CO)12: from fundamental gas phase and surface science studies to focused electron beam induced deposition.

PubMed

P, Ragesh Kumar T; Weirich, Paul; Hrachowina, Lukas; Hanefeld, Marc; Bjornsson, Ragnar; Hrodmarsson, Helgi Rafn; Barth, Sven; Fairbrother, D Howard; Huth, Michael; Ingólfsson, Oddur

2018-01-01

In the current contribution we present a comprehensive study on the heteronuclear carbonyl complex H 2 FeRu 3 (CO) 13 covering its low energy electron induced fragmentation in the gas phase through dissociative electron attachment (DEA) and dissociative ionization (DI), its decomposition when adsorbed on a surface under controlled ultrahigh vacuum (UHV) conditions and exposed to irradiation with 500 eV electrons, and its performance in focused electron beam induced deposition (FEBID) at room temperature under HV conditions. The performance of this precursor in FEBID is poor, resulting in maximum metal content of 26 atom % under optimized conditions. Furthermore, the Ru/Fe ratio in the FEBID deposit (≈3.5) is higher than the 3:1 ratio predicted. This is somewhat surprising as in recent FEBID studies on a structurally similar bimetallic precursor, HFeCo 3 (CO) 12 , metal contents of about 80 atom % is achievable on a routine basis and the deposits are found to maintain the initial Co/Fe ratio. Low temperature (≈213 K) surface science studies on thin films of H 2 FeRu 3 (CO) 13 demonstrate that electron stimulated decomposition leads to significant CO desorption (average of 8-9 CO groups per molecule) to form partially decarbonylated intermediates. However, once formed these intermediates are largely unaffected by either further electron irradiation or annealing to room temperature, with a predicted metal content similar to what is observed in FEBID. Furthermore, gas phase experiments indicate formation of Fe(CO) 4 from H 2 FeRu 3 (CO) 13 upon low energy electron interaction. This fragment could desorb at room temperature under high vacuum conditions, which may explain the slight increase in the Ru/Fe ratio of deposits in FEBID. With the combination of gas phase experiments, surface science studies and actual FEBID experiments, we can offer new insights into the low energy electron induced decomposition of this precursor and how this is reflected in the relatively poor performance of H 2 FeRu 3 (CO) 13 as compared to the structurally similar HFeCo 3 (CO) 12 .

Electron interactions with the heteronuclear carbonyl precursor H2FeRu3(CO)13 and comparison with HFeCo3(CO)12: from fundamental gas phase and surface science studies to focused electron beam induced deposition

PubMed Central

P, Ragesh Kumar T; Weirich, Paul; Hrachowina, Lukas; Hanefeld, Marc; Bjornsson, Ragnar; Hrodmarsson, Helgi Rafn; Barth, Sven; Fairbrother, D Howard; Huth, Michael

2018-01-01

In the current contribution we present a comprehensive study on the heteronuclear carbonyl complex H2FeRu3(CO)13 covering its low energy electron induced fragmentation in the gas phase through dissociative electron attachment (DEA) and dissociative ionization (DI), its decomposition when adsorbed on a surface under controlled ultrahigh vacuum (UHV) conditions and exposed to irradiation with 500 eV electrons, and its performance in focused electron beam induced deposition (FEBID) at room temperature under HV conditions. The performance of this precursor in FEBID is poor, resulting in maximum metal content of 26 atom % under optimized conditions. Furthermore, the Ru/Fe ratio in the FEBID deposit (≈3.5) is higher than the 3:1 ratio predicted. This is somewhat surprising as in recent FEBID studies on a structurally similar bimetallic precursor, HFeCo3(CO)12, metal contents of about 80 atom % is achievable on a routine basis and the deposits are found to maintain the initial Co/Fe ratio. Low temperature (≈213 K) surface science studies on thin films of H2FeRu3(CO)13 demonstrate that electron stimulated decomposition leads to significant CO desorption (average of 8–9 CO groups per molecule) to form partially decarbonylated intermediates. However, once formed these intermediates are largely unaffected by either further electron irradiation or annealing to room temperature, with a predicted metal content similar to what is observed in FEBID. Furthermore, gas phase experiments indicate formation of Fe(CO)4 from H2FeRu3(CO)13 upon low energy electron interaction. This fragment could desorb at room temperature under high vacuum conditions, which may explain the slight increase in the Ru/Fe ratio of deposits in FEBID. With the combination of gas phase experiments, surface science studies and actual FEBID experiments, we can offer new insights into the low energy electron induced decomposition of this precursor and how this is reflected in the relatively poor performance of H2FeRu3(CO)13 as compared to the structurally similar HFeCo3(CO)12. PMID:29527432

A Distributed Control System Prototyping Environment to Support Control Room Modernization

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

Lew, Roger Thomas; Boring, Ronald Laurids; Ulrich, Thomas Anthony

Operators of critical processes, such as nuclear power production, must contend with highly complex systems, procedures, and regulations. Developing human-machine interfaces (HMIs) that better support operators is a high priority for ensuring the safe and reliable operation of critical processes. Human factors engineering (HFE) provides a rich and mature set of tools for evaluating the performance of HMIs, however the set of tools for developing and designing HMIs is still in its infancy. Here we propose a rapid prototyping approach for integrating proposed HMIs into their native environments before a design is finalized. This approach allows researchers and developers tomore » test design ideas and eliminate design flaws prior to fully developing the new system. We illustrate this approach with four prototype designs developed using Microsoft’s Windows Presentation Foundation (WPF). One example is integrated into a microworld environment to test the functionality of the design and identify the optimal level of automation for a new system in a nuclear power plant. The other three examples are integrated into a full-scale, glasstop digital simulator of a nuclear power plant. One example demonstrates the capabilities of next generation control concepts; another aims to expand the current state of the art; lastly, an HMI prototype was developed as a test platform for a new control system currently in development at U.S. nuclear power plants. WPF possesses several characteristics that make it well suited to HMI design. It provides a tremendous amount of flexibility, agility, robustness, and extensibility. Distributed control system (DCS) specific environments tend to focus on the safety and reliability requirements for real-world interfaces and consequently have less emphasis on providing functionality to support novel interaction paradigms. Because of WPF’s large user-base, Microsoft can provide an extremely mature tool. Within process control applications,WPF is platform independent and can communicate with popular full-scope process control simulator vendor plant models and DCS platforms.« less

Application of a Modified Universal Design Survey for Evaluation of Ares 1 Ground Crew Worksites

NASA Technical Reports Server (NTRS)

Blume, Jennifer L.

2010-01-01

Operability is a driving requirement for NASA's Ares 1 launch vehicle. Launch site ground operations include several operator tasks to prepare the vehicle for launch or to perform maintenance. Ensuring that components requiring operator interaction at the launch site are designed for optimal human use is a high priority for operability. To support design evaluation, the Ares 1 Upper Stage (US) element Human Factors Engineering (HFE) group developed a survey based on the Universal Design approach. Universal Design is a process to create products that can be used effectively by as many people as possible. Universal Design per se is not a priority for Ares 1 because launch vehicle processing is a specialized skill and not akin to a consumer product that should be used by all people of all abilities. However, applying principles of Universal Design will increase the probability of an error free and efficient design which is a priority for Ares 1. The Design Quality Evaluation Survey centers on the following seven principles: (1) Equitable use, (2) Flexibility in use, (3) Simple and intuitive use, (4) Perceptible information, (5) Tolerance for error, (6) Low physical effort, (7) Size and space for approach and use. Each principle is associated with multiple evaluation criteria which were rated with the degree to which the statement is true. All statements are phrased in the utmost positive, or the design goal so that the degree to which judgments tend toward "completely agree" directly reflects the degree to which the design is good. The Design Quality Evaluation Survey was employed for several US analyses. The tool was found to be most useful for comparative judgments as opposed to an assessment of a single design option. It provided a useful piece of additional data when assessing possible operator interfaces or worksites for operability

SU-D-201-07: A Survey of Radiation Oncology Residents’ Training and Preparedness to Lead Patient Safety Programs in Clinics

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

Spraker, M; Nyflot, M; Ford, E

Purpose: Safety and quality has garnered increased attention in radiation oncology, and physicians and physicists are ideal leaders of clinical patient safety programs. However, it is not clear whether residency programs incorporate formal patient safety training and adequately equip residents to assume this leadership role. A national survey was conducted to evaluate medical and physics residents’ exposure to safety topics and their confidence with the skills required to lead clinical safety programs. Methods: Radiation oncology residents were identified in collaboration with ARRO and AAPM. The survey was released in February 2016 via email using REDCap. This included questions about exposuremore » to safety topics, confidence leading safety programs, and interest in training opportunities (i.e. workshops). Residents rated their exposure, skills, and confidence on 4 or 5-point scales. Medical and physics residents responses were compared using chi-square tests. Results: Responses were collected from 56 of 248 (22%) physics and 139 of 690 (20%) medical residents. More than two thirds of all residents had no or only informal exposure to incident learning systems (ILS), root cause analysis (RCA), failure mode and effects analysis (FMEA), and the concept of human factors engineering (HFE). Likewise, 63% of residents had not heard of RO-ILS. Response distributions were similar, however more physics residents had formal exposure to FMEA (p<0.0001) and felt they were adequately trained to lead FMEAs in clinic (p<0.001) than medical residents. Only 36% of residents felt their patient safety training was adequate, and 58% felt more training would benefit their education. Conclusion: These results demonstrate that, despite increasing desire for patient safety training, medical and physics residents’ exposure to relevant concepts is low. Physics residents had more exposure to FMEA than medical residents, and were more confident in leading FMEA. This suggests that increasing resident exposure to specific topics may increase their confidence.« less

Flight Trainer Digital Computer Study

DTIC Science & Technology

1951-03-21

b’e "ä"dö|rtedr rfoS^ hfe "digital airplane simulator is .dependent on the accTuracy demanded for representing airp2ane^mo±i6h---as4 on the method...analogue- quantity such as- a vQ.lt:äfa.:e’ .süit;*.v £jr- äc\\t„ü’at.ing an, inst’riMen’t’.i. Since in gene /paiL " ~ instruments, v^𔃻

Radiative efficiencies for fluorinated esters: indirect global warming potentials of hydrofluoroethers.

PubMed

Bravo, Iván; Díaz-de-Mera, Yolanda; Aranda, Alfonso; Moreno, Elena; Nutt, David R; Marston, George

2011-10-14

Density Functional Theory (DFT) has been used with an empirically-derived correction for the wavenumbers of vibrational band positions to predict the infrared spectra of several fluorinated esters (FESs). Radiative efficiencies (REs) were then determined using the method of Pinnock et al. and these were used with atmospheric lifetimes from the literature to determine the direct global warming potentials of FESs. FESs, in particular fluoroalkylacetates, alkylfluoroacetates and fluoroalkylformates, are potential greenhouse gases and their likely long atmospheric lifetimes and relatively large REs, compared to their parent HFEs, make them active contributors to global warming. Here, we use the concept of indirect global warming potential (indirect GWP) to assess the contribution to the warming of several commonly used HFEs emitted from the Earth's surface, explicitly taking into account that these HFEs will be converted into the corresponding FESs in the troposphere. The indirect GWP can be calculated using the radiative efficiencies and lifetimes of the HFE and its degradation FES products. We found that the GWPs of those studied HFEs which have the smallest direct GWP can be increased by 100-1600% when taking account of the cumulative effect due to the secondary FESs formed during HFE atmospheric oxidation. This effect may be particularly important for non-segregated HFEs and some segregated HFEs, which may contribute significantly more to global warming than can be concluded from examination of their direct GWPs.

2007 Weather and Aeolian Sand-Transport Data from the Colorado River Corridor, Grand Canyon, Arizona

USGS Publications Warehouse

Draut, Amy E.; Andrews, Timothy; Fairley, Helen C.; Brown, Christopher R.

2009-01-01

Weather data constitute an integral part of ecosystem monitoring in the Colorado River corridor and are particularly valuable for understanding processes of landscape change that contribute to the stability of archeological sites. Data collected in 2007 are reported from nine weather stations in the Colorado River corridor through Grand Canyon, Ariz. The stations were deployed in February and March 2007 to measure wind speed and direction, rainfall, air temperature, relative humidity, and barometric pressure. Sand traps near each weather station collect windblown sand, from which daily aeolian sand-transport rates are calculated. The data reported here were collected as part of an ongoing study to test and evaluate methods for quantifying processes that affect the physical integrity of archeological sites along the river corridor; as such, these data can be used to identify rainfall events capable of causing gully incision and to predict likely transport pathways for aeolian sand, two landscape processes integral to the preservation of archeological sites. Weather data also have widespread applications to other studies of physical, cultural, and biological resources in Grand Canyon. Aeolian sand-transport data reported here, collected in the year before the March 2008 High-Flow Experiment (HFE) at Glen Canyon Dam, represent baseline data against which the effects of the 2008 HFE on windblown sand will be compared in future reports.

Photochemistry of Fe:H2O Adducts in Argon Matrixes: A Combined Experimental and Theoretical Study in the Mid-IR and UV-Visible Regions.

PubMed

Deguin, Vincent; Mascetti, Joëlle; Simon, Aude; Ben Amor, Nadia; Aupetit, Christian; Latournerie, Sandra; Noble, Jennifer A

2018-01-18

The photochemistry of Fe:H 2 O adducts is of interest in fields as diverse as catalysis and astrochemistry. Industrially, iron can be used as a catalyst to convert H 2 O to H 2 , whereas in the interstellar medium it may be an important component of dust grains, influencing the chemistry on their icy surfaces. This study consisted of the deposition and spectral characterization of binary systems of atomic iron with H 2 O in cryogenic argon matrixes. In this way, we were able to obtain information about the interaction of the two species; we observed the formation of adducts of iron monomers and dimers with water molecules in the mid-IR and UV-visible spectral domains. Upon irradiation with a UV radiation source, the iron species were inserted into the water molecules to form HFeOH and HFe 2 OH, leading in some cases to the formation of FeO possibly accompanied by the production of H 2 . DFT and correlated multireference wave function calculations confirmed our attributions. This combination of IR and UV-visible spectroscopy with theoretical calculations allowed us to determine, for the first time, the spectral characteristics of iron adducts and their photoproducts in the UV-visible and in the OH stretching region of the mid-IR domain.

Altered Erythropoiesis in Mouse Models of Type 3 Hemochromatosis

PubMed Central

Pellegrino, R. M.; Ferbo, L.; Boero, M.; Palmieri, A.; Osella, L.; Pollicino, P.; Miniscalco, B.

2017-01-01

Type 3 haemochromatosis (HFE3) is a rare genetic iron overload disease which ultimately lead to compromised organs functioning. HFE3 is caused by mutations in transferrin receptor 2 (TFR2) gene that codes for two main isoforms (Tfr2α and Tfr2β). Tfr2α is one of the hepatic regulators of iron inhibitor hepcidin. Tfr2β is an intracellular isoform of the protein involved in the regulation of iron levels in reticuloendothelial cells. It has been recently demonstrated that Tfr2 is also involved in erythropoiesis. This study aims to further investigate Tfr2 erythropoietic role by evaluating the erythropoiesis of two Tfr2 murine models wherein either one or both of Tfr2 isoforms have been selectively silenced (Tfr2 KI and Tfr2 KO). The evaluations were performed in bone marrow and spleen, in 14 days' and 10 weeks' old mice, to assess erythropoiesis in young versus adult animals. The lack of Tfr2α leads to macrocytosis with low reticulocyte number and increased hemoglobin values, together with an anticipation of adult BM erythropoiesis and an increased splenic erythropoiesis. On the other hand, lack of Tfr2β (Tfr2 KI mice) causes an increased and immature splenic erythropoiesis. Taken together, these data confirm the role of Tfr2α in modulation of erythropoiesis and of Tfr2β in favoring iron availability for erythropoiesis. PMID:28540293

Building sandbars in the Grand Canyon

USGS Publications Warehouse

Grams, Paul E.; Schmidt, John C.; Wright, Scott A.; Topping, David; Melis, Theodore S.; Rubin, David M.

2015-01-01

Now, by implementing a new strategy that calls for repeated releases of large volumes of water from the dam, the U.S. Department of the Interior (DOI) seeks to increase the size and number of these sandbars. Three years into the "high-flow experiment" (HFE) protocol, the releases appear to be achieving the desired effect. Many sandbars have increased in size following each controlled flood, and the cumulative results of the first three releases suggest that sandbar declines may be reversed if controlled floods can be implemented frequently enough.

Review of Two-phase Electronics Cooling for Army Vehicle Applications

DTIC Science & Technology

2010-09-01

electronics occurred. Mudawar et al. (7) developed a spray cooler as part of the U.S. Department of Energy’s (DOE’s) Power Electronics and Electric...demonstrated by Mudawar (28) on the SEM-E BTPFL-C3 avionics Clamshell Module. By using direct two- phase jet-impingement and FC-72 dielectric fluid...cooling necessary for high heat flux electronic systems. One example is a study performed by Lee and Mudawar (13) with R134A and HFE1700 direct and

Atmospheric chemistry of HFE-7000 (CF(3)CF (2)CF (2)OCH (3)) and 2,2,3,3,4,4,4-heptafluoro-1-butanol (CF (3)CF (2)CF (2)CH (2)OH): kinetic rate coefficients and temperature dependence of reactions with chlorine atoms.

PubMed

Díaz-de-Mera, Yolanda; Aranda, Alfonso; Bravo, Iván; Rodríguez, Diana; Rodríguez, Ana; Moreno, Elena

2008-10-01

The adverse environmental impacts of chlorinated hydrocarbons on the Earth's ozone layer have focused attention on the effort to replace these compounds by nonchlorinated substitutes with environmental acceptability. Hydrofluoroethers (HFEs) and fluorinated alcohols are currently being introduced in many applications for this purpose. Nevertheless, the presence of a great number of C-F bonds drives to atmospheric long-lived compounds with infrared absorption features. Thus, it is necessary to improve our knowledge about lifetimes and global warming potentials (GWP) for these compounds in order to get a complete evaluation of their environmental impact. Tropospheric degradation is expected to be initiated mainly by OH reactions in the gas phase. Nevertheless, Cl atoms reaction may also be important since rate constants are generally larger than those of OH. In the present work, we report the results obtained in the study of the reactions of Cl radicals with HFE-7000 (CF(3)CF(2)CF(2)OCH(3)) (1) and its isomer CF(3)CF(2)CF(2)CH(2)OH (2). Kinetic rate coefficients with Cl atoms have been measured using the discharge flow tube-mass spectrometric technique at 1 Torr of total pressure. The reactions of these chlorofluorocarbons (CFCs) substitutes have been studied under pseudo-first-order kinetic conditions in excess of the fluorinated compounds over Cl atoms. The temperature ranges were 266-333 and 298-353 K for reactions of HFE-7000 and CF(3)CF(2)CF(2)CH(2)OH, respectively. The measured room temperature rate constants were k(Cl+CF(3)CF(2)CF(2)OCH(3)) = (1.24 +/- 0.28) x 10(-13) cm(3) molecule(-1) s(-1)and k(Cl+CF(3)CF(2)CF(2)CH(2)OH) = (8.35 +/- 1.63) x 10(-13) cm(3) molecule(-1) s(-1) (errors are 2sigma + 10% to cover systematic errors). The Arrhenius expression for reaction 1 was k (1)(266-333 K) = (6.1 +/- 3.8) x 10(-13)exp[-(445 +/- 186)/T] cm(3) molecule(-1) s(-1) and k (2)(298-353 K) = (1.9 +/- 0.7) x 10(-12)exp[-(244 +/- 125)/T] cm(3) molecule(-1) s(-1) (errors are 2sigma). The reactions are reported to proceed through the abstraction of an H atom to form HCl and the corresponding halo-alkyl radical. At 298 K and 1 Torr, yields on HCl of 0.95 +/- 0.38 and 0.97 +/- 0.16 (errors are 2sigma) were obtained for CF(3)CF(2)CF(2)OCH(3) and CF(3)CF(2)CF(2)CH(2)OH, respectively. The obtained kinetic rate constants are related to the previous data in the literature, showing a good agreement taking into account the error limits. Comparing the obtained results at room temperature, k (1) and k (2), HFE-7000 is significantly less reactive than its isomer C(3)F(7)CH(2)OH. A similar behavior has been reported for the reactions of other fluorinated alcohols and their isomeric fluorinated ethers with Cl atoms. Literature data, together with the results reported in this work, show that, for both fluorinated ethers and alcohols, the kinetic rate constant may be considered as not dependent on the number of -CF(2)- in the perfluorinated chain. This result may be useful since it is possible to obtain the required physicochemical properties for a given application by changing the number of -CF(2)- without changes in the atmospheric reactivity. Furthermore, lifetimes estimations for these CFCs substitutes are calculated and discussed. The average estimated Cl lifetimes are 256 and 38 years for HFE-7000 and C(3)H(7)CH(2)OH, respectively. The studied CFCs' substitutes are relatively short-lived and OH reaction constitutes their main reactive sink. The average contribution of Cl reactions to global lifetime is about 2% in both cases. Nevertheless, under local conditions as in the marine boundary layer, tau (Cl) values as low as 2.5 and 0.4 years for HFE-7000 and C(3)H(7)CH(2)OH, respectively, are expected, showing that the contribution of Cl to the atmospheric degradation of these CFCs substitutes under such conditions may constitute a relevant sink. In the case of CF(3)CF(2)CF(2)OCH(3), significant activation energy has been measured, thus the use of kinetic rate coefficient only at room temperature would result in underestimations of lifetimes and GWPs. The results obtained in this work may be helpful within the database used in the modeling studies of coastal areas. The knowledge of the atmospheric behavior and the structure-reactivity relationship discussed in this work may also contribute to the development of new environmentally acceptable chemicals. New volatile materials susceptible of emission to the troposphere should be subject to the study of their reactions with OH and Cl in the range of temperature of the troposphere. The knowledge of the temperature dependence of the kinetic rate constants, as it is now reported for the case of reactions 1 and 2, will allow more accurate lifetimes and related magnitudes like GWPs. Nevertheless, a better knowledge of the vertical Cl tropospheric distribution is still required.

Marangoni Effect on the Shape of Freely Receding Evaporating Sessile Droplets of Perfectly Wetting Liquids

NASA Astrophysics Data System (ADS)

Tsoumpas, Yannis; Dehaeck, Sam; Rednikov, Alexey; Colinet, Pierre

2014-11-01

Freely receding evaporating sessile droplets of perfectly wetting liquids (HFE-7100, 7200 and 7500), with small finite contact angles induced by evaporation, are studied with a Mach-Zehnder interferometer. Surprisingly, the experimentally obtained profiles turn out to deviate from the classical macroscopic static shape of a sessile droplet (as determined by gravity and capillarity), often used when modeling evaporating droplets. These deviations can be seen in two ways. Namely, either the droplet appears to be inflated as compared to the classical static shape assuming the same contact angle and contact radius, or the apparent contact angle appears lower than the classical static one assuming the same volume and contact radius. In reality, the experimental profiles exhibit a local decrease of the slope near the contact line, which we attribute to the Marangoni effect in an evaporating sessile droplet. In this case, the radially inward (along the liquid-air interface) direction of the flow delivers more liquid to the center of the droplet making it appear inflated. When the Marangoni effect is weak, as in the case of the poorly volatile HFE-7500, no significant influence is noticed on the drop shape. The experimental results are compared with the predictions of a lubrication-type theoretical model that incorporates the evaporation-induced Marangoni flow. Financial support of FP7 Marie Curie MULTIFLOW Network (PITN-GA-2008-214919), ESA/BELSPO-PRODEX, BELSPO- μMAST (IAP 7/38) & FRS-FNRS is gratefully acknowledged.

Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease.

PubMed

Kotze, Maritha J; van Rensburg, Susan J

2012-09-01

Chronic, multi-factorial conditions caused by a complex interaction between genetic and environmental risk factors frequently share common disease mechanisms, as evidenced by an overlap between genetic risk factors for cardiovascular disease (CVD) and Alzheimer's disease (AD). Single nucleotide polymorphisms (SNPs) in several genes including ApoE, MTHFR, HFE and FTO are known to increase the risk of both conditions. The E4 allele of the ApoE polymorphism is the most extensively studied risk factor for AD and increases the risk of coronary heart disease by approximately 40%. It furthermore displays differential therapeutic responses with use of cholesterol-lowering statins and acetylcholinesterase inhibitors, which may also be due to variation in the CYP2D6 gene in some patients. Disease expression may be triggered by gene-environment interaction causing conversion of minor metabolic abnormalities into major brain disease due to cumulative risk. A growing body of evidence supports the assessment and treatment of CVD risk factors in midlife as a preventable cause of cognitive decline, morbidity and mortality in old age. In this review, the concept of pathology supported genetic testing (PSGT) for CVD is described in this context. PSGT combines DNA testing with biochemical measurements to determine gene expression and to monitor response to treatment. The aim is to diagnose treatable disease subtypes of complex disorders, facilitate prevention of cumulative risk and formulate intervention strategies guided from the genetic background. CVD provides a model to address the lifestyle link in most chronic diseases with a genetic component. Similar preventative measures would apply for optimisation of heart and brain health.

Genetic Influences on Hand Osteoarthritis in Finnish Women – A Replication Study of Candidate Genes

PubMed Central

Hämäläinen, Satu; Solovieva, Svetlana; Vehmas, Tapio; Luoma, Katariina; Leino-Arjas, Päivi; Hirvonen, Ari

2014-01-01

Objectives Our aims were to replicate some previously reported associations of single nucleotide polymorphisms (SNPs) in five genes (A2BP1, COG5, GDF5, HFE, ESR1) with hand osteoarthritis (OA), and to examine whether genes (BCAP29, DIO2, DUS4L, DVWA, HLA, PTGS2, PARD3B, TGFB1 and TRIB1) associated with OA at other joint sites were associated with hand OA among Finnish women. Design We examined the bilateral hand radiographs of 542 occupationally active Finnish female dentists and teachers aged 45 to 63 and classified them according to the presence of OA by using reference images. Data regarding finger joint pain and other risk factors were collected using a questionnaire. We defined two hand OA phenotypes: radiographic OA in at least three joints (ROA) and symptomatic DIP OA. The genotypes were determined by PCR-based methods. In statistical analysis, we used SNPStats software, the chi-square test and logistic regression. Results Of the SNPs, rs716508 in A2BP1 was associated with ROA (OR = 0.7, 95% CI 0.5–0.9) and rs1800470 in TGFB1 with symptomatic DIP OA (1.8, 1.2–2.9). We found an interaction between ESR1 (rs9340799) and occupation: teachers with the minor allele were at an increased risk of symptomatic DIP OA (2.8, 1.3–6.5). We saw no association among the dentists. We also found that the carriage of the COG5 rs3757713 C allele increased the risk of ROA only among women with the BCAP29 rs10953541 CC genotype (2.6; 1.1–6.1). There was also a suggestive interaction between the HFE rs179945 and the ESR1 rs9340799, and the carriage of the minor allele of either of these SNPs was associated with an increased risk of symptomatic DIP OA (2.1, 1.3–2.5). Conclusions Our results support the earlier findings of A2BP1 and TBGF1 being OA susceptibility genes and provide evidence of a possible gene-gene interaction in the genetic influence on hand OA predisposition. PMID:24825461

Statistical Analysis of Bursty Langmuir Waves, Alfvén and Whistler Waves, and Precipitating Electrons Seen by the CHARM II Nightside Sounding Rocket

NASA Astrophysics Data System (ADS)

Dombrowski, M. P.; Labelle, J. W.; Kletzing, C.; Bounds, S. R.; Kaeppler, S. R.

2013-12-01

Bursty Langmuir waves have been interpreted as the result of the superposition of multiple Langmuir normal-mode waves, with the resultant modulation being the beat pattern between waves with e.g. 10 kHz frequency differences. The normal-mode waves could be generated either through wave-wave interactions with VLF waves, or through independent linear processes. The CHARM II sounding rocket was launched into a substorm at 9:49 UT on 15 February 2010, from the Poker Flat Research Range in Alaska. The primary instruments included the Dartmouth High-Frequency Experiment (HFE), a receiver system which effectively yields continuous (100% duty cycle) E-field waveform measurements up to 5 MHz, as well as a number of charged particle detectors, including a wave-particle correlator. The payload also included a magnetometer and several low-frequency wave instruments. CHARM II encountered several regions of strong Langmuir wave activity throughout its 15-minute flight, including several hundred discrete Langmuir-wave bursts. We show results of a statistical analysis of CHARM II data for the entire flight, comparing HFE data with the other payload instruments, specifically looking at timings and correlations between bursty Langmuir waves, Alfvén and whistler-mode waves, and electrons precipitating parallel to the magnetic field. Following a similar analysis on TRICE dayside sounding rocket data, we also calculate the fraction of correlated waves with VLF waves at appropriate frequencies to support the wave-wave interaction bursty Langmuir wave generation mechanism, and compare to results from CHARM II nightside data.

Structure and property correlations in FeS

NASA Astrophysics Data System (ADS)

Kuhn, S. J.; Kidder, M. K.; Parker, D. S.; dela Cruz, C.; McGuire, M. A.; Chance, W. M.; Li, Li; Debeer-Schmitt, L.; Ermentrout, J.; Littrell, K. C.; Eskildsen, M. R.; Sefat, A. S.

2017-03-01

For iron-sulfide (FeS), we investigate the correlation between the structural details, including its dimensionality and composition, with its magnetic and superconducting properties. We compare, theoretically and experimentally, the two-dimensional (2D) layered tetragonal (;t-FeS;) phase with the 3D hexagonal ("h-FeS") phase. X-ray diffraction reveals iron-deficient chemical compositions of t-Fe0.93(1)S and h-Fe0.84(1)S that show no low-temperature structural transitions. First-principles calculations reveal a high sensitivity of the 2D structure to the electronic and magnetic properties, predicting marginal antiferromagnetic instability for our compound (sulfur height of zS = 0.252) with an ordering energy of about 11 meV/Fe, while the 3D phase is magnetically stable. Experimentally, h-Fe0.84S orders magnetically well above room temperature, while t-Fe0.93S shows coexistence of antiferromagnetism at TN = 116 and filamentary superconductivity below Tc = 4 K. Low temperature neutron diffraction data reveals antiferromagnetic commensurate ordering with wave vector km = (0.25,0.25,0) and 0.46(2) μB/Fe. Additionally, neutron scattering measurements were used to find the particle size and iron vacancy arrangement of t-FeS and h-FeS. The structure of iron sulfide has a delicate relationship with the superconducting transition; while our sample with a = 3.6772(7) Å is a filamentary superconductor coexisting with an antiferromagnetic phase, previously reported samples with a > 3.68 Å are bulk superconductors with no magnetism, and those with a ≈ 3.674 Å show magnetic properties.

An immunohistochemical study of placental syncytiotrophoblasts in neonatal hemochromatosis.

PubMed

Shimono, Aiko; Imoto, Yuko; Sakamoto, Haruhiko; Chiba, Yoichi; Matsumoto, Koichi; Kawauchi, Machi; Kusaka, Takashi; Tanaka, Hirokazu; Hata, Toshiyuki; Kushida, Yoshio; Ueno, Masaki

2016-12-01

Neonatal hemochromatosis (NH) is a rare neonatal disorder that results in liver cirrhosis with hemosiderin deposition in the liver and other organs, similarly to hereditary hemochromatosis. Excess iron is transferred from the mother to fetus through the placenta in NH. We examined the expression of iron metabolism-related substances in placental syncytiotrophoblasts (STB) by immunostaining to clarify how the transfer of iron through STB increases in NH. Immunostaining was performed using formalin-fixed, paraffin-embedded sections of placentae from three NH cases, four gestational age-matched controls, and, depending on the antibody examined, five to seven full-term controls. The reactivity of immunostaining was assessed by averages of scores assigned by 3 researchers. On the microvillar surface of STB, the reactions of the antibodies against transferrin receptor 1 (TFR1), transferrin, ferritin, hepcidin, ferroportin, divalent metal transporter-1 (DMT1), hephaestin, and HFE were stronger in NH than in controls. In the cytoplasm, the reactions of antibodies against TFR1, transferrin, ferritin, hepcidin, DMT1, hephaestin, HFE, and ZIP 14 were stronger in NH than in gestational age-matched controls. Among these reactions, those of anti-TFR1 antibody on the surface of STB in NH was especially marked. In the placenta of NH, increases in expressions of TFR1, transferrin, and ferritin of which those of TFR1 were especially marked, reflect increased iron influx from the mother to fetus. The hepcidin observed on the surface and in the cytoplasm of STB of NH is suggested to be from the mother, possibly to compensate for the decreased fetal liver-derived hepcidin. Copyright © 2016 Elsevier Ltd. All rights reserved.

Best practice guidelines for the molecular genetic diagnosis of Type 1 (HFE-related) hereditary haemochromatosis

PubMed Central

King, Caitriona; Barton, David E

2006-01-01

Background Hereditary haemochromatosis (HH) is a recessively-inherited disorder of iron over-absorption prevalent in Caucasian populations. Affected individuals for Type 1 HH are usually either homozygous for a cysteine to tyrosine amino acid substitution at position 282 (C282Y) of the HFE gene, or compound heterozygotes for C282Y and for a histidine to aspartic acid change at position 63 (H63D). Molecular genetic testing for these two mutations has become widespread in recent years. With diverse testing methods and reporting practices in use, there was a clear need for agreed guidelines for haemochromatosis genetic testing. The UK Clinical Molecular Genetics Society has elaborated a consensus process for the development of disease-specific best practice guidelines for genetic testing. Methods A survey of current practice in the molecular diagnosis of haemochromatosis was conducted. Based on the results of this survey, draft guidelines were prepared using the template developed by UK Clinical Molecular Genetics Society. A workshop was held to develop the draft into a consensus document. The consensus document was then posted on the Clinical Molecular Genetics Society website for broader consultation and amendment. Results Consensus or near-consensus was achieved on all points in the draft guidelines. The consensus and consultation processes worked well, and outstanding issues were documented in an appendix to the guidelines. Conclusion An agreed set of best practice guidelines were developed for diagnostic, predictive and carrier testing for hereditary haemochromatosis and for reporting the results of such testing. PMID:17134494

Birth Characteristics and Childhood Leukemia Risk: Correlations With Genetic Markers.

PubMed

Kennedy, Amy E; Kamdar, Kala Y; Lupo, Philip J; Okcu, Mehmet F; Scheurer, Michael E; Dorak, Mehmet T

2015-07-01

Birth characteristics such as birth order, birth weight, birth defects, and Down syndrome showed some of the first risk associations with childhood leukemia. Examinations of correlations between birth characteristics and leukemia risk markers have been limited to birth weight-related genetic polymorphisms. We integrated information on nongenetic and genetic markers by evaluating the relationship of birth characteristics, genetic markers for childhood acute lymphoblastic leukemia (ALL) susceptibility, and ALL risk together. The multiethnic study consisted of cases with childhood ALL (n=161) and healthy controls (n=261). Birth characteristic data were collected through questionnaires, and genotyping was achieved by TaqMan SNP Genotyping Assays. We observed risk associations for birth weight over 4000 g (odds ratios [OR]=1.93; 95% confidence interval [CI], 1.16-3.19), birth length (OR=1.18 per inch; 95% CI, 1.01-1.38), and with gestational age (OR=1.10 per week; 95% CI, 1.00-1.21). Only the HFE tag single-nucleotide polymorphism (SNP) rs9366637 showed an inverse correlation with a birth characteristic, gestational age, with a gene-dosage effect (P=0.005), and in interaction with a transferrin receptor rs3817672 genotype (Pinteraction=0.05). This correlation translated into a strong association for rs9366637 with preterm birth (OR=5.0; 95% CI, 1.19-20.9). Our study provides evidence for the involvement of prenatal events in the development of childhood ALL. The inverse correlation of rs9366637 with gestational age has implications on the design of HFE association studies in birth weight and childhood conditions using full-term newborns as controls.

Ferrate(VI) oxidation of weak-acid dissociable cyanides

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

Ria A. Yngard; Virender K. Sharma; Jan Filip

2008-04-15

Cyanide is commonly found in electroplating, mining, coal gasification, and petroleum refining effluents, which require treatment before being discharged. Cyanide in effluents exists either as free cyanide or as a metal complex. The kinetics of the oxidation of weak-acid dissociable cyanides by an environmentally friendly oxidant, ferrate, were studied as a function of pH (9.1-10.5) and temperature (15-45{sup o}C) using a stopped-flow technique. The weak-acid dissociable cyanides were Cd(CN){sub 4}{sup 2-} and Ni(CN){sub 4}{sup 2-}, and the rate-laws for the oxidation may be -d(Fe(VI))/dt = k (Fe(VI))(M(CN){sub 4}{sup 2-}){sup n} where n = 0.5 and 1 for Cd(CN){sub 4}{sup 2-}more » and Ni(CN){sub 4}{sup 2-}, respectively. The rates decreased with increasing pH and were mostly related to a decrease in concentration of the reactive protonated Fe(VI) species, HFeO{sub 4}{sup -}. The stoichiometries with Fe(VI) were determined to be: 4HFeO{sub 4}{sup -} + M(CN){sub 4}{sup 2-} + 6H{sub 2}O {yields} 4Fe(OH){sub 3} + M{sup 2+} + 4NCO{sup -} + O{sub 2} + 4OH{sup -}. Mechanisms are proposed that agree with the observed reaction rate-laws and stoichiometries of the oxidation of weak-acid dissociable cyanides by Fe(VI). Results indicate that Fe(VI) is effective in removing cyanide in coke oven plant effluent, where organics are also present. 27 refs., 3 figs., 2 tabs.« less

Effects of Experimental High Flow Releases and Increased Fluctuations in Flow from Glen Canyon Dam on Abundance, Growth, and Survival Rates of Early Life Stages of Rainbow Trout in the Lee's Ferry Reach of the Colorado River

NASA Astrophysics Data System (ADS)

Korman, Josh

2010-05-01

The abundance of adult fish populations is controlled by the growth and survival rates of early life stages. Evaluating the effects of flow regimes on early life stages is therefore critical to determine how these regimes affect the abundance of adult populations. Experimental high flow releases from Glen Canyon Dam, primarily intended to conserve fine sediment and improve habitat conditions for native fish in the Colorado River in Grand Canyon, AZ, have been conducted in 1996, 2004, and 2008. These flows potentially affect the Lee's Ferry reach rainbow trout population, located immediately downstream of the dam, which supports a highly valued fishery and likely influences the abundance of rainbow trout in Grand Canyon. Due to concerns about negative effects of high trout abundance on endangered native fish, hourly variation in flow from Glen Canyon Dam was experimentally increased between 2003 and 2005 to reduce trout abundance. This study reports on the effects of experimental high flow releases and fluctuating flows on early life stages of rainbow trout in the Lee's Ferry reach based on monthly sampling of redds (egg nests) and the abundance and growth of age-0 trout between 2003 and 2009. Data on spawn timing, spawning elevations, and intergravel temperatures were integrated in a model to estimate the magnitude and seasonal trend in incubation mortality resulting from redd dewatering due to fluctuations in flow. Experimental fluctuations from January through March promoted spawning at higher elevations where the duration of dewatering was longer and intergravel temperatures exceeded lethal thresholds. Flow-dependent incubation mortality rates were 24% (2003) and 50% (2004) in years with higher flow fluctuations, compared to 5-11% under normal operations (2006-2009). Spatial and temporal predictions of mortality were consistent with direct observations of egg mortality determined from the excavation of 125 redds. The amount of variation in backcalculated hatch date distributions predicted by flow-independent (84-93%) and flow-dependent (82-91%) incubation loss models were similar. Age-0 abundance was generally independent of viable egg deposition, except in one year when egg deposition was 10-fold lower due to reduced spawning activity. There was no evidence from the hatch date or stock-recruitment analysis that flow-dependent incubation losses, although large in experimental years, affected the abundance of the age-0 population. The data indicate that strong compensation in survival rates shortly after emergence mitigated the impact of flow-dependent losses. Multiple lines of evidence demonstrated that the March 2008 high flow experiment (HFE) resulted in a large increase in early survival rates (fertilization to ~1-2 months from emergence) of age-0 trout due an improvement in habitat conditions. A stock-recruitment analysis indicated that age-0 abundance in July 2008 was over four-fold higher than expected given the number of viable redds that produced these fish. A hatch date analysis indicated that early survival rates were much higher for cohorts that emerged about two months after the HFE. These cohorts, which were fertilized after the HFE, were not exposed to high flows and emerged into better quality habitat. Inter annual differences in growth of age-0 trout based on otolith microstructure support this hypothesis. Growth rates in the summer and fall of 2008 (0.44 mm·day-1) were virtually the same as in 2006 (0.46 mm·day-1), the highest recorded over six years, even though abundance was eight-fold greater in 2008. I speculate that high flows in 2008 increased interstitial spaces in the substrate and food availability or quality, leading to higher early survival of recently emerged trout and better growth during summer and fall. Abundance in 2009 was over two-fold higher than expected, possibly indicating that the effect of the HFE on early life stages was somewhat persistent.

National Dam Safety Program. Atwood Lake Dam (MO 31171), Upper Mississippi - Kaskaskia - ST. Louis Basin, Jefferson County, Missouri. Phase I Inspection Report.

DTIC Science & Technology

1980-12-01

investigations are considered necessary. 2-3 SELCTI OdN 7, - VsI -I I N7SVLCF 3.1 FINDINGS a . Gene i’al A v i a , risoec 1, n 1 0f t oe IAt wr> -i k...ar sat is fact ory and conventi onna -; ety fmi-qioc I V’’ t . I iw-vv IfU is reccinmended thqt. the prescr! ied 5<mi i In Iii i nf r i hfe ippl 1w 1

A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?

PubMed

Lucotte, Gérard; Dieterlen, Florent

2003-01-01

The aim of this new meta-analysis (to the end of 2002) is to compile the Y allele frequencies of the C282Y mutation of hereditary hemochromatosis (HFE gene) for 63 European populations, representing a total of 10,708 unrelated people concerning control samples. A new allele map of C282Y frequencies in Europe was constructed. The highest European frequencies are observed in the Celtic populations in Ireland, in the United Kingdom, and in France, but elevated frequencies are also observed in Scandinavia.

Conformational analysis of endomorphin-2 analogs with phenylalanine mimics by NMR and molecular modeling.

PubMed

Shao, Xuan; Gao, Yanfeng; Zhu, Chuanjun; Liu, Xuehui; Yao, Jinlong; Cui, Yuxin; Wang, Rui

2007-05-15

We investigated a series of conformations of endomorphin-2 (EM-2) analogs substituted by phenylglycine (Phg) and homophenylalanine (Hfe) in the position 3 or 4 by two-dimensional (1)H NMR spectroscopy and molecular modeling. Evaluating the aromatic interactions and the dihedral angles in these phenylalanine mimics, we have observed that the conformations in trans isomer have varied from extended to folded as bioactivity decreases. It is suggested that the flexibility of aromatic side chain affects the backbone of EM-2 to adopt folded structures, which may block the ligands in binding to micro-opioid receptor.

HLA haplotype map of river valley populations with hemochromatosis traced through five centuries in Central Sweden.

PubMed

Olsson, K Sigvard; Ritter, Bernd; Hansson, Norbeth; Chowdhury, Ruma R

2008-07-01

The hemochromatosis mutation, C282Y of the HFE gene, seems to have originated from a single event which once occurred in a person living in the north west of Europe carrying human leukocyte antigen (HLA)-A3-B7. In descendants of this ancestor also other haplotypes appear probably caused by local recombinations and founder effects. The background of these associations is unknown. Isolated river valley populations may be fruitful for the mapping of genetic disorders such as hemochromatosis. In this study, we try to test this hypothesis in a study from central Sweden where the haplotyope A1-B8 was common. HLA haplotypes and HFE mutations were studied in hemochromatosis patients with present or past parental origin in a sparsely populated (1/km(2)) rural district (n = 8366 in the year of 2005), in central Sweden. Pedigrees were constructed from the Swedish church book registry. Extended haplotypes were studied to evaluate origin of recombinations. There were 87 original probands, 36 females and 51 males identified during 30 yr, of whom 86% carried C282Y/C282Y and 14% C282Y/H63D. Of 32 different HLA haplotypes A1-B8 was the most common (34%), followed by A3-B7 (16%), both in strong linkage disequilibrium with controls, (P < 0.001). Twenty-nine different families with A1-B8 had a common founder origin 15 generations ago in small bottleneck populations of the late 16th century. A second A1-B8 founder born 1655 was of Norwegian origin. Most of the A3 carriers (n = 26) had a common founder origin 16 generations ago in an even smaller nearby river valley. A fourth founder family carrying HLA-A2 seems to have originated from a recombination along the descendant lines from the A3 ancestor supported by extended haplotype studies. A1-haplotypes with alleles at the B locus different from B8 had a similar recombination origin as HLA-A2 alleles and a common founder origin 11 generations ago. The intergenerational time interval averaged 35.5 +/- 7.9 yr in men and 31.9 +/- 5.9 in females. River valley populations may contain HLA haplotypes reflecting their demographic history. This study has demonstrated that the resistance against recombinations between HLA-A and HFE make HLA haplotypes excellent markers for population movements. Founder effects and genetic drift from bottleneck populations (surviving the plague?) may explain the commonness of the mutation in central Scandinavia. The intergenerational time difference >30 yr was greater than expected and means that the age of the original mutation may be underestimated.

Iron homeostasis and its disruption in mouse lung in iron deficiency and overload.

PubMed

Giorgi, Gisela; D'Anna, María Cecilia; Roque, Marta Elena

2015-10-01

What is the central question of this study? The aim was to explore the role and hitherto unclear mechanisms of action of iron proteins in protecting the lung against the harmful effects of iron accumulation and the ability of pulmonary cells to mobilize iron in iron deficiency. What is the main finding and its importance? We show that pulmonary hepcidin appears not to modify cellular iron mobilization in the lung. We propose pathways for supplying iron to the lung in iron deficiency and for protecting the lung against iron excess in iron overload, mediated by the co-ordinated action of iron proteins, such as divalent metal transporter 1, ZRT-IRE-like-protein 14, transferrin receptor, ferritin, haemochromatosis-associated protein and ferroportin. Iron dyshomeostasis is associated with several forms of chronic lung disease, but its mechanisms of action remain to be elucidated. The aim of the present study was to determine the role of the lung in whole-animal models with iron deficiency and iron overload, studying the divalent metal transporter 1 (DMT1), ZRT-IRE-like protein 14 (ZIP14), transferrin receptor (TfR), haemochromatosis-associated protein (HFE), hepcidin, ferritin and ferroportin (FPN) expression. In each model, adult CF1 mice were divided into the following groups (six mice per group): (i) iron-overload model, iron saccharate i.p. and control group (iron adequate), 0.9% NaCl i.p.; and (ii) iron-deficiency model, induced by repeated bleeding, and control group (sham operated). Proteins were assessed by immunohistochemistry and Western blot. In control mice, DMT1 was localized in the cytoplasm of airway cells, and in iron deficiency and overload it was in the apical membrane. Divalent metal transporter 1 and TfR increased in iron deficiency, without changes in iron overload. ZRT-IRE-like protein 14 decreased in airway cells in iron deficiency and increased in iron overload. In iron deficiency, HFE and FPN were immunolocalized close to the apical membrane. Ferroportin increased in iron overload. Prohepcidin was present in control groups, with no changes in iron deficiency and iron overload. In iron overload, ferritin showed intracytoplasmic localization close to the apical membrane of airway cells and intense immunostaining in macrophage-like cells. The results show that pulmonary hepcidin does not appear to modify cellular iron mobilization in the lung. We propose the following two novel pathways in the lung: (i) for supplying iron in iron deficiency, mediated principally by DMT1 and TfR and regulated by the action of FPN and HFE; and (ii) for iron detoxification in order to protect the lung against iron overload, facilitated by the action of DMT1, ZIP14, FPN and ferritin. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Signatures of Evolutionary Adaptation in Quantitative Trait Loci Influencing Trace Element Homeostasis in Liver

PubMed Central

Sabidó, Eduard; Bosch, Elena

2016-01-01

Essential trace elements possess vital functions at molecular, cellular, and physiological levels in health and disease, and they are tightly regulated in the human body. In order to assess variability and potential adaptive evolution of trace element homeostasis, we quantified 18 trace elements in 150 liver samples, together with the expression levels of 90 genes and abundances of 40 proteins involved in their homeostasis. Additionally, we genotyped 169 single nucleotide polymorphism (SNPs) in the same sample set. We detected significant associations for 8 protein quantitative trait loci (pQTL), 10 expression quantitative trait loci (eQTLs), and 15 micronutrient quantitative trait loci (nutriQTL). Six of these exceeded the false discovery rate cutoff and were related to essential trace elements: 1) one pQTL for GPX2 (rs10133290); 2) two previously described eQTLs for HFE (rs12346) and SELO (rs4838862) expression; and 3) three nutriQTLs: The pathogenic C282Y mutation at HFE affecting iron (rs1800562), and two SNPs within several clustered metallothionein genes determining selenium concentration (rs1811322 and rs904773). Within the complete set of significant QTLs (which involved 30 SNPs and 20 gene regions), we identified 12 SNPs with extreme patterns of population differentiation (FST values in the top 5% percentile in at least one HapMap population pair) and significant evidence for selective sweeps involving QTLs at GPX1, SELENBP1, GPX3, SLC30A9, and SLC39A8. Overall, this detailed study of various molecular phenotypes illustrates the role of regulatory variants in explaining differences in trace element homeostasis among populations and in the human adaptive response to environmental pressures related to micronutrients. PMID:26582562

Identification and characterization of a new multigene family in the human MHC: A candidate autoimmune disease susceptibility element (3.8-1)

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

Harris, J.M.; Venditti, C.P.; Chorney, M.J.

1994-09-01

An association between idiopathic hemochromatosis (HFE) and the HLA-A3 locus has been previously well-established. In an attempt to identify potential HFE candidate genes, a genomic DNA fragment distal to the HLA-A9 breakpoint was used to screen a B cell cDNA library; a member (3.8-1) of a new multigene family, composed of five distinct genomic cross-reactive fragments, was identified. Clone 3.8-1 represents the 3{prime} end of 9.6 kb transcript which is expressed in multiple tissues including the spleen, thymus, lung and kidney. Sequencing and genome database analysis indicate that 3.8-1 is unique, with no homology to any known entries. The genomicmore » residence of 3-8.1, defined by polymorphism analysis and physical mapping using YAC clones, appears to be absent from the genomes of higher primates, although four other cross-reactivities are maintained. The absence of this gene as well as other probes which map in the TNF to HLA-B interval, suggest that this portion of the human HMC, located between the Class I and Class III regions, arose in humans as the result of a post-speciation insertional event. The large size of the 3.8-1 gene and the possible categorization of 3.8-1 as a human-specific gene are significant given the genetic data that place an autoimmune susceptibility element for IDDM and myasthenia gravis in the precise region where this gene resides. In an attempt to isolate the 5{prime} end of this large transcript, we have constructed a cosmid contig which encompasses the genomic locus of this gene and are progressively isolating coding sequences by exon trapping.« less

A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload.

PubMed

Sripetchwandee, Jirapas; Wongjaikam, Suwakon; Krintratun, Warunsorn; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2016-09-22

Iron-overload can cause cognitive impairment due to blood-brain barrier (BBB) breakdown and brain mitochondrial dysfunction. Although deferiprone (DFP) has been shown to exert neuroprotection, the head-to-head comparison among iron chelators used clinically on brain iron-overload has not been investigated. Moreover, since antioxidant has been shown to be beneficial in iron-overload condition, its combined effect with iron chelator has not been tested. Therefore, the hypothesis is that all chelators provide neuroprotection under iron-overload condition, and that a combination of an iron chelator with an antioxidant has greater efficacy than monotherapy. Male Wistar rats (n=42) were assigned to receive a normal diet (ND) or a high-iron diet (HFe) for 4months. At the 2nd month, HFe-fed rats were treated with a vehicle, deferoxamine (DFO), DFP, deferasirox (DFX), n-acetyl cysteine (NAC) or a combination of DFP with NAC, while ND-fed rats received vehicle. At the end of the experiment, rats were decapitated and brains were removed to determine brain iron level and deposition, brain mitochondrial function, BBB protein expression, brain mitochondrial dynamic, brain apoptosis, tau-hyperphosphorylation, amyloid-β (Aβ) accumulation and dendritic spine density. The results showed that iron-overload induced BBB breakdown, brain iron accumulation, brain mitochondrial dysfunction, impaired brain mitochondrial dynamics, tau-hyperphosphorylation, Aβ accumulation and dendritic spine reduction. All treatments, except DFX, attenuated these impairments. Moreover, combined therapy provided a greater efficacy than monotherapy. These findings suggested that iron-overload induced brain iron toxicity and a combination of an iron chelator with an antioxidant provided a greatest efficacy for neuroprotection than monotherapy. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Mössbauer Spectra of Mouse Hearts Reveal Age-dependent Changes in Mitochondrial and Ferritin Iron Levels.

PubMed

Wofford, Joshua D; Chakrabarti, Mrinmoy; Lindahl, Paul A

2017-03-31

Cardiac function requires continuous high levels of energy, and so iron, a critical player in mitochondrial respiration, is an important component of the heart. Hearts from 57 Fe-enriched mice were evaluated by Mössbauer spectroscopy. Spectra consisted of a sextet and two quadrupole doublets. One doublet was due to residual blood, whereas the other was due to [Fe 4 S 4 ] 2+ clusters and low-spin Fe II hemes, most of which were associated with mitochondrial respiration. The sextet was due to ferritin; there was no evidence of hemosiderin, a ferritin decomposition product. Iron from ferritin was nearly absent in young hearts, but increased steadily with age. EPR spectra exhibited signals similar to those of brain, liver, and human cells. No age-dependent EPR trends were apparent. Hearts from HFE -/- mice with hemochromatosis contained slightly more iron overall than controls, including more ferritin and less mitochondrial iron; these differences typify slightly older hearts, perhaps reflecting the burden due to this disease. HFE -/- livers were overloaded with ferritin but had low mitochondrial iron levels. IRP2 -/- hearts contained less ferritin than controls but normal levels of mitochondrial iron. Hearts of young mice born to an iron-deficient mother contained normal levels of mitochondrial iron and no ferritin; the heart from the mother contained low ferritin and normal levels of mitochondrial iron. High-spin Fe II ions were nearly undetectable in heart samples; these were evident in brains, livers, and human cells. Previous Mössbauer spectra of unenriched diseased human hearts lacked mitochondrial and blood doublets and included hemosiderin features. This suggests degradation of iron-containing species during sample preparation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Biological variability of transferrin saturation and unsaturated iron binding capacity

PubMed Central

Adams, PC; Reboussin, DM; Press, RD; Barton, JC; Acton, RT; Moses, GC; Leiendecker-Foster, C; McLaren, GD; Dawkins, FW; Gordeuk, VR; Lovato, L; Eckfeldt, JH

2007-01-01

Background Transferrin saturation is widely considered the preferred screening test for hemochromatosis. Unsaturated iron binding capacity has similar performance at lower cost. However, the within-person biological variability of both these tests may limit their ability at commonly used cut points to detect HFE C282Y homozygous patients. Methods The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 primary care participants for iron overload using tansferrin saturation, unsaturated iron binding capacity, ferritin and HFE C282Y and H63D genotyping. Transferrin saturation and unsaturated iron binding capacity were performed at initial screening and again when selected participants and controls returned for a clinical examination several months later. A missed case was defined as a C282Y homozygote who had transferrin saturation below cut point (45 % women, 50 % men) or unsaturated iron binding capacity above cut point (150 μmol/L women, 125 μmol/L men) at either the initial screening or clinical examination, or both, regardless of serum ferritin. Results There were 209 C282Y previously undiagnosed homozygotes with transferrin saturation and unsaturated iron binding capacity testing done at initial screening and clinical examination. Sixty-eight C282Y homozygotes (33%) would have been missed at these transferrin saturation cut points (19 men, 49 women, median SF 170 μg/L, first and third quartiles 50 and 474 μg/L), and 58 homozygotes (28 %) would have been missed at the unsaturated iron binding capacity cut points (20 men, 38 women, median SF 168 μg/L, quartiles 38 and 454 μg/L). There was no advantage to using fasting samples. Conclusions The within-person biological variability of transferrin saturation and unsaturated iron binding capacity limit their usefulness as an initial screening test for expressing C282Y homozygotes. PMID:17976429

Unraveling the complexity of iron oxides at high pressure and temperature: Synthesis of Fe 5O 6

DOE PAGES

Lavina, Barbara; Meng, Yue

2015-06-26

The iron-oxygen system is the most important reference of rocks’ redox state. Even as minor components, iron oxides can play a critical role in redox equilibria, which affect the speciation of the fluid phases chemical differentiation, melting, and physical properties. Until our recent finding of Fe 4O 5, iron oxides were assumed to comprise only the polymorphs of FeO, Fe 3O 4, and Fe 2O 3. Combining synthesis at high pressure and temperature with micro- diffraction mapping, we have identified yet another distinct iron oxide, Fe 5O 6. The new compound, which has an orthorhombic structure, was obtained in themore » pressure range from 10 to 20 GPa upon laser heating mixtures of iron and hematite at ~2000 K, and is recoverable to ambient conditions. The high-pressure orthorhombic iron oxides Fe 5O 6, Fe 4O 5, and h-Fe 3O 4 display similar iron coordination geometries and structural arrangements, and indeed exhibit coherent systematic behavior of crystallographic parameters and compressibility. Fe 5O 6, along with FeO and Fe 4O 5, is a candidate key minor phase of planetary interiors; as such, it is of major petrological and geo- chemical importance. Here, we are revealing an unforeseen complexity in the Fe-O system with four different compounds—FeO, Fe 5O 6, Fe 4O 5, and h-Fe 3O 4—in a narrow compositional range (0.75 < Fe/O < 1.0). New, finely spaced oxygen buffers at conditions of the Earth’s mantle can be defined.« less

Key-Generation Algorithms for Linear Piece In Hand Matrix Method

NASA Astrophysics Data System (ADS)

Tadaki, Kohtaro; Tsujii, Shigeo

The linear Piece In Hand (PH, for short) matrix method with random variables was proposed in our former work. It is a general prescription which can be applicable to any type of multivariate public-key cryptosystems for the purpose of enhancing their security. Actually, we showed, in an experimental manner, that the linear PH matrix method with random variables can certainly enhance the security of HFE against the Gröbner basis attack, where HFE is one of the major variants of multivariate public-key cryptosystems. In 1998 Patarin, Goubin, and Courtois introduced the plus method as a general prescription which aims to enhance the security of any given MPKC, just like the linear PH matrix method with random variables. In this paper we prove the equivalence between the plus method and the primitive linear PH matrix method, which is introduced by our previous work to explain the notion of the PH matrix method in general in an illustrative manner and not for a practical use to enhance the security of any given MPKC. Based on this equivalence, we show that the linear PH matrix method with random variables has the substantial advantage over the plus method with respect to the security enhancement. In the linear PH matrix method with random variables, the three matrices, including the PH matrix, play a central role in the secret-key and public-key. In this paper, we clarify how to generate these matrices and thus present two probabilistic polynomial-time algorithms to generate these matrices. In particular, the second one has a concise form, and is obtained as a byproduct of the proof of the equivalence between the plus method and the primitive linear PH matrix method.

Investigation of Spray Cooling Schemes for Dynamic Thermal Management

NASA Astrophysics Data System (ADS)

Yata, Vishnu Vardhan Reddy

This study aims to investigate variable flow and intermittent flow spray cooling characteristics for efficiency improvement in active two-phase thermal management systems. Variable flow spray cooling scheme requires control of pump input voltage (or speed), while intermittent flow spray cooling scheme requires control of solenoid valve duty cycle and frequency. Several testing scenarios representing dynamic heat load conditions are implemented to characterize the overall performance of variable flow and intermittent flow spray cooling cases in comparison with the reference, steady flow spray cooling case with constant flowrate, continuous spray cooling. Tests are conducted on a small-scale, closed loop spray cooling system featuring a pressure atomized spray nozzle. HFE-7100 dielectric liquid is selected as the working fluid. Two types of test samples are prepared on 10 mm x 10 mm x 2 mm copper substrates with matching size thick film resistors attached onto the opposite side, to generate heat and simulate high heat flux electronic devices. The test samples include: (i) plain, smooth surface, and (ii) microporous surface featuring 100 ?m thick copper-based coating prepared by dual stage electroplating technique. Experimental conditions involve HFE-7100 at atmospheric pressure and 30°C and 10°C subcooling. Steady flow spray cooling tests are conducted at flow rates of 2-5 ml/cm2.s, by controlling the heat flux in increasing steps, and recording the corresponding steady-state temperatures to obtain cooling curves in the form of surface superheat vs. heat flux. Variable flow and intermittent flow spray cooling tests are done at selected flowrate and subcooling conditions to investigate the effects of dynamic flow conditions on maintaining the target surface temperatures defined based on reference steady flow spray cooling performance.

HDAC1 Governs Iron Homeostasis Independent of Histone Deacetylation in Iron-Overload Murine Models.

PubMed

Yin, Xiangju; Wu, Qian; Monga, Jitender; Xie, Enjun; Wang, Hao; Wang, Shufen; Zhang, Huizhen; Wang, Zhan-You; Zhou, Tianhua; Shi, Yujun; Rogers, Jack; Lin, Hening; Min, Junxia; Wang, Fudi

2018-05-01

Iron-overload disorders are common and could lead to significant morbidity and mortality worldwide. Due to limited treatment options, there is a great need to develop novel strategies to remove the excess body iron. To discover potential epigenetic modulator in hepcidin upregulation and subsequently decreasing iron burden, we performed an epigenetic screen. The in vivo effects of the identified compounds were further tested in iron-overload mouse models, including Hfe -/- , Hjv -/- , and hepatocyte-specific Smad4 knockout (Smad4 fl/fl ;Alb-Cre + ) mice. Entinostat (MS-275), the clinical used histone deacetylase 1 (HDAC1) inhibitor, was identified the most potent hepcidin agonist. Consistently, Hdac1-deficient mice also presented higher hepcidin levels than wild-type controls. Notably, the long-term treatment with entinostat in Hfe -/- mice significantly alleviated iron overload through upregulating hepcidin transcription. In contrast, entinostat showed no effect on hepcidin expression and iron levels in Smad4 fl/fl ;Alb-Cre + mice. Further mechanistic studies revealed that HDAC1 suppressed expression of hepcidin through interacting with SMAD4 rather than deacetylation of SMAD4 or histone-H3 on the hepcidin promoter. The findings uncovered HDAC1 as a novel hepcidin suppressor through complexing with SMAD4 but not deacetylation of either histone 3 or SMAD4. In addition, our study suggested a novel implication of entinostat in treating iron-overload disorders. Based on our results, we conclude that entinostat strongly activated hepcidin in vivo and in vitro. HDAC1 could serve as a novel hepcidin suppressor by binding to SMAD4, effect of which is independent of BMP/SMAD1/5/8 signaling. Antioxid. Redox Signal. 28, 1224-1237.

Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population

PubMed Central

Gordeuk, Victor R.; Reboussin, David M.; McLaren, Christine E.; Barton, James C.; Acton, Ronald T.; McLaren, Gordon D.; Harris, Emily L.; Reiss, Jacob A.; Adams, Paul C.; Speechley, Mark; Phatak, Pradyumna D.; Sholinsky, Phyliss; Eckfeldt, John H.; Chen, Wen-Pin; Passmore, Leah; Dawkins, Fitzroy W.

2013-01-01

How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 μg/L (men), >200 μg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 μg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 μg/L in male C282Y homozygotes is predictive of moderately increased iron stores. PMID:18429050

Maternal iron levels early in pregnancy are not associated with offspring IQ score at age 8, findings from a Mendelian randomization study

PubMed Central

Lewis, S J; Bonilla, C; Brion, M-J; Lawlor, D A; Gunnell, D; Ben-Shlomo, Y; Ness, A; Smith, G D

2014-01-01

Background/Objectives: Iron is fundamental to many basic biological functions, and animal studies suggest that iron deficiency early in life can have a lasting impact on the developing brain. Subjects/Methods: We used a population-based cohort of mothers and their children to assess the effect of iron status among pregnant women on the cognitive ability of their offspring. But to avoid the inherent confounding that occurs within observational epidemiology studies we examined the association of maternal genotype at single-nucleotide polymorphisms in the genes HFE (rs1799945) and (rs1800562), TF (rs3811647) and TMPRSS6 (rs1800562), which are related to iron, haemoglobin or transferrin levels, on their child's cognitive test scores at age 8. Results: We found strong associations between HFE and TMPRSS6 genotypes and mother's haemoglobin levels early in pregnancy (P-values are all ⩽4.1 × 10−5) and a genetic score comprised of alleles at these loci was even more strongly associated with haemoglobin levels (P=3.0 × 10−18), suggesting that this was a good instrument to use to look at the effect of prenatal iron levels on offspring cognition. However, mother's genotype at the above loci was not associated with offspring IQ at age 8. Conclusions: We therefore concluded that there is no evidence of an effect of exposure to low levels of iron (within the normal range) in pregnancy on offspring cognition at age 8. However, pregnant women in the UK with low haemoglobin levels are prescribed iron supplements and so we were unable to look at the effect of iron deficiency in our study. PMID:24398642

Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS Study initial screening

PubMed Central

Barton, James C.; Acton, Ronald T.; Leiendecker-Foster, Catherine; Lovato, Laura; Adams, Paul C.; Eckfeldt, John H.; McLaren, Christine E.; Reiss, Jacob A.; McLaren, Gordon D.; Reboussin, David M.; Gordeuk, Victor R.; Speechley, Mark R.; Press, Richard D.; Dawkins, Fitzroy W.

2013-01-01

There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25–29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25–29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire. PMID:17726683

Clinical expression of haemochromatosis in Irish C282Y homozygotes identified through family screening.

PubMed

Gleeson, F; Ryan, E; Barrett, S; Crowe, J

2004-09-01

In Ireland, the homozygote frequency of the C282Y mutation in the HFE gene is 1/83. The biochemical expression of this mutation is high in haemochromatosis (HH) individuals identified through family screening, but the clinical expression of the mutation in Irish HH subjects to date has not been investigated fully. To determine the clinical, biochemical and histological penetrance of the C282Y mutation in Irish C282Y homozygotes identified through family screening. Two hundred and nine C282Y homozygous individuals comprising of 172 first-degree relatives, 31 second-degree relatives and four unrelated individuals were identified following HFE mutation analysis of 167 families. The following variables were analysed: age at identification, gender, fasting transferrin saturation, fasting serum ferritin, liver enzymes, clinical symptomatology, liver histopathology and histochemical iron staining. An elevated transferrin saturation in combination with an elevated ferritin was present in 43.4% of males and 23.3% of females. Abnormal liver enzymes were found in 32.3% of males. Diabetes, a haemochromatosis-specific association, was noted in 2.8% of males. Of those individuals requiring liver histopathology evaluation, 38% had moderate-to-severe iron staining, and 42% had fibrosis; 2.8% of the biopsied cohort had cirrhosis. Thus, HH cirrhotics were identified in less than 1% of the screened population. Although the homozygote frequency in Ireland is very high, the prevalence of advanced liver disease was less than 1% of the family members screened. Nevertheless, 42% of biopsied patients had histological evidence of iron overload-related architectural change and 2.8% had cirrhosis. This cohort of young people had previously unrecognized biochemical iron overload and histopathological change. This emphasizes the importance and value of both genetic and biochemical screening in first-degree relatives of identified homozygotes.

The modified iron avidity index: a promising phenotypic predictor in HFE-related haemochromatosis.

PubMed

Verhaegh, Pauline L M; Moris, Wenke; Koek, Ger H; van Deursen, Cees Th B M

2016-10-01

Phenotypes of the HFE-related haemochromatosis vary considerably, making it hard to predict the course of iron accumulation. The aim of this retrospective study was to determine if the Iron Avidity Index (IAI) is a good phenotypic predictor of the number of phlebotomies needed per year during maintenance treatment (NPDMT) in patients with homozygous p.C282Y hereditary haemochromatosis (HH). Patients with HH homozygous for p.C282Y, on maintenance treatment for at least 1 year were included. The IAI (ferritin level at diagnosis/age at diagnosis) was calculated. Ninety-five patients were included in the analysis. Linear regression analysis showed the confounding effect of sex on the relationship between IAI and NPDMT. A modified IAI, adjusted for sex, was calculated. As proton pump inhibitor (PPI) use was independently associated with NPDMT, the group was split in PPI- and non-PPI-users. A positive correlation between the modified IAI and the NPDMT was shown in both groups (PPI r = 0.367, P = 0.023; non-PPI r = 0.453, P < 0.001). An ROC was computed to measure the accuracy of the modified IAI to predict who needed 0-2 vs. ≥3 maintenance treatments per year. The AUROC in the PPI and non-PPI group were respectively 0.576 (0.368-0.784) and 0.752 (0.606-0.899). The modified IAI is a fairly good predictor in non-PPI-using homozygous C282Y HH patients, to differentiate who needs ≥3 maintenance phlebotomies per year. Therefore, this index might help to select patients that benefit from an alternative less frequent therapy, e.g. erythrocytapheresis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Hereditary haemochromatosis].

PubMed

Bismuth, Michael; Aguilar-Martinez, Patricia; Michel, Henri

2003-11-08

EPIDEMIOLOGY ADN PHYSIOPATHOLOGY: Hereditary haemochromatosis is the most common genetic disease in France. Its frequency is on average 1 out of 300 French individuals. It is due to excessive dietary iron absorption, leading to accumulation of iron in the body. Mutations of the HFE1 gene are responsible for the majority of the case of haemochromatosis. FROM A CLINICAL POINT OF VIEW: The first clinical manifestations (weakness, sexual dysfunction, arthralgia, cardiac symptoms, dyspnoea on effort) can occur after the age of 30 years in men and 35 years in women (protected for longer by menstruation, pregnancy and delivery). In the absence of diagnosis, severe complications can develop during the 5th decade: nervous breakdown, arthropathy, heart failure, diabetes mellitus, cirrhosis with risk of progression towards carcinoma, responsible for handicaps and premature death. DIAGNOSTIC ELEMENTS: The diagnosis is evoked in the case of an increase in transferrine saturation (>45%), associated or not with excessive ferritin plasma levels. It is confirmed by the genetic test, showing homozygotes for the C282Y mutation or compound heterozygotes for the C282Y and H63D mutations on the HFE1 gene. RMI quantifies hepatic iron loading and generally avoids the need for a liver biopsy. The differential diagnosis must exclude secondary iron overload due to chronic transfusions in congenital or acquired blood diseases, a polymetabolic syndrome, chronic viral or alcoholic hepatic diseases and porphyria cutanea tarda. EFFICIENT TREATMENT: Today, haemochromatosis is still treated by phlebotomy. This consists in withdrawing 400 to 500ml of blood every week at the initial depletion stage and subsequently a maintenance therapy in order to maintain ferritin levels below 50 ng/ml. Paradoxically and through ignorance, hereditary haemochromatosis remains a serious disease, although its diagnosis is easy and the treatment simple and effective.

HLA-A and -B alleles and haplotypes in hemochromatosis probands with HFE C282Y homozygosity in central Alabama.

PubMed

Barton, James C; Acton, Ronald T

2002-10-07

We wanted to quantify HLA-A and -B allele and haplotype frequencies in Alabama hemochromatosis probands with HFE C282Y homozygosity and controls, and to compare results to those in other populations. Alleles were detected using DNA-based typing (probands) and microlymphocytotoxicity (controls). Alleles were determined in 139 probands (1,321 controls) and haplotypes in 118 probands (605 controls). In probands, A*03 positivity was 0.7482 (0.2739 controls; p = or < 0.0001; odds ratio (OR) 7.9); positivity for B*07, B*14, and B*56 was also increased. In probands, haplotypes A*03-B*07 and A*03-B*14 were more frequent (p < 0.0001, respectively; OR = 12.3 and 11.1, respectively). The haplotypes A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*35, A*03-B*44, A*03-B*47, and A*03-B*57 were also significantly more frequent in probands. 37.3% of probands were HLA-haploidentical with other proband(s). A*03 and A*03-B*07 frequencies are increased in Alabama probands, as in other hemochromatosis cohorts. Increased absolute frequencies of A*03-B*35 have been reported only in the present Alabama probands and in hemochromatosis patients in Italy. Increased absolute frequencies of A*01-B*60, A*02-B*39, A*02-B*62, A*03-B*13, A*03-B*15, A*03-B*27, A*03-B*44, A*03-B*47, and A*03-B*57 in hemochromatosis cohorts have not been reported previously.

Clinical cofactors and hepatic fibrosis in hereditary hemochromatosis: the role of diabetes mellitus.

PubMed

Wood, Marnie J; Powell, Lawrie W; Dixon, Jeannette L; Ramm, Grant A

2012-09-01

The risk of hepatic fibrosis and cirrhosis in hereditary hemochromatosis relates to the degree of iron loading, but iron alone does not explain the variability in disease penetrance. This study sought to identify clinical cofactors that increase the risk of progressive liver disease. We identified 291 patients from our database who were homozygous for the C282Y mutation in HFE and had undergone a liver biopsy with quantification of hepatic iron concentration (HIC) and fibrosis staging. Data were collected from a retrospective chart review, including age, gender, alcohol consumption, medical therapy, smoking history, metabolic risk factors, mobilizable iron, and laboratory results. Male gender, excess alcohol consumption, HIC, and the presence of diabetes were independently associated with increasing fibrosis stage in multivariate analysis. Of these, the presence of diabetes showed the strongest association (odds ratio, 7.32; P = 0.03). The presence of steatosis was associated with higher fibrosis scores, but this was of borderline statistical significance. Risk factors for hepatic steatosis were male gender, impaired glucose tolerance, and increased body mass index. The presence of diabetes was associated with more severe hepatic fibrosis independent of iron loading, male gender, and alcohol consumption. The mechanism for this association is unknown and deserves further evaluation; however, it is possible that diabetes produces an additional hepatic oxidative injury from hyperglycemia. Thus, management of such cofactors in patients with hemochromatosis is important to reduce the risk of liver injury and fibrosis. Copyright © 2012 American Association for the Study of Liver Diseases.

Engineering Technical Review Planning Briefing

NASA Technical Reports Server (NTRS)

Gardner, Terrie

2012-01-01

The general topics covered in the engineering technical planning briefing are 1) overviews of NASA, Marshall Space Flight Center (MSFC), and Engineering, 2) the NASA Systems Engineering(SE) Engine and its implementation , 3) the NASA Project Life Cycle, 4) MSFC Technical Management Branch Services in relation to the SE Engine and the Project Life Cycle , 5) Technical Reviews, 6) NASA Human Factor Design Guidance , and 7) the MSFC Human Factors Team. The engineering technical review portion of the presentation is the primary focus of the overall presentation and will address the definition of a design review, execution guidance, the essential stages of a technical review, and the overall review planning life cycle. Examples of a technical review plan content, review approaches, review schedules, and the review process will be provided and discussed. The human factors portion of the presentation will focus on the NASA guidance for human factors. Human factors definition, categories, design guidance, and human factor specialist roles will be addressed. In addition, the NASA Systems Engineering Engine description, definition, and application will be reviewed as background leading into the NASA Project Life Cycle Overview and technical review planning discussion.

Human factors opportunities to improve Ohio's transportation system : executive summary report.

DOT National Transportation Integrated Search

2005-06-01

Human factors engineering or ergonomics is the : area of engineering concerned with the humanmachine : interface. As Ohios road systems are : driven on by people, human factors engineering : is certainly relevant. However, human factors : have oft...

40 CFR 1042.245 - Deterioration factors.

Code of Federal Regulations, 2014 CFR

2014-07-01

... to meet the Tier 1 and Tier 2 emission standards would qualify as established technology. We must... deterioration factors for Category 1 and Category 2 engines, either with an engineering analysis, with pre... deterioration factors for an engine family with established technology based on engineering analysis instead of...

40 CFR 1042.245 - Deterioration factors.

Code of Federal Regulations, 2012 CFR

2012-07-01

... to meet the Tier 1 and Tier 2 emission standards would qualify as established technology. We must... deterioration factors for Category 1 and Category 2 engines, either with an engineering analysis, with pre... deterioration factors for an engine family with established technology based on engineering analysis instead of...

40 CFR 1042.245 - Deterioration factors.

Code of Federal Regulations, 2010 CFR

2010-07-01

... to meet the Tier 1 and Tier 2 emission standards would qualify as established technology. We must... deterioration factors for Category 1 and Category 2 engines, either with an engineering analysis, with pre... deterioration factors for an engine family with established technology based on engineering analysis instead of...

40 CFR 1042.245 - Deterioration factors.

Code of Federal Regulations, 2011 CFR

2011-07-01

... to meet the Tier 1 and Tier 2 emission standards would qualify as established technology. We must... deterioration factors for Category 1 and Category 2 engines, either with an engineering analysis, with pre... deterioration factors for an engine family with established technology based on engineering analysis instead of...

40 CFR 1042.245 - Deterioration factors.

Code of Federal Regulations, 2013 CFR

2013-07-01

... to meet the Tier 1 and Tier 2 emission standards would qualify as established technology. We must... deterioration factors for Category 1 and Category 2 engines, either with an engineering analysis, with pre... deterioration factors for an engine family with established technology based on engineering analysis instead of...

Human-factors engineering control-room design review/audit: Waterford 3 SES Generating Station, Louisiana Power and Light Company

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

Savage, J.W.

1983-03-10

A human factors engineering design review/audit of the Waterford-3 control room was performed at the site on May 10 through May 13, 1982. The report was prepared on the basis of the HFEB's review of the applicant's Preliminary Human Engineering Discrepancy (PHED) report and the human factors engineering design review performed at the site. This design review was carried out by a team from the Human Factors Engineering Branch, Division of Human Factors Safety. The review team was assisted by consultants from Lawrence Livermore National Laboratory (University of California), Livermore, California.

[Molecular genetic diagnostics and screening of hereditary hemochromatosis].

PubMed

Zlocha, J; Kovács, L; Pozgayová, S; Kupcová, V; Durínová, S

2006-06-01

Hereditary hemochromatosis is considered one of the most common hereditary diseases in population of Caucasian origin. In recent years, a candidate gene for HLA-linked hemochromatosis, HFE, has been cloned, and a single G-to-A mutation resulting in a cysteine-to-tyrosine substitution (C282Y) has been identified in up to 80% of study patients with type 1 hereditary hemochromatosis. The purpose of the paper was to confirm the importance of genetic testing for HFE mutations in making the diagnosis of hemochromatosis and find out a suitable diagnostic algorithm for the indication of this form of diagnostics in patients suspected of hereditary hemochromatosis. The examination of C282Y mutation was conducted in 500 subjects. The most frequent indications for DNA analysis were hepatopathy of unknown ethiology, liver cirrhosis, diabetes mellitus, bronze skin pigmentation in connection with high serum iron concentration, elevated transferrin saturation and elevated serum ferritin levels. In our group of patients, 29 homozygotes and 75 heterozygotes for C282Y mutation were identified, 10 patients carried both C282Y and H63D mutations of HFE gene (compound heterozygotes), whereas in 386 subjects the mutation was not found. The genotype-phenotype correlation showed that 22 homozygotes had liver affection proved by imaging and/or histologic methods. Except the liver disorders, the most common symptoms of these patients were type 2 diabetes mellitus or glucose tolerance disorder (10 patients), arthritis or joint pain (9 patients) and cardiovascular disorders, such as cardiomyopathy (2 patients). Bronze skin pigmentation was present in 9 homozygotes. Transferin saturation values were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.05) or wild type subjects (p < 0.001) respectively. Also serum ferritin levels were significantly higher in homozygotes for C282Y mutation as compared to C282Y heterozygotes (p < 0.001), C282Y/H63D compound heterozygotes (p < 0.001) and wild type subjects (p < 0.001) respectively. Our observations confirm that DNA analysis significantly contributes to differential diagnostics of this severe, but in early recognition curable disease. Early detection and phlebotomy treatment prior to the onset of cirrhosis can reduce morbidity and normalize life expectancy. It is readily identified through biochemical testing for iron overload using serum transferrin saturation and genetic testing for C282Y homozygosity. DNA analysis is recommended in patients whose transferrin saturation is 45% or more on a repeated test. General population screening has been waived in preference to targeting high-risk groups such as first-degree relatives of affected individuals and those with secondary iron overload, especially patients with chronic liver disorders and chronic anemia. This screening strategy is likely to continue until uncertainties regarding the natural history of the disease, age-related penetrance, and management of asymptomatic individuals are clarified.

Human Factors Engineering Program Review Model

DTIC Science & Technology

2004-02-01

Institute, 1993). ANSI HFS-100: American National Standard for Human Factors Engineering of Visual Display Terminal Workstations (American National... American National Standard for Human Factors Engineering of Visual Display Terminal Workstations (ANSI HFS-100-1988). Santa Monica, California

Anti-obesity and pro-diabetic effects of hemochromatosis.

PubMed

Abbas, Mousa Al; Abraham, Deveraprabu; Kushner, James P; McClain, Donald A

2014-10-01

Levels of tissue iron contribute to determining diabetes risk, but little is known about the effects of higher iron levels on weight, and on the interaction of weight and iron overload on diabetes risk. Therefore, the effect of iron on body mass index and diabetes in individuals with iron overload from hereditary hemochromatosis (HH), compared to non-HH siblings and historical controls was examined. Chart reviews were performed on a cohort of adults (age ≥40, N = 101) with the common C282Y/C282Y HFE genotype, compared to wild type siblings (N = 32) and comparable NHANES cohorts, with respect to body mass index and diabetes status. Males with HH have lower body mass index (BMI) than control siblings. Females had a trend toward decreased BMI that was not significant, possibly related to decreased degrees of iron overload. In both males and females, increased rates of diabetes were seen, especially in the overweight or obese. High tissue iron levels may be both pro- and anti-diabetic. The prevalence of obesity and diabetes in HH is likely dependent upon the degree of iron overload, caloric intake, and other genetic and environmental factors, contributing to the observed heterogeneity in the frequency of disease-related morbidities in HH. Copyright © 2014 The Obesity Society.

Anti-Obesity and Pro-Diabetic Effects of Hemochromatosis

PubMed Central

Abbas, Mousa Al; Abraham, Deveraprabu; Kushner, James P.; McClain, Donald A.

2014-01-01

Objective Levels of tissue iron contribute to determining diabetes risk, but little is known about the effects of higher iron levels on weight, nor on the interaction of weight and iron overload on diabetes risk. We therefore examined the effect of iron on body mass index and diabetes in individuals with iron overload from hereditary hemochromatosis (HH), compared to non-HH siblings and historical controls. Methods Chart reviews were performed on a cohort of adults (age ≥40, N=101) with the common C282Y/C282Y HFE genotype, compared to wild type siblings (N=32) and comparable NHANES cohorts, with respect to body mass index and diabetes status. Results Males with HH have lower body mass index (BMI) than control siblings. Females had a trend toward decreased BMI that was not significant, possibly related to decreased degrees of iron overload. In both males and females, increased rates of diabetes were seen, especially in the overweight or obese. Conclusions High tissue iron levels may be both pro- and anti-diabetic. The prevalence of obesity and diabetes in HH is likely dependent upon the degree of iron overload, caloric intake, and other genetic and environmental factors, contributing to the observed heterogeneity in the frequency of disease-related morbidities in HH. PMID:25044717

Using video-based observation research methods in primary care health encounters to evaluate complex interactions.

PubMed

Asan, Onur; Montague, Enid

2014-01-01

The purpose of this paper is to describe the use of video-based observation research methods in primary care environment and highlight important methodological considerations and provide practical guidance for primary care and human factors researchers conducting video studies to understand patient-clinician interaction in primary care settings. We reviewed studies in the literature which used video methods in health care research, and we also used our own experience based on the video studies we conducted in primary care settings. This paper highlighted the benefits of using video techniques, such as multi-channel recording and video coding, and compared "unmanned" video recording with the traditional observation method in primary care research. We proposed a list that can be followed step by step to conduct an effective video study in a primary care setting for a given problem. This paper also described obstacles, researchers should anticipate when using video recording methods in future studies. With the new technological improvements, video-based observation research is becoming a promising method in primary care and HFE research. Video recording has been under-utilised as a data collection tool because of confidentiality and privacy issues. However, it has many benefits as opposed to traditional observations, and recent studies using video recording methods have introduced new research areas and approaches.

40 CFR 1039.245 - How do I determine deterioration factors from exhaust durability testing?

Code of Federal Regulations, 2014 CFR

2014-07-01

... with an engineering analysis, with pre-existing test data, or with new emission measurements. Apply... factors for an engine family with established technology based on engineering analysis instead of testing... an engine family under paragraph (a) or (b) of this section, select engines, subsystems, or...

40 CFR 1039.245 - How do I determine deterioration factors from exhaust durability testing?

Code of Federal Regulations, 2012 CFR

2012-07-01

... with an engineering analysis, with pre-existing test data, or with new emission measurements. Apply... factors for an engine family with established technology based on engineering analysis instead of testing... an engine family under paragraph (a) or (b) of this section, select engines, subsystems, or...

40 CFR 1039.245 - How do I determine deterioration factors from exhaust durability testing?

Code of Federal Regulations, 2010 CFR

2010-07-01

... with an engineering analysis, with pre-existing test data, or with new emission measurements. Apply... factors for an engine family with established technology based on engineering analysis instead of testing... an engine family under paragraph (a) or (b) of this section, select engines, subsystems, or...

40 CFR 1039.245 - How do I determine deterioration factors from exhaust durability testing?

Code of Federal Regulations, 2013 CFR

2013-07-01

... with an engineering analysis, with pre-existing test data, or with new emission measurements. Apply... factors for an engine family with established technology based on engineering analysis instead of testing... an engine family under paragraph (a) or (b) of this section, select engines, subsystems, or...

40 CFR 1039.245 - How do I determine deterioration factors from exhaust durability testing?

Code of Federal Regulations, 2011 CFR

2011-07-01

... with an engineering analysis, with pre-existing test data, or with new emission measurements. Apply... factors for an engine family with established technology based on engineering analysis instead of testing... an engine family under paragraph (a) or (b) of this section, select engines, subsystems, or...

40 CFR 92.508 - Calculation and reporting of test results.

Code of Federal Regulations, 2010 CFR

2010-07-01

... specified in § 92.506(a). These results must also include the green engine factor, if applicable. The... engine, including: (A) Configuration and engine family identification; (B) Year, make, and build date; (C... accumulated on locomotive or locomotive engine prior to testing; and (E) Description of green engine factor...

Iron Storage Disease: Facts, Fiction and Progress

PubMed Central

Beutler, Ernest

2007-01-01

There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves. PMID:17540589

Motivational factors, gender and engineering education

NASA Astrophysics Data System (ADS)

Kolmos, Anette; Mejlgaard, Niels; Haase, Sanne; Egelund Holgaard, Jette

2013-06-01

Based on survey data covering the full population of students enrolled in Danish engineering education in autumn 2010, we explore the motivational factors behind educational choice, with a particular aim of comparing male and female students1 reasons for choosing a career in engineering. We find that women are significantly more influenced by mentors than men, while men tend to be more motivated by intrinsic and financial factors, and by the social importance of the engineering profession. Parental influence is low across all programmes and by differentiating between specific clusters of engineering programmes, we further show that these overall gender differences are subtle and that motivational factors are unequally important across the different educational programmes. The findings from this study clearly indicate that intrinsic and social motivations are the most important motivational factors; however, gender and programme differentiation needs to be taken into account, and points towards diverse future strategies for attracting students to engineering education.

Understanding safety and production risks in rail engineering planning and protection.

PubMed

Wilson, John R; Ryan, Brendan; Schock, Alex; Ferreira, Pedro; Smith, Stuart; Pitsopoulos, Julia

2009-07-01

Much of the published human factors work on risk is to do with safety and within this is concerned with prediction and analysis of human error and with human reliability assessment. Less has been published on human factors contributions to understanding and managing project, business, engineering and other forms of risk and still less jointly assessing risk to do with broad issues of 'safety' and broad issues of 'production' or 'performance'. This paper contains a general commentary on human factors and assessment of risk of various kinds, in the context of the aims of ergonomics and concerns about being too risk averse. The paper then describes a specific project, in rail engineering, where the notion of a human factors case has been employed to analyse engineering functions and related human factors issues. A human factors issues register for potential system disturbances has been developed, prior to a human factors risk assessment, which jointly covers safety and production (engineering delivery) concerns. The paper concludes with a commentary on the potential relevance of a resilience engineering perspective to understanding rail engineering systems risk. Design, planning and management of complex systems will increasingly have to address the issue of making trade-offs between safety and production, and ergonomics should be central to this. The paper addresses the relevant issues and does so in an under-published domain - rail systems engineering work.

A Systematic Literature Review of Engineering Identity: Definitions, Factors, and Interventions Affecting Development, and Means of Measurement

ERIC Educational Resources Information Center

Morelock, John R.

2017-01-01

Studies exploring what it means to be an engineer professionally have been conducted for decades, but have boomed in recent years. This systematic literature review aims to organise extant studies on engineering identity by coding around four key variables: (a) definitions of engineering identity, (b) factors affecting engineering identity…

GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.

PubMed

Barton, James C; Chen, Wen-Pin; Emond, Mary J; Phatak, Pradyumna D; Subramaniam, V Nathan; Adams, Paul C; Gurrin, Lyle C; Anderson, Gregory J; Ramm, Grant A; Powell, Lawrie W; Allen, Katrina J; Phillips, John D; Parker, Charles J; McLaren, Gordon D; McLaren, Christine E

2017-03-01

GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. We defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin <674.1pmol/L (<300μg/L) or either age≥40y with iron ≤2.5g iron by induction phlebotomy or age≥50y with ≤3.0g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). The mean age of 56 participants (94.6% men) was 55±10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p=0.0126). GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption. Copyright © 2016 Elsevier Inc. All rights reserved.

Serum Iron Levels and the Risk of Parkinson Disease: A Mendelian Randomization Study

PubMed Central

Gögele, Martin; Lill, Christina M.; Bertram, Lars; Do, Chuong B.; Eriksson, Nicholas; Foroud, Tatiana; Myers, Richard H.; Nalls, Michael; Keller, Margaux F.; Benyamin, Beben; Whitfield, John B.; Pramstaller, Peter P.; Hicks, Andrew A.; Thompson, John R.; Minelli, Cosetta

2013-01-01

Background Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. Methods and Findings We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron. Conclusions Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. Please see later in the article for the Editors' Summary PMID:23750121

Physical exercise counteracts the increase in velocity of propagation of cortical spreading depression imposed by early over-nutrition in rats.

PubMed

Monteiro, Heloísa Mirelle Costa; de Mendonça, Débora Carneiro; Sousa, Mariana Séfora Bezerra; Amancio-Dos-Santos, Angela

2018-06-01

This investigation studied whether physical exercise could modulate cortical spreading depression (CSD) propagation velocity in adult rat offspring from dams that had received a high-fat (HF) diet during lactation. Wistar male rats suckled by dams fed either control (C) or HF diet ad libitum. After weaning, pups received standard laboratory chow. From 40 to 60 days of life, half of the animals exercised on a treadmill (group E); the other half remained sedentary (group S). Two additional HF groups (E and S) received fluoxetine (F; 10 mg/kg/day, orogastrically) from 40 to 60 days of life (groups HF/EF and HF/F). At 40 days of life, rats from the maternal HF diet presented higher weight, thoracic circumference, and Lee Index than C animals and remained heavier at 60 days of life. Physical exercise decreased abdominal circumference. HF diet increased CSD propagation velocity (mean ± SD; mm/min) in sedentaries (HF/S 3.47 ± 0.31 versus C/S 3.24 ± 0.26). Treadmill exercise decelerated CSD propagation in both groups C/E (2.94 ± 0.28) and HF/E (2.97 ± 0.40). Fluoxetine alone decreased CSD propagation (HF/F 2.88 ± 0.45) compared with HF/S group. The combination of fluoxetine + exercise under HF condition (2.98 ± 0.27) was similar to HF/E group. Physical exercise is able to reduce CSD propagation velocity in rat adult brains even when they have suffered over-nourishing during lactation. The effects of exercise alone or fluoxetine alone on CSD were similar to the effects of fluoxetine + exercise, under the HF condition. Data reinforce malnutrition during lactation modifies cortical electrophysiology even when the HF condition no longer exists.

Screening and Identification of Peptides Specifically Targeted to Gastric Cancer Cells from a Phage Display Peptide Library

PubMed

Sahin, Deniz; Taflan, Sevket Onur; Yartas, Gizem; Ashktorab, Hassan; Smoot, Duane T

2018-04-25

Background: Gastric cancer is the second most common cancer among the malign cancer types. Inefficiency of traditional techniques both in diagnosis and therapy of the disease makes the development of alternative and novel techniques indispensable. As an alternative to traditional methods, tumor specific targeting small peptides can be used to increase the efficiency of the treatment and reduce the side effects related to traditional techniques. The aim of this study is screening and identification of individual peptides specifically targeted to human gastric cancer cells using a phage-displayed peptide library and designing specific peptide sequences by using experimentally-eluted peptide sequences. Methods: Here, MKN-45 human gastric cancer cells and HFE-145 human normal gastric epithelial cells were used as the target and control cells, respectively. 5 rounds of biopannning with a phage display 12-peptide library were applied following subtraction biopanning with HFE-145 control cells. The selected phage clones were established by enzyme-linked immunosorbent assay and immunofluorescence detection. We first obtain random phage clones after five biopanning rounds, determine the binding levels of each individual clone. Then, we analyze the frequencies of each amino acid in best binding clones to determine positively overexpressed amino acids for designing novel peptide sequences. Results: DE532 (VETSQYFRGTLS) phage clone was screened positive, showing specific binding on MKN-45 gastric cancer cells. DE-Obs (HNDLFPSWYHNY) peptide, which was designed by using amino acid frequencies of experimentally selected peptides in the 5th round of biopanning, showed specific binding in MKN-45 cells. Conclusion: Selection and characterization of individual clones may give us specifically binding peptides, but more importantly, data extracted from eluted phage clones may be used to design theoretical peptides with better binding properties than even experimentally selected ones. Both peptides, experimental and designed, may be potential candidates to be developed as useful diagnostic or therapeutic ligand molecules in gastric cancer research. Creative Commons Attribution License

[Molecular genetic analysis and clinical aspects of patients with hereditary hemochromatosis].

PubMed

Lange, U; Teichmann, J; Dischereit, G

2014-08-01

The purpose of the study was to perform a molecular genetic analysis and to document clinical aspects in patients with hereditary hemochromatosis. The study included 33 outpatients (23 males average age 50.6 years and 10 females average age 60.6 years) with a disorder of iron metabolism (transferrin saturation > 75 %) as confirmation of hemochromatosis who were subjected to molecular genetic and clinical analyses. A homozygous mutation of the hemochromatosis (HFE) gene (C282YY) was detected in 63.6 %, a compound heterozygous mutation (C282Y/H63D) in 30.3% and no mutation of the HFE gene was detected in 6.1 %. The following organ manifestations could be objectified: arthralgia (78.8 %), liver disease (39.9 %), skin hyperpigmentation (30.3 %), osteoporosis (24.2 %), diabetes mellitus (24.2 %) and cardiomyopathy (12.1 %). Comparison between patients with heterozygous and homozygous hemochromatosis revealed the following differences: compound heterozygote patients presented less frequently with osteoarthritis of the metacarpophalangeal (MCP) joints and hands (85.7 %/71.4 % homozygotes vs. 60 %/60 % heterozygotes). Osteoarthritis of the shoulder joints and osteoporosis as well as hypothyroidism were more frequent in compound heterozygote patients, whereas osteoarthritis of the knee and hip joints as well as liver disease were more common in homozygote patients. No differences between both groups were seen with respect to the clinical manifestations of cardiomyopathy and diabetes mellitus. Prevalent causes of death in hereditary hemochromatosis are heart failure, liver disease (cirrhosis and hepatocellular carcinoma) and portal hypertension. Therefore, an early diagnosis, adequate therapy and genetic screening of family members are of great importance. Medicinal treatment will only effectively prevent deleterious organ involvement and subsequent complications if initiated at an early stage. Furthermore, an overview of the current data is given.

Lead-Related Genetic Loci, Cumulative Lead Exposure and Incident Coronary Heart Disease: The Normative Aging Study

PubMed Central

Weisskopf, Marc G.; Sparrow, David; Schwartz, Joel; Hu, Howard; Park, Sung Kyun

2016-01-01

Background Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. Objectives We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events. Methods We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study. Results Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50–3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063). Conclusions Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data. PMID:27584680

[Kinetics modeling and reaction mechanism of ferrate(VI) oxidation of triclosan].

PubMed

Yang, Bin; Ying, Guang-Guo; Zhao, Jian-Liang

2011-09-01

Triclosan (TCS) is a broad-spectrum antibacterial agent widely used in many personal care products. We investigated oxidation of TCS by aqueous ferrate Fe(VI) to determine reaction kinetics, interpreted the reaction mechanism by a linear free-energy relationship, and evaluated the degradation efficiency. Second-order reaction kinetics was used to model Fe (VI) oxidation of TCS, with the apparent second-order rate constant (k(app)) being 531.9 L x (mol x s)(-1) at pH 8.5 and (24 +/- 1) degrees C. The half life (t1/2) is 25.8 s for an Fe( VI) concentration of 10 mg x L(-1). The rate constants of the reaction decrease with increasing pH values. These pH-dependent variations in k(app) could be distributed by considering species-specific reactions between Fe(VI) species and acid-base species of an ionizable TCS. Species-specific second-order reaction rate constants, k, were determined for reaction of HFeO4(-) with each of TCS's acid-base species. The value of k determined for neutral TCS was (4.1 +/- 3.5) x 10(2) L x (mol x s)(-1), while that measured for anionic TCS was (1.8 +/- 0.1) x 10(4) L x (mol x s)(-1). The reaction between HFeO4(-) and the dissociated TCS controls the overall reaction. A linear free-energy relationship illustrated the electrophilic oxidation mechanism. Fe (VI) reacts initially with TCS by electrophilic attack at the latter's phenol moiety. At a n[Fe(VI)]: n(TCS) > 7: 1, complete removal of TCS was achieved. And lower concentration of the humic acid could enhance the k(app) of Fe( VI) with TCS. In conclusion, Fe(VI) oxidation technology appears to be a promising tool for applications of WWTPs effluents and other decontamination processes.

Women: Support Factors and Persistence in Engineering. Research in Engineering and Technology Education

ERIC Educational Resources Information Center

Duncan, John R.; Zeng, Yong

2005-01-01

Limited information is available regarding the factors that promote persistence by women in engineering programs. Stated simply, the problem is that the number of women engineers continues to fall short in comparison to the gender ratio of women to men in the population in the U.S. (BEST, 2002) and worldwide (Hersh, 2000). More women engineers are…

Motivational and adaptational factors of successful women engineers

NASA Astrophysics Data System (ADS)

Bornsen, Susan Edith

It is no surprise that there is a shortage of women engineers. The reasons for the shortage have been researched and discussed in myriad papers, and suggestions for improvement continue to evolve. However, there are few studies that have specifically identified the positive aspects that attract women to engineering and keep them actively engaged in the field. This paper examines how women engineers view their education, their work, and their motivation to remain in the field. A qualitative research design was used to understand the motivation and adaptability factors women use to support their decision to major in engineering and stay in the engineering profession. Women engineers were interviewed using broad questions about motivation and adaptability. Interviews were transcribed and coded, looking for common threads of factors that suggest not only why women engineers persist in the field, but also how they thrive. Findings focus on the experiences, insights, and meaning of women interviewed. A grounded theory approach was used to describe the success factors found in practicing women engineers. The study found categories of attraction to the field, learning environment, motivation and adaptability. Sub-categories of motivation are intrinsic motivational factors such as the desire to make a difference, as well as extrinsic factors such as having an income that allows the kind of lifestyle that supports the family. Women engineers are comfortable with and enjoy working with male peers and when barriers arise, women learn to adapt in the male dominated field. Adaptability was indicated in areas of gender, culture, and communication. Women found strength in the ability to 'read' their clients, and provide insight to their teams. Sufficient knowledge from the field advances theory and offers strategies to programs for administrators and faculty of schools of engineering as well as engineering firms, who have interest in recruitment, and retention of female students. Future research includes expanding the research to other areas of the United States, and improving engineering education pedagogy with more active and experiential learning.

Emissions factors for gaseous and particulate pollutants from offshore diesel engine vessels in China

NASA Astrophysics Data System (ADS)

Zhang, F.; Chen, Y.; Tian, C.; Li, J.; Zhang, G.; Matthias, V.

2015-09-01

Shipping emissions have significant influence on atmospheric environment as well as human health, especially in coastal areas and the harbor districts. However, the contribution of shipping emissions on the environment in China still need to be clarified especially based on measurement data, with the large number ownership of vessels and the rapid developments of ports, international trade and shipbuilding industry. Pollutants in the gaseous phase (carbon monoxide, sulfur dioxide, nitrogen oxides, total volatile organic compounds) and particle phase (particulate matter, organic carbon, elemental carbon, sulfates, nitrate, ammonia, metals) in the exhaust from three different diesel engine power offshore vessels in China were measured in this study. Concentrations, fuel-based and power-based emissions factors for various operating modes as well as the impact of engine speed on emissions were determined. Observed concentrations and emissions factors for carbon monoxide, nitrogen oxides, total volatile organic compounds, and particulate matter were higher for the low engine power vessel than for the two higher engine power vessels. Fuel-based average emissions factors for all pollutants except sulfur dioxide in the low engine power engineering vessel were significantly higher than that of the previous studies, while for the two higher engine power vessels, the fuel-based average emissions factors for all pollutants were comparable to the results of the previous studies. The fuel-based average emissions factor for nitrogen oxides for the small engine power vessel was more than twice the International Maritime Organization standard, while those for the other two vessels were below the standard. Emissions factors for all three vessels were significantly different during different operating modes. Organic carbon and elemental carbon were the main components of particulate matter, while water-soluble ions and elements were present in trace amounts. Best-fit engine speeds during actual operation should be based on both emissions factors and economic costs.

Role of Human Factors and Engineering Psychology in Undergraduate and Graduate Engineering Curriculum

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

Piyush Sabharwall; Jesse Rebol

The engineering discipline is a profession of acquiring and applying technical knowledge, and the focus of engineering psychology is to optimize the effectiveness and efficiency with which human activities are conducted. Having human factors and engineering psychology be a permanent part of the engineering curriculum will make students aware of them, so they can learn from past experiences and avoid making the same mistakes their peers made. (Should be close to 200 words)

Women Engineers: Factors and Obstacles Related to the Pursuit of a Degree in Engineering

NASA Astrophysics Data System (ADS)

Wentling, Rose Mary; Camacho, Cristina

Research on women in engineering confirms the presence of gender barriers that affect the recruitment and retention of women in engineering. These barriers stop some women from choosing engineering as a field of study, and impede some women from completing a degree in engineering. However, there are some young female students who complete their engineering education despite the presence of obstacles throughout their college years. This study addressed the factors that have hindered, motivated, and assisted women who graduated with a degree in engineering. By studying and understanding the barriers that hinder women in deciding to pursue and in completing a degree in engineering, as well as the factors that assist and encourage them, we can learn how to break down the barriers and how to facilitate the educational journey of female engineering students. This study provides valuable insights and created a framework from which high schools, universities, researchers, and female students can directly benefit.

40 CFR 94.508 - Calculation and reporting of test results.

Code of Federal Regulations, 2010 CFR

2010-07-01

... must also include the Green Engine Factor, if applicable. Round these results to the number of decimal... engine, including: (A) Configuration and engine family identification; (B) Year, make, and build date; (C... (E) Description of Green Engine Factor; how it is determined and how it is applied; (ii) Location(s...

Motivating Factors that Affect Enrolment and Student Performance in an ODL Engineering Program

ERIC Educational Resources Information Center

Dadigamuwa, P. R.; Senanayake, Samans

2012-01-01

The present study was carried out to determine the motivating factors for enrolling in an engineering study programme in open and distance learning (ODL) and the factors that affect the students' performance. The study was conducted with two convenient samples of students following distance learning courses in engineering technology, conducted by…

Air and Space Operations Center (AOC) Facility Design Guidelines: A Human Factors Engineering Perspective

DTIC Science & Technology

2006-07-01

31 July 1995 3. Human Engineering Guide to Equipment Design, Department of Defense, Washington D.C., 1972 4. American National Standard for Human Factors Engineering of Visual Display Terminal Workstations , ANSI

40 CFR 94.218 - Deterioration factor determination.

Code of Federal Regulations, 2011 CFR

2011-07-01

... family. (b) Calculation procedures—(1) For engines not utilizing aftertreatment technology (e.g... technology (e.g., catalyst). For each applicable emission constituent, a multiplicative deterioration factor.... (iii) Engineering analysis for established technologies. In the case where an engine family uses...

A systematic literature review of engineering identity: definitions, factors, and interventions affecting development, and means of measurement

NASA Astrophysics Data System (ADS)

Morelock, John R.

2017-11-01

Studies exploring what it means to be an engineer professionally have been conducted for decades, but have boomed in recent years. This systematic literature review aims to organise extant studies on engineering identity by coding around four key variables: (a) definitions of engineering identity, (b) factors affecting engineering identity development, (c) interventions affecting engineering identity development, and (d) means of measuring identity. In doing so, this review provides strategies for future research and educational interventions to advance work related to engineering identity. Publications were selected for inclusion by screening and appraising results obtained from databases and keywords refined through a scoping study. Derived from key findings, suggestions for future research include bridging disparate strands of engineering identity literature and incorporating more varied methodological approaches. Also from key findings, suggestions for future practice involve better connecting existing definitions of engineering identity and factors known to affect identity development with identity-related interventions.

40 CFR 89.117 - Test fleet selection.

Code of Federal Regulations, 2010 CFR

2010-07-01

...) CONTROL OF EMISSIONS FROM NEW AND IN-USE NONROAD COMPRESSION-IGNITION ENGINES Emission Standards and... establishing deterioration factors, the manufacturer shall select the engines, subsystems, or components to be used to determine exhaust emission deterioration factors for each engine-family control system...

Using video-based observation research methods in primary care health encounters to evaluate complex interactions

PubMed Central

Asan, Onur; Montague, Enid

2015-01-01

Objective The purpose of this paper is to describe the use of video-based observation research methods in primary care environment and highlight important methodological considerations and provide practical guidance for primary care and human factors researchers conducting video studies to understand patient-clinician interaction in primary care settings. Methods We reviewed studies in the literature which used video methods in health care research and, we also used our own experience based on the video studies we conducted in primary care settings. Results This paper highlighted the benefits of using video techniques such as multi-channel recording and video coding and compared “unmanned” video recording with the traditional observation method in primary care research. We proposed a list, which can be followed step by step to conduct an effective video study in a primary care setting for a given problem. This paper also described obstacles researchers should anticipate when using video recording methods in future studies. Conclusion With the new technological improvements, video-based observation research is becoming a promising method in primary care and HFE research. Video recording has been under-utilized as a data collection tool because of confidentiality and privacy issues. However, it has many benefits as opposed to traditional observations, and recent studies using video recording methods have introduced new research areas and approaches. PMID:25479346

Engineering Play: Exploring Associations with Executive Function, Mathematical Ability, and Spatial Ability in Preschool

NASA Astrophysics Data System (ADS)

Gold, Zachary Samuel

Engineering play is a new perspective on preschool education that views constructive play as an engineering design process that parallels the way engineers think and work when they develop engineered solutions to human problems (Bairaktarova, Evangelou, Bagiati, & Brophy, 2011). Early research from this perspective supports its use in framing play as a key learning context. However, no research to date has examined associations between engineering play and other factors linked with early school success, such as executive function, mathematical ability, and spatial ability. Additionally, more research is needed to further validate a new engineering play observational measure. This study had two main goals: (1) to gather early validity data on the engineering play measure as a potentially useful instrument for documenting the occurrence of children's engineering play behaviors in educational contexts, such as block play. This was done by testing the factor structure of the engineering play behaviors in this sample and their association with preschoolers' planning, a key aspect of the engineering design process; (2) to explore associations between preschoolers' engineering play and executive function, mathematical ability, and spatial ability. Participants included 110 preschoolers (62 girls; 48 boys; M = 58.47 months) from 10 classrooms in the Midwest United States coded for their frequency of engagement in each of the nine engineering play behaviors. A confirmatory factor analysis resulted in one engineering play factor including six of the engineering play behaviors. A series of marginal regression models revealed that the engineering play factor was significantly and positively associated with the spatial horizontal rotation transformation. However, engineering play was not significantly related to planning ability, executive function, informal mathematical abilities, or other spatial transformation skills. Follow-up analyses revealed significant positive associations between engineering play and planning, executive function, and geometry for only a subgroup of children (n = 27) who had individualized education program (IEP) status. This was the first of a series of studies planned to evaluate the potential of the engineering play perspective as a tool for understanding young children's development and learning across multiple developmental domains. Although most hypotheses regarding engineering play and cognitive skills were not supported, the study provided partial evidence for the reliability and validity of the engineering play observation measure. Future research should include larger sample sizes with more statistical power, continued refinement of the engineering play observation measure, examination of potential associations with specific early learning domains, including spatial ability and language, and more comparisons of engineering play between typically developing children and children with disabilities.

Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity.

PubMed

Aminkeng, Folefac; Ross, Colin J D; Rassekh, Shahrad R; Hwang, Soomi; Rieder, Michael J; Bhavsar, Amit P; Smith, Anne; Sanatani, Shubhayan; Gelmon, Karen A; Bernstein, Daniel; Hayden, Michael R; Amstutz, Ursula; Carleton, Bruce C

2016-09-01

Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT. © 2016 The British Pharmacological Society.

Recommendations for genetic testing to reduce the incidence of anthracycline‐induced cardiotoxicity

PubMed Central

Aminkeng, Folefac; Ross, Colin J. D.; Rassekh, Shahrad R.; Hwang, Soomi; Rieder, Michael J.; Bhavsar, Amit P.; Smith, Anne; Sanatani, Shubhayan; Gelmon, Karen A.; Bernstein, Daniel; Hayden, Michael R.; Amstutz, Ursula

2016-01-01

Aims Anthracycline‐induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline‐based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence‐based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. Methods We followed a standard guideline development process, including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. Results RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B – moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow‐up, as well as therapeutic options within the current standard of clinical practice. Conclusions Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT. PMID:27197003

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

PubMed

Kang, J H; Loomis, S J; Yaspan, B L; Bailey, J C; Weinreb, R N; Lee, R K; Lichter, P R; Budenz, D L; Liu, Y; Realini, T; Gaasterland, D; Gaasterland, T; Friedman, D S; McCarty, C A; Moroi, S E; Olson, L; Schuman, J S; Singh, K; Vollrath, D; Wollstein, G; Zack, D J; Brilliant, M; Sit, A J; Christen, W G; Fingert, J; Forman, J P; Buys, E S; Kraft, P; Zhang, K; Allingham, R R; Pericak-Vance, M A; Richards, J E; Hauser, M A; Haines, J L; Wiggs, J L; Pasquale, L R

2014-06-01

Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

The Human Side of Information's Converging Technology.

ERIC Educational Resources Information Center

Williams, Berney

1982-01-01

Discusses current issues in the design of information systems, noting contributions from three professions--computer science, human factors engineering, and information science. The eclectic nature of human factors engineering and the difficulty of drawing together studies with human engineering or software psychological components from diverse…

Sustainability Metrics of a Small Scale Turbojet Engine

NASA Astrophysics Data System (ADS)

Ekici, Selcuk; Sohret, Yasin; Coban, Kahraman; Altuntas, Onder; Karakoc, T. Hikmet

2018-05-01

Over the last decade, sustainable energy consumption has attracted the attention of scientists and researchers. The current paper presents sustainability indicators of a small scale turbojet engine, operated on micro-aerial vehicles, for discussion of the sustainable development of the aviation industry from a different perspective. Experimental data was obtained from an engine at full power load and utilized to conduct an exergy-based sustainability analysis. Exergy efficiency, waste exergy ratio, recoverable exergy ratio, environmental effect factor, exergy destruction factor and exergetic sustainability index are evaluated as exergetic sustainability indicators of the turbojet engine under investigation in the current study. The exergy efficiency of the small scale turbojet engine is calculated as 27.25 % whereas the waste exergy ratio, the exergy destruction factor and the sustainability index of the engine are found to be 0.9756, 0.5466 and 0.2793, respectively.

How to Retain Postgraduate Students in Engineering Programmes: A Practical Perspective

ERIC Educational Resources Information Center

Le, Khoa N.; Tam, Vivian W. Y.

2008-01-01

Six factors for pursuing an engineering postgraduate programme at Griffith University including (i) programme quality; (ii) employment prospects; (iii) practicality; (iv) personal interest; (v) popularity; and (vi) reputation; and 11 factors for not pursuing this engineering programme including (i) employment prospects; (ii) degree of difficulty;…

Personality Profiles and Selection for Courses.

ERIC Educational Resources Information Center

Barker, Dennis

1989-01-01

Personality profiles for 364 civil engineers were compared to the British Norms for the 16PF Questionnaire. Civil engineers differ from the British norms on 5 of the 20 factors derived from the questionnaire. These factors indicate the questions on which to concentrate when selecting students for civil engineering courses. (Author/MLW)