Inflammatory Bowel Disease and the Risk of Autoimmune Diseases.

PubMed

Wilson, J Claire; Furlano, Raoul I; Jick, Susan S; Meier, Christoph R

2016-02-01

An increased risk of autoimmune disease has been reported in patients with inflammatory bowel disease [IBD]. Using data from the Clinical Practice Research Datalink [CPRD], this study set out to further examine this relationship. Patients with a first-time IBD diagnosis were randomly matched to an equal-sized IBD-free comparison group. Incidence rates for new-onset autoimmune diseases were estimated. A nested case-control analysis comprising IBD patients was conducted, using conditional logistic regression to assess whether IBD severity, duration, or treatment influences the risk of developing autoimmune diseases. During follow-up, 1069 IBD and 585 IBD-free patients developed an incident autoimmune disease. An increased incidence of autoimmune disease was observed in IBD patients (incidence rate [IR] 9.65, 95% confidence interval [CI] 9.09-10.24) compared with the non-IBD comparison group [IR 5.22, 95% CI 4.82-5.66]. In IBD patients, increased disease severity was associated with an increased risk of autoimmune disease development (odds ratio [OR] 1.62, 95% CI 1.28-2.05). Current antibiotic use was also associated with an increased risk [adjusted OR 1.72, 95% CI 1.07-2.78]. A reduced risk of incident autoimmune diseases was observed for current long-term users of aminosalicylates [adjusted OR 0.72, 95% CI 0.57-0.91]. Individuals with IBD had an increased risk of developing an autoimmune disease. Increased disease severity and current antibiotic use were associated with an increased relative risk of developing additional autoimmune diseases in IBD patients. Long-term current aminosalicylate use was associated with a reduced risk. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Advances on Fungal Phytotoxins and Their Role in Grapevine Trunk Diseases.

PubMed

Masi, Marco; Cimmino, Alessio; Reveglia, Pierluigi; Mugnai, Laura; Surico, Giuseppe; Evidente, Antonio

2018-06-20

Grapevines are produced worldwide with important impact on local economies. Several biotic stresses induce serious diseases of grapevine, which severely affect the quantity and quality of production. One of the most important problems of vineyards worldwide is the high incidence of grapevine trunk diseases (GTD) induced by fungi belonging to several genera. Environmentally friendly methods for GTD control are being studied. This perspective offers an advanced overview on the fungal phytotoxins involved in GTD and their eventual role in the development of disease symptoms.

EV-A71 vaccine licensure: a first step for multivalent enterovirus vaccine to control HFMD and other severe diseases

PubMed Central

Mao, Qunying; Wang, Yiping; Bian, Lianlian; Xu, Miao; Liang, Zhenglun

2016-01-01

Enteroviruses (EVs) are the most common viral agents in humans. Although most infections are mild or asymptomatic, there is a wide spectrum of clinical manifestations that may be caused by EV infections with varying degrees of severity. Among these viruses, EV-A71 and coxsackievirus (CV) CV-A16 from group A EVs attract the most attention because they are responsible for hand, foot and mouth disease (HFMD). Other EV-A viruses such as CV-A6 and CV-A10 were also reported to cause HFMD outbreaks in several countries or regions. Group B EVs such as CV-B3, CV-B5 and echovirus 30 were reported to be the main pathogens responsible for myocarditis and encephalitis epidemics and were also detected in HFMD patients. Vaccines are the best tools to control infectious diseases. In December 2015, China's Food and Drug Administration approved two inactivated EV-A71 vaccines for preventing severe HFMD.The CV-A16 vaccine and the EV-A71-CV-A16 bivalent vaccine showed substantial efficacy against HFMD in pre-clinical animal models. Previously, research on EV-B group vaccines was mainly focused on CV-B3 vaccine development. Because the HFMD pathogen spectrum has changed, and the threat from EV-B virus-associated severe diseases has gradually increased, it is necessary to develop multivalent HFMD vaccines. This study summarizes the clinical symptoms of diseases caused by EVs, such as HFMD, myocarditis and encephalitis, and the related EV vaccine development progress. In conclusion, developing multivalent EV vaccines should be strongly recommended to prevent HFMD, myocarditis, encephalitis and other severe diseases. PMID:27436364

EV-A71 vaccine licensure: a first step for multivalent enterovirus vaccine to control HFMD and other severe diseases.

PubMed

Mao, Qunying; Wang, Yiping; Bian, Lianlian; Xu, Miao; Liang, Zhenglun

2016-07-20

Enteroviruses (EVs) are the most common viral agents in humans. Although most infections are mild or asymptomatic, there is a wide spectrum of clinical manifestations that may be caused by EV infections with varying degrees of severity. Among these viruses, EV-A71 and coxsackievirus (CV) CV-A16 from group A EVs attract the most attention because they are responsible for hand, foot and mouth disease (HFMD). Other EV-A viruses such as CV-A6 and CV-A10 were also reported to cause HFMD outbreaks in several countries or regions. Group B EVs such as CV-B3, CV-B5 and echovirus 30 were reported to be the main pathogens responsible for myocarditis and encephalitis epidemics and were also detected in HFMD patients. Vaccines are the best tools to control infectious diseases. In December 2015, China's Food and Drug Administration approved two inactivated EV-A71 vaccines for preventing severe HFMD.The CV-A16 vaccine and the EV-A71-CV-A16 bivalent vaccine showed substantial efficacy against HFMD in pre-clinical animal models. Previously, research on EV-B group vaccines was mainly focused on CV-B3 vaccine development. Because the HFMD pathogen spectrum has changed, and the threat from EV-B virus-associated severe diseases has gradually increased, it is necessary to develop multivalent HFMD vaccines. This study summarizes the clinical symptoms of diseases caused by EVs, such as HFMD, myocarditis and encephalitis, and the related EV vaccine development progress. In conclusion, developing multivalent EV vaccines should be strongly recommended to prevent HFMD, myocarditis, encephalitis and other severe diseases.

Retinal vasculitis associated with Crohn's disease.

PubMed Central

Garcia-Diaz, M.; Mira, M.; Nevado, L.; Galván, A.; Berenguer, A.; Bureo, J. C.

1995-01-01

Although systemic vasculitis can be a complication of inflammatory bowel disease at several locations (skin, eyes, brain, mesentery, and lung) the association of retinal vasculitis with Crohn's disease is rare. We studied a 26-year-old woman with biopsy-demonstrated Crohn's disease who developed a severe bilateral retinal arteritis and phlebitis, with acute loss of vision. Images Figure 1 Figure 2 PMID:7746779

Correlation Of Deviance In Arterial Oxygenation With Severity Of Chronic Liver Disease.

PubMed

Shaukat, Al-Aman; Zar, Adnan; Zuhaid, Muhammad; Afridi, Safa Saadat

2016-01-01

Hepatitis B and C related chronic liver diseases have led to development of a serious threat to the people of South Asia. The main aim of this study was to evaluate the correlation of magnitude of arterial deoxygention to the severity of liver disease. It was a hospital based cross-sectional descriptive study, carried out in the Medical Department of Khyber Teaching Hospital Peshawar. All in all 115 patients were assessed for the severity of the liver diseases and were correlated with arterial deoxygenation using linear regression models. Male to female ratio was 1.5:1. Males infected with hepatitis B, hepatitis C and both were 9, 60 and 1, while females suffered from hepatitis B, Hepatitis C and both were 2, 42 and 1 respectively. The linear relationship between A-a DO2 with severity of liver disease showed positive correlation while PO2 showed negative correlation with severity of liver disease. There was a positive correlation between A-a DO2 and severity of liver diseases while PO2 and severity of liver diseases showed negative correlation.

Garlic Organosulfur Compounds Reduce Inflammation and Oxidative Stress during Dengue Virus Infection

PubMed Central

Hall, Alex; Troupin, Andrea; Londono-Renteria, Berlin; Colpitts, Tonya M.

2017-01-01

Dengue virus (DENV) is a mosquito-borne flavivirus that causes significant global human disease and mortality. One approach to develop treatments for DENV infection and the prevention of severe disease is through investigation of natural medicines. Inflammation plays both beneficial and harmful roles during DENV infection. Studies have proposed that the oxidative stress response may be one mechanism responsible for triggering inflammation during DENV infection. Thus, blocking the oxidative stress response could reduce inflammation and the development of severe disease. Garlic has been shown to both reduce inflammation and affect the oxidative stress response. Here, we show that the garlic active compounds diallyl disulfide (DADS), diallyl sulfide (DAS) and alliin reduced inflammation during DENV infection and show that this reduction is due to the effects on the oxidative stress response. These results suggest that garlic could be used as an alternative treatment for DENV infection and for the prevention of severe disease development. PMID:28644404

Cholinesterase inhibitors: a patent review (2007 - 2011).

PubMed

de los Ríos, Cristóbal

2012-08-01

Cholinesterase inhibitors participate in the maintenance of the levels of the neurotransmitter acetylcholine by inhibiting the enzymes implicated in its degradation, namely, butyrylcholinesterase and acetylcholinesterase. This pharmacological action has an important role in several diseases, including neurodegenerative diseases such as Alzheimer's. This article reviews recent advances in the development of cholinesterase enzyme inhibitors, covering the development of new chemical entities, new pharmaceutical formulations with known inhibitors or treatments in combination with other drug families. The development of cholinesterase inhibitors has to face several issues, including the fact that the principal indication for these drugs, Alzheimer's disease, is not currently believed to derivate from a cholinergic deficiency, although most of the drugs clinically used for these disease are cholinesterase inhibitors. Moreover, the adverse effects found when administering cholinesterase inhibitors limit their use in other diseases, such as gastrointestinal diseases, glaucoma, or analgesia.

Antibody-dependent enhancement of severe dengue disease in humans*

PubMed Central

Katzelnick, Leah C.; Gresh, Lionel; Halloran, M. Elizabeth; Mercado, Juan Carlos; Kuan, Guillermina; Gordon, Aubree; Balmaseda, Angel; Harris, Eva

2018-01-01

For dengue viruses (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement (ADE) of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of pre-existing anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern. PMID:29097492

The involvement of autoimmunity against retinal antigens in determining disease severity in toxoplasmosis.

PubMed

Vallochi, Adriana Lima; da Silva Rios, Lília; Nakamura, Marceli Vicente; Silveira, Cláudio; Muccioli, Cristina; Martins, Maria Cristina; Belfort, Rubens; Rizzo, Luiz Vicente

2005-02-01

Ocular lesions are frequent in various individuals infected with Toxoplasma gondii. Disease intensity in ocular toxoplasmosis varies greatly between patients. Autoimmunity has been suggested as a possible component to retinal destruction. Immunologic parameters in the response to retina antigens were evaluated in infected persons with and without ocular lesions and in non-infected controls. Subjects were divided into groups on the basis of titers of serum antibodies to T. gondii, presence and severity of ocular lesions, and clinical history. Peripheral blood mononuclear cells from patients with mild disease responded to one or more retinal antigens with a significantly higher frequency than patients without disease or with severe disease. Interestingly, the cytokines produced by the proliferating mononuclear cells did not follow any specific patterns, except for the fact that IL-4 and IL-5 were seldom detected. Our results suggest that although the presence of an immune response towards autoantigens is not protective against the development of ocular lesions by the T. gondii, it may protect against the development of severe disease.

Nervous System Abnormalities and Legionnaire's Disease.

PubMed

Halperin, John J

2017-03-01

Although patients with Legionnaire's disease frequently develop alterations of consciousness, this is no more frequent than in patients hospitalized with other, equally severe forms of bacterial pneumonia. Legionella meningitis occurs rarely, if ever. Patients with Legionnaire's are susceptible to critical illness polyneuropathy/myopathy, as are other critically ill patients. Legionnaire's patients may develop MRI hyperdensities in the splenium of the corpus callosum, as may other patients with severe infections. Patients with Legionnaire's may be at increased risk of, and rarely develop, immune-mediated multifocal brain (acute disseminated encephalomyelitis) or peripheral nerve disease (Guillain-Barré syndrome). Copyright © 2016 Elsevier Inc. All rights reserved.

National prevalence of coronary heart disease and its relationship with human development index: A systematic review.

PubMed

Zhu, Ke-Fu; Wang, Yu-Ming; Zhu, Jin-Zhou; Zhou, Qin-Yi; Wang, Ning-Fu

2016-03-01

Coronary heart disease has become a major health concern over the past several decades. Several reviews have assessed the effects of socioeconomic status on the coronary heart disease epidemic in communities and countries, but only a few reviews have been performed at a global level. This study was to explore the relationship between the prevalence of coronary heart disease and socioeconomic development worldwide using the Human Development Index. Systematic review. The data in this study were collected from the MEDLINE database. Cross-sectional studies reporting the prevalence of coronary heart disease until November 2014 were collected. The Human Development Index was sourced from the United Nations Development Programme Database and was used to measure the socioeconomic achievements of countries. Each country was classified as a developing or developed country based on its level of development according to the Human Development Index value. Based on the data analysis on the global level, coronary heart disease prevalence had no association with the national Human Development Index (rho = 0.07). However, there was a positive association between coronary heart disease prevalence and the national Human Development Index in developing countries, although a negative association existed in developed countries (rho = 0.47 and -0.34, respectively). In addition, the past decades have witnessed a growing coronary heart disease epidemic in developing countries, with reverse trends observed in developed countries (P = 0.021 and 0.002, respectively). With the development of socioeconomic status, as measured by the Human Development Index, the prevalence of coronary heart disease is growing in developing countries, while declining in developed countries. Future research needs to pay more attention to the reasonable allocation of medical resources and control of coronary heart disease risk factors. © The European Society of Cardiology 2015.

Severe systemic autoimmune disease associated with Epstein-Barr virus infection.

PubMed

Sevilla, Julián; del Carmen Escudero, Maria; Jiménez, Raquel; González-Vicent, Marta; Manzanares, Javier; García-Novo, Dolores; Madero, Luis

2004-12-01

Infection with Epstein-Barr virus (EBV) has been associated with different autoimmune manifestations. The authors describe a girl who developed a severe systemic autoimmune disease with severe autoimmune hemolytic anemia, mild autoimmune thrombopenia, antineutrophil antibodies, and fatal autoimmune hepatitis after EBV infection. Despite immunosuppressive treatment and ultimately liver transplantation, this patient could not overcome her clinical condition and died. The etiopathogenesis of this complex disease and the association with EBV infection is discussed.

Addison's disease.

PubMed

Sarkar, Soumya Brata; Sarkar, Subrata; Ghosh, Supratim; Bandyopadhyay, Subhankar

2012-10-01

Addison's disease is a rare endocrinal disorder, with several oral and systemic manifestations. A variety of pathological processes may cause Addison's disease. Classically, hyperpigmentation is associated with the disease, and intraoral pigmentation is perceived as the initial sign and develops earlier than the dermatological pigmentation. The symptoms of the disease usually progress slowly and an event of illness or accident can make the condition worse and may lead to a life-threatening crisis. In this case, several oral as well as systemic manifestation of the Addison's disease was encountered.

Addison's disease

PubMed Central

Sarkar, Soumya Brata; Sarkar, Subrata; Ghosh, Supratim; Bandyopadhyay, Subhankar

2012-01-01

Addison's disease is a rare endocrinal disorder, with several oral and systemic manifestations. A variety of pathological processes may cause Addison's disease. Classically, hyperpigmentation is associated with the disease, and intraoral pigmentation is perceived as the initial sign and develops earlier than the dermatological pigmentation. The symptoms of the disease usually progress slowly and an event of illness or accident can make the condition worse and may lead to a life-threatening crisis. In this case, several oral as well as systemic manifestation of the Addison's disease was encountered. PMID:23633816

Modeling Human Neurological and Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Neuronal Differentiation and Its Applications in Neurotrauma.

PubMed

Bahmad, Hisham; Hadadeh, Ola; Chamaa, Farah; Cheaito, Katia; Darwish, Batoul; Makkawi, Ahmad-Kareem; Abou-Kheir, Wassim

2017-01-01

With the help of several inducing factors, somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) lines. The success is in obtaining iPSCs almost identical to embryonic stem cells (ESCs), therefore various approaches have been tested and ultimately several ones have succeeded. The importance of these cells is in how they serve as models to unveil the molecular pathways and mechanisms underlying several human diseases, and also in its potential roles in the development of regenerative medicine. They further aid in the development of regenerative medicine, autologous cell therapy and drug or toxicity screening. Here, we provide a comprehensive overview of the recent development in the field of iPSCs research, specifically for modeling human neurological and neurodegenerative diseases, and its applications in neurotrauma. These are mainly characterized by progressive functional or structural neuronal loss rendering them extremely challenging to manage. Many of these diseases, including Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) have been explored in vitro . The main purpose is to generate patient-specific iPS cell lines from the somatic cells that carry mutations or genetic instabilities for the aim of studying their differentiation potential and behavior. This new technology will pave the way for future development in the field of stem cell research anticipating its use in clinical settings and in regenerative medicine in order to treat various human diseases, including neurological and neurodegenerative diseases.

Highlights of the 11th International Bordetella Symposium: from Basic Biology to Vaccine Development

PubMed Central

Wirsing von König, Carl Heinz; Lan, Ruiting; Cotter, Peggy A.; Deora, Rajendar; Merkel, Tod J.; van Els, Cécile A.; Locht, Camille; Hozbor, Daniela; Rodriguez, Maria E.

2016-01-01

Pertussis is a severe respiratory disease caused by infection with the bacterial pathogen Bordetella pertussis. The disease affects individuals of all ages but is particularly severe and sometimes fatal in unvaccinated young infants. Other Bordetella species cause diseases in humans, animals, and birds. Scientific, clinical, public health, vaccine company, and regulatory agency experts on these pathogens and diseases gathered in Buenos Aires, Argentina from 5 to 8 April 2016 for the 11th International Bordetella Symposium to discuss recent advances in our understanding of the biology of these organisms, the diseases they cause, and the development of new vaccines and other strategies to prevent these diseases. Highlights of the meeting included pertussis epidemiology in developing nations, genomic analysis of Bordetella biology and evolution, regulation of virulence factor expression, new model systems to study Bordetella biology and disease, effects of different vaccines on immune responses, maternal immunization as a strategy to prevent newborn disease, and novel vaccine development for pertussis. In addition, the group approved the formation of an International Bordetella Society to promote research and information exchange on bordetellae and to organize future meetings. A new Bordetella.org website will also be developed to facilitate these goals. PMID:27655886

Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease

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

Johnson, Reed F.; Hammoud, Dima A.; Lackemeyer, Matthew G.

Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log{submore » 10} PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases. - Highlights: • Small particle aerosol exposure of rhesus results in a severe respiratory disease. • CT findings correlated with peripheral oxygen saturation and monocyte increases. • Virus dissemination was limited and mainly confined to the respiratory tract. • CT provides insight into pathogenesis to aid development of animal models of disease.« less

ICD-9-CM and ICD-10-CM mapping of the AAST Emergency General Surgery disease severity grading systems: Conceptual approach, limitations, and recommendations for the future.

PubMed

Utter, Garth H; Miller, Preston R; Mowery, Nathan T; Tominaga, Gail T; Gunter, Oliver; Osler, Turner M; Ciesla, David J; Agarwal, Suresh K; Inaba, Kenji; Aboutanos, Michel B; Brown, Carlos V R; Ross, Steven E; Crandall, Marie L; Shafi, Shahid

2015-05-01

The American Association for the Surgery of Trauma (AAST) recently established a grading system for uniform reporting of anatomic severity of several emergency general surgery (EGS) diseases. There are five grades of severity for each disease, ranging from I (lowest severity) to V (highest severity). However, the grading process requires manual chart review. We sought to evaluate whether International Classification of Diseases, 9th and 10th Revisions, Clinical Modification (ICD-9-CM, ICD-10-CM) codes might allow estimation of AAST grades for EGS diseases. The Patient Assessment and Outcomes Committee of the AAST reviewed all available ICD-9-CM and ICD-10-CM diagnosis codes relevant to 16 EGS diseases with available AAST grades. We then matched grades for each EGS disease with one or more ICD codes. We used the Official Coding Guidelines for ICD-9-CM and ICD-10-CM and the American Hospital Association's "Coding Clinic for ICD-9-CM" for coding guidance. The ICD codes did not allow for matching all five AAST grades of severity for each of the 16 diseases. With ICD-9-CM, six diseases mapped into four categories of severity (instead of five), another six diseases into three categories of severity, and four diseases into only two categories of severity. With ICD-10-CM, five diseases mapped into four categories of severity, seven diseases into three categories, and four diseases into two categories. Two diseases mapped into discontinuous categories of grades (two in ICD-9-CM and one in ICD-10-CM). Although resolution is limited, ICD-9-CM and ICD-10-CM diagnosis codes might have some utility in roughly approximating the severity of the AAST grades in the absence of more precise information. These ICD mappings should be validated and refined before widespread use to characterize EGS disease severity. In the long-term, it may be desirable to develop alternatives to ICD-9-CM and ICD-10-CM codes for routine collection of disease severity characteristics.

Human louse-transmitted infectious diseases.

PubMed

Badiaga, S; Brouqui, P

2012-04-01

Several of the infectious diseases associated with human lice are life-threatening, including epidemic typhus, relapsing fever, and trench fever, which are caused by Rickettsia prowazekii, Borrelia recurrentis, and Bartonella quintana, respectively. Although these diseases have been known for several centuries, they remain a major public health concern in populations living in poor-hygiene conditions because of war, social disruption, severe poverty, or gaps in public health management. Poor-hygiene conditions favour a higher prevalence of body lice, which are the main vectors for these diseases. Trench fever has been reported in both developing and developed countries in populations living in poor conditions, such as homeless individuals. In contrast, outbreaks of epidemic typhus and epidemic relapsing fever have occurred in jails and refugee camps in developing countries. However, reports of a significantly high seroprevalence for epidemic typhus and epidemic relapsing fever in the homeless populations of developed countries suggest that these populations remain at high risk for outbreaks of these diseases. Additionally, experimental laboratory studies have demonstrated that the body louse can transmit other emerging or re-emerging pathogens, such as Acinetobacter baumannii and Yersinia pestis. Therefore, a strict survey of louse-borne diseases and the implementation of efficient delousing strategies in these populations should be public health priorities. © 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.

Spatial prediction of wheat Septoria leaf blotch (Septoria tritici) disease severity in central Ethiopia

USGS Publications Warehouse

Wakie, Tewodros; Kumar, Sunil; Senay, Gabriel; Takele, Abera; Lencho, Alemu

2016-01-01

A number of studies have reported the presence of wheat septoria leaf blotch (Septoria tritici; SLB) disease in Ethiopia. However, the environmental factors associated with SLB disease, and areas under risk of SLB disease, have not been studied. Here, we tested the hypothesis that environmental variables can adequately explain observed SLB disease severity levels in West Shewa, Central Ethiopia. Specifically, we identified 50 environmental variables and assessed their relationships with SLB disease severity. Geographically referenced disease severity data were obtained from the field, and linear regression and Boosted Regression Trees (BRT) modeling approaches were used for developing spatial models. Moderate-resolution imaging spectroradiometer (MODIS) derived vegetation indices and land surface temperature (LST) variables highly influenced SLB model predictions. Soil and topographic variables did not sufficiently explain observed SLB disease severity variation in this study. Our results show that wheat growing areas in Central Ethiopia, including highly productive districts, are at risk of SLB disease. The study demonstrates the integration of field data with modeling approaches such as BRT for predicting the spatial patterns of severity of a pathogenic wheat disease in Central Ethiopia. Our results can aid Ethiopia's wheat disease monitoring efforts, while our methods can be replicated for testing related hypotheses elsewhere.

Framework for evaluating disease severity measures in older adults with comorbidity.

PubMed

Boyd, Cynthia M; Weiss, Carlos O; Halter, Jeff; Han, K Carol; Ershler, William B; Fried, Linda P

2007-03-01

Accounting for the influence of concurrent conditions on health and functional status for both research and clinical decision-making purposes is especially important in older adults. Although approaches to classifying severity of individual diseases and conditions have been developed, the utility of these classification systems has not been evaluated in the presence of multiple conditions. We present a framework for evaluating severity classification systems for common chronic diseases. The framework evaluates the: (a) goal or purpose of the classification system; (b) physiological and/or functional criteria for severity graduation; and (c) potential reliability and validity of the system balanced against burden and costs associated with classification. Approaches to severity classification of individual diseases were not originally conceived for the study of comorbidity. Therefore, they vary greatly in terms of objectives, physiological systems covered, level of severity characterization, reliability and validity, and costs and burdens. Using different severity classification systems to account for differing levels of disease severity in a patient with multiple diseases, or, assessing global disease burden may be challenging. Most approaches to severity classification are not adequate to address comorbidity. Nevertheless, thoughtful use of some existing approaches and refinement of others may advance the study of comorbidity and diagnostic and therapeutic approaches to patients with multimorbidity.

Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases

PubMed Central

Hudson, Gavin; Gomez-Duran, Aurora; Wilson, Ian J.; Chinnery, Patrick F.

2014-01-01

Mitochondrial DNA (mtDNA) is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the “missing heritability” of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases. PMID:24852434

Activin in acute pancreatitis: Potential risk-stratifying marker and novel therapeutic target.

PubMed

Staudacher, Jonas J; Yazici, Cemal; Carroll, Timothy; Bauer, Jessica; Pang, Jingbo; Krett, Nancy; Xia, Yinglin; Wilson, Annette; Papachristou, Georgios; Dirmeier, Andrea; Kunst, Claudia; Whitcomb, David C; Fantuzzi, Giamila; Jung, Barbara

2017-10-06

Acute Pancreatitis is a substantial health care challenge with increasing incidence. Patients who develop severe disease have considerable mortality. Currently, no reliable predictive marker to identify patients at risk for severe disease exists. Treatment is limited to rehydration and supporting care suggesting an urgent need to develop novel approaches to improve standard care. Activin is a critical modulator of inflammatory responses, but has not been assessed in pancreatitis. Here, we demonstrate that serum activin is elevated and strongly correlates with disease severity in two established murine models of acute pancreatitis induced by either cerulein or IL-12 + IL-18. Furthermore, in mice, inhibition of activin conveys survival benefits in pancreatitis. In addition, serum activin levels were measured from a retrospective clinical cohort of pancreatitis patients and high activin levels in patients at admission are predictive of worse outcomes, indicated by longer overall hospital and intensive care unit stays. Taken together, activin is a novel candidate as a clinical marker to identify those acute pancreatitis patients with severe disease who would benefit from aggressive treatment and activin may be a therapeutic target in severe acute pancreatitis.

Natural history of aortic valve disease following intervention for rheumatic mitral valve disease.

PubMed

Namboodiri, Narayanan; Remash, Krishnan; Tharakan, Jaganmohan A; Shajeem, Othayoth; Nair, Krishnakumar; Titus, Thomas; Ajitkumar, Valaparambil K; Sivasankaran, Sivasubramonian; Krishnamoorthy, Kavassery M; Harikrishnan, Sivadasan P; Harikrishnan, Madhavankutty S; Bijulal, Sasidharan

2009-01-01

A significant proportion of patients who require interventions for rheumatic mitral valve (MV) disease have coexisting aortic valve (AV) disease. To date, little is known of the natural history of AV disease in these patients. The details of a cohort of 200 patients (146 females, 54 males; mean age at MV intervention 30.3 +/- 9.9 years) with rheumatic heart disease were retrospectively reviewed. The patients had undergone an index MV intervention (either closed or balloon mitral valvotomy) or MV replacement between 1994 and 1996, and received long-term regular follow up examinations. The clinical and echocardiographic data at entry and at follow up were noted. Patients were allocated to two groups, based on whether the AV disease was absent (group I, n=98) or present (group II, n=102) at baseline. The AV disease was categorized as thickening only (group IIA), isolated aortic regurgitation (AR) (group IIB), or combined aortic stenosis (AS) and AR (group IIC). No patient had isolated AS at baseline. The mean follow up period was 9.3 +/- 1.07 years; during which 10 patients in group I developed new AV disease, which included AV thickening only (n=2), trivial-mild AR (n=7) and mild AS with trivial AR (n=1). Of 16 patients in group IIA, 11 developed isolated AR, and one patient progressed to have mild AS and AR. Among 69 patients in group IIB, 22 (31.9%) developed AS, and all had either mild (n=8) or moderate (n=14) AR with mild AS. Group IIC included 17 patients with mild combined AV disease at baseline, except for moderate AS and moderate AR in one patient each. Among 16 patients with mild AS in group IIC, six progressed to moderate AS and two to severe AS. AR became moderate in 10 patients and severe in one patient. The two patients who progressed to severe AS requiring AV replacement had mild AS at baseline. No patient who developed new combined AV disease had lesions with severity more than mild AS or moderate AR. On logistic regression analysis of the variables predisposing to progression of AV disease, such as age, gender, history of rheumatic fever (RF) and recurrence, and interval from RF episode to symptom onset, only the initial AV gradient was identified as being statistically significant (beta coefficient 0.528, SE = 0.17, p < 0.0001). Patients with no or mild AV disease at the time of MV intervention rarely develop severe AV disease, and seldom require AV surgery over the long-term follow up. The presence of mild AS at baseline is predictive in the minority of cases where AV disease will progress relatively more rapidly.

Disease staging as a measure of disease severity.

PubMed

Kohyama, Jun; Fujitani, Shigeki; Umesato, Yoshimasa; Kataoka, Hitomi

2015-06-24

Disease staging, first developed in 1970, has been used to assess the levels of biological severity, defined as the risk of organ failure or death, of specific medical diseases. Because few studies to date have evaluated disease staging in Japan, a small pilot study was designed to determine whether disease staging is available and useful in actual medical practice in Japan. The relationships between disease staging and length of stay, medical costs and age were retrospectively evaluated in patients admitted to Japan Association for Development of Community Medicine - Tokyo Bay Urayasu Ichikawa Medical Center for appendicitis, type 2 diabetes mellitus, and cerebrovascular diseases from April 2012 to March 2013. Patients were easily staged based on information at the time of hospital discharge. Disease stages were found to be affected significantly by length of hospital stay and medical costs. Age also affected disease stages in patients with appendicitis. These findings indicate that disease staging was available in Japan and was affected by hospital resources, including length of hospital stay and medical costs.

Identification and Severity Determination of Wheat Stripe Rust and Wheat Leaf Rust Based on Hyperspectral Data Acquired Using a Black-Paper-Based Measuring Method.

PubMed

Wang, Hui; Qin, Feng; Ruan, Liu; Wang, Rui; Liu, Qi; Ma, Zhanhong; Li, Xiaolong; Cheng, Pei; Wang, Haiguang

2016-01-01

It is important to implement detection and assessment of plant diseases based on remotely sensed data for disease monitoring and control. Hyperspectral data of healthy leaves, leaves in incubation period and leaves in diseased period of wheat stripe rust and wheat leaf rust were collected under in-field conditions using a black-paper-based measuring method developed in this study. After data preprocessing, the models to identify the diseases were built using distinguished partial least squares (DPLS) and support vector machine (SVM), and the disease severity inversion models of stripe rust and the disease severity inversion models of leaf rust were built using quantitative partial least squares (QPLS) and support vector regression (SVR). All the models were validated by using leave-one-out cross validation and external validation. The diseases could be discriminated using both distinguished partial least squares and support vector machine with the accuracies of more than 99%. For each wheat rust, disease severity levels were accurately retrieved using both the optimal QPLS models and the optimal SVR models with the coefficients of determination (R2) of more than 0.90 and the root mean square errors (RMSE) of less than 0.15. The results demonstrated that identification and severity evaluation of stripe rust and leaf rust at the leaf level could be implemented based on the hyperspectral data acquired using the developed method. A scientific basis was provided for implementing disease monitoring by using aerial and space remote sensing technologies.

Identification and Severity Determination of Wheat Stripe Rust and Wheat Leaf Rust Based on Hyperspectral Data Acquired Using a Black-Paper-Based Measuring Method

PubMed Central

Ruan, Liu; Wang, Rui; Liu, Qi; Ma, Zhanhong; Li, Xiaolong; Cheng, Pei; Wang, Haiguang

2016-01-01

It is important to implement detection and assessment of plant diseases based on remotely sensed data for disease monitoring and control. Hyperspectral data of healthy leaves, leaves in incubation period and leaves in diseased period of wheat stripe rust and wheat leaf rust were collected under in-field conditions using a black-paper-based measuring method developed in this study. After data preprocessing, the models to identify the diseases were built using distinguished partial least squares (DPLS) and support vector machine (SVM), and the disease severity inversion models of stripe rust and the disease severity inversion models of leaf rust were built using quantitative partial least squares (QPLS) and support vector regression (SVR). All the models were validated by using leave-one-out cross validation and external validation. The diseases could be discriminated using both distinguished partial least squares and support vector machine with the accuracies of more than 99%. For each wheat rust, disease severity levels were accurately retrieved using both the optimal QPLS models and the optimal SVR models with the coefficients of determination (R2) of more than 0.90 and the root mean square errors (RMSE) of less than 0.15. The results demonstrated that identification and severity evaluation of stripe rust and leaf rust at the leaf level could be implemented based on the hyperspectral data acquired using the developed method. A scientific basis was provided for implementing disease monitoring by using aerial and space remote sensing technologies. PMID:27128464

Updates on the risk markers and outcomes of severe juvenile idiopathic arthritis-associated uveitis

PubMed Central

Angeles-Han, Sheila T; Yeh, Steven; Vogler, Larry B

2013-01-01

Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis, which is the most common systemic cause of uveitis in children. Known risk factors for uveitis include antinuclear antibody seropositivity, young age of arthritis onset, specific juvenile idiopathic arthritis subtype and short duration of disease. Risk markers for severe ocular disease include gender, age and complications at initial visit. Due to the risk for vision-compromising sequelae such as cataracts, band keratopathy, glaucoma, vision loss and blindness, an understanding of the risk factors for uveitis development and severe ocular disease is crucial to help prevent serious visual disability and complications. This paper reviews the pathogenesis of uveitis, known risk factors for uveitis development and severe visual outcome, and addresses the need for additional biomarkers of uveitis risk, prognosis and remission. PMID:24187594

Development and validation of standard area diagrams as assessment aids for estimating the severity of citrus canker on unripe oranges

USDA-ARS?s Scientific Manuscript database

Canker (caused by Xanthomonas citri subsp. citri) is an important disease of citrus in Brazil and elsewhere in the world, and can cause severe disease on the fruit. The severity of citrus canker of fruit must often be estimated visually. The objective of this research was to construct and validate s...

First Experimental In Vivo Model of Enhanced Dengue Disease Severity through Maternally Acquired Heterotypic Dengue Antibodies

PubMed Central

Ng, Jowin Kai Wei; Zhang, Summer Lixin; Tan, Hwee Cheng; Yan, Benedict; Maria Martinez Gomez, Julia; Tan, Wei Yu; Lam, Jian Hang; Tan, Grace Kai Xin; Ooi, Eng Eong; Alonso, Sylvie

2014-01-01

Dengue (DEN) represents the most serious arthropod-borne viral disease. DEN clinical manifestations range from mild febrile illness to life-threatening hemorrhage and vascular leakage. Early epidemiological observations reported that infants born to DEN-immune mothers were at greater risk to develop the severe forms of the disease upon infection with any serotype of dengue virus (DENV). From these observations emerged the hypothesis of antibody-dependent enhancement (ADE) of disease severity, whereby maternally acquired anti-DENV antibodies cross-react but fail to neutralize DENV particles, resulting in higher viremia that correlates with increased disease severity. Although in vitro and in vivo experimental set ups have indirectly supported the ADE hypothesis, direct experimental evidence has been missing. Furthermore, a recent epidemiological study has challenged the influence of maternal antibodies in disease outcome. Here we have developed a mouse model of ADE where DENV2 infection of young mice born to DENV1-immune mothers led to earlier death which correlated with higher viremia and increased vascular leakage compared to DENV2-infected mice born to dengue naïve mothers. In this ADE model we demonstrated the role of TNF-α in DEN-induced vascular leakage. Furthermore, upon infection with an attenuated DENV2 mutant strain, mice born to DENV1-immune mothers developed lethal disease accompanied by vascular leakage whereas infected mice born to dengue naïve mothers did no display any clinical manifestation. In vitro ELISA and ADE assays confirmed the cross-reactive and enhancing properties towards DENV2 of the serum from mice born to DENV1-immune mothers. Lastly, age-dependent susceptibility to disease enhancement was observed in mice born to DENV1-immune mothers, thus reproducing epidemiological observations. Overall, this work provides direct in vivo demonstration of the role of maternally acquired heterotypic dengue antibodies in the enhancement of dengue disease severity and offers a unique opportunity to further decipher the mechanisms involved. PMID:24699622

The prevalence of severe fatigue in rheumatic diseases: an international study.

PubMed

Overman, Cécile L; Kool, Marianne B; Da Silva, José A P; Geenen, Rinie

2016-02-01

Fatigue is a common, disabling, and difficult-to-manage problem in rheumatic diseases. Prevalence estimates of fatigue within rheumatic diseases vary considerably. Data on the prevalence of severe fatigue across multiple rheumatic diseases using a similar instrument is missing. Our aim was to provide an overview of the prevalence of severe fatigue across a broad range of rheumatic diseases and to examine its association with clinical and demographic variables. Online questionnaires were filled out by an international sample of 6120 patients (88 % female, mean age 47) encompassing 30 different rheumatic diseases. Fatigue was measured with the RAND(SF)-36 Vitality scale. A score of ≤35 was taken as representing severe fatigue (90 % sensitivity and 81 % specificity for chronic fatigue syndrome). Severe fatigue was present in 41 to 57 % of patients with a single inflammatory rheumatic disease such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögren's syndrome, psoriatic arthritis, and scleroderma. Severe fatigue was least prevalent in patients with osteoarthritis (35 %) and most prevalent in patients with fibromyalgia (82 %). In logistic regression analysis, severe fatigue was associated with having fibromyalgia, having multiple rheumatic diseases without fibromyalgia, younger age, lower education, and language (French: highest prevalence; Dutch: lowest prevalence). In conclusion, one out of every two patients with a rheumatic disease is severely fatigued. As severe fatigue is detrimental to the patient, the near environment, and society at large, unraveling the underlying mechanisms of fatigue and developing optimal treatment should be top priorities in rheumatologic research and practice.

Predicting and explaining inflammation in Crohn's disease patients using predictive analytics methods and electronic medical record data.

PubMed

Reddy, Bhargava K; Delen, Dursun; Agrawal, Rupesh K

2018-01-01

Crohn's disease is among the chronic inflammatory bowel diseases that impact the gastrointestinal tract. Understanding and predicting the severity of inflammation in real-time settings is critical to disease management. Extant literature has primarily focused on studies that are conducted in clinical trial settings to investigate the impact of a drug treatment on the remission status of the disease. This research proposes an analytics methodology where three different types of prediction models are developed to predict and to explain the severity of inflammation in patients diagnosed with Crohn's disease. The results show that machine-learning-based analytic methods such as gradient boosting machines can predict the inflammation severity with a very high accuracy (area under the curve = 92.82%), followed by regularized regression and logistic regression. According to the findings, a combination of baseline laboratory parameters, patient demographic characteristics, and disease location are among the strongest predictors of inflammation severity in Crohn's disease patients.

Wireless Monitoring for Patients with Cardiovascular Diseases and Parkinson's Disease.

PubMed

Kefaliakos, Antonios; Pliakos, Ioannis; Charalampidou, Martha; Diomidous, Marianna

2016-01-01

The use of applications for mobile devices and wireless sensors is common for the sector of telemedicine. Recently various studies and systems were developed in order to help patients suffering from severe diseases such as cardiovascular diseases and Parkinson's disease. They present a challenge for the sector because such systems demand the flow of accurate data in real time and the use of specialized sensors. In this review will be presented some very interesting applications developed for patients with cardiovascular diseases and Parkinson's disease.

Genetic control of hepatitis A severity and susceptibility to allergy

PubMed Central

Chatenoud, Lucienne; Bach, Jean-François

2011-01-01

Hepatitis A virus (HAV) usually results in asymptomatic infection or mild disease, but in a small subset of patients it can lead to severe disease and even liver failure. In this issue of the JCI, Kim et al. identify a polymorphism associated with this increased disease risk in the gene that encodes the HAV receptor — TIM1. Importantly, this TIM1 gene polymorphism protects from the development of atopic diseases in HAV-seropositive individuals. PMID:21339636

An interesting case of peripheral vascular disease, vascular reperfusion, and subsequent development of pain due to Paget's disease of bone.

PubMed

Kwun, Sunna; Tucci, Joseph R

2013-01-01

To present a case of Paget's disease of bone that was unmasked after vascular reperfusion. In this case study, we review the presentation, evaluation, diagnosis, and management of a patient with Paget's disease and peripheral vascular disease. A 79-year-old-woman with a history of coronary artery heart disease and recent finding of a T5 compression fracture was hospitalized for evaluation of right lower extremity claudication. Angiography demonstrated a focal complete occlusion of the distal right femoral and popliteal arteries. A self-expanding stent was placed in the distal femoral and popliteal arteries. Approximately 48 hours after the procedure, the patient developed severe, right lower leg pain. On endocrine evaluation, the patient was found to have clinical signs suggesting Paget's disease of bone, which was subsequently confirmed by imaging. This patient's development of severe pain following reperfusion of distal femoral and popliteal arteries is in keeping with the known and aforementioned hypervascularity of pagetic bone. The finding of increased warmth over an area of skeletal deformation should always raise the possibility of Paget's disease of bone.

Fish Vaccine Development and Use to Prevent Streptococcal Diseases

USDA-ARS?s Scientific Manuscript database

An important pathogen of tilapia, hybrid striped bass and trout raised in intensive aquaculture is Streptococcus sp., a cause of severe economic losses in the fish farming industry. Infected fish experience severe to moderate mortality due to Streptococcus iniae and/or S. agalactiae. The diseased ...

Association of cytokine gene polymorphisms in CWP and its severity in Turkish coal workers

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

Ates, I.; Suzen, H.S.; Yucesoy, B.

2008-10-15

Cytokines appear to play a key role in some inflammatory reactions affecting the interactions among pro- and anti-inflammatory mechanisms that result in several diseases such as coal workers' pneumoconiosis (CWP). In this study, to determine the cytokine gene profiles of Turkish coal miners, we performed genotyping analysis to investigate the polymorphisms of CWP-related pro-inflammatory (TNFA, IL1A, IL1B, and IL6) and anti-inflammatory cytokines (IL-1RN and TGFB1). Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. TNFA (-238) gene polymorphism principally affected CWP development and severity (OR=3.47: 95% CI, 1.12-10.77 and OR=4.30: 95% CI, 1.25-14.74, respectively) and alsomore » risk of CWP (OR=3.79: 95% CI, 1.37-10.46). The TNFA (-308) variant was associated with a risk for the CWP severity (OR = 2.84: 95% CI, 1.08-7.39). A protective effect of IL6 was found on the development (OR = 0.48: 95% CI, 0.21-0.93) and severity of CWP (OR = 0.37: 95% CI, 0.15-0.91). We suggest that TNFA (-238) variant may be a risk factor in both development and the severity, of CWP while TNFA (-308) variant seems to be important only in disease severity On the other hand, IL6 variant may have a protective effect on the development and disease severity.« less

Fetal growth and risk of childhood asthma and allergic disease

PubMed Central

Tedner, S G; Örtqvist, A K; Almqvist, C

2012-01-01

Introduction Early genetic and environmental factors have been discussed as potential causes for the high prevalence of asthma and allergic disease in the western world, and knowledge on fetal growth and its consequence on future health and disease development is emerging. Objective This review article is an attempt to summarize research on fetal growth and risk of asthma and allergic disease. Current knowledge and novel findings will be reviewed and open research questions identified, to give basic scientists, immunologists and clinicians an overview of an emerging research field. Methods PubMed-search on pre-defined terms and cross-references. Results Several studies have shown a correlation between low birth weight and/or gestational age and asthma and high birth weight and/or gestational age and atopy. The exact mechanism is not yet clear but both environmental and genetic factors seem to contribute to fetal growth. Some of these factors are confounders that can be adjusted for, and twin studies have been very helpful in this context. Suggested mechanisms behind fetal growth are often linked to the feto-maternal circulation, including the development of placenta and umbilical cord. However, the causal link between fetal growth restriction and subsequent asthma and allergic disease remains unexplained. New research regarding the catch-up growth following growth restriction has posited an alternative theory that diseases later on in life result from rapid catch-up growth rather than intrauterine growth restriction per se. Several studies have found a correlation between a rapid weight gain after birth and development of asthma or wheezing in childhood. Conclusion and clinical relevance Asthma and allergic disease are multifactorial. Several mechanisms seem to influence their development. Additional studies are needed before we fully understand the causal links between fetal growth and development of asthma and allergic diseases. PMID:22994341

Combination therapeutics in complex diseases.

PubMed

He, Bing; Lu, Cheng; Zheng, Guang; He, Xiaojuan; Wang, Maolin; Chen, Gao; Zhang, Ge; Lu, Aiping

2016-12-01

The biological redundancies in molecular networks of complex diseases limit the efficacy of many single drug therapies. Combination therapeutics, as a common therapeutic method, involve pharmacological intervention using several drugs that interact with multiple targets in the molecular networks of diseases and may achieve better efficacy and/or less toxicity than monotherapy in practice. The development of combination therapeutics is complicated by several critical issues, including identifying multiple targets, targeting strategies and the drug combination. This review summarizes the current achievements in combination therapeutics, with a particular emphasis on the efforts to develop combination therapeutics for complex diseases. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Curing genetic disease with gene therapy.

PubMed

Williams, David A

2014-01-01

Development of viral vectors that allow high efficiency gene transfer into mammalian cells in the early 1980s foresaw the treatment of severe monogenic diseases in humans. The application of gene transfer using viral vectors has been successful in diseases of the blood and immune systems, albeit with several curative studies also showing serious adverse events (SAEs). In children with X-linked severe combined immunodeficiency (SCID-X1), chronic granulomatous disease, and Wiskott-Aldrich syndrome, these SAEs were caused by inappropriate activation of oncogenes. Subsequent studies have defined the vector sequences responsible for these transforming events. Members of the Transatlantic Gene Therapy Consortium [TAGTC] have collaboratively developed new vectors that have proven safer in preclinical studies and used these vectors in new clinical trials in SCID-X1. These trials have shown evidence of early efficacy and preliminary integration analysis data from the SCID-X1 trial suggest an improved safety profile.

Curing Genetic Disease with Gene Therapy

PubMed Central

Williams, David A.

2014-01-01

Development of viral vectors that allow high efficiency gene transfer into mammalian cells in the early 1980s foresaw the treatment of severe monogenic diseases in humans. The application of gene transfer using viral vectors has been successful in diseases of the blood and immune systems, albeit with several curative studies also showing serious adverse events (SAEs). In children with X-linked severe combined immunodeficiency (SCID-X1), chronic granulomatous disease, and Wiskott-Aldrich syndrome, these SAEs were caused by inappropriate activation of oncogenes. Subsequent studies have defined the vector sequences responsible for these transforming events. Members of the Transatlantic Gene Therapy Consortium [TAGTC] have collaboratively developed new vectors that have proven safer in preclinical studies and used these vectors in new clinical trials in SCID-X1. These trials have shown evidence of early efficacy and preliminary integration analysis data from the SCID-X1 trial suggest an improved safety profile. PMID:25125725

A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever

PubMed Central

Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Shen, Kui; Horne, Eva J.; Scott, Dana P.; Feldmann, Heinz; Ebihara, Hideki

2016-01-01

Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF. PMID:27976688

A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever.

PubMed

Marzi, Andrea; Banadyga, Logan; Haddock, Elaine; Thomas, Tina; Shen, Kui; Horne, Eva J; Scott, Dana P; Feldmann, Heinz; Ebihara, Hideki

2016-12-15

Marburg virus (MARV), a close relative of Ebola virus, is the causative agent of a severe human disease known as Marburg hemorrhagic fever (MHF). No licensed vaccine or therapeutic exists to treat MHF, and MARV is therefore classified as a Tier 1 select agent and a category A bioterrorism agent. In order to develop countermeasures against this severe disease, animal models that accurately recapitulate human disease are required. Here we describe the development of a novel, uniformly lethal Syrian golden hamster model of MHF using a hamster-adapted MARV variant Angola. Remarkably, this model displayed almost all of the clinical features of MHF seen in humans and non-human primates, including coagulation abnormalities, hemorrhagic manifestations, petechial rash, and a severely dysregulated immune response. This MHF hamster model represents a powerful tool for further dissecting MARV pathogenesis and accelerating the development of effective medical countermeasures against human MHF.

[Intestinal and hepatic parasitic diseases: diagnosis and treatment].

PubMed

Gétaz, L; Chappuis, F; Loutan, L

2007-05-16

Intestinal parasites represent an important burden of disease mainly in developing countries. Physicians practicing in Europe can be exposed to these diseases, mainly seen in immigrants or travellers returning from tropical countries. Several parasitic diseases remain ubiquitous and can be contracted in developed countries. Most often, parasitic infections cause no or only few symptoms, but some can lead to serious disease in immuno-compromised patients. Diagnostic procedures and treatments available are discussed.

Soil Temperature Determines the Reaction of Olive Cultivars to Verticillium dahliae Pathotypes

PubMed Central

Calderón, Rocío; Lucena, Carlos; Trapero-Casas, José L.; Zarco-Tejada, Pablo J.; Navas-Cortés, Juan A.

2014-01-01

Background Development of Verticillium wilt in olive, caused by the soil-borne fungus Verticillium dahliae, can be influenced by biotic and environmental factors. In this study we modeled i) the combined effects of biotic factors (i.e., pathotype virulence and cultivar susceptibility) and abiotic factors (i.e., soil temperature) on disease development and ii) the relationship between disease severity and several remote sensing parameters and plant stress indicators. Methodology Plants of Arbequina and Picual olive cultivars inoculated with isolates of defoliating and non-defoliating V. dahliae pathotypes were grown in soil tanks with a range of soil temperatures from 16 to 32°C. Disease progression was correlated with plant stress parameters (i.e., leaf temperature, steady-state chlorophyll fluorescence, photochemical reflectance index, chlorophyll content, and ethylene production) and plant growth-related parameters (i.e., canopy length and dry weight). Findings Disease development in plants infected with the defoliating pathotype was faster and more severe in Picual. Models estimated that infection with the defoliating pathotype was promoted by soil temperatures in a range of 16 to 24°C in cv. Picual and of 20 to 24°C in cv. Arbequina. In the non-defoliating pathotype, soil temperatures ranging from 16 to 20°C were estimated to be most favorable for infection. The relationship between stress-related parameters and disease severity determined by multinomial logistic regression and classification trees was able to detect the effects of V. dahliae infection and colonization on water flow that eventually cause water stress. Conclusions Chlorophyll content, steady-state chlorophyll fluorescence, and leaf temperature were the best indicators for Verticillium wilt detection at early stages of disease development, while ethylene production and photochemical reflectance index were indicators for disease detection at advanced stages. These results provide a better understanding of the differential geographic distribution of V. dahliae pathotypes and to assess the potential effect of climate change on Verticillium wilt development. PMID:25330093

Acute lower motor neuron tetraparesis.

PubMed

Añor, Sònia

2014-11-01

Flaccid nonambulatory tetraparesis or tetraplegia is an infrequent neurologic presentation; it is characteristic of neuromuscular disease (lower motor neuron [LMN] disease) rather than spinal cord disease. Paresis beginning in the pelvic limbs and progressing to the thoracic limbs resulting in flaccid tetraparesis or tetraplegia within 24 to 72 hours is a common presentation of peripheral nerve or neuromuscular junction disease. Complete body flaccidity develops with severe decrease or complete loss of spinal reflexes in pelvic and thoracic limbs. Animals with acute generalized LMN tetraparesis commonly show severe motor dysfunction in all limbs and severe generalized weakness in all muscles. Copyright © 2014 Elsevier Inc. All rights reserved.

Influenza Virus and Glycemic Variability in Diabetes: A Killer Combination?

PubMed Central

Hulme, Katina D.; Gallo, Linda A.; Short, Kirsty R.

2017-01-01

Following the 2009 H1N1 influenza virus pandemic, numerous studies identified the striking link between diabetes mellitus and influenza disease severity. Typically, influenza virus is a self-limiting infection but in individuals who have a pre-existing chronic illness, such as diabetes mellitus, severe influenza can develop. Here, we discuss the latest clinical and experimental evidence for the role of diabetes in predisposing the host to severe influenza. We explore the possible mechanisms that underlie this synergy and highlight the, as yet, unexplored role that blood glucose oscillations may play in disease development. Diabetes is one of the world’s fastest growing chronic diseases and influenza virus represents a constant and pervasive threat to human health. It is therefore imperative that we understand how diabetes increases influenza severity in order to mitigate the burden of future influenza epidemics and pandemics. PMID:28588558

[Severe Yellow fever vaccine-associated disease: a case report and current overview].

PubMed

Slesak, Günther; Gabriel, Martin; Domingo, Cristina; Schäfer, Johannes

2017-08-01

History and physical examination  A 56-year-old man developed high fever with severe headaches, fatigue, impaired concentration skills, and an exanthema 5 days after a yellow fever (YF) vaccination. Laboratory tests  Liver enzymes and YF antibody titers were remarkably elevated. YF vaccine virus was detected in urine by PCR. Diagnosis and therapy  Initially, severe YF vaccine-associated visceral disease was suspected and treated symptomatically. Clinical Course  His fever ceased after 10 days in total, no organ failure developed. However, postencephalitic symptoms persisted with fatigue and impaired concentration, memory, and reading skills and partly incapability to work for over 3 months. A diagnosis was made of suspected YF vaccine-associated neurotropic disease. Conclusion  Severe vaccine-derived adverse effects need to be considered in the indication process for YF vaccination. © Georg Thieme Verlag KG Stuttgart · New York.

Toll-like receptors and chronic inflammation in rheumatic diseases: new developments.

PubMed

Joosten, Leo A B; Abdollahi-Roodsaz, Shahla; Dinarello, Charles A; O'Neill, Luke; Netea, Mihai G

2016-06-01

In the past few years, new developments have been reported on the role of Toll-like receptors (TLRs) in chronic inflammation in rheumatic diseases. The inhibitory function of TLR10 has been demonstrated. Receptors that enhance the function of TLRs, and several TLR inhibitors, have been identified. In addition, the role of the microbiome and TLRs in the onset of rheumatic diseases has been reported. We review novel insights on the role of TLRs in several inflammatory joint diseases, including rheumatoid arthritis, systemic lupus erythematosus, gout and Lyme arthritis, with a focus on the signalling mechanisms mediated by the Toll-IL-1 receptor (TIR) domain, the exogenous and endogenous ligands of TLRs, and the current and future therapeutic strategies to target TLR signalling in rheumatic diseases.

The Role of Viral, Host, and Secondary Bacterial Factors in Influenza Pathogenesis

PubMed Central

Kash, John C.; Taubenberger, Jeffery K.

2016-01-01

Influenza A virus infections in humans generally cause self-limited infections, but can result in severe disease, secondary bacterial pneumonias, and death. Influenza viruses can replicate in epithelial cells throughout the respiratory tree and can cause tracheitis, bronchitis, bronchiolitis, diffuse alveolar damage with pulmonary edema and hemorrhage, and interstitial and airspace inflammation. The mechanisms by which influenza infections result in enhanced disease, including development of pneumonia and acute respiratory distress, are multifactorial, involving host, viral, and bacterial factors. Host factors that enhance risk of severe influenza disease include underlying comorbidities, such as cardiac and respiratory disease, immunosuppression, and pregnancy. Viral parameters enhancing disease risk include polymerase mutations associated with host switch and adaptation, viral proteins that modulate immune and antiviral responses, and virulence factors that increase disease severity, which can be especially prominent in pandemic viruses and some zoonotic influenza viruses causing human infections. Influenza viral infections result in damage to the respiratory epithelium that facilitates secondary infection with common bacterial pneumopathogens and can lead to secondary bacterial pneumonias that greatly contribute to respiratory distress, enhanced morbidity, and death. Understanding the molecular mechanisms by which influenza and secondary bacterial infections, coupled with the role of host risk factors, contribute to enhanced morbidity and mortality is essential to develop better therapeutic strategies to treat severe influenza. PMID:25747532

A key player in biomedical sciences and clinical service in China, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC).

PubMed

Zhan, Qimin; Liu, Depei

2007-08-01

The Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC) is the largest medical institution in China and has a leading high-level multidisciplinary medical research and medial service. Under the CAMS and PUMC infrastructure, there are 17 biomedical institutes and 6 large hospitals, which cover most fields of the human disease-related research. CAMS and PUMC has always attached great emphasis on the control and cure of severe diseases, as well as a series of innovative drug researches, and has made significant progress in those fields. The long-term goals for CAMS and PUMC in the future development are: reaching the international advanced level in the areas of severe disease prediction, prevention, control, diagnosis, and research on drug innovation; establishing theoretical and technological system for explanation of the mechanism of severe diseases, which possesses Chinese style and represents the frontier level in the world, and at the same time, providing scientific support for the prevention and treatment of severe disease and making contribution to the establishment and development of a harmonious society in China.

New and developing therapies for atopic dermatitis*

PubMed Central

Hajar, Tamar; Gontijo, João Renato Vianna; Hanifin, Jon M

2018-01-01

Atopic dermatitis is a common inflammatory skin disease. New understanding in disease pathogenesis has led to a considerable number of promising new drugs in development. New topical agents can be especially helpful for children, providing an alternative to the need for chronic topical corticosteroid use. While many patients with mild or moderate disease can be managed with topical treatments, there are unmet needs for recalcitrant and severe cases. New and developing therapies hold promise for real advances in management of this complex disease. PMID:29641707

Nairobi sheep disease virus/Ganjam virus.

PubMed

M D, Baron; B, Holzer

2015-08-01

Nairobi sheep disease virus (NSDV) is a tick-borne virus which causes a severe disease in sheep and goats, and has been responsible for several outbreaks of disease in East Africa. The virus is also found in the Indian subcontinent, where it is known as Ganjam virus. The virus only spreads through the feeding of competent infected ticks, and is therefore limited in its geographic distribution by the distribution of those ticks, Rhipicephalus appendiculata in Africa and Haemaphysalis intermedia in India. Animals bred in endemic areas do not normally develop disease, and the impact is therefore primarily on animals being moved for trade or breeding purposes. The disease caused by NSDV has similarities to several other ruminant diseases, and laboratory diagnosis is necessary for confirmation. There are published methods for diagnosis based on polymerase chain reaction, for virus growth in cell culture and for other simple diagnostic tests, though none has been commercialised. There is no established vaccine against NSDV, although cell-culture attenuated strains have been developed which show promise and could be put into field trials if it were deemed necessary. The virus is closely related to Crimean-Congo haemorrhagic fever virus, and studies on NSDV may therefore be useful in understanding this important human pathogen.

Investigating the Pathogenesis of Severe Malaria: A Multidisciplinary and Cross-Geographical Approach

PubMed Central

Wassmer, Samuel C.; Taylor, Terrie E.; Rathod, Pradipsinh K.; Mishra, Saroj K.; Mohanty, Sanjib; Arevalo-Herrera, Myriam; Duraisingh, Manoj T.; Smith, Joseph D.

2015-01-01

More than a century after the discovery of Plasmodium spp. parasites, the pathogenesis of severe malaria is still not well understood. The majority of malaria cases are caused by Plasmodium falciparum and Plasmodium vivax, which differ in virulence, red blood cell tropism, cytoadhesion of infected erythrocytes, and dormant liver hypnozoite stages. Cerebral malaria coma is one of the most severe manifestations of P. falciparum infection. Insights into its complex pathophysiology are emerging through a combination of autopsy, neuroimaging, parasite binding, and endothelial characterizations. Nevertheless, important questions remain regarding why some patients develop life-threatening conditions while the majority of P. falciparum-infected individuals do not, and why clinical presentations differ between children and adults. For P. vivax, there is renewed recognition of severe malaria, but an understanding of the factors influencing disease severity is limited and remains an important research topic. Shedding light on the underlying disease mechanisms will be necessary to implement effective diagnostic tools for identifying and classifying severe malaria syndromes and developing new therapeutic approaches for severe disease. This review highlights progress and outstanding questions in severe malaria pathophysiology and summarizes key areas of pathogenesis research within the International Centers of Excellence for Malaria Research program. PMID:26259939

Seasonality and autoimmune diseases: The contribution of the four seasons to the mosaic of autoimmunity.

PubMed

Watad, Abdulla; Azrielant, Shir; Bragazzi, Nicola Luigi; Sharif, Kassem; David, Paula; Katz, Itay; Aljadeff, Gali; Quaresma, Mariana; Tanay, Galya; Adawi, Mohammad; Amital, Howard; Shoenfeld, Yehuda

2017-08-01

Autoimmune diseases (ADs) are a heterogeneous groups of diseases that occur as a results of loss of tolerance to self antigens. While the etiopathogeneis remain obscure, different environmental factors were suggested to have a role in the development of autoimmunity, including infections, low vitamin D levels, UV radiation, and melatonin. Interestingly, such factors possess seasonal variation patterns that could influence disease development, severity and progression. Vitamin D levels which reach a nadir during late winter and early spring is correlated with increased disease activity, clinical severity as well as relapse rates in several disease entities including multiple sclerosis (MS), non-cutaneous flares of systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis (RA). Additionally, immunomodulatory actions of melatonin secretion ameliorate the severity of several ADs including MS and SLE. Melatonin levels are lowest during spring, a finding that correlates with the highest exacerbation rates of MS. Further, melatonin is postulated to be involved in the etiopathogenesis of inflammatory bowel diseases (IBD) through it influence on adhesion molecule and therefore transcription factor expression. Moreover, infections can mount to ADs through pro-inflammatory cytokine release and human antigen mimicry. Seasonal patterns of infectious diseases are correlated with the onset and exacerbation of ADs. During the winter, increased incidence of Epstein-Barr virus (EBV) infectious are associated with MS and SLE flares/onset respectively. In addition, higher Rotavirus infections during the winter precedes type 1 diabetes mellitus onset (T1DM). Moreover, Escherichia coli (E. coli) infection prior to primary biliary cirrhosis (PBC) and T1DM disease onset subsequent to Coxachievirus infections are seen to occur during late summer, a finding that correlate with infectious agents' pattern of seasonality. In this review, the effects of seasonality on the onset, relapses and activity of various ADs were discussed. Consideration of seasonal variation patterns of ADs can possibly provide clues to diseases pathogenesis and lead to development of new approaches in treatment and preventative care. Copyright © 2017 Elsevier Ltd. All rights reserved.

Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study.

PubMed

Hagström, Hannes; Nasr, Patrik; Ekstedt, Mattias; Hammar, Ulf; Stål, Per; Hultcrantz, Rolf; Kechagias, Stergios

2018-01-01

Most patients with nonalcoholic fatty liver disease (NAFLD) are overweight or obese. However, a significant proportion of patients have a normal body mass index (BMI), denoted as lean NAFLD. The long-term prognosis of lean NAFLD is unclear. We conducted a cohort study of 646 patients with biopsy-proven NAFLD. Patients were defined as lean (BMI < 25.0), overweight (BMI 25.0-29.9), or obese (BMI ≥ 30.0) at the time of biopsy. Each case was matched for age, sex, and municipality to 10 controls. Overall mortality and development of severe liver disease were evaluated using population-based registers. Cox regression models adjusted for age, sex, type 2 diabetes, and fibrosis stage were used to examine the long-term risk of mortality and liver-related events in lean and nonlean NAFLD. Lean NAFLD was seen in 19% of patients, while 52% were overweight and 29% were obese. Patients with lean NAFLD were older, had lower transaminases, lower stages of fibrosis, and lower prevalence of nonalcoholic steatohepatitis at baseline compared to patients with a higher BMI. During a mean follow-up of 19.9 years (range 0.4-40 years) representing 12,631 person years and compared to patients who were overweight, patients with lean NAFLD had no increased risk for overall mortality (hazard ratio 1.06; P =  0.73) while an increased risk for development of severe liver disease was found (hazard ratio 2.69; P =  0.007). Conclusion : Although patients with lean NAFLD have lower stages of fibrosis, they are at higher risk for development of severe liver disease compared to patients with NAFLD and a higher BMI, independent of available confounders. ( Hepatology Communications 2018;2:48-57).

Loss in lung volume and changes in the immune response demonstrate disease progression in African green monkeys infected by small-particle aerosol and intratracheal exposure to Nipah virus.

PubMed

Cong, Yu; Lentz, Margaret R; Lara, Abigail; Alexander, Isis; Bartos, Christopher; Bohannon, J Kyle; Hammoud, Dima; Huzella, Louis; Jahrling, Peter B; Janosko, Krisztina; Jett, Catherine; Kollins, Erin; Lackemeyer, Matthew; Mollura, Daniel; Ragland, Dan; Rojas, Oscar; Solomon, Jeffrey; Xu, Ziyue; Munster, Vincent; Holbrook, Michael R

2017-04-01

Nipah virus (NiV) is a paramyxovirus (genus Henipavirus) that emerged in the late 1990s in Malaysia and has since been identified as the cause of sporadic outbreaks of severe febrile disease in Bangladesh and India. NiV infection is frequently associated with severe respiratory or neurological disease in infected humans with transmission to humans through inhalation, contact or consumption of NiV contaminated foods. In the work presented here, the development of disease was investigated in the African Green Monkey (AGM) model following intratracheal (IT) and, for the first time, small-particle aerosol administration of NiV. This study utilized computed tomography (CT) and magnetic resonance imaging (MRI) to temporally assess disease progression. The host immune response and changes in immune cell populations over the course of disease were also evaluated. This study found that IT and small-particle administration of NiV caused similar disease progression, but that IT inoculation induced significant congestion in the lungs while disease following small-particle aerosol inoculation was largely confined to the lower respiratory tract. Quantitative assessment of changes in lung volume found up to a 45% loss in IT inoculated animals. None of the subjects in this study developed overt neurological disease, a finding that was supported by MRI analysis. The development of neutralizing antibodies was not apparent over the 8-10 day course of disease, but changes in cytokine response in all animals and activated CD8+ T cell numbers suggest the onset of cell-mediated immunity. These studies demonstrate that IT and small-particle aerosol infection with NiV in the AGM model leads to a severe respiratory disease devoid of neurological indications. This work also suggests that extending the disease course or minimizing the impact of the respiratory component is critical to developing a model that has a neurological component and more accurately reflects the human condition.

Loss in lung volume and changes in the immune response demonstrate disease progression in African green monkeys infected by small-particle aerosol and intratracheal exposure to Nipah virus

PubMed Central

Cong, Yu; Lentz, Margaret R.; Lara, Abigail; Alexander, Isis; Bartos, Christopher; Bohannon, J. Kyle; Hammoud, Dima; Huzella, Louis; Jahrling, Peter B.; Janosko, Krisztina; Jett, Catherine; Kollins, Erin; Lackemeyer, Matthew; Mollura, Daniel; Ragland, Dan; Rojas, Oscar; Solomon, Jeffrey; Xu, Ziyue; Munster, Vincent

2017-01-01

Nipah virus (NiV) is a paramyxovirus (genus Henipavirus) that emerged in the late 1990s in Malaysia and has since been identified as the cause of sporadic outbreaks of severe febrile disease in Bangladesh and India. NiV infection is frequently associated with severe respiratory or neurological disease in infected humans with transmission to humans through inhalation, contact or consumption of NiV contaminated foods. In the work presented here, the development of disease was investigated in the African Green Monkey (AGM) model following intratracheal (IT) and, for the first time, small-particle aerosol administration of NiV. This study utilized computed tomography (CT) and magnetic resonance imaging (MRI) to temporally assess disease progression. The host immune response and changes in immune cell populations over the course of disease were also evaluated. This study found that IT and small-particle administration of NiV caused similar disease progression, but that IT inoculation induced significant congestion in the lungs while disease following small-particle aerosol inoculation was largely confined to the lower respiratory tract. Quantitative assessment of changes in lung volume found up to a 45% loss in IT inoculated animals. None of the subjects in this study developed overt neurological disease, a finding that was supported by MRI analysis. The development of neutralizing antibodies was not apparent over the 8–10 day course of disease, but changes in cytokine response in all animals and activated CD8+ T cell numbers suggest the onset of cell-mediated immunity. These studies demonstrate that IT and small-particle aerosol infection with NiV in the AGM model leads to a severe respiratory disease devoid of neurological indications. This work also suggests that extending the disease course or minimizing the impact of the respiratory component is critical to developing a model that has a neurological component and more accurately reflects the human condition. PMID:28388650

Dengue vaccine development: strategies and challenges.

PubMed

Ramakrishnan, Lakshmy; Pillai, Madhavan Radhakrishna; Nair, Radhakrishnan R

2015-03-01

Infection with dengue virus may result in dengue fever or a more severe outcome, such as dengue hemorrhagic syndrome/shock. Dengue virus infection poses a threat to endemic regions for four reasons: the presence of four serotypes, each with the ability to cause a similar disease outcome, including fatality; difficulties related to vector control; the lack of specific treatment; and the nonavailability of a suitable vaccine. Vaccine development is considered challenging due to the severity of the disease observed in individuals who have acquired dengue-specific immunity, either passively or actively. Therefore, the presence of vaccine-induced immunity against a particular serotype may prime an individual to severe disease on exposure to dengue virus. Vaccine development strategies include live attenuated vaccines, chimeric, DNA-based, subunit, and inactivated vaccines. Each of the candidates is in various stages of preclinical and clinical development. Issues pertaining to selection pressures, viral interaction, and safety still need to be evaluated in order to induce a complete protective immune response against all four serotypes. This review highlights the various strategies that have been employed in vaccine development, and identifies the obstacles to producing a safe and effective vaccine.

Larval western bean cutworm feeding damage encourages the development of Gibberella ear rot on field corn.

PubMed

Parker, Nicole S; Anderson, Nolan R; Richmond, Douglas S; Long, Elizabeth Y; Wise, Kiersten A; Krupke, Christian H

2017-03-01

A 2 year study was conducted to determine whether western bean cutworm (Striacosta albicosta Smith) (WBC) larval feeding damage increases severity of the fungal disease Gibberella ear rot [Fusarium graminearum (Schwein.) Petch] in field corn (Zea mays L.). The effect of a quinone-outside inhibiting fungicide, pyraclostrobin, on Gibberella ear rot severity and mycotoxin production, both with and without WBC pressure, was also evaluated. The impact of each variable was assessed individually and in combination to determine the effect of each upon ear disease severity. There was a positive correlation between the presence of WBC larvae in field corn and Gibberella ear rot severity under inoculated conditions in the 2 years of the experiment. An application of pyraclostrobin did not impact Gibberella ear rot development when applied at corn growth stage R1 (silks first emerging). Feeding damage from WBC larvae significantly increases the development of F. graminearum in field corn. We conclude that an effective integrated management strategy for Gibberella ear rot should target the insect pest first, in an effort to limit disease severity and subsequent mycotoxin production by F. graminearum in kernels. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases.

PubMed

Choudhary, Mayur; Malek, Goldis

2016-12-01

Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment.

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases

PubMed Central

Choudhary, Mayur; Malek, Goldis

2017-01-01

Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment. PMID:27455994

The effects of Zebra Chip disease development and bacterial titer on biochemical properties in relation to the time of infection

USDA-ARS?s Scientific Manuscript database

Potato tuber biochemical responses to ‘Candidatus’ Liberibacter solanacearum (Lso), the causal agent of Zebra chip disease, were evaluated both within infected tubers and across different infection dates. Tuber biochemistry also was related to symptom severity and bacterial titer. Symptom severity w...

Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease

USDA-ARS?s Scientific Manuscript database

During the 2009 pandemic, several studies associated recent seasonal influenza vaccination with increased severity of clinical illness after pandemic H1N1 (pH1N1) infection. We developed a swine model to evaluate mismatched influenza vaccination associated enhanced respiratory disease (VAERD) follow...

Clinical endpoints in the controlled human challenge model for Shigella: A call for standardization and the development of a disease severity score

PubMed Central

Lynen, Amanda; Riddle, Mark S.; Talaat, Kawsar; Sack, David; Gutiérrez, Ramiro L.; McKenzie, Robin; DeNearing, Barbara; Feijoo, Brittany; Kaminski, Robert W.; Taylor, David N.; Kirkpatrick, Beth D.; Bourgeois, A. Louis

2018-01-01

Background Since 1946 the controlled human infection model (CHIM) for Shigella has been used to improve understanding of disease pathogenesis, describe clinical and immunologic responses to infection and as a tool for vaccine development. As the frequency and intent for use in vaccine comparisons increases, standardization of the primary endpoint definition is necessary. Methods Subject-level data were obtained from previously conducted experimental Shigella CHIM studies. Signs and symptoms severity were categorized consistently across all studies. Sign and symptom correlations were estimated and univariate models were utilized to describe the association between stool output and other Shigella-attributable signs and symptoms. Multiple correspondence and hierarchical clustering analyses were performed to describe the co-occurrence of signs and symptoms. A disease score is proposed based on the co-occurrence of these events. Results Data were obtained on 54 subjects receiving 800 to 2000 colony forming units (cfu) of S. flexneri. The median maximum 24 hour stool output was 514 ml (IQR: 300, 998 ml) with a median frequency of 6 (IQR: 4, 9). Subjects reported abdominal pain or cramps (81.5%), headache (66.7%) and anorexia (64.8%), 50.0% had a fever and 27.8% had gross blood in multiple loose stools. Multiple correspondence analyses highlighted co-occurrence of symptoms based on severity. A 3-parameter disease severity score predicted shigellosis endpoints and better differentiated disease spectrum. Conclusion Dichotomous endpoints for Shigella CHIM fail to fully account for disease variability. An ordinal disease score characterizing the breadth of disease severity may enable a better characterization of shigellosis and can decrease sample size requirements. Furthermore, the disease severity score may be a useful tool for portfolio management by enabling prioritization across vaccine candidates with comparable efficacy estimates using dichotomous endpoints. PMID:29590182

[Homeostasis and Disorder of Musculoskeletal System.Diagnosis and Treatment of Congenital Musculoskeletal Diseases.

PubMed

Michigami, Toshimi

Congenital skeletal dysplasias have been considered to be fundamentally untreatable diseases. However, molecular diagnosis by genetic testing has become more prevalent, and efforts are being made to develop novel therapies based on the pathogenesis. As treatments for osteogenesis imperfecta, in addition to anti-resorptive agents, neutralizing antibodies against sclerostin and transforming growth factor(TGF)-β and chemical chaperones can be beneficial. Enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has been recently developed to treat hypophosphatasia and has much improved the prognosis of the patients affected with severe forms of the disease. To treat the severe short stature in achondroplasia, drugs targeting the fibroblast growth factor receptor 3(FGFR3)-mediated signal are in development for clinical use.

TLR9 deficiency breaks tolerance to RNA-associated antigens and upregulates TLR7 protein in Sle1 mice.

PubMed

Celhar, Teja; Yasuga, Hiroko; Lee, Hui-Yin; Zharkova, Olga; Tripathi, Shubhita; Thornhill, Susannah I; Lu, Hao K; Au, Bijin; Lim, Lina H K; Thamboo, Thomas P; Akira, Shizuo; Wakeland, Edward K; Connolly, John E; Fairhurst, Anna-Marie

2018-04-24

Toll-like receptors (TLRs) 7 and 9 are important innate signaling molecules with opposing roles in the development and progression of Systemic Lupus Erythematosus (SLE). While multiple studies support a dependency on TLR7 for disease development, genetic ablation of TLR9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. The present study was designed to examine the suppressive role of TLR9 in the development of severe lupus. We crossed Sle1 lupus-prone mice with TLR9-deficient mice to generate Sle1TLR9 -/- . These mice were aged and evaluated for severe autoimmunity by assessing splenomegaly, GN, immune cell populations, autoantibody and total immunoglobulin profiles, kidney dendritic cell (DC) function and TLR7 protein expression. Young mice were used for functional B cell studies, immunoglobulin profiling and TLR7 expression. Sle1TLR9 -/- mice developed severe disease similar to TLR9-deficient MRL and Nba2 models. Sle1TLR9 -/- B cells produced more class-switched antibodies and the autoantibody repertoire was skewed towards RNA-containing antigens. GN in these mice was associated with DC infiltration and purified Sle1TLR9 -/- renal DCs were more efficient at TLR7-dependent antigen presentation and expressed higher levels of TLR7 protein. Importantly, this increase in TLR7 expression occurred prior to disease development, indicating a role in the initiation stages of tissue destruction. The increase in TLR7-reactive immune complexes (IC) and the concomitant enhanced expression of their receptor, promotes inflammation and disease in Sle1TLR9 -/- mice. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Forecast and virtual weather driven plant disease risk modeling system

USDA-ARS?s Scientific Manuscript database

We describe a system in use and development that leverages public weather station data, several spatialized weather forecast types, leaf wetness estimation, generic plant disease models, and online statistical evaluation. Convergent technological developments in all these areas allow, with funding f...

Genetic Expression in Cystic Fibrosis Related Bone Disease. An Observational, Transversal, Cross-Sectional Study.

PubMed

Ciuca, Ioana M; Pop, Liviu L; Rogobete, Alexandru F; Onet, Dan I; Guta-Almajan, Bogdan; Popa, Zoran; Horhat, Florin G

2016-09-01

Cystic fibrosis (CF) is the most frequent monogenic genetic disease with autosomal recessive transmission and characterized by important clinical polymorphism and significant lethal prospective. CF related bone disease occurs frequently in adults with CF. Childhood is the period of bone formation, and therefore, children are more susceptible to low bone density. Several factors like pancreatic insufficiency, hormone imbalance, and physical inactivity contribute to CF bone disease development. Revealing this would be important for prophylactic treatment against bone disease occurrence. The study was observational, transversal, with a cross-sectional design. The study included 68 children with cystic fibrosis, genotyped and monitored in the National CF Centre. At the annual assessment, besides clinical examination, biochemical evaluation for pancreatic insufficiency, and diabetes, they were evaluated for bone mineral density using dual energy X-ray absorptiometry (DXA). Twenty-six patients, aged over 10 years were diagnosed with CF bone disease, without significant gender gap. Bone disease was frequent in patients aged over 10 years with exocrine pancreatic insufficiency, carriers of severe mutations, and CF liver disease. CF carriers of a severe genotype which associates pancreatic insufficiency and CF liver disease, are more likely predisposed to low bone mineral density. Further studies should discover other significant influences in order to prevent the development of CF bone disease and an improved quality of life in cystic fibrosis children.

Iodine-131 induced hepatotoxicity in previously healthy patients with Grave's disease.

PubMed

Jhummon, Navina Priya; Tohooloo, Bhavna; Qu, Shen

2013-01-01

To describe the association of the rare and serious complication of liver toxicity in previously healthy Grave's disease (GD) patients after the treatment with radioactive iodine (131)I (RAI). We report the clinical, laboratory and pathologic findings of 2 cases of severe liver toxicity associated with the treatment with RAI in previously healthy patients with GD. Clinical examination and laboratory investigations excluded viral hepatitis, autoimmune hepatitis, granulomatous disease, primary biliary disease, extrahepatic biliary obstruction, and heart failure. Case 1: A previously healthy 52-years old man reportedly having a typical GD but following RAI treatment, concomitantly developed severe liver toxicity that required 1 week of treatment in hospital. Case 2: A previously healthy 34-years old woman is reported as having a typical GD but developed jaundice following RAI treatment that required several weeks of in hospital treatment in the hepato-biliary department. In both cases, the liver dysfunction resolved after intensive treatment with hepato-protective agents. In this report the therapeutic considerations as well as the pathogenetic possibilities are reviewed. To the best of our knowledge, this is the first description of the association observed, which is rare but may be severe and should be considered in any case of thyrotoxicosis where a liver dysfunction develops after the treatment with radioactive iodine (131)I.

Periodontal diseases of children and adolescents.

PubMed

Children and adolescents are subject to several periodontal diseases. Although there is a much lower prevalence of destructive periodontal diseases in children than in adults, children can develop severe forms of periodontitis. In some cases, this destructive disease is a manifestation of a known underlying systemic disease. In other young patients, the underlying cause for increased susceptibility and early onset of disease is unknown. These diseases are often familial, suggesting a genetic predisposition for aggressive disease. Current modalities for managing periodontal diseases of children and adolescents may include antibiotic therapy in combination with non-surgical and/or surgical therapy. Since early diagnosis ensures the greatest chance for successful treatment, it is important that children receive a periodontal examination as part of their routine dental visits.

Position paper: periodontal diseases of children and adolescents.

PubMed

Califano, Joseph V

2003-11-01

Children and adolescents are subject to several periodontal diseases. Although there is a much lower prevalence of destructive periodontal diseases in children than in adults, children can develop severe forms of periodontitis. In some cases, this destructive disease is a manifestation of a known underlying systemic disease. In other young patients, the underlying cause for increased susceptibility and early onset of disease is unknown. These diseases are often familial, suggesting a genetic predisposition for aggressive disease. Current modalities for managing periodontal diseases of children and adolescents may include antibiotic therapy in combination with non-surgical and/or surgical therapy. Since early diagnosis ensures the greatest chance for successful treatment, it is important that children receive a periodontal examination as part of their routine dental visits.

[Role of serum leptin in the severity of coronary artery disease in patients with stable angina].

PubMed

Jerez-Valero, Miguel; Meliveo-García, Ana; Jordán-Martínez, Laura; Carrasco-Chinchilla, Fernando; Moreno-Santos, Inmaculada; Ordóñez, Antonio; Sánchez-Fernández, Pedro L; Vázquez, Rafael; Hernández-García, José M; Gómez-Doblas, Juan J; Pérez-Belmonte, Luis M; de Teresa-Galván, Eduardo; Jiménez-Navarro, Manuel

2016-07-01

Leptin is a plasmatic peptide hormone that has been related to cardiovascular homeostasis and atherosclerosis but much is still unknown about its relationship with coronary artery disease. The aim of this study was to evaluate the value of serum leptin in patients with stable angina and its relationship with the severity of coronary disease. 204 patients, 152 with stable angina (coronary artery disease group) and 52 without coronary disease excluded by cardiac computerized tomography (control group) were included. The coronary artery disease group was divided into 2 subgroups according to severity of coronary disease (single or multivessel disease, 46 and 106 patients, respectively). Serum leptin levels were determined by Enzyme-Linked InmunoSorbent Assay. Leptin levels were significantly higher in patients with multivessel disease and were independently associated with a greater severity of coronary artery disease when compared with controls (OR 1.14; 95%CI: 1.03-1.27; p=0.014) and with patients with single vessel disease (OR 1.12; 95%CI: 1.01-1.25; p=0.036). Serum leptin was tested as a diagnostic marker of multivessel disease with an area under the curve obtained from Receiver Operating Characteristics of 0.6764 (95%CI 0.5765-0.7657). Serum leptin levels were associated in patients with stable angina with the severity of coronary artery disease, suggesting its value in the development of coronary disease and as a future therapeutic target. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

The complexities of malaria disease manifestations with a focus on asymptomatic malaria

PubMed Central

2012-01-01

Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted. PMID:22289302

Fatigue and multidimensional disease severity in chronic obstructive pulmonary disease.

PubMed

Inal-Ince, Deniz; Savci, Sema; Saglam, Melda; Calik, Ebru; Arikan, Hulya; Bosnak-Guclu, Meral; Vardar-Yagli, Naciye; Coplu, Lutfi

2010-06-30

Fatigue is associated with longitudinal ratings of health in patients with chronic obstructive pulmonary disease (COPD). Although the degree of airflow obstruction is often used to grade disease severity in patients with COPD, multidimensional grading systems have recently been developed. The aim of this study was to investigate the relationship between perceived and actual fatigue level and multidimensional disease severity in patients with COPD. Twenty-two patients with COPD (aged 52-74 years) took part in the study. Multidimensional disease severity was measured using the SAFE and BODE indices. Perceived fatigue was assessed using the Fatigue Severity Scale (FSS) and the Fatigue Impact Scale (FIS). Peripheral muscle endurance was evaluated using the number of sit-ups, squats, and modified push-ups that each patient could do. Thirteen patients (59%) had severe fatigue, and their St George's Respiratory Questionnaire scores were significantly higher (p < 0.05). The SAFE index score was significantly correlated with the number of sit-ups, number of squats, FSS score and FIS score (p < 0.05). The BODE index was significantly associated with the numbers of sit-ups, squats and modified push-ups, and with the FSS and FIS scores (p < 0.05). Peripheral muscle endurance and fatigue perception in patients with COPD was related to multidimensional disease severity measured with both the SAFE and BODE indices. Improvements in perceived and actual fatigue levels may positively affect multidimensional disease severity and health status in COPD patients. Further research is needed to investigate the effects of fatigue perception and exercise training on patients with different stages of multidimensional COPD severity.

[Clinical and neurophysiological aspects of severe forms of autism in children].

PubMed

Simashkova, N V; Iakupova, L P; Bashina, V M

2006-01-01

The aim of the study was to elucidate fundamentals for the phenomenon of universality of childhood autism by comparison of clinical and neurophysiological features of its severest forms--children endogenous autism (CEA) and Rett's syndrome (RS). Each group included 20 patients. Both groups were similar by age-at-disease-onset, clinical appearances during the disease course and dynamics of psychopathological syndromes. The theta-rhythm is common for CEA and RS at the disease stage with marked signs of disease acuity, autism, regress and, therefore, may be regarded as a marker of severity and development delay. The universality of autism phenomenon in its severe forms was confirmed both at the clinical and neurophysiological levels.

Thymus activity measured by T-cell receptor excision circles in patients with different severities of respiratory syncytial virus infection.

PubMed

Gul, Kiran Aftab; Sonerud, Tonje; Fjærli, Hans O; Nakstad, Britt; Abrahamsen, Tore Gunnar; Inchley, Christopher S

2017-01-05

Respiratory syncytial virus (RSV) infection is an important cause of hospitalization in previously healthy infants. Immunological mechanisms predisposing infants to severe disease are poorly understood. Early biomarkers for disease severity may assist clinical decisions. We investigated T-cell receptor excision circles (TREC), episomal DNA made during thymic T-cell receptor rearrangement, and a marker for thymus activity, both during disease and in neonatal screening cards as a risk factor for RSV disease severity. One hundred thirteen patients hospitalized with RSV infection <12 months of age, grouped by disease severity, were available for this investigation, in which we conducted both a prospective and a case-control study. The prospective study included 47 RSV positive infants (mild n = 13, moderate n = 10, severe n = 24). TREC counts were determined by PCR of DNA extracted from EDTA-blood collected on hospitalization, and corrected for lymphocytes using ANCOVA. The case-control study included 85 newborns who later in infancy became RSV positive (mild n = 32, moderate n = 24, severe n = 29) and 47 newborns who never developed RSV disease as healthy controls included from health centres in the same catchment area. TRECs were measured using DNA extracted from dry blood spots from stored neonatal screening cards, followed by PCR. Student's T-test compared patients with controls, ANOVA compared disease severity groups. During RSV infection patients in the severe disease group had significantly lower (p = 0.017) TREC/200 μL blood compared to the other two disease groups, after correction for lymphocyte count. Newborn TREC levels, were significantly higher in RSV patients compared to controls (p < 0.0001). No significant differences in TREC copies at birth were found between disease severities. During acute RSV infection a lower number of TREC is found in the severe disease group. TREC has potential as an immunological marker for severe RSV infection. Higher neonatal TREC counts indicate that infants later presenting with severe RSV do not have reduced thymic activity at birth and probably no congenital T-cell defect.

A Sickle Cell Disease Patient with Severe Tricuspid Regurgitation and Early Developed Pulmonary Hypertension.

PubMed

Vaidya, Gaurang; Sarwar, Muhammad; Sun, Zongxia; Wei, Tiemin; Liu, Kan

2015-01-01

Pulmonary hypertension (PH) worsens the mortality of the patients with sickle cell disease (SCD). The exact mechanism of PH development/progression in SCD, including the role of tricuspid regurgitation (TR), remains unclear. We herein report an unusual SCD case, complicated by chronic thromboembolic disorder, who developed severe TR and an accelerated progression of PH. Tricuspid valve surgery significantly ameliorated the patient's symptoms and reduced hospital readmission. The early detection and management of the reversible disorder accelerating the PH development in SCD patients may alter the clinical course, improve the quality of life, and potentially affect the long-term outcome.

"Nanoantibiotics": a new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era.

PubMed

Huh, Ae Jung; Kwon, Young Jik

2011-12-10

Despite the fact that we live in an era of advanced and innovative technologies for elucidating underlying mechanisms of diseases and molecularly designing new drugs, infectious diseases continue to be one of the greatest health challenges worldwide. The main drawbacks for conventional antimicrobial agents are the development of multiple drug resistance and adverse side effects. Drug resistance enforces high dose administration of antibiotics, often generating intolerable toxicity, development of new antibiotics, and requests for significant economic, labor, and time investments. Recently, nontraditional antibiotic agents have been of tremendous interest in overcoming resistance that is developed by several pathogenic microorganisms against most of the commonly used antibiotics. Especially, several classes of antimicrobial nanoparticles (NPs) and nanosized carriers for antibiotics delivery have proven their effectiveness for treating infectious diseases, including antibiotics resistant ones, in vitro as well as in animal models. This review summarizes emerging efforts in combating against infectious diseases, particularly using antimicrobial NPs and antibiotics delivery systems as new tools to tackle the current challenges in treating infectious diseases. Copyright © 2011 Elsevier B.V. All rights reserved.

How glyphosate affects plant disease development: it is more than enhanced susceptibility.

PubMed

Hammerschmidt, Ray

2018-05-01

Glyphosate has been shown to affect the development of plant disease in several ways. Plants utilize phenolic and other shikimic acid pathway-derived compounds as part of their defense against pathogens, and glyphosate inhibits the biosynthesis of these compounds via its mode of action. Several studies have shown a correlation between enhanced disease and suppression of phenolic compound production after glyphosate. Glyphosate-resistant crop plants have also been studied for changes in resistance as a result of carrying the glyphosate resistance trait. The evidence indicates that neither the resistance trait nor application of glyphosate to glyphosate-resistant plants increases susceptibility to disease. The only exceptions to this are cases where glyphosate has been shown to reduce rust diseases on glyphosate-resistant crops, supporting a fungicidal role for this chemical. Finally, glyphosate treatment of weeds or volunteer crops can cause a temporary increase in soil-borne pathogens that may result in disease development if crops are planted too soon after glyphosate application. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Newcastle Disease: Progress and gaps in the development of vaccines and diagnostic tools

USDA-ARS?s Scientific Manuscript database

Newcastle disease (ND) is a contagious disease of birds that can have severe economic consequences for any poultry producer, including a serious impact on the international trade of poultry and eggs. Newcastle disease virus (NDV) isolates are also called avian paramyxovirus serotype-1 isolates, but ...

Dual Beam Doppler Optical Coherence Angiography

NASA Astrophysics Data System (ADS)

Yasuno, Yoshiaki; Makita, Shuichi; Jaillon, Franck

The ocular vasculature and circulation play a crucial role in the development of several eye diseases including glaucoma [1], diabetic retinopathy [2], and exudative macular diseases [3]. Modalities that are capable of investigating the ocular vasculature and circulation are important for both understanding the mechanisms of the diseases and diagnosing these diseases.

77 FR 58849 - Prescription Drug User Fee Act Patient-Focused Drug Development; Public Meeting and Request for...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-24

... the impact of the disease on patients, the spectrum of severity for those who have the disease, the... glomerular diseases. Narcolepsy. Huntington's Disease. Depression. Autism. Peripheral neuropathy.... Cancer and depression. Clotting disorders (e.g., hemophilia A (factor VIII deficiency) and von Willebrand...

Virus like particle-based vaccines against emerging infectious disease viruses.

PubMed

Liu, Jinliang; Dai, Shiyu; Wang, Manli; Hu, Zhihong; Wang, Hualin; Deng, Fei

2016-08-01

Emerging infectious diseases are major threats to human health. Most severe viral disease outbreaks occur in developing regions where health conditions are poor. With increased international travel and business, the possibility of eventually transmitting infectious viruses between different countries is increasing. The most effective approach in preventing viral diseases is vaccination. However, vaccines are not currently available for numerous viral diseases. Virus-like particles (VLPs) are engineered vaccine candidates that have been studied for decades. VLPs are constructed by viral protein expression in various expression systems that promote the selfassembly of proteins into structures resembling virus particles. VLPs have antigenicity similar to that of the native virus, but are non-infectious as they lack key viral genetic material. VLP vaccines have attracted considerable research interest because they offer several advantages over traditional vaccines. Studies have shown that VLP vaccines can stimulate both humoral and cellular immune responses, which may offer effective antiviral protection. Here we review recent developments with VLP-based vaccines for several highly virulent emerging or re-emerging infectious diseases. The infectious agents discussed include RNA viruses from different virus families, such as the Arenaviridae, Bunyaviridae, Caliciviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Togaviridae families.

Underlying Rheumatic Disease: An Important Determinant of Outcome in Tricuspid Valve Repair.

PubMed

Munasur, Mandhir; Naidoo, Datshana

2016-03-01

Tricuspid regurgitation (TR) accompanying severe left-sided valve disease occurs on a functional basis, secondary to pulmonary hypertension and tricuspid annular dilatation. In the context of endemic left-sided rheumatic heart disease, non-recognition of organic disease of the tricuspid valve may adversely influence surgical decision-making, resulting in suboptimal outcomes. A retrospective analysis of the perioperative and follow up data of 30 patients who underwent tricuspid valve surgery with concomitant left-sided valve replacement was undertaken. Preoperative evaluation by two-dimensional transthoracic echocardiography was routinely employed. Outcomes were analyzed by evaluation of the perioperative and two-year follow up clinical and echocardiographic data. All subjects had severe TR. Mixed tricuspid valve disease occurred in 11 subjects (36.7%). Tricuspid valve repair was performed in 28 patients. A significant improvement (p <0.05) in the following parameters occurred at six weeks postoperatively: NYHA functional class, tricuspid annular diameter, systolic pulmonary artery pressure, severity of TR and tricuspid transvalvular gradient. Severe residual postoperative TR occurred in 26.7% of patients, but there were no identifiable predictors for this phenomenon. Severe residual postoperative TR was not associated with major adverse cardiovascular events. Preoperative (p = 0.013) and postoperative (p<0.002) pulmonary hypertension were associated with the development of major adverse cardiovascular events. The technique of tricuspid valve repair was not associated with the occurrence of major adverse cardiovascular events, nor with the development of severe residual postoperative TR. A satisfactory outcome was observed in only 40% of the study population. The coexistence of mixed tricuspid valve disease in rheumatic heart disease patients undergoing left-sided valve surgery is an important determinant of outcome in tricuspid valve repair. The persistence of severe TR contributes to poor long-term outcomes, and its incidence may be lowered by the adoption of appropriate perioperative imaging techniques to delineate valve morphology.

Factors Associated with Myelosuppression Related to Low-Dose Methotrexate Therapy for Inflammatory Rheumatic Diseases

PubMed Central

Mori, Shunsuke; Hidaka, Michihiro; Kawakita, Toshiro; Hidaka, Toshihiko; Tsuda, Hiroyuki; Yoshitama, Tamami; Migita, Kiyoshi; Ueki, Yukitaka

2016-01-01

Objective Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity. Methods We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups. Results Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively). Conclusions Myelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia. PMID:27128679

Prediction of Disease Case Severity Level To Determine INA CBGs Rate

NASA Astrophysics Data System (ADS)

Puspitorini, Sukma; Kusumadewi, Sri; Rosita, Linda

2017-03-01

Indonesian Case-Based Groups (INA CBGs) is case-mix payment system using software grouper application. INA CBGs consisting of four digits code where the last digits indicating the severity level of disease cases. Severity level influence by secondary diagnosis (complications and co-morbidity) related to resource intensity level. It is medical resources used to treat a hospitalized patient. Objectives of this research is developing decision support system to predict severity level of disease cases and illustrate INA CBGs rate by using data mining decision tree classification model. Primary diagnosis (DU), first secondary diagnosis (DS 1), and second secondary diagnosis (DS 2) are attributes that used as input of severity level. The training process using C4.5 algorithm and the rules will represent in the IF-THEN form. Credibility of the system analyzed through testing process and confusion matrix present the results. Outcome of this research shows that first secondary diagnosis influence significant to form severity level predicting rules from new disease cases and INA CBGs rate illustration.

Vaccines and immunization strategies for dengue prevention

PubMed Central

Liu, Yang; Liu, Jianying; Cheng, Gong

2016-01-01

Dengue is currently the most significant arboviral disease afflicting tropical and sub-tropical countries worldwide. Dengue vaccines, such as the multivalent attenuated, chimeric, DNA and inactivated vaccines, have been developed to prevent dengue infection in humans, and they function predominantly by stimulating immune responses against the dengue virus (DENV) envelope (E) and nonstructural-1 proteins (NS1). Of these vaccines, a live attenuated chimeric tetravalent DENV vaccine developed by Sanofi Pasteur has been licensed in several countries. However, this vaccine renders only partial protection against the DENV2 infection and is associated with an unexplained increased incidence of hospitalization for severe dengue disease among children younger than nine years old. In addition to the virus-based vaccines, several mosquito-based dengue immunization strategies have been developed to interrupt the vector competence and effectively reduce the number of infected mosquito vectors, thus controlling the transmission of DENV in nature. Here we summarize the recent progress in the development of dengue vaccines and novel immunization strategies and propose some prospective vaccine strategies for disease prevention in the future. PMID:27436365

Recent advances in prostate development and links to prostatic diseases

PubMed Central

Powers, Ginny L.

2013-01-01

The prostate is a branched ductal-acinar gland that is part of the male reproductive tract. Prostate development depends upon the integration of steroid hormone signals, paracrine interactions between the stromal and epithelial tissue layers, and the actions of cell autonomous factors. Several genes and signalling pathways are known to be required for one or more steps of prostate development including epithelial budding, duct elongation, branching morphogenesis, and/or cellular differentiation. Recent progress in the field of prostate development has included the application of genome-wide technologies including serial analysis of gene expression (SAGE), expression profiling microarrays, and other large scale approaches to identify new genes and pathways that are essential for prostate development. The aggregation of experimental results into online databases by organized multi-lab projects including the Genitourinary Developmental Molecular Atlas Project (GUDMAP) has also accelerated the understanding of molecular pathways that function during prostate development and identified links between prostate anatomy and molecular signaling. Rapid progress has also recently been made in understanding the nature and role of candidate stem cells in the developing and adult prostate. This has included the identification of putative prostate stem cell markers, lineage tracing, and organ reconstitution studies. However, several issues regarding their origin, precise nature, and possible role(s) in disease remain unresolved. Nevertheless, several links between prostatic developmental mechanisms and the pathogenesis of prostatic diseases including benign prostatic hyperplasia and prostate cancer have led to recent progress on targeting developmental pathways as therapeutic strategies for these diseases. PMID:23335485

Effects of sunlight exposure on grapevine powdery mildew development.

PubMed

Austin, Craig N; Wilcox, Wayne F

2012-09-01

Natural and artificially induced shade increased grapevine powdery mildew (Erysiphe necator) severity in the vineyard, with foliar disease severity 49 to 75% higher relative to leaves in full sun, depending on the level of natural shading experienced and the individual experiment. Cluster disease severities increased by 20 to 40% relative to those on check vines when ultraviolet (UV) radiation was filtered from sunlight reaching vines in artificial shading experiments. Surface temperatures of leaves in full sunlight averaged 5 to 8°C higher than those in natural shade, and in one experiment, filtering 80% of all wavelengths of solar radiation, including longer wavelengths responsible for heating irradiated tissues, increased disease more than filtering UV alone. In controlled environment experiments, UV-B radiation reduced germination of E. necator conidia and inhibited both colony establishment (hyphal formation and elongation) and maturity (latent period). Inhibitory effects of UV-B radiation were significantly greater at 30°C than at 20 or 25°C. Thus, sunlight appears to inhibit powdery mildew development through at least two mechanisms, i.e., (i) UV radiation's damaging effects on exposed conidia and thalli of the pathogen; and (ii) elevating temperatures of irradiated tissues to a level supraoptimal or inhibitory for pathogen development. Furthermore, these effects are synergistic at temperatures near the upper threshold for disease development.

Risk factors and pathogenic significance of severe sepsis and septic shock in 2286 patients with gram-negative bacteremia.

PubMed

Kang, Cheol-In; Song, Jae-Hoon; Chung, Doo Ryeon; Peck, Kyong Ran; Ko, Kwan Soo; Yeom, Joon-Sup; Ki, Hyun Kyun; Son, Jun Seong; Lee, Seung Soon; Kim, Yeon-Sook; Jung, Sook-In; Kim, Shin-Woo; Chang, Hyun-Ha; Ryu, Seong Yeol; Kwon, Ki Tae; Lee, Hyuck; Moon, Chisook

2011-01-01

The aim of this study was to identify risk factors for development of severe sepsis or septic shock and to evaluate the clinical impact of severe sepsis on outcome in patients with gram-negative bacteremia (GNB). From the database of a nationwide surveillance for bacteremia, patients with GNB were analyzed. Data of patients with severe sepsis or septic shock were compared with those of patient with sepsis. Of 2286 patients with GNB, 506 (22.1%) fulfilled the criteria of severe sepsis or septic shock. Factors associated with severe sepsis or septic shock in the multivariate analysis included renal disease, indwelling urinary catheter, hematologic malignancy, and neutropenia. The 30-day mortality of patients with severe sepsis or septic shock was significantly higher than that of patients with sepsis (39.5% [172/435] vs. 7.4% [86/1170]; P < 0.001). Multivariable analysis revealed that solid tumor, liver disease, pulmonary disease, pneumonia, and pathogens other than Escherichia coli, which were risk factors of development of severe sepsis or septic shock, were also found to be strong predictors of mortality. Severe sepsis or septic shock was a significant factor associated with mortality (OR, 3.34; 95% CI, 2.35-4.74), after adjustment for other variables predicting poor prognosis. Severe sepsis or septic shock was a common finding in patients with GNB, predicting a higher mortality rate. Renal disease and indwelling urinary catheter were the most important risk factors significantly associated with severe sepsis or septic shock among patients with GNB. Copyright © 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

The global burden of oral diseases and risks to oral health.

PubMed Central

Petersen, Poul Erik; Bourgeois, Denis; Ogawa, Hiroshi; Estupinan-Day, Saskia; Ndiaye, Charlotte

2005-01-01

This paper outlines the burden of oral diseases worldwide and describes the influence of major sociobehavioural risk factors in oral health. Despite great improvements in the oral health of populations in several countries, global problems still persist. The burden of oral disease is particularly high for the disadvantaged and poor population groups in both developing and developed countries. Oral diseases such as dental caries, periodontal disease, tooth loss, oral mucosal lesions and oropharyngeal cancers, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-related oral disease and orodental trauma are major public health problems worldwide and poor oral health has a profound effect on general health and quality of life. The diversity in oral disease patterns and development trends across countries and regions reflects distinct risk profiles and the establishment of preventive oral health care programmes. The important role of sociobehavioural and environmental factors in oral health and disease has been shown in a large number of socioepidemiological surveys. In addition to poor living conditions, the major risk factors relate to unhealthy lifestyles (i.e. poor diet, nutrition and oral hygiene and use of tobacco and alcohol), and limited availability and accessibility of oral health services. Several oral diseases are linked to noncommunicable chronic diseases primarily because of common risk factors. Moreover, general diseases often have oral manifestations (e.g. diabetes or HIV/AIDS). Worldwide strengthening of public health programmes through the implementation of effective measures for the prevention of oral disease and promotion of oral health is urgently needed. The challenges of improving oral health are particularly great in developing countries. PMID:16211157

Gut microbiota and liver diseases

PubMed Central

Minemura, Masami; Shimizu, Yukihiro

2015-01-01

Several studies revealed that gut microbiota are associated with various human diseases, e.g., metabolic diseases, allergies, gastroenterological diseases, and liver diseases. The liver can be greatly affected by changes in gut microbiota due to the entry of gut bacteria or their metabolites into the liver through the portal vein, and the liver-gut axis is important to understand the pathophysiology of several liver diseases, especially non-alcoholic fatty liver disease and hepatic encephalopathy. Moreover, gut microbiota play a significant role in the development of alcoholic liver disease and hepatocarcinogenesis. Based on these previous findings, trials using probiotics have been performed for the prevention or treatment of liver diseases. In this review, we summarize the current understanding of the changes in gut microbiota associated with various liver diseases, and we describe the therapeutic trials of probiotics for those diseases. PMID:25684933

Cystic fibrosis modifier genes.

PubMed Central

Davies, Jane; Alton, Eric; Griesenbach, Uta

2005-01-01

Since the recognition that CFTR genotype was not a good predictor of pulmonary disease severity in CF, several candidate modifier genes have been identified. It is unlikely that a single modifier gene will be found, but more probable that several haplotypes in combination may contribute, which in itself presents a major methodological challenge. The aims of such studies are to increase our understanding of disease pathogenesis, to aid prognosis and ultimately to lead to the development of novel treatments. PMID:16025767

A conceptual framework for evaluating impairments in myasthenia gravis.

PubMed

Barnett, Carolina; Bril, Vera; Kapral, Moira; Kulkarni, Abhaya; Davis, Aileen M

2014-01-01

Myasthenia gravis is characterized by weakness and fatigability of different muscle groups, including ocular, bulbar and the limbs. Therefore, a measure of disease severity at the impairment level in myasthenia needs to reflect all the relevant impairments, as well as their variations with activity and fatigue. We conducted a qualitative study of patients with myasthenia, to explore their experiences and related impairments, aimed at developing a conceptual framework of disease severity at the impairment level in myasthenia gravis. Twenty patients representing the spectrum of disease participated in semi-structured interviews. Interviews were recorded and the transcripts were analyzed by content analysis using an inductive approach with line-by-line open coding. Themes were generated from these codes. Two main themes were identified: the severity of the impairments and fatigability (i.e., triggering or worsening of an impairment with activity). The impairments were further classified within body regions (ocular, bulbar and axial/limbs). Fatigability was described as a phenomenon affecting the whole body but also affecting specific impairments, and was associated with fluctuation of the symptoms. Patients were concerned that clinical examination at a single point in time might not reflect their true clinical state due to fatigability and fluctuations in severity. This conceptual framework reflects the relevance of both severity and fatigability in understanding impairment-based disease severity in myasthenia. This framework could inform the development of impairment measures in myasthenia gravis.

Periodontal therapy.

PubMed

Niemiec, Brook A

2008-05-01

Periodontal disease is the most common disease in small animal patients. It not only creates severe localized infection, but it has been linked to numerous severe systemic maladies. Proper therapy of this disease process results in a significant increase in the overall health of the patient. The treatment of periodontal disease is currently evolving due to the acceptance of the specific plaque hypothesis of periodontal disease. These findings have led to the development of the "one-stage full-mouth disinfection" treatment as well as a vaccine against these organisms. However, the cornerstone of therapy is still meticulous plaque control. This control is achieved via a combination of regular dental prophylaxis and home care. With progressive disease, advanced periodontal surgery or extraction becomes necessary.

Injection of celiac disease patient sera or immunoglobulins to mice reproduces a condition mimicking early developing celiac disease.

PubMed

Kalliokoski, Suvi; Caja, Sergio; Frias, Rafael; Laurila, Kaija; Koskinen, Outi; Niemelä, Onni; Mäki, Markku; Kaukinen, Katri; Korponay-Szabó, Ilma R; Lindfors, Katri

2015-01-01

Typical features of celiac disease are small-bowel villus atrophy, crypt hyperplasia, and inflammation which develop gradually concomitant with ingestion of gluten. In addition, patients have anti-transglutaminase 2 (TG2) autoantibodies in their serum and tissues. The aim of this study was to establish whether celiac disease can be passively transferred to mice by serum or immunoglobulins. Serum aliquots or purified immunoglobulins (Ig) were intraperitoneally injected into Hsd:Athymic Nude-Foxn1nu mice for 8 or 27 days. As mice do not have proper IgA transport from peritoneum to blood, sera with a high content of IgG class anti-TG2 antibodies from untreated IgA-deficient celiac patients were used. Mouse sera were tested for celiac disease-specific autoantibodies, and several tissues were analyzed for autoantibody deposits targeted to TG2. Morphological assessment was made of the murine small intestinal mucosa. Injection of celiac disease patient sera or total IgG led to a significant delay in weight gain and mild diarrhea in a subset of mice. The mice injected with celiac patient sera or IgG had significantly decreased villus height crypt depth (Vh/CrD) ratios and celiac disease-specific autoantibody deposits targeted to TG2 in several tissues, including the small intestine. None of these features were observed in control mice. We conclude that administration of IgA-deficient celiac disease patient serum or total IgG induces both deterioration of the intestinal mucosa and clinical features of celiac disease in mice. The experimentally induced condition in the mice injected with patient serum or IgG resembles early developing celiac disease in humans. Celiac disease patient sera or total IgG was injected into athymic mice. A significant delay in weight gain and mild diarrhea was observed. Mice evinced significantly decreased villus height crypt depth ratios. Celiac disease-specific autoantibody deposits were present in several tissues. The condition in mice resembles early stage celiac disease in humans.

The DALY, context and the determinants of the severity of disease: an exploratory comparison of paraplegia in Australia and Cameroon.

PubMed

Allotey, Pascale; Reidpath, Daniel; Kouamé, Aka; Cummins, Robert

2003-09-01

This paper summarises the findings of an empirical investigation of some of the technical and social assumptions on which the disability adjusted life year (DALY) is based. The objectives of the study were to examine the notion that the burden of disease is broadly similar without regard to country, environment, gender or socio-economic status and to develop detailed descriptions of the experiences of the burden of disease as they related to these contextual factors. The study was a multi-factorial exploratory study employing qualitative and quantitative techniques to obtain data on the effects of country (development), environment (urban versus rural), gender and socio-economic status on people with paraplegia. The data provided an extensive and detailed compilation of context rich descriptions of living with paraplegia. Striking features of the data were the differences between countries with respect to the impact of the health conditions on functioning and highlight a context in which paraplegia of like clinical severity can be fatal in one environment and not in another. While there has been some focus on the control of social determinants of disease, there has been little work on the social determinants of the severity of disease. The underlying assumptions of the DALY, which ignore context in the assessment of the burden of disease, risk exacerbating inequalities by undervaluing the burden of disease in less-developed countries. There is a need to continue to subject the development of indicators to rigorous debate to determine a balance between the assumption of a global "average social milieu" and the treatment of each individual as belonging to their own context in the assessment of population health in order for indicators to be meaningful cross-culturally.

Research on Hygiene Based on Fieldwork and Experimental Studies.

PubMed

Yajima, Ichiro

2017-01-01

Several experimental studies on hygiene have recently been performed and fieldwork studies are also important and essential tools. However, the implementation of experimental studies is insufficient compared with that of fieldwork studies on hygiene. Here, we show our well-balanced implementation of both fieldwork and experimental studies of toxic-element-mediated diseases including skin cancer and hearing loss. Since the pollution of drinking well water by toxic elements induces various diseases including skin cancer, we performed both fieldwork and experimental studies to determine the levels of toxic elements and the mechanisms behind the development of toxic-element-related diseases and to develop a novel remediation system. Our fieldwork studies in several countries including Bangladesh, Vietnam and Malaysia demonstrated that drinking well water was polluted with high concentrations of several toxic elements including arsenic, barium, iron and manganese. Our experimental studies using the data from our fieldwork studies demonstrated that these toxic elements caused skin cancer and hearing loss. Further experimental studies resulted in the development of a novel remediation system that adsorbs toxic elements from polluted drinking water. A well-balanced implementation of both fieldwork and experimental studies is important for the prediction, prevention and therapy of toxic-element-mediated diseases.

Influence of the Circadian System on Disease Severity

PubMed Central

Litinski, Mikhail; Scheer, Frank AJL; Shea, Steven A

2009-01-01

Synopsis The severity of many diseases varies across the day and night. For example, adverse cardiovascular incidents peak in the morning, asthma is often worse at night and temporal lobe epileptic seizures are most prevalent in the afternoon. These patterns may be due to the day/night rhythm in environment and behavior, and/or endogenous circadian rhythms in physiology. Furthermore, chronic misalignment between the endogenous circadian timing system and the behavioral cycles could be a cause of increased risk of diabetes, obesity, cardiovascular disease and certain cancers in shift workers. Here we describe the magnitude, relevance and potential biological basis of such daily changes in disease severity and of circadian/behavioral misalignment, and present how these insights may help in the development of appropriate chronotherapy. PMID:20161149

Development of a sheep challenge model for Rift Valley fever

USDA-ARS?s Scientific Manuscript database

Rift Valley fever (RVF) is a zoonotic disease that causes severe epizootic disease in ruminants, characterized by mass abortion and high mortality rates in younger animals. The development of a reliable challenge model is an important prerequisite for evaluation of existing and novel vaccines. A stu...

Retrospective Analysis of Long-Term Outcomes After Combat Injury: A Hidden Cost of War.

PubMed

Stewart, Ian J; Sosnov, Jonathan A; Howard, Jeffrey T; Orman, Jean A; Fang, Raymond; Morrow, Benjamin D; Zonies, David H; Bollinger, Mary; Tuman, Caroline; Freedman, Brett A; Chung, Kevin K

2015-12-01

During the conflicts in Iraq and Afghanistan, 52,087 service members have been wounded in combat. The long-term sequelae of these injuries have not been carefully examined. We sought to determine the relation between markers of injury severity and the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. Retrospective cohort study of critically injured US military personnel wounded in Iraq or Afghanistan from February 1, 2002 to February 1, 2011. Patients were then followed until January 18, 2013. Chronic disease outcomes were assessed by International Classification of Diseases, 9th edition codes and causes of death were confirmed by autopsy. From 6011 admissions, records were excluded because of missing data or if they were for an individual's second admission. Patients with a disease diagnosis of interest before the injury date were also excluded, yielding a cohort of 3846 subjects for analysis. After adjustment for other factors, each 5-point increment in the injury severity score was associated with a 6%, 13%, 13%, and 15% increase in incidence rates of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease, respectively. Acute kidney injury was associated with a 66% increase in rates of hypertension and nearly 5-fold increase in rates of chronic kidney disease. In Iraq and Afghanistan veterans, the severity of combat injury was associated with the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. © 2015 American Heart Association, Inc.

Minocycline-Induced Drug Hypersensitivity Syndrome Followed by Multiple Autoimmune Sequelae

PubMed Central

Brown, Rebecca J.; Rother, Kristina I.; Artman, Henry; Mercurio, Mary Gail; Wang, Roger; Looney, R. John; Cowen, Edward W.

2010-01-01

Background Drug hypersensitivity syndrome (DHS) is a severe, multisystem adverse drug reaction that may occur following the use of numerous medications, including anticonvulsants, sulfonamides, and minocycline hydrochloride. Long-term autoimmune sequelae of DHS have been reported, including hypothyroidism. Observations A 15-year-old female adolescent developed DHS 4 weeks after starting minocycline therapy for acne vulgaris. Seven weeks later she developed autoimmune hyperthyroidism (Graves disease), and 7 months after discontinuing minocycline therapy she developed autoimmune type 1 diabetes mellitus. In addition, she developed elevated titers of several markers of systemic autoimmune disease, including antinuclear, anti-Sjögren syndrome A, and anti-Smith antibodies. Conclusions Minocycline-associated DHS may be associated with multiple autoimmune sequelae, including thyroid disease, type 1 diabetes mellitus, and elevated markers of systemic autoimmunity. Long-term follow-up is needed in patients with DHS to determine the natural history of DHS-associated sequelae. PMID:19153345

Chorioamnionitis and chronic lung disease of prematurity: a path analysis of causality.

PubMed

Dessardo, Nada Sindičić; Mustać, Elvira; Dessardo, Sandro; Banac, Srđan; Peter, Branimir; Finderle, Aleksandar; Marić, Marinko; Haller, Herman

2012-02-01

Current evidence suggests that additional pathogenetic factors could play a role in the development of chronic lung disease of prematurity, other than mechanical ventilation and free radical injury. The introduction of the concept of "fetal inflammatory response syndrome" offers a new perspective on the pathogenesis of chronic lung disease of prematurity. New statistical approaches could be useful tools in evaluating causal relationships in the development of chronic morbidity in preterm infants. The aim of this study was to test a new statistical framework incorporating path analysis to evaluate causality between exposure to chorioamnionitis and fetal inflammatory response syndrome and the development of chronic lung disease of prematurity. We designed a prospective cohort study that included consecutively born premature infants less than 32 weeks of gestation whose placentas were collected for histological analysis. Histological chorioamnionitis, clinical data, and neonatal outcomes were related to chronic lung disease. Along with standard statistical methods, a path analysis was performed to test the relationship between histological chorioamnionitis, gestational age, mechanical ventilation, and development of chronic lung disease of prematurity. Among the newborns enrolled in the study, 69/189 (36%) had histological chorioamnionitis. Of those with histological chorioamnionitis, 28/69 (37%) were classified as having fetal inflammatory response syndrome, according to the presence of severe chorioamnionitis and funisitis. Histological chorioamnionitis was associated with a lower birth weight, shorter gestation, higher frequency of patent ductus arteriosus, greater use of surfactant, and higher frequency of chronic lung disease of prematurity. Severe chorioamnionitis and funisitis were significantly associated with lower birth weight, lower gestational age, lower Apgar score at 5 minutes, more frequent use of mechanical ventilatory support and surfactant, as well as higher frequency of patent ductus arteriosus and chronic lung disease. The results of the path analysis showed that fetal inflammatory response syndrome has a significant direct (0.66), indirect (0.11), and overall (0.77) effect on chronic lung disease. This study demonstrated a strong positive correlation between exposure of the fetus to a severe inflammatory response and the development of chronic lung disease of prematurity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Quality of care in patients with psoriasis: an initial clinical study of an international disease management programme.

PubMed

de Korte, J; Van Onselen, J; Kownacki, S; Sprangers, M A G; Bos, J D

2005-01-01

Patients with psoriasis have to cope with their disease for many years or even throughout their entire life. To provide optimal care, a disease management programme was developed. This programme consisted of disease education, disease management training, and psychological support, together with topical treatment. To test a disease management programme in dermatological practice, to assess patients' satisfaction with this programme, and adherence to topical treatment. Additionally, disease severity and quality of life were assessed. An initial clinical investigation was conducted in 10 European treatment centres. A total of 330 patients were included. Patient satisfaction, adherence, disease severity and quality of life were measured with study-specific and standardized self-report questionnaires. Patients reported a high degree of satisfaction with the programme, and a high degree of adherence to topical treatment. Disease severity and quality of life significantly improved. The programme was well received by the participating professionals. The disease management programme was found to be a useful tool in the management of psoriasis, providing patients with relief from the burden of psoriasis in everyday life. A full-scale evaluation is recommended.

Reliability and validity of the Wolfram Unified Rating Scale (WURS)

PubMed Central

2012-01-01

Background Wolfram syndrome (WFS) is a rare, neurodegenerative disease that typically presents with childhood onset insulin dependent diabetes mellitus, followed by optic atrophy, diabetes insipidus, deafness, and neurological and psychiatric dysfunction. There is no cure for the disease, but recent advances in research have improved understanding of the disease course. Measuring disease severity and progression with reliable and validated tools is a prerequisite for clinical trials of any new intervention for neurodegenerative conditions. To this end, we developed the Wolfram Unified Rating Scale (WURS) to measure the severity and individual variability of WFS symptoms. The aim of this study is to develop and test the reliability and validity of the Wolfram Unified Rating Scale (WURS). Methods A rating scale of disease severity in WFS was developed by modifying a standardized assessment for another neurodegenerative condition (Batten disease). WFS experts scored the representativeness of WURS items for the disease. The WURS was administered to 13 individuals with WFS (6-25 years of age). Motor, balance, mood and quality of life were also evaluated with standard instruments. Inter-rater reliability, internal consistency reliability, concurrent, predictive and content validity of the WURS were calculated. Results The WURS had high inter-rater reliability (ICCs>.93), moderate to high internal consistency reliability (Cronbach’s α = 0.78-0.91) and demonstrated good concurrent and predictive validity. There were significant correlations between the WURS Physical Assessment and motor and balance tests (rs>.67, p<.03), between the WURS Behavioral Scale and reports of mood and behavior (rs>.76, p<.04) and between WURS Total scores and quality of life (rs=-.86, p=.001). The WURS demonstrated acceptable content validity (Scale-Content Validity Index=0.83). Conclusions These preliminary findings demonstrate that the WURS has acceptable reliability and validity and captures individual differences in disease severity in children and young adults with WFS. PMID:23148655

Targeting Wolman Disease and Cholesteryl Ester Storage Disease: Disease Pathogenesis and Therapeutic Development

PubMed Central

Aguisanda, Francis; Thorne, Natasha; Zheng, Wei

2017-01-01

Wolman disease (WD) and cholesteryl ester storage disease (CESD) are lysosomal storage diseases (LSDs) caused by a deficiency in lysosomal acid lipase (LAL) due to mutations in the LIPA gene. This enzyme is critical to the proper degradation of cholesterol in the lysosome. LAL function is completely lost in WD while some residual activity remains in CESD. Both are rare diseases with an incidence rate of less than 1/100,000 births for WD and approximate 2.5/100,000 births for CESD. Clinical manifestation of WD includes hepatosplenomegaly, calcified adrenal glands, severe malabsorption and a failure to thrive. As in CESD, histological analysis of WD tissues reveals the accumulation of triglycerides (TGs) and esterified cholesterol (EC) in cellular lysosomes. However, the clinical presentation of CESD is less severe and more variable than WD. This review is to provide an overview of the disease pathophysiology and the current state of therapeutic development for both of WD and CESD. The review will also discuss the application of patient derived iPSCs for further drug discovery. PMID:28401034

Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A.

PubMed

Fledrich, Robert; Mannil, Manoj; Leha, Andreas; Ehbrecht, Caroline; Solari, Alessandra; Pelayo-Negro, Ana L; Berciano, José; Schlotter-Weigel, Beate; Schnizer, Tuuli J; Prukop, Thomas; Garcia-Angarita, Natalia; Czesnik, Dirk; Haberlová, Jana; Mazanec, Radim; Paulus, Walter; Beissbarth, Tim; Walter, Maggie C; Triaal, Cmt-; Hogrel, Jean-Yves; Dubourg, Odile; Schenone, Angelo; Baets, Jonathan; De Jonghe, Peter; Shy, Michael E; Horvath, Rita; Pareyson, Davide; Seeman, Pavel; Young, Peter; Sereda, Michael W

2017-11-01

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Iodine-131 induced hepatotoxicity in previously healthy patients with Grave’s disease

PubMed Central

2013-01-01

Objective To describe the association of the rare and serious complication of liver toxicity in previously healthy Grave’s disease (GD) patients after the treatment with radioactive iodine 131I (RAI). Case presentation We report the clinical, laboratory and pathologic findings of 2 cases of severe liver toxicity associated with the treatment with RAI in previously healthy patients with GD. Clinical examination and laboratory investigations excluded viral hepatitis, autoimmune hepatitis, granulomatous disease, primary biliary disease, extrahepatic biliary obstruction, and heart failure. Case 1: A previously healthy 52-years old man reportedly having a typical GD but following RAI treatment, concomitantly developed severe liver toxicity that required 1 week of treatment in hospital. Case 2: A previously healthy 34-years old woman is reported as having a typical GD but developed jaundice following RAI treatment that required several weeks of in hospital treatment in the hepato-biliary department. In both cases, the liver dysfunction resolved after intensive treatment with hepato-protective agents. In this report the therapeutic considerations as well as the pathogenetic possibilities are reviewed. Conclusion To the best of our knowledge, this is the first description of the association observed, which is rare but may be severe and should be considered in any case of thyrotoxicosis where a liver dysfunction develops after the treatment with radioactive iodine 131I. PMID:23497434

SSR Markers Assessed for Peanut Smut Disease Resistance

USDA-ARS?s Scientific Manuscript database

Peanut smut disease, caused by Thecaphora frezii (Carranza & Lindquist), can result in yield losses higher than 50%. Several strategies have been developed for disease management but they are still insufficient. The smut genetic resistance found in wild species and Bolivian landraces is currently th...

Risk Factors for Severe Infection, Hospitalization, and Prolonged Antimicrobial Therapy in Patients with Babesiosis.

PubMed

Mareedu, Neeharik; Schotthoefer, Anna M; Tompkins, Jason; Hall, Matthew C; Fritsche, Thomas R; Frost, Holly M

2017-10-01

Babesiosis is an emerging tick-borne disease transmitted by the hard tick Ixodes scapularis , which also transmits Lyme disease. Better gradation of prognostic indicators are needed to determine which patients may develop serious complications requiring hospitalization, and to provide early guidance on appropriate therapy. In this study, we evaluated 128 patients with smear or real time polymerase chain reaction-confirmed Babesia microti infections over a period of 16 years. Patients with asplenia or immunocompromising conditions were more likely to have severe infection ( P < 0.01), require hospitalization ( P < 0.01), or receive prolonged courses of antimicrobials ( P < 0.01). Nausea or vomiting ( P < 0.01) and diarrhea ( P < 0.01) along with hyperbilirubinemia ( P < 0.01) were predictive of severe infection, hospitalization, and prolonged antimicrobial therapy. Patients with concurrent Lyme disease were less likely to require hospitalization and had similar severity of disease and length of antibiotic treatment compared with those without Lyme disease.

The revised dengue fever classification in German travelers: clinical manifestations and indicators for severe disease.

PubMed

Hoffmeister, B; Suttorp, N; Zoller, T

2015-02-01

The number of dengue cases imported to Germany has increased significantly in recent years. Among returning travelers, dengue is now a frequent cause of hospitalization. The aim of this study was to determine the proportion of patients with severe disease hospitalized in a European, non-endemic country applying the revised 2009 WHO classification system and to determine predictors of severe disease. A retrospective single-center analysis of clinical data from 56 patients, 31 (55 %) women and 25 (45 %) men, between 14 and 70 years of age treated in a tertiary care hospital between 1996 and 2010 was conducted. Thirty-nine patients (69.6 %) presented with dengue fever without warning signs, 11 (19.6 %) with warning signs and 6 (10.7 %) with signs for severe dengue fever. Two patients (4 %) developed dengue shock syndrome. Non-European descent (p = 0.001), plasma protein level <6.5 mg/dl (p = 0.001), platelets <30/nl (p = 0.017) and activated partial thromboplastin time (aPTT) >44 s (p = 0.003) were associated with severe disease. A significant proportion of patients hospitalized with symptomatic imported dengue fever in Germany have evidence of severe disease. Simple routine laboratory parameters such as complete blood count, plasma protein level and aPTT are helpful tools for identifying adult patients at risk for severe disease.

Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires.

PubMed

Aslan, Nuray; Watkin, Levi B; Gil, Anna; Mishra, Rabinarayan; Clark, Fransenio G; Welsh, Raymond M; Ghersi, Dario; Luzuriaga, Katherine; Selin, Liisa K

2017-12-05

Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M1 58 (IAV-M1) and EBV BMLF1 280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer + frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer + cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter. IMPORTANCE The pathogenic impact of immune responses that by chance cross-react to unrelated viruses has not been established in human infections. Here, we demonstrate that the severity of acute infectious mononucleosis (AIM), an Epstein-Barr virus (EBV)-induced disease prevalent in young adults but not children, is associated with increased frequencies of T cells cross-reactive to EBV and the commonly acquired influenza A virus (IAV). The T-cell receptor (TCR) repertoire and functions of these cross-reactive T cells differed between mild- and severe-AIM patients, most likely because these two groups of patients had selected different memory TCR repertoires in response to IAV infections encountered earlier. This heterologous immunity may explain variability in disease outcome and why young adults with more-developed IAV-specific memory T-cell pools have more-severe disease than children, who have less-developed memory pools. This study provides a new framework for understanding the role of heterologous immunity in human health and disease and highlights an important developing field examining the role of T-cell repertoires in the mediation of immunopathology. Copyright © 2017 Aslan et al.

Animal Models of Zika Virus

PubMed Central

Bradley, Michael P; Nagamine, Claude M

2017-01-01

Zika virus has garnered great attention over the last several years, as outbreaks of the disease have emerged throughout the Western Hemisphere. Until quite recently Zika virus was considered a fairly benign virus, with limited clinical severity in both people and animals. The size and scope of the outbreak in the Western Hemisphere has allowed for the identification of severe clinical disease that is associated with Zika virus infection, most notably microcephaly among newborns, and an association with Guillian–Barré syndrome in adults. This recent association with severe clinical disease, of which further analysis strongly suggested causation by Zika virus, has resulted in a massive increase in the amount of both basic and applied research of this virus. Both small and large animal models are being used to uncover the pathogenesis of this emerging disease and to develop vaccine and therapeutic strategies. Here we review the animal-model–based Zika virus research that has been performed to date. PMID:28662753

Animal Models of Zika Virus.

PubMed

Bradley, Michael P; Nagamine, Claude M

2017-06-01

Zika virus has garnered great attention over the last several years, as outbreaks of the disease have emerged throughout the Western Hemisphere. Until quite recently Zika virus was considered a fairly benign virus, with limited clinical severity in both people and animals. The size and scope of the outbreak in the Western Hemisphere has allowed for the identification of severe clinical disease that is associated with Zika virus infection, most notably microcephaly among newborns, and an association with Guillian-Barré syndrome in adults. This recent association with severe clinical disease, of which further analysis strongly suggested causation by Zika virus, has resulted in a massive increase in the amount of both basic and applied research of this virus. Both small and large animal models are being used to uncover the pathogenesis of this emerging disease and to develop vaccine and therapeutic strategies. Here we review the animal-model-based Zika virus research that has been performed to date.

Feeding difficulties, a key feature of the Drosophila NDUFS4 mitochondrial disease model

PubMed Central

Foriel, Sarah; Eidhof, Ilse

2018-01-01

ABSTRACT Mitochondrial diseases are associated with a wide variety of clinical symptoms and variable degrees of severity. Patients with such diseases generally have a poor prognosis and often an early fatal disease outcome. With an incidence of 1 in 5000 live births and no curative treatments available, relevant animal models to evaluate new therapeutic regimes for mitochondrial diseases are urgently needed. By knocking down ND-18, the unique Drosophila ortholog of NDUFS4, an accessory subunit of the NADH:ubiquinone oxidoreductase (Complex I), we developed and characterized several dNDUFS4 models that recapitulate key features of mitochondrial disease. Like in humans, the dNDUFS4 KD flies display severe feeding difficulties, an aspect of mitochondrial disorders that has so far been largely ignored in animal models. The impact of this finding, and an approach to overcome it, will be discussed in the context of interpreting disease model characterization and intervention studies. This article has an associated First Person interview with the first author of the paper. PMID:29590638

An epigenetic view of developmental diseases: new targets, new therapies.

PubMed

Xie, Pei; Zang, Li-Qun; Li, Xue-Kun; Shu, Qiang

2016-08-01

Function of epigenetic modifications is one of the most competitive fields in life science. Over the past several decades, it has been revealed that epigenetic modifications play essential roles in development and diseases including developmental diseases. In the present review, we summarize the recent progress about the function of epigenetic regulation, especially DNA and RNA modifications in developmental diseases. Original research articles and literature reviews published in PubMed-indexed journals. DNA modifications including methylation and demethylation can regulate gene expression, and are involved in development and multiple diseases including Rett syndrome, Autism spectrum disorders, congenital heart disease and cancer, etc. RNA methylation and demethylation play important roles in RNA processing, reprogramming, circadian, and neuronal activity, and then modulate development. DNA and RNA modifications play important roles in development and diseases through regulating gene expression. Epigenetic components could serve as novel targets for the treatment of developmental diseases.

Respiratory nanoparticle-based vaccines and challenges associated with animal models and translation.

PubMed

Renukaradhya, Gourapura J; Narasimhan, Balaji; Mallapragada, Surya K

2015-12-10

Vaccine development has had a huge impact on human health. However, there is a significant need to develop efficacious vaccines for several existing as well as emerging respiratory infectious diseases. Several challenges need to be overcome to develop efficacious vaccines with translational potential. This review focuses on two aspects to overcome some barriers - 1) the development of nanoparticle-based vaccines, and 2) the choice of suitable animal models for respiratory infectious diseases that will allow for translation. Nanoparticle-based vaccines, including subunit vaccines involving synthetic and/or natural polymeric adjuvants and carriers, as well as those based on virus-like particles offer several key advantages to help overcome the barriers to effective vaccine development. These include the ability to deliver combinations of antigens, target the vaccine formulation to specific immune cells, enable cross-protection against divergent strains, act as adjuvants or immunomodulators, allow for sustained release of antigen, enable single dose delivery, and potentially obviate the cold chain. While mouse models have provided several important insights into the mechanisms of infectious diseases, they are often a limiting step in translation of new vaccines to the clinic. An overview of different animal models involved in vaccine research for respiratory infections, with advantages and disadvantages of each model, is discussed. Taken together, advances in nanotechnology, combined with the right animal models for evaluating vaccine efficacy, has the potential to revolutionize vaccine development for respiratory infections. Copyright © 2015 Elsevier B.V. All rights reserved.

Development and Validation of a Symptom-Based Activity Index for Adults with Eosinophilic Esophagitis

PubMed Central

Schoepfer, Alain M.; Straumann, Alex; Panczak, Radoslaw; Coslovsky, Michael; Kuehni, Claudia E.; Maurer, Elisabeth; Haas, Nadine A.; Romero, Yvonne; Hirano, Ikuo; Alexander, Jeffrey A.; Gonsalves, Nirmala; Furuta, Glenn T.; Dellon, Evan S.; Leung, John; Collins, Margaret H.; Bussmann, Christian; Netzer, Peter; Gupta, Sandeep K.; Aceves, Seema S.; Chehade, Mirna; Moawad, Fouad J.; Enders, Felicity T.; Yost, Kathleen J.; Taft, Tiffany H.; Kern, Emily; Zwahlen, Marcel; Safroneeva, Ekaterina

2015-01-01

BACKGROUND & AIMS Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE), to provide endpoints for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patients’ assessments of disease severity. We also evaluated relationships between patients’ assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS We collected information from 186 patients with EoE in Switzerland and the US (69.4% male; median age, 43 years) via surveys (n = 135), focus groups (n = 27), and semi-structured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patients’ assessment of EoE severity. The PRO instrument was prospectively used in 153 adult patients with EoE (72.5% male; median age, 38 years), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 years). RESULTS Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patients’ assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity and PRO score was 0.13 (on a scale from 0 to 10). CONCLUSIONS We developed and validated an EoE scoring system based on 7 PRO items that assesses symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263. PMID:25160980

Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Path to a Dengue Vaccine: Learning from Human Natural Dengue Infection Studies and Vaccine Trials.

PubMed

de Silva, Aravinda M; Harris, Eva

2018-06-01

Dengue virus (DENV) is the most common arthropod-borne viral disease of humans. Although effective vaccines exist against other flaviviral diseases like yellow fever and Japanese encephalitis, dengue vaccine development is complicated by the presence of four virus serotypes and the possibility of partial immunity enhancing dengue disease severity. Several live attenuated dengue vaccines are being tested in human clinical trials. Initial results are mixed, with variable efficacy depending on DENV serotype and previous DENV exposure. Here, we highlight recent discoveries about the human antibody response to DENV and propose guidelines for advancing development of safe and effective dengue vaccines. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Unbiased approaches to biomarker discovery in neurodegenerative diseases

PubMed Central

Chen-Plotkin, Alice S.

2014-01-01

Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia have several important features in common. They are progressive, they affect a relatively inaccessible organ, and we have no disease-modifying therapies for them. For these brain-based diseases, current diagnosis and evaluation of disease severity rely almost entirely on clinical examination, which may only be a rough approximation of disease state. Thus, the development of biomarkers – objective, relatively easily measured and precise indicators of pathogenic processes – could improve patient care and accelerate therapeutic discovery. Yet existing, rigorously tested neurodegenerative disease biomarkers are few, and even fewer biomarkers have translated into clinical use. To find new biomarkers for these diseases, an unbiased, high-throughput screening approach may be needed. In this review, I will describe the potential utility of such an approach to biomarker discovery, using Parkinson’s disease as a case example. PMID:25442938

Targeting Dysbiosis for the Treatment of Liver Disease.

PubMed

Anand, Gobind; Zarrinpar, Amir; Loomba, Rohit

2016-02-01

The gut microbiome is composed of a vast number of microbes in the gastrointestinal tract, which benefit host metabolism, aid in digestion, and contribute to normal immune function. Alterations in microbial composition can result in intestinal dysbiosis, which has been implicated in several diseases including obesity, inflammatory bowel disease, and liver diseases. Over the past several years, significant interactions between the intestinal microbiota and liver have been discovered, with possible mechanisms for the development as well as progression of liver disease and promising therapeutic targets to either prevent or halt the progression of liver disease. In this review the authors examine mechanisms of dysbiosis-induced liver disease; highlight current knowledge regarding the role of dysbiosis in nonalcoholic liver disease, alcoholic liver disease, and cirrhosis; and discuss potential therapeutic targets. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Common susceptibility alleles and SQSTM1 mutations predict disease extent and severity in a multinational study of patients with Paget's disease.

PubMed

Albagha, Omar M E; Visconti, Micaela Rios; Alonso, Nerea; Wani, Sachin; Goodman, Kirsteen; Fraser, William D; Gennari, Luigi; Merlotti, Daniela; Gianfrancesco, Fernando; Esposito, Teresa; Rendina, Domenico; di Stefano, Marco; Isaia, Giancarlo; Brandi, Maria Luisa; Giusti, Francesca; Del Pino-Montes, Javier; Corral-Gudino, Luis; Gonzalez-Sarmiento, Rogelio; Ward, Lynley; Rea, Sarah L; Ratajczak, Thomas; Walsh, John P; Ralston, Stuart H

2013-11-01

Paget's disease of bone (PDB) has a strong genetic component. Here, we investigated possible associations between genetic variants that predispose to PDB and disease severity. Allelic variants identified as predictors of PDB from genome-wide association studies were analyzed in 1940 PDB patients from the United Kingdom, Italy, Western Australia, and Spain. A cumulative risk allele score was constructed by adding the variants together and relating this to markers of disease severity, alone and in combination with SQSTM1 mutations. In SQSTM1-negative patients, risk allele scores in the highest tertile were associated with a 27% increase in disease extent compared with the lowest tertile (p < 0.00001) with intermediate values in the middle tertile (20% increase; p = 0.0007). The effects were similar for disease severity score, which was 15% (p = 0.01) and 25% (p < 0.00001) higher in the middle and upper tertiles, respectively. Risk allele score remained a significant predictor of extent and severity when SQSTM-positive individuals were included, with an effect size approximately one-third of that observed with SQSTM1 mutations. A genetic risk score was developed by combining information from both markers, which identified subgroups of individuals with low, medium, and high levels of severity with a specificity of 70% and sensitivity of 55%. Risk allele scores and SQSTM1 mutations both predict extent and severity of PDB. It is possible that with further refinement, genetic profiling may be of clinical value in identifying individuals at high risk of severe disease who might benefit from enhanced surveillance and early intervention. © 2013 American Society for Bone and Mineral Research.

Clinical pharmacology of novel anti-Alzheimer disease modifying medications.

PubMed

Caraci, Filippo; Bosco, Paolo; Leggio, Gian Marco; Malaguarnera, Michele; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore

2013-01-01

In recent years, efforts have been directed to develop "disease-modifying" medications to treat Alzheimer's disease (AD), able to halt or slow the pathological process. Because the earlier the treatment starts, the greater is the possibility of efficacy, it is important to set up biomarkers for early diagnosis of functional brain abnormalities, before the clinical manifestation of the overt disease. Up to now, strategies to develop disease-modifying drugs have mainly targeted β amyloid (Aβ, accumulation, aggregation, clearance) and/or tau protein (phosphorylation and aggregation). Active and passive immunotherapy is the main strategy aimed at increasing Aβ clearance. Unfortunately several candidate diseasemodifying drugs have failed in phase III clinical trials conducted in mild to moderate AD. More recently, in phase III studies, bapineuzumab has been discontinued because it did not prove clinically effective (despite its significant effect on biomarkers), while solaneuzumab has been found effective in slowing AD progression. Several methological problems have been recently pointed out to explain the lack of clinical efficacy of novel disease-modifying drug-treatments; moreover, new insights in pathophysiology of AD give the premise to develop novel drug targeting. Clinical trials recently completed and/or still ongoing are discussed in the present review.

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

PubMed Central

Saiz, Juan-Carlos; Martín-Acebes, Miguel A.; Bueno-Marí, Rubén; Salomón, Oscar D.; Villamil-Jiménez, Luis C.; Heukelbach, Jorg; Alencar, Carlos H.; Armstrong, Paul K.; Ortiga-Carvalho, Tania M.; Mendez-Otero, Rosalia; Rosado-de-Castro, Paulo H.; Pimentel-Coelho, Pedro M.

2017-01-01

Zika is a viral disease transmitted mainly by mosquitoes of the genus Aedes. In recent years, it has expanded geographically, changing from an endemic mosquito-borne disease across equatorial Asia and Africa, to an epidemic disease causing large outbreaks in several areas of the world. With the recent Zika virus (ZIKV) outbreaks in the Americas, the disease has become a focus of attention of public health agencies and of the international research community, especially due to an association with neurological disorders in adults and to the severe neurological and ophthalmological abnormalities found in fetuses and newborns of mothers exposed to ZIKV during pregnancy. A large number of studies have been published in the last 3 years, revealing the structure of the virus, how it is transmitted and how it affects human cells. Many different animal models have been developed, which recapitulate several features of ZIKV disease and its neurological consequences. Moreover, several vaccine candidates are now in active preclinical development, and three of them have already entered phase I clinical trials. Likewise, many different compounds targeting viral and cellular components are being tested in in vitro and in experimental animal models. This review aims to discuss the current state of this rapidly growing literature from a multidisciplinary perspective, as well as to present an overview of the public health response to Zika and of the perspectives for the prevention and treatment of this disease. PMID:28878742

Collaboration for rare disease drug discovery research.

PubMed

Litterman, Nadia K; Rhee, Michele; Swinney, David C; Ekins, Sean

2014-01-01

Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives.

Collaboration for rare disease drug discovery research

PubMed Central

Litterman, Nadia K.; Rhee, Michele; Swinney, David C.; Ekins, Sean

2014-01-01

Rare disease research has reached a tipping point, with the confluence of scientific and technologic developments that if appropriately harnessed, could lead to key breakthroughs and treatments for this set of devastating disorders. Industry-wide trends have revealed that the traditional drug discovery research and development (R&D) model is no longer viable, and drug companies are evolving their approach. Rather than only pursue blockbuster therapeutics for heterogeneous, common diseases, drug companies have increasingly begun to shift their focus to rare diseases. In academia, advances in genetics analyses and disease mechanisms have allowed scientific understanding to mature, but the lack of funding and translational capability severely limits the rare disease research that leads to clinical trials. Simultaneously, there is a movement towards increased research collaboration, more data sharing, and heightened engagement and active involvement by patients, advocates, and foundations. The growth in networks and social networking tools presents an opportunity to help reach other patients but also find researchers and build collaborations. The growth of collaborative software that can enable researchers to share their data could also enable rare disease patients and foundations to manage their portfolio of funded projects for developing new therapeutics and suggest drug repurposing opportunities. Still there are many thousands of diseases without treatments and with only fragmented research efforts. We will describe some recent progress in several rare diseases used as examples and propose how collaborations could be facilitated. We propose that the development of a center of excellence that integrates and shares informatics resources for rare diseases sponsored by all of the stakeholders would help foster these initiatives. PMID:25685324

Innovation for the 'bottom 100 million': eliminating neglected tropical diseases in the Americas.

PubMed

Hotez, Peter J; Dumonteil, Eric; Heffernan, Michael J; Bottazzi, Maria E

2013-01-01

An estimated 100 million people in the Latin American and Caribbean (LAC) region live on less than US$2 per day, while another 46 million people in the US live below that nation's poverty line. Almost all of the 'bottom 100 million' people suffer from at least one neglected tropical disease (NTD), including one-half of the poorest people in the region infected with hookworms, 10% with Chagas disease, and up to 1-2% with dengue, schistosomiasis, and/or leishmaniasis. In the US, NTDs such as Chagas disease, cysticercosis, toxocariasis, and trichomoniasis are also common among poor populations. These NTDs trap the poorest people in the region in poverty, because of their impact on maternal and child health, and occupational productivity. Through mass drug administration (MDA), several NTDs are on the verge of elimination in the Americas, including lymphatic filariasis, onchocerciasis, trachoma, and possibly leprosy. In addition, schistosomiasis may soon be eliminated in the Caribbean. However, for other NTDs including hookworm infection, Chagas disease, dengue, schistosomiasis, and leishmaniasis, a new generation of 'anti-poverty vaccines' will be required. Several vaccines for dengue are under development by multinational pharmaceutical companies, whereas others are being pursued through non-profit product development partnerships (PDPs), in collaboration with developing country manufacturers in Brazil and Mexico. The Sabin Vaccine Institute PDP is developing a primarily preventive bivalent recombinant human hookworm vaccine, which is about to enter phase 1 clinical testing in Brazil, as well as a new therapeutic Chagas disease vaccine in collaboration with several Mexican institutions. The Chagas disease vaccine would be administered to seropositive patients to delay or prevent the onset of Chagasic cardiomyopathy (secondary prevention). Together, MDA and the development of new anti-poverty vaccines afford an opportunity to implement effective control and elimination strategies for the major NTDs in the Americas.

Cation Homeostasis in Red Cells From Patients With Sickle Cell Disease Heterologous for HbS and HbC (HbSC Genotype).

PubMed

Hannemann, A; Rees, D C; Tewari, S; Gibson, J S

2015-11-01

Sickle cell disease (SCD) in patients of HbSC genotype is considered similar, albeit milder, to that in homozygous HbSS individuals--but with little justification. In SCD, elevated red cell cation permeability is critical as increased solute loss causes dehydration and encourages sickling. Recently, we showed that the KCl cotransporter (KCC) activity in red cells from HbSC patients correlated significantly with disease severity, but that in HbSS patients did not. Two transporters involved in red cell dehydration, the conductive channels Psickle and the Gardos channel, behaved similarly in red cells from the two genotypes, but were significantly less active in HbSC patients. By contrast, KCC activity was quantitatively greater in HbSC red cells. Results suggest that KCC is likely to have greater involvement in red cell dehydration in HbSC patients, which could explain its association with disease severity in this genotype. This work supports the hypothesis that SCD in HbSC patients is a distinct disease entity to that in HbSS patients. Results suggest the possibility of designing specific treatments of particular benefit to HbSC patients and a rationale for the development of prognostic markers, to inform early treatment of children likely to develop more severe complications of the disease.

Effects of fish age and parasite dose on the development of whirling disease in rainbow trout.

PubMed

Ryce, Eileen K N; Zale, Alexander V; MacConnell, Elizabeth

2004-06-11

We determined the ages at which juvenile rainbow trout Oncorhynchus mykiss became resistant to the effects of whirling disease following exposure to a range of parasite doses. Heretofore, the development and severity of whirling disease in salmonids was known to be generally dependent on the age or size of fish when first exposed to the triactinomyxon spores of Myxobolus cerebralis; larger, older individuals tended to be less diseased. However, no systematic determination had been made of the exact age at which fish become resistant to the development of the disease. We exposed rainbow trout at 9 ages (1 to 17 wk post-hatch) to 4 parasite dose levels (0, 100, 1000 and 10,000 triactinomyxons per fish). Disease severity was measured using mortality, clinical signs, microscopic pathology, and myxospore counts. Disease and mortality were substantially reduced when exposure to the parasite occurred for the first time at 9 wk post-hatch (756 degree-days at 12 degrees C) or older. High doses elicited more disease among the younger age groups, but the effect was dampened in groups exposed at about 9 to 11 wk post-hatch and absent thereafter. Rainbow trout reared in M. cerebralis-free waters for 9 wk post-hatch or longer, whether in the wild or in a hatchery situation, should experience greater survival and less disease than fish first exposed to the parasite at younger ages.

Natural history of severe atheromatous disease of the thoracic aorta: a transesophageal echocardiographic study.

PubMed

Montgomery, D H; Ververis, J J; McGorisk, G; Frohwein, S; Martin, R P; Taylor, W R

1996-01-01

This study sought to prospectively observe the morphologic and clinical natural history of severe atherosclerotic disease of the thoracic aorta as defined by transesophageal echocardiography. Atherosclerosis of the thoracic aorta has been shown to be highly associated with risk for embolic events in transesophageal studies, but the natural history of the disease under clinical conditions has not been reported. During a 20-month period, 191 of 264 patients undergoing transesophageal echocardiography had adequate visualization of the aorta to allow atherosclerotic severity to be graded as follows: grade I = normal (44 patients); grade II = intimal thickening (52 patients); grade III = atheroma < 5 mm (62 patients); grade IV = atheroma > or = 5 mm (19 patients); grade V = mobile lesion (14 patients). All available patients with grades IV (8 patients) and V (10 patients) disease as well as a subgroup of 12 patients with grade III disease had follow-up transesophageal echocardiographic studies (mean [+/- SD] 11.7 +/- 0.9 months, range 6 to 22). Of 30 patients undergoing follow-up transesophageal echocardiographic studies, 20 (66%) had no change in atherosclerotic severity grade. Of the remaining 10 patients, atherosclerotic severity progressed one grade in 7 and decreased in 3 with resolved mobile lesions. Of 18 patients with grade IV or V disease of the aorta who underwent a follow-up study, 11 (61%) demonstrated formation of new mobile lesions. Of 10 patients with grade V disease on initial study who underwent follow-up study, 7 (70%) demonstrated resolution of a specific previously documented mobile lesion. However, seven patients (70%) with grade V disease also demonstrated development of a new mobile lesion. Of 33 patients with grade IV or V disease, 8 (24%) died during the study period, and 1 (3%) had a clinical embolic event. The presence of severe atherosclerotic disease of the thoracic aorta as defined by transesophageal echocardiography is associated with a high mortality rate. Although the morphologic natural history of the disease process itself is marked by stability over a 1-year period, individual lesion morphology is dynamic, with formation and resolution of mobile components occurring frequently over the same period. The dynamic nature of individual lesion morphology potentially enhances the possibility of developing a successful therapeutic strategy.

Land use change and human health

NASA Astrophysics Data System (ADS)

Patz, Jonathan A.; Norris, Douglas E.

Disease emergence events have been documented following several types of land use change. This chapter reviews several health-relevant land use changes recognized today, including: 1) urbanization and urban sprawl; 2) water projects and agricultural development; 3) road construction and deforestation in the tropics; and 4) regeneration of temperate forests. Because habitat or climatic change substantially affects intermediate invertebrate hosts involved in many prevalent diseases, this chapter provides a basic description of vector-borne disease biology as a foundation for analyzing the effects of land use change. Urban sprawl poses health challenges stemming from heat waves exacerbated by the "urban heat island" effect, as well as from water contamination due to expanses of impervious road and concrete surfaces. Dams, irrigation and agricultural development have long been associated with diseases such as schistosomiasis and filariasis. Better management methods are required to address the trade-offs between expanded food production and altered habitats promoting deadly diseases. Deforestation can increase the nature and number of breeding sites for vector-borne diseases, such as malaria and onchocerciasis. Human host and disease vector interaction further increases risk, as can a change in arthropod-vector species composition.

Evolution in a transmissible cancer: a study of the chromosomal changes in devil facial tumor (DFT) as it spreads through the wild Tasmanian devil population.

PubMed

Pearse, Anne-Maree; Swift, Kate; Hodson, Pamela; Hua, Bobby; McCallum, Hamish; Pyecroft, Stephen; Taylor, Robyn; Eldridge, Mark D B; Belov, Katherine

2012-03-01

Tasmanian devils (Sarcophilus harrisii) are the largest extant marsupial carnivores. This species, now confined to Tasmania, is endangered from the emergence of a transmissible cancer, devil facial tumor disease (DFTD). In the present study, we use cytogenetic and molecular techniques to examine the stability of devil facial tumor (DFT) cell lines across time and space. This article describes disease progression from February 2004 to June 2011. We demonstrate evolutionary changes in the disease, which affects devils in different sites across Tasmania and over a period of several years, producing several chromosomal variants (strains) that are capable of transmission between devils. We describe the evolution of DFTs in the field and speculate on the possible impacts on the disease, including (1) development of less aggressive forms of the disease; (2) development of more aggressive forms of the disease; (3) development of forms capable of affecting closely related species of dasyurids (e.g., quolls); (4) extinction of the disease as it acquires additional deleterious mutations that affect either cell viability or transmissibility; and (5) co-evolution of the disease and the host. We also speculate about the future of the Tasmanian devil in the wild. We note that although DFTs are regarded as unstable by comparison with another much older transmissible cancer, canine transmissible venereal tumor (CTVT), the potential for development of less aggressive forms of DFTs or for development of resistance in devils is limited by devils' small numbers, low genetic diversity, and restricted geographical distribution. Copyright © 2012 Elsevier Inc. All rights reserved.

Diet and Inflammation in Alzheimer's Disease and Related Chronic Diseases: A Review.

PubMed

Gardener, Samantha L; Rainey-Smith, Stephanie R; Martins, Ralph N

2016-01-01

Inflammation is one of the pathological features of the neurodegenerative disease, Alzheimer's disease (AD). A number of additional disorders are likewise associated with a state of chronic inflammation, including obesity, cardiovascular disease, and type-2 diabetes, which are themselves risk factors for AD. Dietary components have been shown to modify the inflammatory process at several steps of the inflammatory pathway. This review aims to evaluate the published literature on the effect of consumption of pro- or anti-inflammatory dietary constituents on the severity of both AD pathology and related chronic diseases, concentrating on the dietary constituents of flavonoids, spices, and fats. Diet-based anti-inflammatory components could lead to the development of potent novel anti-inflammatory compounds for a range of diseases. However, further work is required to fully characterize the therapeutic potential of such compounds, including gaining an understanding of dose-dependent relationships and limiting factors to effectiveness. Nutritional interventions utilizing anti-inflammatory foods may prove to be a valuable asset in not only delaying or preventing the development of age-related neurodegenerative diseases such as AD, but also treating pre-existing conditions including type-2 diabetes, cardiovascular disease, and obesity.

Vaccines for Canine Leishmaniasis

PubMed Central

Palatnik-de-Sousa, Clarisa B.

2012-01-01

Leishmaniasis is the third most important vector-borne disease worldwide. Visceral leishmaniasis (VL) is a severe and frequently lethal protozoan disease of increasing incidence and severity due to infected human and dog migration, new geographical distribution of the insect due to global warming, coinfection with immunosuppressive diseases, and poverty. The disease is an anthroponosis in India and Central Africa and a canid zoonosis (ZVL) in the Americas, the Middle East, Central Asia, China, and the Mediterranean. The ZVL epidemic has been controlled by one or more measures including the culling of infected dogs, treatment of human cases, and insecticidal treatment of homes and dogs. However, the use of vaccines is considered the most cost–effective control tool for human and canine disease. Since the severity of the disease is related to the generation of T-cell immunosuppression, effective vaccines should be capable of sustaining or enhancing the T-cell immunity. In this review we summarize the clinical and parasitological characteristics of ZVL with special focus on the cellular and humoral canine immune response and review state-of-the-art vaccine development against human and canine VL. Experimental vaccination against leishmaniasis has evolved from the practice of leishmanization with living parasites to vaccination with crude lysates, native parasite extracts to recombinant and DNA vaccination. Although more than 30 defined vaccines have been studied in laboratory models no human formulation has been licensed so far; however three second-generation canine vaccines have already been registered. As expected for a zoonotic disease, the recent preventive vaccination of dogs in Brazil has led to a reduction in the incidence of canine and human disease. The recent identification of several Leishmania proteins with T-cell epitopes anticipates development of a multiprotein vaccine that will be capable of protecting both humans and dogs against VL. PMID:22566950

Lyme Disease Presenting as a Spontaneous Knee Effusion.

PubMed

Matzkin, Elizabeth; Suslavich, Kaytelin; Curry, Emily J

2015-11-01

Musculoskeletal complaints, which are frequently associated with Lyme disease, often prompt patients to see a physician. In particular, transient episodes of spontaneous knee effusion are common early in the progression of Lyme disease, and, if left untreated, 60% of patients diagnosed with the disease develop Lyme arthritis. This disease is easily treated with antibiotics; therefore, inclusion of Lyme disease in the differential diagnosis as a potential cause of a spontaneous knee effusion can prevent the development of more severe symptoms associated with the disease. However, the time required to receive test results and the inconsistencies between serum and synovial tests can complicate diagnosis of the disease. Copyright 2015 by the American Academy of Orthopaedic Surgeons.

Opportunities and challenges of disease biomarkers: a new section in the Journal of Translational Medicine.

PubMed

Wang, Xiangdong; Ward, Peter A

2012-12-05

Disease biomarkers are defined to diagnose various phases of diseases, monitor severities of diseases and responses to therapies, or predict prognosis of patients. Disease-specific biomarkers should benefit drug discovery and development, integrate multidisciplinary sciences, be validated by molecular imaging. The opportunities and challenges in biomarker development are emphasized and considered. The Journal of Translational Medicine opens a new Section of Disease Biomarkers to bridge identification and validation of gene or protein-based biomarkers, network biomarkers, dynamic network biomarkers in human diseases, patient phenotypes, and clinical applications. Disease biomarkers are also important for determining drug effects, target specificities and binding, dynamic metabolism and pharmacological kinetics, or toxicity profiles.

A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

PubMed Central

Kim, Hye Young; Eyheramonho, María Belén; Pichavant, Muriel; Gonzalez Cambaceres, Carlos; Matangkasombut, Ponpan; Cervio, Guillermo; Kuperman, Silvina; Moreiro, Rita; Konduru, Krishnamurthy; Manangeeswaran, Mohanraj; Freeman, Gordon J.; Kaplan, Gerardo G.; DeKruyff, Rosemarie H.; Umetsu, Dale T.; Rosenzweig, Sergio D.

2011-01-01

During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy. PMID:21339644

Transcatheter aortic valve-in-valve implantation for severe bioprosthetic stenosis after Bentall operation using a homograft in a patient with Behçet's disease.

PubMed

Joo, Hyung Joon; Hong, Soon Jun; Yu, Cheol Woong

2015-03-01

A 43-year-old man presented with severe aortic stenosis. Eight years previously, he had undergone primary surgical aortic valve replacement (AVR) for severe aortic regurgitation, but one year later developed cardiac arrest and complete atrioventricular block as a result of non-bacterial thrombotic endocarditis with severe valvular dehiscence. Following the diagnosis of prosthetic valve failure caused by Behçet's disease, the patient underwent a Bentall operation using 23 mm aortic homograft with permanent pacemaker implantation and coronary artery bypass grafting. Subsequently, he was stable with steroid administration and azathioprine for seven years after the second operation, but recently suffered from severe dyspnea and chest pain. Echocardiography revealed the development of severe aortic stenosis. A preprocedural evaluation demonstrated a porcelain aorta with severe calcification in the previous homograft valve on computed tomography, and critical stenosis at the ostium of the left circumflex artery on coronary angiography. After percutaneous coronary intervention for the ostium of the left circumflex artery, a transcatheter AVR was successfully performed using a 26 mm Edwards SAPIEN XT valve. The patient recovered without any complications after the procedure. This is the first report of a successful transcatheter aortic valve-in valve implantation for severe homograft aortic stenosis after a Bentall operation, using a homograft, in a patient with Behçet's disease.

Fibrocalcific aortic valve disease: Opportunity to understand disease mechanisms using mouse models

PubMed Central

Weiss, Robert M.; Miller, Jordan D.; Heistad, Donald D.

2013-01-01

Studies in vitro and in vivo continue to identify complex regulated mechanisms leading to overt fibrocalcific aortic valve disease (FCAVD). Assessment of the functional impact of those processes requires careful studies of models of FCAVD in vivo. Although the genetic basis for FCVAD is unknown for most patients with FCAVD, several disease-associated genes have been identified in humans and mice. Some gene products which regulate valve development in utero also protect against fibro-calcific disease during postnatal aging. Valve calcification can occur via processes that resemble bone formation. But valve calcification can also occur by non-osteogenic mechanisms, such as formation of calcific apoptotic nodules. Anti-calcific interventions might preferentially target either osteogenic or non-osteogenic calcification. Although FCAVD and atherosclerosis share several risk factors and mechanisms, there are fundamental differences between arteries and the aortic valve, with respect to disease mechanisms and responses to therapeutic interventions. Both innate and acquired immunity are likely to contribute to FCAVD. Angiogenesis is a feature of inflammation, but may also contribute independently to progression of FCAVD, possibly by actions of pericytes that are associated with new blood vessels. Several therapeutic interventions appear to be effective in attenuating development of FCAVD in mice. Therapies which are effective early in the course of FCAVD, however, are not necessarily effective in established disease. PMID:23833295

The Impact of Therapeutic Antibodies on the Management of Digestive Diseases: History, Current Practice, and Future Directions.

PubMed

Sofia, M Anthony; Rubin, David T

2017-04-01

The development of therapeutic antibodies represents a revolutionary change in medical therapy for digestive diseases. Beginning with the initial studies that confirmed the pathogenicity of cytokines in inflammatory bowel disease, the development and application of therapeutic antibodies brought challenges and insights into their potential and optimal use. Infliximab was the first biological drug approved for use in Crohn's disease and ulcerative colitis. The lessons learned from infliximab include the importance of immunogenicity and the influence of pharmacokinetics on disease response and outcomes. Building on this foundation, other therapeutic antibodies achieved approval for inflammatory bowel disease and many more are in development for several digestive diseases. In this review, we reflect on the history of therapeutic antibodies and discuss current practice and future directions for the field.

Modeling Viral Infectious Diseases and Development of Antiviral Therapies Using Human Induced Pluripotent Stem Cell-Derived Systems.

PubMed

Trevisan, Marta; Sinigaglia, Alessandro; Desole, Giovanna; Berto, Alessandro; Pacenti, Monia; Palù, Giorgio; Barzon, Luisa

2015-07-13

The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs), which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host-pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance.

Blount disease

MedlinePlus

... Unlike bowlegs , which tend to straighten as the child develops, Blount disease slowly gets worse. It can cause severe bowing of one or both legs. This condition is more common among African American children. It is also associated with obesity ...

[Advanced Parkinson's disease: clinical characteristics and treatment (part 1)].

PubMed

Kulisevsky, J; Luquin, M R; Arbelo, J M; Burguera, J A; Carrillo, F; Castro, A; Chacón, J; García-Ruiz, P J; Lezcano, E; Mir, P; Martinez-Castrillo, J C; Martínez-Torres, I; Puente, V; Sesar, A; Valldeoriola-Serra, F; Yañez, R

2013-10-01

A large percentage of patients with Parkinson's disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced Parkinson's disease. To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Spontaneous haemothorax in Osler-Weber-Rendu disease.

PubMed Central

Karnik, A. M.; Sughayer, A.; Fenech, F. F.

1983-01-01

A case of hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu disease) is described who presented with severe, central chest pain mimicking acute myocardial infarction, a presentation which has not been described before. He was found to have developed spontaneous haemothorax which is a very rare complication of this disease. PMID:6622342

Maternal Zika Virus Disease Severity, Virus Load, Prior Dengue Antibodies, and Their Relationship to Birth Outcomes.

PubMed

Halai, Umme-Aiman; Nielsen-Saines, Karin; Moreira, Maria Lopes; de Sequeira, Patricia Carvalho; Junior, Jose Paulo Pereira; de Araujo Zin, Andrea; Cherry, James; Gabaglia, Claudia Raja; Gaw, Stephanie L; Adachi, Kristina; Tsui, Irena; Pilotto, Jose Henrique; Nogueira, Rita Ribeiro; de Filippis, Ana Maria Bispo; Brasil, Patricia

2017-09-15

Congenital Zika virus (ZIKV) syndrome is a newly identified condition resulting from infection during pregnancy. We analyzed outcome data from a mother-infant cohort in Rio de Janeiro in order to assess whether clinical severity of maternal ZIKV infection was associated with maternal virus load, prior dengue antibodies, or abnormal pregnancy/infant outcomes. A clinical severity assessment tool was developed based on duration of fever, severity of rash, multisystem involvement, and duration of symptoms during ZIKV infection. ZIKV-RNA load was quantified by polymerase chain reaction (PCR) cycles in blood/ urine. Dengue immunoglobulin G (IgG) antibodies were measured at baseline. Adverse outcomes were defined as fetal loss or a live infant with grossly abnormal clinical or brain imaging findings. Regression models were used to study potential associations. 131 ZIKV-PCR positive pregnant women were scored for clinical disease severity, 6 (4.6%) had mild disease, 98 (74.8%) had moderate disease, and 27 (20.6%) severe manifestations of ZIKV infection. There were 58 (46.4%) abnormal outcomes with 9 fetal losses (7.2%) in 125 pregnancies. No associations were found between: disease severity and abnormal outcomes (P = .961; odds ratio [OR]: 1.00; 95% confidence interval [CI]: 0.796-1.270); disease severity and viral load (P = .994); viral load and adverse outcomes (P = .667; OR: 1.02; 95% CI: 0.922-1.135); or existence of prior dengue antibodies (88% subjects) with severity score, ZIKV-RNA load or adverse outcomes (P = .667; OR: 0.78; 95% CI: 0.255-2.397). Congenital ZIKV syndrome does not appear to be associated with maternal disease severity, ZIKV-RNA load at time of infection or existence of prior dengue antibodies. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Proposed national strategies for the prevention of leading work-related diseases and injuries. Part 1

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

Not Available

1986-01-01

Preliminary strategies developed at the National Symposium on the Prevention of Leading Work Related Diseases and Injuries, held in Atlanta, Georgia on May 1 to 3, 1985 were revised, elaborated, and further developed. Strategies were developed for the prevention of occupational lung diseases, musculoskeletal injuries, occupational cancers, severe occupational traumatic injuries, and occupational cardiovascular diseases. Lung diseases considered included silicosis, asbestosis, lung cancer mesothelioma, coal workers' pneumoconiosis, byssinosis, occupational asthma, hypersensitivity pneumonitis, asphyxiation, irritation, pulmonary edema, brucellosis, psitticosis, anthrax, mycobacterioses, histoplasmosis, aspergillosis, and coccidioidomycosis. Occupational cancers were discussed as they occur in the lung, pleura, peritoneum, bladder, kidneys, blood, nasalmore » cavity, skin, nasal sinuses, and liver.« less

Severe extra-articular manifestations of rheumatoid arthritis in absence of concomitant joint involvement following long-term spontaneous remission. A case report.

PubMed

Lagrutta, Mariana; Alle, Gelsomina; Parodi, Roberto Leandro; Greca, Alcides Alejandro

2016-01-01

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease occasionally associated with severe extra-articular manifestations, mostly in cases of longstanding highly active disease. We report the case of a 56 year-old woman diagnosed with active RA at the age of 40. After 5 years of high activity, her arthritis subsides spontaneously during pregnancy despite the lack of treatment with disease-modifying anti-rheumatic drugs. She remains without articular symptoms for 7 years, and then she develops a Felty's syndrome requiring steroid treatment and splenectomy. Following steroid withdrawal she develops pericarditis with massive serohematic pericardial effusion, still in absence of articular activity, and responds to immunosuppressive therapy and colchicine. We emphasize the unusual spontaneous and sustained joint remission without specific treatment, and the development of severe extra-articular manifestations of RA in absence of concomitant articular activity, as well as the importance of controlling inflammation. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Osteoprotegerin concentration is associated with the presence and severity of peripheral arterial disease in type 2 diabetes mellitus.

PubMed

Demková, Katarína; Kozárová, Miriam; Malachovská, Zuzana; Javorský, Martin; Tkáč, Ivan

2018-02-01

Osteoprotegerin plays a role in the development of several bone diseases. In addition, osteoprotegerin may contribute to the development of vascular disease. Little is known about the association between serum osteoprotegerin levels and the presence or severity of peripheral arterial disease (PAD). The aim of this study was to examine the association between serum osteoprotegerin levels and both the presence as well as the severity of lower extremity arterial disease in patients with type 2 diabetes (T2DM). The study included 165 consecutive patients with T2DM (57 % males, mean age 65.0 ± 0.7 years). PAD was diagnosed by measurement of the toe-brachial index (TBI). Serum osteoprotegerin was measured using ELISA. The mean osteoprotegerin level was significantly higher in patients with PAD in comparison to patients without PAD (18.2 ± 1.0 vs. 13.1 ± 2.0 pmol/L, p = 0.014). Significant univariate correlations between TBI and osteoprotegerin level (r = -0.308; p < 0.001), age, body mass index, and HDL cholesterol were observed. In the multivariate linear regression analysis, serum osteoprotegerin (β = -0.005; p = 0.020), higher age, and male gender were significant predictors of TBI. When 25(OH) vitamin D was introduced into the mentioned model, OPG was no longer a significant predictor of TBI and was replaced in the model with vitamin D (β = 0.009, p = 0.001). This finding suggests a role of OPG as a mediator of the effects of 25(OH) vitamin D. Serum osteoprotegerin level is significantly associated with both the presence and severity of PAD in patients with T2D. Osteoprotegerin might be a biomarker for the presence of atherosclerotic disease in patients with T2DM.

Bioclinical Test to Predict Nephropathia Epidemica Severity at Hospital Admission.

PubMed

Hentzien, Maxime; Mestrallet, Stéphanie; Halin, Pascale; Pannet, Laure-Anne; Lebrun, Delphine; Dramé, Moustapha; Bani-Sadr, Firouzé; Galempoix, Jean-Marc; Strady, Christophe; Reynes, Jean-Marc; Penalba, Christian; Servettaz, Amélie

2018-06-01

We conducted a multicenter, retrospective cohort study of hospitalized patients with serologically proven nephropathia epidemica (NE) living in Ardennes Department, France, during 2000-2014 to develop a bioclinical test predictive of severe disease. Among 205 patients, 45 (22.0%) had severe NE. We found the following factors predictive of severe NE: nephrotoxic drug exposure (p = 0.005, point value 10); visual disorders (p = 0.02, point value 8); microscopic or macroscopic hematuria (p = 0.04, point value 7); leukocyte count >10 × 10 9 cells/L (p = 0.01, point value 9); and thrombocytopenia <90 × 10 9 /L (p = 0.003, point value 11). When point values for each factor were summed, we found a score of <10 identified low-risk patients (3.3% had severe disease), and a score >20 identified high-risk patients (45.3% had severe disease). If validated in future studies, this test could be used to stratify patients by severity in research studies and in clinical practice.

Relevance of Non-communicable Comorbidities for the Development of the Severe Forms of Dengue: A Systematic Literature Review.

PubMed

Toledo, Joao; George, Leyanna; Martinez, Eric; Lazaro, Adhara; Han, Wai Wai; Coelho, Giovanini E; Runge Ranzinger, Silvia; Horstick, Olaf

2016-01-01

Patients with dengue fever and comorbidities seem to be at higher risk of developing complications and/or severe dengue compared to healthier individuals. This study systematically reviews the evidence related to comorbidities and dengue. A systematic literature review was performed in five databases (EMBASE, PUBMED, Global Health, SciELO, Cochrane) and grey literature for full-text articles since its inceptions until October 10, 2015. A total of 230 articles were retrieved. Sixteen studies were analysed after applying all inclusion and exclusion criteria. Seven case control studies and nine retrospective cohort studies showed that comorbidities may contribute to severe dengue, especially 1) cardiovascular disease, 2) stroke, 3) diabetes, 4) respiratory disease and 5) renal disease, as well as old age. However, due to heterogeneity in studies, the real estimate effect of comorbidities as modifiers of dengue severity could not be established. Further research in regions with high prevalence of dengue infection would contribute to a better understanding of the relevance of comorbidities in severe dengue, especially with a standardised protocol, for outcomes, specific comorbidities, study design-best using prospective designs-and sample sizes.

Evolution of anti-Trypanosoma cruzi antibody production in patients with chronic Chagas disease: Correlation between antibody titers and development of cardiac disease severity

PubMed Central

Georg, Ingebourg; Hasslocher-Moreno, Alejandro Marcel; Xavier, Sergio Salles; de Holanda, Marcelo Teixeira; Bonecini-Almeida, Maria da Gloria

2017-01-01

Chagas disease is one of the most important endemic infections in Latin America affecting around 6–7 million people. About 30–50% of patients develop the cardiac form of the disease, which can lead to severe cardiac dysfunction and death. In this scenario, the identification of immunological markers of disease progression would be a valuable tool for early treatment and reduction of death rates. In this observational study, the production of anti-Trypanosoma cruzi antibodies through a retrospective longitudinal follow-up in chronic Chagas disease patients´ cohort and its correlation with disease progression and heart commitment was evaluated. Strong inverse correlation (ρ = -0.6375, p = 0.0005) between anti-T. cruzi IgG1 titers and left ventricular ejection fraction (LVEF) in chronic Chagas cardiomyopathy (CCC) patients were observed after disease progression. Elevated levels of anti-T. cruzi IgG3 titers were detected in all T. cruzi-infected patients, indicating a lack of correlation of this IgG isotype with disease progression. Furthermore, low levels of anti-T. cruzi IgG2, IgG4, and IgA were detected in all patients through the follow-up. Although without statistical significance anti-T. cruzi IgE tends to be more reactive in patients with the indeterminate form (IND) of the disease (p = 0.0637). As this study was conducted in patients with many years of chronic disease no anti-T. cruzi IgM was detected. Taken together, these results indicate that the levels of anti-T. cruzi IgG1 could be considered to seek for promising biomarkers to predict the severity of chronic Chagas disease cardiomyopathy. PMID:28723905

Uveitis in children.

PubMed

Angeles-Han, Sheila T; Rabinovich, Consuelo Egla

2016-09-01

The review provides updates on novel risk markers for the development of pediatric inflammatory uveitis and a severe disease course, on treatment of refractory disease, and on the measurement of visual outcomes. There are several new genetic markers, biomarkers, and clinical factors that may influence a child's uveitis disease course. It is important to identify children at risk for poor visual outcomes and who are refractory to traditional therapy. Racial disparities have recently been reported. We describe agents of potential benefit. In addition, we discuss the importance of patient reported outcomes in this population. Uveitis can lead to vision-threatening complications. Timely and aggressive treatment of children identified to be at risk for a severe uveitis course may lead to improved outcomes.

PAX genes in development and disease: the role of PAX2 in urogenital tract development.

PubMed

Eccles, Michael R; He, Shujie; Legge, Michael; Kumar, Rajiv; Fox, Jody; Zhou, Chaoming; French, Michelle; Tsai, Robert W S

2002-01-01

PAX genes play an important role in fetal development. Moreover, heterozygous mutations in several PAX genes cause human disease. Here we review the role of PAX2 in kidney development, focusing on the morphological effects of PAX2 mutations. We discuss the role of PAX2 in the context of an inhibitory field model of kidney branching morphogenesis and summarize recent progress in this area.

Corneal pain without stain: is it real?

PubMed

Rosenthal, Perry; Baran, Inna; Jacobs, Deborah S

2009-01-01

Clinicians often encounter patients who report corneal pain suggestive of dry eye disease, yet lack equivalent signs. These patients represent a diagnostic and therapeutic challenge that is more easily dismissed than addressed. We review the physiology of pain and the pathophysiological mechanisms of neuropathic corneal pain and speculate on the mechanisms of certain etiopathogenic triggers, such as LASIK, severe dry eye disease, and Sjogren syndrome. Recognizing corneal neuropathic pain as a disease in its own right is the first step toward developing more effective treatments for these severely disabled and presently inadequately served patients.

Rift Valley Fever.

PubMed

Hartman, Amy

2017-06-01

Rift Valley fever (RVF) is a severe veterinary disease of livestock that also causes moderate to severe illness in people. The life cycle of RVF is complex and involves mosquitoes, livestock, people, and the environment. RVF virus is transmitted from either mosquitoes or farm animals to humans, but is generally not transmitted from person to person. People can develop different diseases after infection, including febrile illness, ocular disease, hemorrhagic fever, or encephalitis. There is a significant risk for emergence of RVF into new locations, which would affect human health and livestock industries. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of Weather Conditions Associated with the Occurrence, Severity, and Incidence of Black Seed Disease of Strawberry Caused by Mycosphaerella fragariae.

PubMed

Carisse, Odile; McNealis, Vanessa

2018-01-01

Black seed disease (BSD) of strawberry is a sporadic disease caused by Mycosphaerella fragariae. Because little is known about potential crop losses or the weather conditions conducive to disease development, fungicides are generally not applied or are applied based on a preset schedule. Data collected from 2000 to 2011 representing 50 farm-years (total of 186 strawberry fields) were used to determine potential crop losses and to study the influence of weather on disease occurrence and development. First, logistic regression was used to model the relationship between occurrence of BSD and weather variables. Second, linear and nonlinear regressions were used to model the number of black seed per berry (severity) and the percentage of diseased berries (incidence). Of the 186 fields monitored, 78 showed black seed symptoms, and the number of black seed per berry ranged from 1 to 10, whereas the percentage of diseased berries ranged from 3 to 32%. The most influential weather variable was total rainfall (in millimeters) in May, with a threshold of 103 mm of rain (absence of BSD < 103 mm < presence of BSD). Similarly, nonlinear models with the total rainfall in May accurately predicted both disease severity and incidence (r = 0.94 and 0.97, respectively). Considering that management actions such as fungicide application are not needed every year in every field, these models could be used to identify fields that are at risk of BSD.

Plus Disease in Retinopathy of Prematurity: Improving Diagnosis by Ranking Disease Severity and Using Quantitative Image Analysis.

PubMed

Kalpathy-Cramer, Jayashree; Campbell, J Peter; Erdogmus, Deniz; Tian, Peng; Kedarisetti, Dharanish; Moleta, Chace; Reynolds, James D; Hutcheson, Kelly; Shapiro, Michael J; Repka, Michael X; Ferrone, Philip; Drenser, Kimberly; Horowitz, Jason; Sonmez, Kemal; Swan, Ryan; Ostmo, Susan; Jonas, Karyn E; Chan, R V Paul; Chiang, Michael F

2016-11-01

To determine expert agreement on relative retinopathy of prematurity (ROP) disease severity and whether computer-based image analysis can model relative disease severity, and to propose consideration of a more continuous severity score for ROP. We developed 2 databases of clinical images of varying disease severity (100 images and 34 images) as part of the Imaging and Informatics in ROP (i-ROP) cohort study and recruited expert physician, nonexpert physician, and nonphysician graders to classify and perform pairwise comparisons on both databases. Six participating expert ROP clinician-scientists, each with a minimum of 10 years of clinical ROP experience and 5 ROP publications, and 5 image graders (3 physicians and 2 nonphysician graders) who analyzed images that were obtained during routine ROP screening in neonatal intensive care units. Images in both databases were ranked by average disease classification (classification ranking), by pairwise comparison using the Elo rating method (comparison ranking), and by correlation with the i-ROP computer-based image analysis system. Interexpert agreement (weighted κ statistic) compared with the correlation coefficient (CC) between experts on pairwise comparisons and correlation between expert rankings and computer-based image analysis modeling. There was variable interexpert agreement on diagnostic classification of disease (plus, preplus, or normal) among the 6 experts (mean weighted κ, 0.27; range, 0.06-0.63), but good correlation between experts on comparison ranking of disease severity (mean CC, 0.84; range, 0.74-0.93) on the set of 34 images. Comparison ranking provided a severity ranking that was in good agreement with ranking obtained by classification ranking (CC, 0.92). Comparison ranking on the larger dataset by both expert and nonexpert graders demonstrated good correlation (mean CC, 0.97; range, 0.95-0.98). The i-ROP system was able to model this continuous severity with good correlation (CC, 0.86). Experts diagnose plus disease on a continuum, with poor absolute agreement on classification but good relative agreement on disease severity. These results suggest that the use of pairwise rankings and a continuous severity score, such as that provided by the i-ROP system, may improve agreement on disease severity in the future. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Lysosomal β-glucuronidase regulates Lyme and rheumatoid arthritis severity

PubMed Central

Bramwell, Kenneth K.C.; Ma, Ying; Weis, John H.; Chen, Xinjian; Zachary, James F.; Teuscher, Cory; Weis, Janis J.

2013-01-01

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most prevalent arthropod-borne illness in the United States and remains a clinical and social challenge. The spectrum of disease severity among infected patients suggests that host genetics contribute to pathogenic outcomes, particularly in patients who develop arthritis. Using a forward genetics approach, we identified the lysosomal enzyme β-glucuronidase (GUSB), a member of a large family of coregulated lysosomal enzymes, as a key regulator of Lyme-associated arthritis severity. Severely arthritic C3H mice possessed a naturally occurring hypomorphic allele, Gusbh. C57BL/6 mice congenic for the C3H Gusb allele were prone to increased Lyme-associated arthritis severity. Radiation chimera experiments revealed that resident joint cells drive arthritis susceptibility. C3H mice expressing WT Gusb as a transgene were protected from severe Lyme arthritis. Importantly, the Gusbh allele also exacerbated disease in a serum transfer model of rheumatoid arthritis. A known GUSB function is the prevention of lysosomal accumulation of glycosaminoglycans (GAGs). Development of Lyme and rheumatoid arthritis in Gusbh-expressing mice was associated with heightened accumulation of GAGs in joint tissue. We propose that GUSB modulates arthritis pathogenesis by preventing accumulation of proinflammatory GAGs within inflamed joint tissue, a trait that may be shared by other lysosomal exoglycosidases. PMID:24334460

Destructive discovertebral degenerative disease of the lumbar spine.

PubMed

Charran, A K; Tony, G; Lalam, R; Tyrrell, P N M; Tins, B; Singh, J; Eisenstein, S M; Balain, B; Trivedi, J M; Cassar-Pullicino, V N

2012-09-01

The uncommon variant of degenerative hip joint disease, termed rapidly progressive osteoarthritis, and highlighted by severe joint space loss and osteochondral disintegration, is well established. We present a similar unusual subset in the lumbar spine termed destructive discovertebral degenerative disease (DDDD) with radiological features of vertebral malalignment, severe disc resorption, and "bone sand" formation secondary to vertebral fragmentation. Co-existing metabolic bone disease is likely to promote the development of DDDD of the lumbar spine, which presents with back pain and sciatica due to nerve root compression by the "bone sand" in the epidural space. MRI and CT play a complimentary role in making the diagnosis.

[Celiac crisis with quadriplegia due to potassium depletion as presenting feature of celiac disease].

PubMed

Atikou, A; Rabhi, M; Hidani, H; El Alaoui Faris, M; Toloune, F

2009-06-01

Adult coeliac disease revealed by coeliac crisis and quadriplegia due to potassium depletion is an extremely rare situation. A 26-year-old woman presented with a suddenly developed weakness of all four limbs and a severe diarrhea. Authors emphasize coeliac crisis, which is a presenting feature of coeliac disease, characterized by acute diarrhea with life-threatening acid base and electrolyte abnormalities. The patient improved with correction of hypokalemia and gluten-free diet. A severe acute diarrhea with metabolic and systemic complications, the so-called coeliac crisis, is a possible presenting clinical feature of a previously undiagnosed adult celiac disease.

Critical Role of Airway Macrophages in Modulating Disease Severity during Influenza Virus Infection of Mice ▿

PubMed Central

Tate, Michelle D.; Pickett, Danielle L.; van Rooijen, Nico; Brooks, Andrew G.; Reading, Patrick C.

2010-01-01

Airway macrophages provide a first line of host defense against a range of airborne pathogens, including influenza virus. In this study, we show that influenza viruses differ markedly in their abilities to infect murine macrophages in vitro and that infection of macrophages is nonproductive and no infectious virus is released. Virus strain BJx109 (H3N2) infected macrophages with high efficiency and was associated with mild disease following intranasal infection of mice. In contrast, virus strain PR8 (H1N1) was poor in its ability to infect macrophages and highly virulent for mice. Depletion of airway macrophages by clodronate-loaded liposomes led to the development of severe viral pneumonia in BJx109-infected mice but did not modulate disease severity in PR8-infected mice. The severe disease observed in macrophage-depleted mice infected with BJx109 was associated with exacerbated virus replication in the airways, leading to severe airway inflammation, pulmonary edema, and vascular leakage, indicative of lung injury. Thymic atrophy, lymphopenia, and dysregulated cytokine and chemokine production were additional systemic manifestations associated with severe disease. Thus, airway macrophages play a critical role in limiting lung injury and associated disease caused by BJx109. Furthermore, the inability of PR8 to infect airway macrophages may be a critical factor contributing to its virulence for mice. PMID:20504924

Enzyme replacement therapy in a patient with Fabry disease and the development of IgE antibodies against agalsidase beta but not agalsidase alpha.

PubMed

Tanaka, Akemi; Takeda, Taisuke; Hoshina, Takao; Fukai, Kazuyoshi; Yamano, Tsunekazu

2010-12-01

Fabry disease is an X-linked inherited lysosomal storage disorder caused by an inborn deficiency of the enzyme α-galactosidase A. Enzyme replacement therapy (ERT) with agalsidase alpha or beta isozymes is an effective treatment. Cross-reactivity of immunoglobulin G (IgG) antibodies with agalsidase alpha and beta has been reported, but no such reaction has been recorded for IgE antibodies. We present the case of a patient with Fabry disease who developed antiagalsidase beta IgE antibodies without cross-reactivity to agalsidase alpha. A 17-year-old boy with Fabry disease had suffered from severe atopic dermatitis since infancy, and he complained for several years of peripheral pain during the summer months and when exercising. Fabry disease was confirmed by family history and a positive enzyme test, and ERT was commenced. Following infusion of agalsidase beta (1.0 mg/kg), the patient complained of a high temperature in his hands and feet, and purulent eczema developed. The infusion dose was reduced to 0.2 mg/kg, but the hyperthermia did not change, although its duration decreased. After three infusions, eosinophilia developed (9.4%; 573 cells/μl blood) and remained unresolved after four infusions with agalsidase beta. Treatment with this enzyme was discontinued, and agalsidase alpha (0.2 mg/kg) started. This produced immediate resolution of the eosinophilia, which has been maintained during follow-up. In conclusion, this patient developed IgE antibodies against agalsidase beta, which demonstrated no cross-reactivity to agalsidase alpha. These findings emphasize the importance of analyzing IgE antibodies against both enzymes when patients exhibit severe infusion-related events.

Neonatal Screening Tests.

ERIC Educational Resources Information Center

Vigue, Charles L.

1986-01-01

Describes several laboratory experiments that are adaptations of clinical tests for certain genetic diseases in babies. Information and procedures are provided for tests for phenylketonuria (PKU), galactosemia, tyrosinemia, cystinuria, and mucopolysaccharidosis. Discusses the effects of each disease on the infants' development. (TW)

Biophysical Aspects of Alzheimer's Disease: Implications for Pharmaceutical Sciences : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla.

PubMed

Arosio, Paolo

2017-12-01

An increasing amount of findings suggests that the aggregation of soluble peptides and proteins into amyloid fibrils is a relevant upstream process in the complex cascade of events leading to the pathology of Alzheimer's disease and several other neurodegenerative disorders. Nevertheless, several aspects of the correlation between the aggregation process and the onset and development of the pathology remain largely elusive. In this context, biophysical and biochemical studies in test tubes have proven extremely powerful in providing quantitative information about the structure and the reactivity of amyloids at the molecular level. In this review we use selected recent examples to illustrate the importance of such biophysical research to complement phenomenological studies based on cellular and molecular biology, and we discuss the implications for pharmaceutical applications associated with Alzheimer's disease and other neurodegenerative disorders in both academic and industrial contexts.

Children Reared in a Reverse Isolation Environment: Effects on Cognitive and Emotional Development.

ERIC Educational Resources Information Center

Tamaroff, Michael H.; And Others

1986-01-01

The study examined cognitive and emotional aspects of development in four infants treated from 10 to 52 months in a reverse isolation environment because of congenital severe combined immunodeficiency disease. Case material is discussed with reference to severe disruption of oral feeding experience, quality of parental involvement, and sensory…

Association of ERAP1, IL23R and PTGER4 Polymorphisms with Radiographic Severity of Ankylosing Spondylitis

PubMed Central

Ozen, Gulsen; Deniz, Rabia; Eren, Fatih; Erzik, Can; Unal, Ali Ugur; Yavuz, Sule; Aydin, Sibel Zehra; Inanc, Nevsun; Direskeneli, Haner; Atagunduz, Pamir

2017-01-01

Background: Radiographic severity of ankylosing spondylitis (AS) shows such great variance that some patients never develop syndesmophytes throughout the entire disease span, whereas some develop bamboo spine relatively early. Objective: To study the association between ERAP1, IL23R and PTGER4 single nucleotide polymorphisms (SNPs) and radiographic severity in AS patients. Methods: rs27044 and rs30187 (ERAP1), rs11209032 (IL23R) and rs10440635 (PTGER4) SNPs were genotyped in 235 AS patients fulfilling the modified New York criteria. Patients were classified as mild- and severe-AS according to modified Stoke AS spinal score (mSASSS). Mild-AS is defined as having mSASSS of “0” following at least 10 years of disease duration. Severe-AS is defined as having mSASSS of >20 (patients with mild vertebral changes (i.e. squaring or erosions) were omitted for clear stratification) regardless of disease duration. Results: The genotype distributions and allele frequencies of ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs were similar in mild- (n=171, mSASSS=0, 55.6% HLA-B27 positive) and severe-AS patients (n=64, mSASSS=48.5±17.8, 73.4% HLA-B27 positive). After adjustment for clinical differences between groups (gender, disease duration, HLA-B27 and smoking status) by logistic regression analysis, none of the alleles in the investigated SNPs were found to be associated with radiographic severity of AS. Conclusion: In radiographically well-categorized AS patients, ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs are not found to be associated with radiographic severity of AS. PMID:28400866

Association of ERAP1, IL23R and PTGER4 Polymorphisms with Radiographic Severity of Ankylosing Spondylitis.

PubMed

Ozen, Gulsen; Deniz, Rabia; Eren, Fatih; Erzik, Can; Unal, Ali Ugur; Yavuz, Sule; Aydin, Sibel Zehra; Inanc, Nevsun; Direskeneli, Haner; Atagunduz, Pamir

2017-01-01

Radiographic severity of ankylosing spondylitis (AS) shows such great variance that some patients never develop syndesmophytes throughout the entire disease span, whereas some develop bamboo spine relatively early. To study the association between ERAP1 , IL23R and PTGER4 single nucleotide polymorphisms (SNPs) and radiographic severity in AS patients. rs27044 and rs30187 ( ERAP1 ), rs11209032 ( IL23R ) and rs10440635 ( PTGER4 ) SNPs were genotyped in 235 AS patients fulfilling the modified New York criteria. Patients were classified as mild- and severe-AS according to modified Stoke AS spinal score (mSASSS). Mild-AS is defined as having mSASSS of "0" following at least 10 years of disease duration. Severe-AS is defined as having mSASSS of >20 (patients with mild vertebral changes ( i.e. squaring or erosions) were omitted for clear stratification) regardless of disease duration. The genotype distributions and allele frequencies of ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs were similar in mild- (n=171, mSASSS=0, 55.6% HLA-B27 positive) and severe-AS patients (n=64, mSASSS=48.5±17.8, 73.4% HLA-B27 positive). After adjustment for clinical differences between groups (gender, disease duration, HLA-B27 and smoking status) by logistic regression analysis, none of the alleles in the investigated SNPs were found to be associated with radiographic severity of AS. In radiographically well-categorized AS patients, ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs are not found to be associated with radiographic severity of AS.

Annosus Root Disease Hazard Rating, Detection, and Management Strategies in the Southeastern United States

Treesearch

S. A. Alexander

1989-01-01

Annosus root disease (ARD), is the major root disease of pines in the southeastern United States where severely affected trees exhibit growth loss. Assessing the potential damage of ARD is essential for making effective disease control and management decisions. A soil hazard rating system developed to identify potential for tree mortality is described. The Annosus...

Considering Valproate as a Risk Factor for Rapid Exacerbation of Complex Movement Disorder in Progressed Stages of Late-Infantile CLN2 Disease.

PubMed

Johannsen, Jessika; Nickel, Miriam; Schulz, Angela; Denecke, Jonas

2016-06-01

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease, OMIM 204500) is a rare autosomal-recessive lysosomal storage disorder. It is one of the most common neurodegenerative disorders in childhood. Symptoms include epilepsy, rapid motor and language regression, dementia, visual loss, and a complex movement disorder in later stages of the disease. We report on two children with genetically confirmed late-infantile CLN2 disease who developed a severe exacerbation of their complex movement disorder leading to hyperthermia, hyper-CK-emia and decreased level of consciousness over several weeks despite different therapeutic approaches. Both patients were on long-term antiepileptic treatment with valproate and only after the withdrawal of valproate, the movement disorder disappeared and level of consciousness improved. These observations emphasize that valproate has to be considered as a possible risk factor in patients in later stages of late-infantile CLN2 disease who develop a rapidly progressive complex movement disorder. Georg Thieme Verlag KG Stuttgart · New York.

Hyperthyroid vs hypothyroid eye disease: the same severity and activity

PubMed Central

Kashkouli, M B; Pakdel, F; Kiavash, V; Heidari, I; Heirati, A; Jam, S

2011-01-01

Purpose To compare demographics, severity, and activity of thyroid eye disease (TED) in patients with hyperthyroidism (Hr-TED) vs primary hypothyroidism (Ho-TED). Patients and Methods In a cross-sectional study, demographics, complete eye examination, severity score (NOSPECS, total hundred eye score), clinical activity score, and Rundle grading were recorded for patients with TED and different thyroid disorders referred from an endocrinology clinic from 2003 to 2006. Results TED was clinically found in 303 patients (303/851, 35.6%). The majority of them (280/303, 92.4%) had Graves' hyperthyroidism and 23 (23/303, 7.5%) had primary hypothyroidism. Mean age, gender, mean severity score, mean activity score, Rundle grade, unilateral presentation of TED, smoking habit, mean duration of eye disease, and mean interval time of thyroid to TED were not significantly different between the two groups (0.06

A review of QSAR studies to discover new drug-like compounds actives against leishmaniasis and trypanosomiasis.

PubMed

Castillo-Garit, Juan Alberto; Abad, Concepción; Rodríguez-Borges, J Enrique; Marrero-Ponce, Yovani; Torrens, Francisco

2012-01-01

The neglected tropical diseases (NTDs) affect more than one billion people (one-sixth of the world's population) and occur primarily in undeveloped countries in sub-Saharan Africa, Asia, and Latin America. Available drugs for these diseases are decades old and present an important number of limitations, especially high toxicity and, more recently, the emergence of drug resistance. In the last decade several Quantitative Structure-Activity Relationship (QSAR) studies have been developed in order to identify new organic compounds with activity against the parasites responsible for these diseases, which are reviewed in this paper. The topics summarized in this work are: 1) QSAR studies to identify new organic compounds actives against Chaga's disease; 2) Development of QSAR studies to discover new antileishmanial drusg; 3) Computational studies to identify new drug-like compounds against human African trypanosomiasis. Each topic include the general characteristics, epidemiology and chemotherapy of the disease as well as the main QSAR approaches to discovery/identification of new actives compounds for the corresponding neglected disease. The last section is devoted to a new approach know as multi-target QSAR models developed for antiparasitic drugs specifically those actives against trypanosomatid parasites. At present, as a result of these QSAR studies several promising compounds, active against these parasites, are been indentify. However, more efforts will be required in the future to develop more selective (specific) useful drugs.

Procalcitonin as a biomarker for severe Plasmodium falciparum disease: a critical appraisal of a semi-quantitative point-of-care test in a cohort of travellers with imported malaria.

PubMed

Hesselink, Dennis A; Burgerhart, Jan-Steven; Bosmans-Timmerarends, Hanna; Petit, Pieter; van Genderen, Perry J J

2009-09-01

Imported malaria occurs as a relatively rare event in developed countries. As a consequence, most clinicians have little experience in making clinical assessments of disease severity and decisions regarding the need for parenteral therapy or high-level monitoring. In this study, the diagnostic accuracy of procalcitonin (PCT) for severe Plasmodium falciparum disease was assessed in a cohort of 100 consecutive travellers with various species of imported malaria. In all patients, PCT was measured on admission with a semi-quantitative 'point-of-care' test. Patients with severe P. falciparum malaria had significantly higher median PCT levels on admission as compared with patients with uncomplicated P. falciparum disease. In addition, PCT levels in patients with non-falciparum malaria were also higher compared with patients with non-severe falciparum malaria but lower compared with severe P. falciparum malaria. At a cut-off point of 10 ng/mL, PCT had a sensitivity of 0,67 and a specificity of 0,94 for severe falciparum disease. However, at lower cut-off points the specificity and positive predictive value were rather poor although the sensitivity and negative predictive value remained high. Potential drawbacks in the interpretation of elevated PCT levels on admission may be caused by infections with non-falciparum species and by concomitant bacterial infections. Semi-quantitative determination of PCT on admission is of limited use in the initial clinical assessment of disease severity in travellers with imported malaria, especially in settings with limited experience with the treatment of malaria.

A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis.

PubMed

Colpitts, Sara L; Kasper, Eli J; Keever, Abigail; Liljenberg, Caleb; Kirby, Trevor; Magori, Krisztian; Kasper, Lloyd H; Ochoa-Repáraz, Javier

2017-11-02

The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

Pathogenesis of canine distemper virus in experimentally infected raccoon dogs, foxes, and minks.

PubMed

Zhao, Jianjun; Shi, Ning; Sun, Yangang; Martella, Vito; Nikolin, Veljko; Zhu, Chunsheng; Zhang, Hailing; Hu, Bo; Bai, Xue; Yan, Xijun

2015-10-01

Canine distemper virus (CDV) infects a broad range of carnivores and causes a highly contagious disease with severe immunosuppression. The disease severity markedly varies in different species. To investigate the pathogenesis of CDV in raccoon dog (Nyctereutes procyonoides), fox (Vulpes vulpes) and mink (Neovison vison) species, three groups of CDV sero-negative animals were infected with CDV strain LN(10)1. This CDV strain belongs to the Asia-1 genotype, which is epidemiologically predominant in carnivores in China. CDV infection provoked marked differences in virulence in the three species that were studied. Raccoon dogs developed fever, severe conjunctivitis, and pathological lesions, with 100% (5/5) mortality and with high viral RNA loads in organs within 15 days post infection (dpi). In infected foxes, the onset of the disease was delayed, with 40% (2/5) mortality by 21 dpi. Infected minks developed only mild clinical signs and pathological lesions, and mortality was not observed. Raccoon dogs and foxes showed more severe immune suppression (lymphopenia, decreased lymphocyte proliferation, viremia and low-level virus neutralizing antibodies) than minks. We also observed a distinct pattern of cytokine mRNA transcripts at different times after infection. Decreased IFN-γ and IL-4 mRNA responses were evident in the animals with fatal disease, while up-regulation of these cytokines was observed in the animals surviving the infection. Increased TNF-α response was detected in animals with mild or severe clinical signs. Based on the results, we could distinguish three different patterns of disease after experimental CDV infection, e.g. a mild form in minks, a moderate form in foxes and a severe disease in raccoon dogs. The observed differences in susceptibility to CDV could be related to distinct host cytokine profiles. Comparative evaluation of CDV pathogenesis in various animal species is pivotal to generate models suitable for the evaluation of CDV-host interactions and of vaccine response. Copyright © 2015 Elsevier B.V. All rights reserved.

Enabling breakthroughs in Parkinson’s disease with wearable technologies and big data analytics

PubMed Central

Cohen, Shahar; Martig, Adria K.

2016-01-01

Parkinson’s disease (PD) is a progressive, degenerative disorder of the central nervous system that is diagnosed and measured clinically by the Unified Parkinson’s Disease Rating Scale (UPDRS). Tools for continuous and objective monitoring of PD motor symptoms are needed to complement clinical assessments of symptom severity to further inform PD therapeutic development across several arenas, from developing more robust clinical trial outcome measures to establishing biomarkers of disease progression. The Michael J. Fox Foundation for Parkinson’s Disease Research and Intel Corporation have joined forces to develop a mobile application and an Internet of Things (IoT) platform to support large-scale studies of objective, continuously sampled sensory data from people with PD. This platform provides both population and per-patient analyses, measuring gait, activity level, nighttime activity, tremor, as well as other structured assessments and tasks. All data collected will be available to researchers on an open-source platform. Development of the IoT platform raised a number of engineering considerations, including wearable sensor choice, data management and curation, and algorithm validation. This project has successfully demonstrated proof of concept that IoT platforms, wearable technologies and the data they generate offer exciting possibilities for more robust, reliable, and low-cost research methodologies and patient care strategies. PMID:28293596

Enabling breakthroughs in Parkinson's disease with wearable technologies and big data analytics.

PubMed

Cohen, Shahar; Bataille, Lauren R; Martig, Adria K

2016-01-01

Parkinson's disease (PD) is a progressive, degenerative disorder of the central nervous system that is diagnosed and measured clinically by the Unified Parkinson's Disease Rating Scale (UPDRS). Tools for continuous and objective monitoring of PD motor symptoms are needed to complement clinical assessments of symptom severity to further inform PD therapeutic development across several arenas, from developing more robust clinical trial outcome measures to establishing biomarkers of disease progression. The Michael J. Fox Foundation for Parkinson's Disease Research and Intel Corporation have joined forces to develop a mobile application and an Internet of Things (IoT) platform to support large-scale studies of objective, continuously sampled sensory data from people with PD. This platform provides both population and per-patient analyses, measuring gait, activity level, nighttime activity, tremor, as well as other structured assessments and tasks. All data collected will be available to researchers on an open-source platform. Development of the IoT platform raised a number of engineering considerations, including wearable sensor choice, data management and curation, and algorithm validation. This project has successfully demonstrated proof of concept that IoT platforms, wearable technologies and the data they generate offer exciting possibilities for more robust, reliable, and low-cost research methodologies and patient care strategies.

Sycamore diseases

Treesearch

F. I. McCracken

1989-01-01

The canker stain disease, one of several fungi that cause cankers of sycamore, can cause serious loss of sycamores in natural stands, plantations, and urban areas. As many as 35 percent of the trees in some stands may be diseased. Affected trees develop thin crowns, twig dieback, small leaves and epicormic branches. The narrow, elongate, bark covered, flat, spiraling...

Transgenic Citrus Expressing an Arabidopsis NPR1 Gene Exhibit Enhanced Resistance against Huanglongbing (HLB; Citrus Greening).

PubMed

Dutt, Manjul; Barthe, Gary; Irey, Michael; Grosser, Jude

2015-01-01

Commercial sweet orange cultivars lack resistance to Huanglongbing (HLB), a serious phloem limited bacterial disease that is usually fatal. In order to develop sustained disease resistance to HLB, transgenic sweet orange cultivars 'Hamlin' and 'Valencia' expressing an Arabidopsis thaliana NPR1 gene under the control of a constitutive CaMV 35S promoter or a phloem specific Arabidopsis SUC2 (AtSUC2) promoter were produced. Overexpression of AtNPR1 resulted in trees with normal phenotypes that exhibited enhanced resistance to HLB. Phloem specific expression of NPR1 was equally effective for enhancing disease resistance. Transgenic trees exhibited reduced diseased severity and a few lines remained disease-free even after 36 months of planting in a high-disease pressure field site. Expression of the NPR1 gene induced expression of several native genes involved in the plant defense signaling pathways. The AtNPR1 gene being plant derived can serve as a component for the development of an all plant T-DNA derived consumer friendly GM tree.

Increased Lymphatic Vessel Length Is Associated With the Fibroblast Reticulum and Disease Severity in Usual Interstitial Pneumonia and Nonspecific Interstitial Pneumonia

PubMed Central

Cosgrove, Gregory P.; Janssen, William J.; Huie, Tristan J.; Burnham, Ellen L.; Heinz, David E.; Curran-Everett, Douglas; Sahin, Hakan; Schwarz, Marvin I.; Cool, Carlyne D.; Groshong, Steve D.; Geraci, Mark W.; Tuder, Rubin M.; Hyde, Dallas M.; Henson, Peter M.

2012-01-01

Background: Lymphangiogenesis responds to tissue injury as a key component of normal wound healing. The development of fibrosis in the idiopathic interstitial pneumonias may result from abnormal wound healing in response to injury. We hypothesize that increased lymphatic vessel (LV) length, a marker of lymphangiogenesis, is associated with parenchymal components of the fibroblast reticulum (organizing collagen, fibrotic collagen, and fibroblast foci), and its extent correlates with disease severity. Methods: We assessed stereologically the parenchymal structure of fibrotic lungs and its associated lymphatic network, which was highlighted immunohistochemically in age-matched samples of usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) with FVC < 80%, COPD with a Global Initiative for Obstructive Lung Disease stage 0, and normal control lungs. Results: LV length density, as opposed to vessel volume density, was found to be associated with organizing and fibrotic collagen density (P < .0001). Length density of LVs and the volume density of organizing and fibrotic collagen were significantly associated with severity of both % FVC (P < .001) and diffusing capacity of the lung for carbon monoxide (P < .001). Conclusions: Severity of disease in UIP and NSIP is associated with increased LV length and is strongly associated with components of the fibroblast reticulum, namely organizing and fibrotic collagen, which supports a pathogenic role of LVs in these two diseases. Furthermore, the absence of definable differences between UIP and NSIP suggests that LVs are a unifying mechanism for the development of fibrosis in these fibrotic lung diseases. PMID:22797508

The Role of Heterotypic DENV-specific CD8+T Lymphocytes in an Immunocompetent Mouse Model of Secondary Dengue Virus Infection.

PubMed

Talarico, Laura B; Batalle, Juan P; Byrne, Alana B; Brahamian, Jorge M; Ferretti, Adrián; García, Ayelén G; Mauri, Aldana; Simonetto, Carla; Hijano, Diego R; Lawrence, Andrea; Acosta, Patricio L; Caballero, Mauricio T; Paredes Rojas, Yésica; Ibañez, Lorena I; Melendi, Guillermina A; Rey, Félix A; Damonte, Elsa B; Harris, Eva; Polack, Fernando P

2017-06-01

Dengue is the most prevalent arthropod-borne viral disease worldwide and is caused by the four dengue virus serotypes (DENV-1-4). Sequential heterologous DENV infections can be associated with severe disease manifestations. Here, we present an immunocompetent mouse model of secondary DENV infection using non mouse-adapted DENV strains to investigate the pathogenesis of severe dengue disease. C57BL/6 mice infected sequentially with DENV-1 (strain Puerto Rico/94) and DENV-2 (strain Tonga/74) developed low platelet counts, internal hemorrhages, and increase of liver enzymes. Cross-reactive CD8 + T lymphocytes were found to be necessary and sufficient for signs of severe disease by adoptively transferring of DENV-1-immune CD8 + T lymphocytes before DENV-2 challenge. Disease signs were associated with production of tumor necrosis factor (TNF)-α and elevated cytotoxicity displayed by heterotypic anti-DENV-1 CD8 + T lymphocytes. These findings highlight the critical role of heterotypic anti-DENV CD8 + T lymphocytes in manifestations of severe dengue disease. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Development of anti-inflammatory drugs - the research and development process.

PubMed

Knowles, Richard Graham

2014-01-01

The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, 'improving on the Beatles' in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti-inflammatory medicines. © 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.

Quality of life in patients with Parkinson's disease: development of a questionnaire.

PubMed Central

de Boer, A G; Wijker, W; Speelman, J D; de Haes, J C

1996-01-01

OBJECTIVES--To develop and test a questionnaire for measuring quality of life in patients with Parkinson's disease. METHODS--An item pool was developed based on the experience of patients with Parkinson's disease and of neurologists; medical literature on the problems of patients with Parkinson's disease; and other quality of life questionnaires. To reduce the item pool, 13 patients identified items that were a problem to them and rated their importance. Items which were most often chosen and rated most important were included in the Parkinson's disease quality of life questionnaire (PDQL). The PDQL consists of 37 items. To evaluate the discriminant validity of the PDQL three groups of severity of disease were compared. To test for convergent validity, the scores of the PDQL were tested for correlation with standard indices of quality of life. RESULTS--The PDQL was filled out by 384 patients with Parkinson's disease. It consisted of four subscales: parkinsonian symptoms, systemic symptoms, emotional functioning, and social functioning. The internal-consistency reliability coefficients of the PDQL subscales were high (0.80-0.87). Patients with higher disease severity had significantly lower quality of life on all PDQL subscales (P < 0.05). Almost all PDQL subscales correlated highly (P < 0.001) with the corresponding scales of the standard quality of life indices. CONCLUSION--The PDQL is a relevant, reliable, and valid measure of the quality of life of patients with Parkinson's disease. Images PMID:8676165

Prevalence of periodontal disease, its association with systemic diseases and prevention

PubMed Central

Nazir, Muhammad Ashraf

2017-01-01

Periodontal diseases are prevalent both in developed and developing countries and affect about 20-50% of global population. High prevalence of periodontal disease in adolescents, adults, and older individuals makes it a public health concern. Several risk factors such as smoking, poor oral hygiene, diabetes, medication, age, hereditary, and stress are related to periodontal diseases. Robust evidence shows the association of periodontal diseases with systemic diseases such as cardiovascular disease, diabetes, and adverse pregnancy outcomes. Periodontal disease is likely to cause 19% increase in the risk of cardiovascular disease, and this increase in relative risk reaches to 44% among individuals aged 65 years and over. Type 2 diabetic individuals with severe form of periodontal disease have 3.2 times greater mortality risk compared with individuals with no or mild periodontitis. Periodontal therapy has been shown to improve glycemic control in type 2 diabetic subjects. Periodontitis is related to maternal infection, preterm birth, low birth weight, and preeclampsia. Oral disease prevention strategies should be incorporated in chronic systemic disease preventive initiatives to curtail the burden of disease in populations. The reduction in the incidence and prevalence of periodontal disease can reduce its associated systemic diseases and can also minimize their financial impact on the health-care systems. It is hoped that medical, dental practitioners, and other health-care professionals will get familiar with perio-systemic link and risk factors, and need to refer to the specialized dental or periodontal care. PMID:28539867

Prevalence of periodontal disease, its association with systemic diseases and prevention.

PubMed

Nazir, Muhammad Ashraf

2017-01-01

Periodontal diseases are prevalent both in developed and developing countries and affect about 20-50% of global population. High prevalence of periodontal disease in adolescents, adults, and older individuals makes it a public health concern. Several risk factors such as smoking, poor oral hygiene, diabetes, medication, age, hereditary, and stress are related to periodontal diseases. Robust evidence shows the association of periodontal diseases with systemic diseases such as cardiovascular disease, diabetes, and adverse pregnancy outcomes. Periodontal disease is likely to cause 19% increase in the risk of cardiovascular disease, and this increase in relative risk reaches to 44% among individuals aged 65 years and over. Type 2 diabetic individuals with severe form of periodontal disease have 3.2 times greater mortality risk compared with individuals with no or mild periodontitis. Periodontal therapy has been shown to improve glycemic control in type 2 diabetic subjects. Periodontitis is related to maternal infection, preterm birth, low birth weight, and preeclampsia. Oral disease prevention strategies should be incorporated in chronic systemic disease preventive initiatives to curtail the burden of disease in populations. The reduction in the incidence and prevalence of periodontal disease can reduce its associated systemic diseases and can also minimize their financial impact on the health-care systems. It is hoped that medical, dental practitioners, and other health-care professionals will get familiar with perio-systemic link and risk factors, and need to refer to the specialized dental or periodontal care.

The coronafacoyl phytotoxins: structure, biosynthesis, regulation and biological activities.

PubMed

Bignell, Dawn R D; Cheng, Zhenlong; Bown, Luke

2018-05-01

Phytotoxins are secondary metabolites that contribute to the development and/or severity of diseases caused by various plant pathogenic microorganisms. The coronafacoyl phytotoxins are an important family of plant toxins that are known or suspected to be produced by several phylogenetically distinct plant pathogenic bacteria, including the gammaproteobacterium Pseudomonas syringae and the actinobacterium Streptomyces scabies. At least seven different family members have been identified, of which coronatine was the first to be described and is the best-characterized. Though nonessential for disease development, coronafacoyl phytotoxins appear to enhance the severity of disease symptoms induced by pathogenic microbes during host infection. In addition, the identification of coronafacoyl phytotoxin biosynthetic genes in organisms not known to be plant pathogens suggests that these metabolites may have additional roles other than as virulence factors. This review focuses on our current understanding of the structures, biosynthesis, regulation, biological activities and evolution of coronafacoyl phytotoxins as well as the different methods that are used to detect these metabolites and the organisms that produce them.

MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2.

PubMed

Kim, Richard Y; Horvat, Jay C; Pinkerton, James W; Starkey, Malcolm R; Essilfie, Ama T; Mayall, Jemma R; Nair, Prema M; Hansbro, Nicole G; Jones, Bernadette; Haw, Tatt Jhong; Sunkara, Krishna P; Nguyen, Thi Hiep; Jarnicki, Andrew G; Keely, Simon; Mattes, Joerg; Adcock, Ian M; Foster, Paul S; Hansbro, Philip M

2017-02-01

Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease. We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches. Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated. Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21-specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens. We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Cation Homeostasis in Red Cells From Patients With Sickle Cell Disease Heterologous for HbS and HbC (HbSC Genotype)

PubMed Central

Hannemann, A.; Rees, D.C.; Tewari, S.; Gibson, J.S.

2015-01-01

Sickle cell disease (SCD) in patients of HbSC genotype is considered similar, albeit milder, to that in homozygous HbSS individuals — but with little justification. In SCD, elevated red cell cation permeability is critical as increased solute loss causes dehydration and encourages sickling. Recently, we showed that the KCl cotransporter (KCC) activity in red cells from HbSC patients correlated significantly with disease severity, but that in HbSS patients did not. Two transporters involved in red cell dehydration, the conductive channels Psickle and the Gardos channel, behaved similarly in red cells from the two genotypes, but were significantly less active in HbSC patients. By contrast, KCC activity was quantitatively greater in HbSC red cells. Results suggest that KCC is likely to have greater involvement in red cell dehydration in HbSC patients, which could explain its association with disease severity in this genotype. This work supports the hypothesis that SCD in HbSC patients is a distinct disease entity to that in HbSS patients. Results suggest the possibility of designing specific treatments of particular benefit to HbSC patients and a rationale for the development of prognostic markers, to inform early treatment of children likely to develop more severe complications of the disease. PMID:26870793

MIF and D-DT are potential disease severity modifiers in male MS subjects

PubMed Central

Benedek, Gil; Meza-Romero, Roberto; Jordan, Kelley; Zhang, Ying; Nguyen, Ha; Kent, Gail; Li, Jia; Siu, Edwin; Frazer, Jenny; Piecychna, Marta; Du, Xin; Sreih, Antoine; Leng, Lin; Wiedrick, Jack; Caillier, Stacy J.; Offner, Halina; Oksenberg, Jorge R.; Yadav, Vijayshree; Bourdette, Dennis; Bucala, Richard; Vandenbark, Arthur A.

2017-01-01

Little is known about mechanisms that drive the development of progressive multiple sclerosis (MS), although inflammatory factors, such as macrophage migration inhibitory factor (MIF), its homolog D-dopachrome tautomerase (D-DT), and their common receptor CD74 may contribute to disease worsening. Our findings demonstrate elevated MIF and D-DT levels in males with progressive disease compared with relapsing-remitting males (RRMS) and female MS subjects, with increased levels of CD74 in females vs. males with high MS disease severity. Furthermore, increased MIF and D-DT levels in males with progressive disease were significantly correlated with the presence of two high-expression promoter polymorphisms located in the MIF gene, a −794CATT5–8 microsatellite repeat and a −173 G/C SNP. Conversely, mice lacking MIF or D-DT developed less-severe signs of experimental autoimmune encephalomyelitis, a murine model of MS, thus implicating both homologs as copathogenic contributors. These findings indicate that genetically controlled high MIF expression (and D-DT) promotes MS progression in males, suggesting that these two factors are sex-specific disease modifiers and raising the possibility that aggressive anti-MIF treatment of clinically isolated syndrome or RRMS males with a high-expresser genotype might slow or prevent the onset of progressive MS. Additionally, selective targeting of MIF:CD74 signaling might provide an effective, trackable therapeutic approach for MS subjects of both sexes. PMID:28923927

Virulence Factor Targeting of the Bacterial Pathogen Staphylococcus aureus for Vaccine and Therapeutics

PubMed Central

Kane, Trevor L.; Carothers, Katelyn E.; Lee, Shaun W.

2018-01-01

Background Staphylococcus aureus is a major bacterial pathogen capable of causing a range of infections in humans from gastrointestinal disease, skin and soft tissue infections, to severe outcomes such as sepsis. Staphylococcal infections in humans can be frequent and recurring, with treatments becoming less effective due to the growing persistence of antibiotic resistant S. aureus strains. Due to the prevalence of antibiotic resistance, and the current limitations on antibiotic development, an active and highly promising avenue of research has been to develop strategies to specifically inhibit the activity of virulence factors produced S. aureus as an alternative means to treat disease. Objective In this review we specifically highlight several major virulence factors produced by S. aureus for which recent advances in antivirulence approaches may hold promise as an alternative means to treating diseases caused by this pathogen. Strategies to inhibit virulence factors can range from small molecule inhibitors, to antibodies, to mutant and toxoid forms of the virulence proteins. Conclusion The major prevalence of antibiotic resistant strains of S. aureus combined with the lack of new antibiotic discoveries highlight the need for vigorous research into alternative strategies to combat diseases caused by this highly successful pathogen. Current efforts to develop specific antivirulence strategies, vaccine approaches, and alternative therapies for treating severe disease caused by S. aureus have the potential to stem the tide against the limitations that we face in the post-antibiotic era. PMID:27894236

Tocilizumab: therapy and safety management.

PubMed

Pham, Thao; Claudepierre, Pascal; Constantin, Arnaud; de Bandt, Michel; Fautrel, Bruno; Gossec, Laure; Gottenberg, Jacques-Eric; Goupille, Philippe; Guillaume, Séverine; Hachulla, Eric; Masson, Charles; Morel, Jacques; Puéchal, Xavier; Saraux, Alain; Schaeverbeke, Thierry; Wendling, Daniel; Bruckert, Eric; Pol, Stanislas; Mariette, Xavier; Sibilia, Jean

2010-06-01

To develop fact sheets about tocilizumab, in order to assist physicians in the management of patients with inflammatory joint disease. 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The 20 experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of RA. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Société Francaise de Rhumatologie. Each fact sheet was revised by several. experts and the overall process was coordinated by three experts. Several topics of major interest were selected: contraindications of tocilizumab; the management of adverse effects and concomitant diseases that may develop during tocilizumab therapy; and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: Several topics of major interest were selected: contraindications of tocilizumab; the management of adverse effects and concomitant diseases that may develop during tocilizumab therapy; and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA, initiation and monitoring of tocilizumab therapy, management of patients with specific past histories, and specific clinical situations such as pregnancy; 2. diseases other than RA, such as juvenile idiopathic arthritis; 3. models of letters for informing the rheumatologist and general practitioner; 4. and patient information. These tocilizumab fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on tocilizumab therapy. They will be available continuously at www.cri-net.com and updated at appropriate intervals. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Severe vincristine-induced polyneuropathy in a teenager with anaplastic medulloblastoma and undiagnosed Charcot-Marie-Tooth disease.

PubMed

Aghajan, Yasmin; Yoon, Janet M; Crawford, John Ross

2017-04-24

Severe neuropathy is a known adverse effect of vincristine in patients with Charcot-Marie-Tooth disease (CMT). We present the case of a 16-year-old girl with anaplastic medulloblastoma treated with gross total resection and high-dose craniospinal radiation with adjuvant vincristine chemotherapy who developed acute-onset severe quadriplegia and vocal cord paralysis. Vincristine and radiation therapy were discontinued. Although her neuropathy slowly improved over several weeks, she developed metastatic extraneural medulloblastoma and died 5 months after diagnosis. Subsequent genetic testing revealed previously asymptomatic and undiagnosed CMT1A. Our case highlights the importance of early recognition of acute vincristine neurotoxicity that should raise suspicion of an underlying hereditary neuropathy. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Exome sequencing identifies SUCO mutations in mesial temporal lobe epilepsy.

PubMed

Sha, Zhiqiang; Sha, Longze; Li, Wenting; Dou, Wanchen; Shen, Yan; Wu, Liwen; Xu, Qi

2015-03-30

Mesial temporal lobe epilepsy (mTLE) is the main type and most common medically intractable form of epilepsy. Severity of disease-based stratified samples may help identify new disease-associated mutant genes. We analyzed mRNA expression profiles from patient hippocampal tissue. Three of the seven patients had severe mTLE with generalized-onset convulsions and consciousness loss that occurred over many years. We found that compared with other groups, patients with severe mTLE were classified into a distinct group. Whole-exome sequencing and Sanger sequencing validation in all seven patients identified three novel SUN domain-containing ossification factor (SUCO) mutations in severely affected patients. Furthermore, SUCO knock down significantly reduced dendritic length in vitro. Our results indicate that mTLE defects may affect neuronal development, and suggest that neurons have abnormal development due to lack of SUCO, which may be a generalized-onset epilepsy-related gene. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Can metagenetic studies of soil microbial communities provide insights toward developing novel management approaches for Armillaria root disease?

Treesearch

Mee-Sook Kim; Amy L. Ross-Davis; Jane E. Stewart; John W. Hanna; Marcus V. Warwell; Paul J. Zambino; Christy Cleaver; Geral I. McDonald; Deborah Page-Dumroese; Bruce Moltzan; Ned B. Klopfenstein

2016-01-01

Armillaria root diseases are among the most damaging and broadly distributed group of forest diseases in the world (Lockman et al. in press). Armillaria root disease is typically more severe in highly susceptible tree species and in trees that are maladapted due to rapidly changing climatic conditions (Ayres and Lombardero 2000, Kliejunas et al. 2009, Sturrock...

Inflammatory bowel disease in India - Past, present and future.

PubMed

Ray, Gautam

2016-09-28

There is rising incidence and prevalence of inflammatory bowel disease (IBD) in India topping the Southeast Asian (SEA) countries. The common genes implicated in disease pathogenesis in the West are not causal in Indian patients and the role of "hygiene hypothesis" is unclear. There appears to be a North-South divide with more ulcerative colitis (UC) in north and Crohn's disease (CD) in south India. IBD in second generation Indian migrants to the West takes the early onset and more severe form of the West whereas it retains the nature of its country of origin in migrants to SEA countries. The clinical presentation is much like other SEA countries (similar age and sex profile, low positive family history and effect of smoking, roughly similar disease location, use of aminosalicylates for CD, low use of biologics and similar surgical rates) with some differences (higher incidence of inflammatory CD, lower perianal disease, higher use of aminosalicylates and azathioprine and lower current use of corticosteroids). UC presents more with extensive disease not paralleled in severity clinically or histologically, follows benign course with easy medical control and low incidence of fulminant disease, cancer, complications, and surgery. UC related colorectal cancer develop in an unpredictable manner with respect to disease duration and site questioning the validity of strict screening protocol. About a third of CD patients get antituberculosis drugs and a significant number presents with small intestinal bleed which is predominantly afflicted by aggressive inflammation. Biomarkers have inadequate diagnostic sensitivity and specificity for both. Pediatric IBD tends to be more severe than adult. Population based studies are needed to address the lacunae in epidemiology and definition of etiological factors. Newer biomarkers and advanced diagnostic techniques (in the field of gastrointestinal endoscopy, molecular pathology and genetics) needs to be developed for proper disease definition and treatment.

The specialist physician’s approach to rheumatoid arthritis in South Africa

PubMed Central

Bester, Frederik C. J.; Bosch, Fredricka J.; van Rensburg, Barend J. Jansen

2016-01-01

Rheumatoid arthritis (RA) is expected to increase in Africa and South Africa. Due to the low numbers of rheumatologists in South Africa, specialist physicians also have to care for patients with RA. Furthermore several new developments have taken place in recent years which improved the management and outcome of RA. Classification criteria were updated, assessment follow-up tools were refined and above all, several new biological disease-modifying anti-rheumatic drugs were developed. Therefore it is imperative for specialist physicians to update themselves with the newest developments in the management of RA. This article provides an overview of the newest developments in the management of RA in the South African context. This approach may well apply to countries with similar specialist to patient ratios and disease profiles. PMID:26932399

The specialist physician's approach to rheumatoid arthritis in South Africa.

PubMed

Bester, Frederik C J; Bosch, Fredricka J; van Rensburg, Barend J Jansen

2016-03-01

Rheumatoid arthritis (RA) is expected to increase in Africa and South Africa. Due to the low numbers of rheumatologists in South Africa, specialist physicians also have to care for patients with RA. Furthermore several new developments have taken place in recent years which improved the management and outcome of RA. Classification criteria were updated, assessment follow-up tools were refined and above all, several new biological disease-modifying anti-rheumatic drugs were developed. Therefore it is imperative for specialist physicians to update themselves with the newest developments in the management of RA. This article provides an overview of the newest developments in the management of RA in the South African context. This approach may well apply to countries with similar specialist to patient ratios and disease profiles.

Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice.

PubMed

Sharpton, Thomas; Lyalina, Svetlana; Luong, Julie; Pham, Joey; Deal, Emily M; Armour, Courtney; Gaulke, Christopher; Sanjabi, Shomyseh; Pollard, Katherine S

2017-01-01

The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where damped transforming growth factor β (TGF-β) signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including damped acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, levels of lipooligosaccharide transporter abundance diverge prior to immune activation, indicating that it could be a predisease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundances of particular taxa, including several species of Bacteroides , correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed-effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering the potential mechanisms through which the gut microbiome becomes altered in IBD. IMPORTANCE IBD patients harbor distinct microbial communities with functional capabilities different from those seen with healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading to disease onset. By performing weekly metagenomic sequencing and mixed-effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study was novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development.

Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice

PubMed Central

Sharpton, Thomas; Lyalina, Svetlana; Luong, Julie; Pham, Joey; Deal, Emily M.; Armour, Courtney; Gaulke, Christopher; Sanjabi, Shomyseh

2017-01-01

ABSTRACT The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where damped transforming growth factor β (TGF-β) signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including damped acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, levels of lipooligosaccharide transporter abundance diverge prior to immune activation, indicating that it could be a predisease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundances of particular taxa, including several species of Bacteroides, correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed-effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering the potential mechanisms through which the gut microbiome becomes altered in IBD. IMPORTANCE IBD patients harbor distinct microbial communities with functional capabilities different from those seen with healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading to disease onset. By performing weekly metagenomic sequencing and mixed-effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study was novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development. PMID:28904997

Naval Medical Research and Development News. Volume 7, Issue 11

DTIC Science & Technology

2015-11-01

diseases such as shigellosis and typhoid fever . The goal of the laboratory is to research, understand, and develop protective strategies against...public health significance in the region, including malaria and dengue fever , yellow fever , viral encephalitis, leishmaniasis, and enteric...waterborne disease, is characterized by fever , cramps and sometimes severe bloody diarrhea,” said Cmdr. Christopher Duplessis, lead researcher in

Health Gain through Screening--Coronary Heart Disease and Stroke: Developing Primary Health Care Services for People with Intellectual Disability.

ERIC Educational Resources Information Center

Wells, M. B.; Turner, S.; Martin, D. M.; Roy, A.

1997-01-01

A study of 120 British adults with intellectual disability found they had higher risk factors of developing coronary heart disease and stroke than the general population. There was a greater incidence of obesity and considerably lower physical activity levels than the general population. Several also had abnormal cholesterol readings. (CR)

Hendra Virus and Nipah Virus Animal Vaccines

PubMed Central

Weir, Dawn L.; Reid, Peter A.

2016-01-01

Hendra virus (HeV) and Nipah virus (NiV) are zoonotic viruses that emerged in the mid to late 1990s causing disease outbreaks in livestock and people. HeV appeared in Queensland, Australia in 1994 causing a severe respiratory disease in horses along with a human case fatality. NiV emerged a few years later in Malaysia and Singapore in 1998-99 causing a large outbreak of encephalitis with high mortality in people and also respiratory disease in pigs which served as amplifying hosts. The key pathological elements of HeV and NiV infection in several species of mammals, and also in people, are a severe systemic and often fatal neurologic and/or respiratory disease. In people, both HeV and NiV are also capable of causing relapsed encephalitis following recovery from an acute infection. The known reservoir hosts of HeV and NiV are several species of pteropid fruit bats. Spillovers of HeV into horses continue to occur in Australia and NiV has caused outbreaks in people in Bangladesh and India nearly annually since 2001, making HeV and NiV important transboundary biological threats. NiV in particular possesses several features that underscore its potential as a pandemic threat, including its ability to infect humans directly from natural reservoirs or indirectly from other susceptible animals, along with a capacity of limited human-to-human transmission. Several HeV and NiV animal challenge models have been developed which have facilitated an understanding of pathogenesis and allowed for the successful development of both active and passive immunization countermeasures. PMID:27154393

Hendra virus and Nipah virus animal vaccines.

PubMed

Broder, Christopher C; Weir, Dawn L; Reid, Peter A

2016-06-24

Hendra virus (HeV) and Nipah virus (NiV) are zoonotic viruses that emerged in the mid to late 1990s causing disease outbreaks in livestock and people. HeV appeared in Queensland, Australia in 1994 causing a severe respiratory disease in horses along with a human case fatality. NiV emerged a few years later in Malaysia and Singapore in 1998-1999 causing a large outbreak of encephalitis with high mortality in people and also respiratory disease in pigs which served as amplifying hosts. The key pathological elements of HeV and NiV infection in several species of mammals, and also in people, are a severe systemic and often fatal neurologic and/or respiratory disease. In people, both HeV and NiV are also capable of causing relapsed encephalitis following recovery from an acute infection. The known reservoir hosts of HeV and NiV are several species of pteropid fruit bats. Spillovers of HeV into horses continue to occur in Australia and NiV has caused outbreaks in people in Bangladesh and India nearly annually since 2001, making HeV and NiV important transboundary biological threats. NiV in particular possesses several features that underscore its potential as a pandemic threat, including its ability to infect humans directly from natural reservoirs or indirectly from other susceptible animals, along with a capacity of limited human-to-human transmission. Several HeV and NiV animal challenge models have been developed which have facilitated an understanding of pathogenesis and allowed for the successful development of both active and passive immunization countermeasures. Published by Elsevier Ltd.

Retinoic acid signaling pathways in development and diseases.

PubMed

Das, Bhaskar C; Thapa, Pritam; Karki, Radha; Das, Sasmita; Mahapatra, Sweta; Liu, Ting-Chun; Torregroza, Ingrid; Wallace, Darren P; Kambhampati, Suman; Van Veldhuizen, Peter; Verma, Amit; Ray, Swapan K; Evans, Todd

2014-01-15

Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging. Copyright © 2013 Elsevier Ltd. All rights reserved.

Whole Grains in Amelioration of Metabolic Derangements

PubMed Central

Develaraja, Samir; Reddy, Anup; Yadav, Mukesh; Jain, Shalini; Yadav, Hariom

2017-01-01

Daily diet influences whole body metabolism, and intricately linked to the prevention or progression of metabolic diseases including obesity, diabetes and cardiovascular diseases. Several epidemiological and large scale studies have shown that diets enriched with whole grains improves metabolic function and protect from the development of metabolic diseases. Direct impact of whole grain diet can be mediated on several levels of metabolic functions i.e. reduced glycemic index, improved fat oxidation potential, increased cholesterol clearance or decreased cholesterol biosynthesis and modulation of gut microbiome. In this article we reviewed several studies indicating the beneficial effects of whole grain diets on metabolic functions, as well as discussed the potential active phytochemicals present in these whole grain foods to contribute in modulation of metabolic function in our body. PMID:28944285

Uveitis in Children

PubMed Central

Angeles-Han, Sheila T.; Rabinovich, C. Egla

2016-01-01

Purpose of review This review provides updates on novel risk markers for the development of pediatric inflammatory uveitis and a severe disease course, on treatment of refractory disease, and on the measurement of visual outcomes. Recent findings There are several new genetic markers, biomarkers and clinical factors that may influence a child’s uveitis disease course. It is important to identify children at risk for poor visual outcomes and who are refractory to traditional therapy. Racial disparities have recently been reported. We describe agents of potential benefit. In addition, we discuss the importance of patient reported outcomes in this population. Summary Uveitis can lead to vision threatening complications. Timely and aggressive treatment of children identified to be at risk for a severe uveitis course may lead to improved outcomes. PMID:27328333

Vaccination against mosquito borne viral infections: current status.

PubMed

Wiwanitkit, Viroj

2007-12-01

Mosquito borne infectious diseases are among important group of diseases worldwide. Vaccination is available for some tropical mosquito-borne diseases, especially for Japanese encephalitis virus infection and yellow fever. There are also several attempts to develop new vaccines for the other mosquito-borne diseases such as malaria, dengue infection and West Nile virus infection. In this article, the author reviews the issues on vaccination of some important tropical mosquito borne infectious diseases.

Oligonucleotide-based therapy for neurodegenerative diseases.

PubMed

Magen, Iddo; Hornstein, Eran

2014-10-10

Molecular genetics insight into the pathogenesis of several neurodegenerative diseases, such as Alzheimer׳s disease, Parkinson׳s disease, Huntington׳s disease and amyotrophic lateral sclerosis, encourages direct interference with the activity of neurotoxic genes or the molecular activation of neuroprotective pathways. Oligonucleotide-based therapies are recently emerging as an efficient strategy for drug development and these can be employed as new treatments of neurodegenerative states. Here we review advances in this field in recent years which suggest an encouraging assessment that oligonucleotide technologies for targeting of RNAs will enable the development of new therapies and will contribute to preservation of brain integrity. Copyright © 2014 Elsevier B.V. All rights reserved.

Relationship between Packed Red Blood Cell Transfusion and Severe Form of Necrotizing Enterocolitis: A Case Control Study.

PubMed

Garg, Parvesh M; Ravisankar, Srikanth; Bian, Hui; Macgilvray, Scott; Shekhawat, Prem S

2015-12-01

To determine if packed red blood cell transfusion is associated with onset of necrotizing enterocolitis, and whether withholding feed has any association with it. Case records of 100 preterm neonates, (<34 weeks gestation) who developed necrotizing enterocolitis and 99 random age-and gestation-matched controls were evaluated for any blood transfusion 48 h before onset of necrotizing enterocolitis. During the study period 26% infants received packed red blood cell transfusion within 48-hours prior to onset of disease and 84% of these infants were not fed around the time of transfusion. Infants who developed necrotizing enterocolitis after transfusion were older, of lower gestational age, birth weight and more likely to develop stage 3 disease. They had a lower hematocrit at birth and before onset of disease and withholding feeds around transfusion did not prevent necrotizing enterocolitis. Odds of mortality in these infants was 2.83 (95% CI 0.97-8.9) and survivors had no significant difference in incidence of periventricular leukomalacia and length of hospital stay. Blood Transfusion associated necrotizing enterocolitis is a severe, mainly surgical form of disease.

Development of a disease-specific instrument to measure quality of life in patients with alopecia areata.

PubMed

Endo, Yuichiro; Miyachi, Yoshiki; Arakawa, Akiko

2012-01-01

Alopecia areata (AA) is a common hair loss disorder that frequently follows a chronic course. Although AA is apparently associated with disturbance of quality of life (QoL), no disease-specific instrument to measure the QoL has been developed. This study was conducted to develop a disease-specific self-administered instrument to measure AA patients' QoL (AAQ). A two-step cross-sectional study was conducted. Items were generated from qualitative interviews with five patients with AA (two men and three women, age 28±6.4 years). Then, a preliminary questionnaire was produced and delivered to the patients (n=122). The AAQ was examined in terms of statistical performance. The AAQ included 7 items in the following three subscales: 'restriction of activity', 'concealment' and 'adaptation'. The reliability of internal consistency was fair with Cronbach's alpha coefficients of 0.59-81 for each subscale. Confirmatory factor analysis and correlation analysis demonstrated that the AAQ had good construct validity. Interestingly, the AAQ was only correlated with subjective severity scores as rated by the patients, but not with objective disease severity assessed by investigators.

Computed Tomographic Airway Morphology in Chronic Obstructive Pulmonary Disease. Remodeling or Innate Anatomy?

PubMed

Diaz, Alejandro A; Estépar, Raul San José; Washko, George R

2016-01-01

Computed tomographic measures of central airway morphology have been used in clinical, epidemiologic, and genetic investigation as an inference of the presence and severity of small-airway disease in smokers. Although several association studies have brought us to believe that these computed tomographic measures reflect airway remodeling, a careful review of such data and more recent evidence may reveal underappreciated complexity to these measures and limitations that prompt us to question that belief. This Perspective offers a review of seminal papers and alternative explanations of their data in the light of more recent evidence. The relationships between airway morphology and lung function are observed in subjects who never smoked, implying that native airway structure indeed contributes to lung function; computed tomographic measures of central airways such as wall area, lumen area, and total bronchial area are smaller in smokers with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease; and the airways are smaller as disease severity increases. The observations suggest that (1) native airway morphology likely contributes to the relationships between computed tomographic measures of airways and lung function; and (2) the presence of smaller airways in those with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease as well as their decrease with disease severity suggests that smokers with chronic obstructive pulmonary disease may simply have smaller airways to begin with, which put them at greater risk for the development of smoking-related disease.

The BRICS (Bronchiectasis Radiologically Indexed CT Score): A Multicenter Study Score for Use in Idiopathic and Postinfective Bronchiectasis.

PubMed

Bedi, Pallavi; Chalmers, James D; Goeminne, Pieter C; Mai, Cindy; Saravanamuthu, Pira; Velu, Prasad Palani; Cartlidge, Manjit K; Loebinger, Michael R; Jacob, Joe; Kamal, Faisal; Schembri, Nicola; Aliberti, Stefano; Hill, Uta; Harrison, Mike; Johnson, Christopher; Screaton, Nicholas; Haworth, Charles; Polverino, Eva; Rosales, Edmundo; Torres, Antoni; Benegas, Michael N; Rossi, Adriano G; Patel, Dilip; Hill, Adam T

2018-05-01

The goal of this study was to develop a simplified radiological score that could assess clinical disease severity in bronchiectasis. The Bronchiectasis Radiologically Indexed CT Score (BRICS) was devised based on a multivariable analysis of the Bhalla score and its ability in predicting clinical parameters of severity. The score was then externally validated in six centers in 302 patients. A total of 184 high-resolution CT scans were scored for the validation cohort. In a multiple logistic regression model, disease severity markers significantly associated with the Bhalla score were percent predicted FEV 1 , sputum purulence, and exacerbations requiring hospital admission. Components of the Bhalla score that were significantly associated with the disease severity markers were bronchial dilatation and number of bronchopulmonary segments with emphysema. The BRICS was developed with these two parameters. The receiver operating-characteristic curve values for BRICS in the derivation cohort were 0.79 for percent predicted FEV 1 , 0.71 for sputum purulence, and 0.75 for hospital admissions per year; these values were 0.81, 0.70, and 0.70, respectively, in the validation cohort. Sputum free neutrophil elastase activity was significantly elevated in the group with emphysema on CT imaging. A simplified CT scoring system can be used as an adjunct to clinical parameters to predict disease severity in patients with idiopathic and postinfective bronchiectasis. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Co-existent sickle cell disease and juvenile rheumatoid arthritis. Two cases with delayed diagnosis and severe destructive arthropathy.

PubMed

Nistala, K; Murray, K J

2001-09-01

We describe 2 pediatric patients with sickle cell disease (SCD) who developed seropositive juvenile rheumatoid arthritis (JRA). Both patients have severe joint damage, the compound effect of both disease processes. The bone and cartilage destruction, which poses serious therapeutic challenges, highlights the difficulty of making a diagnosis of chronic inflammatory disease in the setting of SCD. There may be a correlation between increased levels of tumor necrosis factor-alpha in the synovial tissue of joints damaged by arthritis and local sickling. The resultant ischemia and corresponding inflammatory infiltrates could in turn worsen existing synovial proliferation and cartilage destruction as well as trigger further sickling.

Important role of translational science in rare disease innovation, discovery, and drug development.

PubMed

Pariser, Anne R; Gahl, William A

2014-08-01

Rare diseases play a leading role in innovation and the advancement of medical and pharmaceutical science. Most rare diseases are genetic disorders or atypical manifestations of infectious, immunologic, or oncologic diseases; they all provide opportunities to study extremes of human pathology and provide insight into both normal and aberrant physiology. Recently, drug development has become increasingly focused on classifying diseases largely on genetic grounds; this has allowed the identification of molecularly defined targets and the development of targeted therapies. Clinical trials are now focusing on progressively smaller subgroups within both common and rare disease populations, often based on genetic tests or biomarkers. Drug developers, researchers, and regulatory agencies face a variety of challenges throughout the life cycle of drug research and development for rare diseases. These include the small numbers of patients available for study, lack of knowledge of the disease's natural history, incomplete understanding of the basic mechanisms causing the disorder, and variability in disease severity, expression, and course. Traditional approaches to rare disease clinical research have not kept pace with advances in basic science, and increased attention to translational science is needed to address these challenges, especially diagnostic testing, registries, and novel trial designs.

Military-civilian cooperative emergency response to infectious disease prevention and control in China.

PubMed

Ma, Hui; Dong, Ji-Ping; Zhou, Na; Pu, Wei

2016-01-01

In recent years, the incidence of severe infectious diseases has increased, and the number of emerging infectious diseases continues to increase. The Chinese government and military forces have paid a great deal of attention to infectious disease prevention and control, and using military-civilian cooperation, they have successfully prevented numerous severe epidemic situations, such as severe acute respiratory syndrome (SARS), influenza A (H1N1), avian influenza H5N1 and H7N9, and Ebola hemorrhagic fever, while actively maintained public health, economic development, and national construction. This paper focuses on the mechanisms of the military-cooperative emergency response to infectious diseases--the joint working mechanism, the information-sharing mechanism, the research collaboration mechanism, and the joint disposal mechanism--and presents a sorted summary of the practices and experiences of cooperative emergency responses to infectious diseases. In the future, the Chinese military and the civilian sector will further strengthen the cooperative joint command system and emergency rescue force and will reinforce their collaborative information-sharing platform and technical equipment system to further improve military-civilian collaborative emergency infectious diseases disposal, advance the level of infectious disease prevention and control, and maintain public health.

Absence of Association between Cord Specific Antibody Levels and Severe Respiratory Syncytial Virus (RSV) Disease in Early Infants: A Case Control Study from Coastal Kenya.

PubMed

Nyiro, Joyce Uchi; Sande, Charles Jumba; Mutunga, Martin; Kiyuka, Patience Kerubo; Munywoki, Patrick Kioo; Scott, John Anthony G; Nokes, David James

2016-01-01

The target group for severe respiratory syncytial virus (RSV) disease prevention is infants under 6 months of age. Vaccine boosting of antibody titres in pregnant mothers could protect these young infants from severe respiratory syncytial virus (RSV) associated disease. Quantifying protective levels of RSV-specific maternal antibody at birth would inform vaccine development. A case control study nested in a birth cohort (2002-07) was conducted in Kilifi, Kenya; where 30 hospitalised cases of RSV-associated severe disease were matched to 60 controls. Participants had a cord blood and 2 subsequent 3-monthly blood samples assayed for RSV-specific neutralising antibody by the plaque reduction neutralisation test (PRNT). Two sample paired t test and conditional logistic regression were used in analyses of log2PRNT titres. The mean RSV log2PRNT titre at birth for cases and controls were not significantly different (P = 0.4) and remained so on age-stratification. Cord blood PRNT titres showed considerable overlap between cases and controls. The odds of RSV disease decreased with increase in log2PRNT cord blood titre. There was a 30% reduction in RSV disease per unit increase in log2PRNT titre (<3months age group) but not significant (P = 0.3). From this study, there is no strong evidence of protection by maternal RSV specific antibodies from severe RSV disease. Cord antibody levels show wide variation with considerable overlap between cases and controls. It is likely that, there are additional factors to specific PRNT antibody levels which determine susceptibility to severe RSV disease. In addition, higher levels of neutralizing antibody beyond the normal range may be required for protection; which it is hoped can be achieved by a maternal RSV vaccine.

Multiple Targets for the Management of Alzheimer's Disease.

PubMed

Ahmad, Syed Sayeed; Akhtar, Salman; Jamal, Qazi Mohammad Sajid; Rizvi, Syed Mohd Danish; Kamal, Mohammad A; Khan, M Kalim A; Siddiqui, Mohd Haris

2016-01-01

AD is a progressive and irreversible neurodegenerative disease and the most common cause of dementia in the elderly population. Βeta- amyloid cascade formation along with several cytoskeleton abnormalities succeeding to the hyperphosphorylation of microtubule-associated tau protein in neurons leads to the elicitation of several neurotoxic incidents. As an outcome of these phenomena, steady growth of dementia in aged population is becoming ubiquitous in both developed and developing countries. Thus, the key aspiration is to endow with stable daily life functionality to the person suffering from dementia and to cut down or slower the symptoms of disease leading to disruptive behavior. In sight of this, the proteins amyloid-beta, BACE-1, RAGE and AChE are being aimed for the treatment of AD successfully. Currently, there are several medicines for the treatment of AD under survey like Galangin, Cymserine, Tolserine, Bisnorcymserine and Huperzine A. The article emphasizes clinical and neurobiological aspects of AD. The purpose of this review article is to provide a brief introduction of AD along with the related concept of beta-secretase, beta amyloid and neurotransmitter in the progression of disease. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and neurotransmitter in the AD.

Histone methylations in heart development, congenital and adult heart diseases.

PubMed

Zhang, Qing-Jun; Liu, Zhi-Ping

2015-01-01

Heart development comprises myocyte specification, differentiation and cardiac morphogenesis. These processes are regulated by a group of core cardiac transcription factors in a coordinated temporal and spatial manner. Histone methylation is an emerging epigenetic mechanism for regulating gene transcription. Interplay among cardiac transcription factors and histone lysine modifiers plays important role in heart development. Aberrant expression and mutation of the histone lysine modifiers during development and in adult life can cause either embryonic lethality or congenital heart diseases, and influences the response of adult hearts to pathological stresses. In this review, we describe current body of literature on the role of several common histone methylations and their modifying enzymes in heart development, congenital and adult heart diseases.

Side-by-side comparison of gene-based smallpox vaccine with MVA in nonhuman primates.

PubMed

Golden, Joseph W; Josleyn, Matthew; Mucker, Eric M; Hung, Chien-Fu; Loudon, Peter T; Wu, T C; Hooper, Jay W

2012-01-01

Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA.

Side-by-Side Comparison of Gene-Based Smallpox Vaccine with MVA in Nonhuman Primates

PubMed Central

Golden, Joseph W.; Josleyn, Matthew; Mucker, Eric M.; Hung, Chien-Fu; Loudon, Peter T.; Wu, T. C.; Hooper, Jay W.

2012-01-01

Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA. PMID:22860117

Vocal symptoms in Parkinson disease treated with levodopa. A case report.

PubMed

Schley, W S; Fenton, E; Niimi, S

1982-01-01

This is a report of a patient with unusually severe hoarseness in the absence of vocal fold pathology demonstrating Parkinson disease as one of the neurological diseases in which vocal symptoms occur. Although it is classifiably a severe, progressive, degenerative disorder, the popularity of pharmacotherapy for Parkinson disease during the past decade has resulted in improved functionality for an undetermined course of time in most patients. The classically described deterioration of speech ad voice may develop in a variant manner difficult to distinguish as disease-related, as this case report illustrates. An explanation of the hoarseness based on dyssynchronous vocal fold motion related to the disease is suggested by the acoustic methods (spectrography, waveform analysis) used in this study, and supported by strobe light laryngoscopy. This conclusion is important because of the extremely high incidences of varying degrees of hoarseness reported in recent studies of Parkinson disease.

Lessons from rare diseases of cartilage and bone.

PubMed

Gallagher, James A; Ranganath, Lakshminarayan R; Boyde, Alan

2015-06-01

Studying severe phenotypes of rare syndromes can elucidate disease mechanisms of more common disorders and identify potential therapeutic targets. Lessons from rare bone diseases contributed to the development of the most successful class of bone active agents, the bisphosphonates. More recent research on rare bone diseases has helped elucidate key pathways and identify new targets in bone resorption and bone formation including cathepsin K and sclerostin, for which drugs are now in clinical trials. By contrast, there has been much less focus on rare cartilage diseases and osteoarthritis (OA) remains a common disease with no effective therapy. Investigation of rare cartilage syndromes is identifying new potential targets in OA including GDF5 and lubricin. Research on the arthropathy of the ultra-rare disease alkaptonuria has identified several new features of the OA phenotype, including high density mineralized protrusions (HDMPs) which constitute a newly identified mechanism of joint destruction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Obesity and Cardiovascular Disease: a Risk Factor or a Risk Marker?

PubMed

Mandviwala, Taher; Khalid, Umair; Deswal, Anita

2016-05-01

In the USA, 69 % of adults are either overweight or obese and 35 % are obese. Obesity is associated with an increased incidence of various cardiovascular disorders. Obesity is a risk marker for cardiovascular disease, in that it is associated with a much higher prevalence of comorbidities such as diabetes, hypertension, and metabolic syndrome, which then increase the risk for cardiovascular disease. However, in addition, obesity may also be an independent risk factor for the development of cardiovascular disease. Furthermore, although obesity has been shown to be an independent risk factor for several cardiovascular diseases, it is often associated with improved survival once the diagnosis of the cardiovascular disease has been made, leading to the term "obesity paradox." Several pathways linking obesity and cardiovascular disease have been described. In this review, we attempt to summarize the complex relationship between obesity and cardiovascular disorders, in particular coronary atherosclerosis, heart failure, and atrial fibrillation.

Language impairment in Alzheimer’s disease and benefits of acetylcholinesterase inhibitors

PubMed Central

Ferris, Steven H; Farlow, Martin

2013-01-01

Alzheimer’s disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer’s disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer’s disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer’s disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important. PMID:23946647

Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies

PubMed Central

2016-01-01

N-Methyl-D-aspartate receptors (NMDARs) have two opposing roles in the brain. On the one hand, NMDARs control critical events in the formation and development of synaptic organization and synaptic plasticity. On the other hand, the overactivation of NMDARs can promote neuronal death in neuropathological conditions. Ca2+ influx acts as a primary modulator after NMDAR channel activation. An imbalance in Ca2+ homeostasis is associated with several neurological diseases including schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These chronic conditions have a lengthy progression depending on internal and external factors. External factors such as acute episodes of brain damage are associated with an earlier onset of several of these chronic mental conditions. Here, we will review some of the current evidence of how traumatic brain injury can hasten the onset of several neurological conditions, focusing on the role of NMDAR distribution and the functional consequences in calcium homeostasis associated with synaptic dysfunction and neuronal death present in this group of chronic diseases. PMID:27630777

Thalassaemia.

PubMed

Taher, Ali T; Weatherall, David J; Cappellini, Maria Domenica

2018-01-13

Inherited haemoglobin disorders, including thalassaemia and sickle-cell disease, are the most common monogenic diseases worldwide. Several clinical forms of α-thalassaemia and β-thalassaemia, including the co-inheritance of β-thalassaemia with haemoglobin E resulting in haemoglobin E/β-thalassaemia, have been described. The disease hallmarks include imbalance in the α/β-globin chain ratio, ineffective erythropoiesis, chronic haemolytic anaemia, compensatory haemopoietic expansion, hypercoagulability, and increased intestinal iron absorption. The complications of iron overload, arising from transfusions that represent the basis of disease management in most patients with severe thalassaemia, might further complicate the clinical phenotype. These pathophysiological mechanisms lead to an array of clinical manifestations involving numerous organ systems. Conventional management primarily relies on transfusion and iron-chelation therapy, as well as splenectomy in specific cases. An increased understanding of the molecular and pathogenic factors that govern the disease process have suggested routes for the development of new therapeutic approaches that address the underlying chain imbalance, ineffective erythropoiesis, and iron dysregulation, with several agents being evaluated in preclinical models and clinical trials. Copyright © 2018 Elsevier Ltd. All rights reserved.

Association of Severe Atopic Dermatitis with month of birth in Armenian pediatric patients.

PubMed

Sargsyan, Anna; Gupta, Jayanta; Ghosh, Debajyoti

2018-04-26

Atopic dermatitis (AD) is a chronic relapsing skin disease which affects 15-20% of children worldwide.(1) It is also considered as a major risk factor for developing other atopic diseases including food allergy, asthma and allergic rhinitis later in life - a phenomenon known as the "atopic march". Multiple factors, including season of birth and associated perinatal environmental conditions, have been known to play important roles in the manifestation of AD.(2) Moreover, about 20% of patients with AD have moderate-to-severe disease, which is associated with significantly lower quality of life, imposing considerable burden on the nation's health-care resources.(3) Therefore, studying severe AD patients might be very important in managing overall AD-related disease burden. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Ayurvedic medicinal plants for Alzheimer's disease: a review

PubMed Central

2012-01-01

Alzheimer's disease is an age-associated, irreversible, progressive neurodegenerative disease that is characterized by severe memory loss, unusual behavior, personality changes, and a decline in cognitive function. No cure for Alzheimer's exists, and the drugs currently available to treat the disease have limited effectiveness. It is believed that therapeutic intervention that could postpone the onset or progression of Alzheimer's disease would dramatically reduce the number of cases in the next 50 years. Ayurvedic medicinal plants have been the single most productive source of leads for the development of drugs, and over a hundred new products are already in clinical development. Indeed, several scientific studies have described the use of various Ayurvedic medicinal plants and their constituents for treatment of Alzheimer's disease. Although the exact mechanism of their action is still not clear, phytochemical studies of the different parts of the plants have shown the presence of many valuable compounds, such as lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids, that show a wide spectrum of pharmacological activities, including anti-inflammatory, anti-amyloidogenic, anti-cholinesterase, hypolipidemic, and antioxidant effects. This review gathers research on various medicinal plants that have shown promise in reversing the Alzheimer's disease pathology. The report summarizes information concerning the phytochemistry, biological, and cellular activities and clinical applications of these various plants in order to provide sufficient baseline information that could be used in drug discovery campaigns and development process, thereby providing new functional leads for Alzheimer's disease. PMID:22747839

Wnt3a stimulates maturation of impaired neutrophils developed from severe congenital neutropenia patient-derived pluripotent stem cells.

PubMed

Hiramoto, Takafumi; Ebihara, Yasuhiro; Mizoguchi, Yoko; Nakamura, Kazuhiro; Yamaguchi, Kiyoshi; Ueno, Kazuko; Nariai, Naoki; Mochizuki, Shinji; Yamamoto, Shohei; Nagasaki, Masao; Furukawa, Yoichi; Tani, Kenzaburo; Nakauchi, Hiromitsu; Kobayashi, Masao; Tsuji, Kohichiro

2013-02-19

The derivation of induced pluripotent stem (iPS) cells from individuals of genetic disorders offers new opportunities for basic research into these diseases and the development of therapeutic compounds. Severe congenital neutropenia (SCN) is a serious disorder characterized by severe neutropenia at birth. SCN is associated with heterozygous mutations in the neutrophil elastase [elastase, neutrophil-expressed (ELANE)] gene, but the mechanisms that disrupt neutrophil development have not yet been clarified because of the current lack of an appropriate disease model. Here, we generated iPS cells from an individual with SCN (SCN-iPS cells). Granulopoiesis from SCN-iPS cells revealed neutrophil maturation arrest and little sensitivity to granulocyte-colony stimulating factor, reflecting a disease status of SCN. Molecular analysis of the granulopoiesis from the SCN-iPS cells vs. control iPS cells showed reduced expression of genes related to the wingless-type mmtv integration site family, member 3a (Wnt3a)/β-catenin pathway [e.g., lymphoid enhancer-binding factor 1], whereas Wnt3a administration induced elevation lymphoid enhancer-binding factor 1-expression and the maturation of SCN-iPS cell-derived neutrophils. These results indicate that SCN-iPS cells provide a useful disease model for SCN, and the activation of the Wnt3a/β-catenin pathway may offer a novel therapy for SCN with ELANE mutation.

Determinants of marginal traction alopecia in African girls and women.

PubMed

Khumalo, Nonhlanhla P; Jessop, Susan; Gumedze, Freedom; Ehrlich, Rodney

2008-09-01

Our recent population studies reported a prevalence of traction alopecia (TA) of 17.1% in African schoolgirls (6-21 years) and of 31.7% in women (18-86 years). More schoolgirls had chemically treated hair than women and disease presence was associated with hairstyles. The aim of this study was to investigate determinants of TA presence and severity in girls and women using data from both studies. Clinical assessment and a Marginal TA Severity score were used for diagnosis and disease severity, respectively. The data used included 574 schoolgirls and 604 women. The first analysis was multiple logistic regression for disease presence. Exploratory associations for disease severity were assessed using the Spearman rank correlation test. Adults were defined as age 18 years or older, irrespective of study. The odds ratio for TA was higher in adults than in children (<18 years) (1.87 [P < .001, 95% confidence interval 1.28-2.72]) and was higher with braiding-related than chemical-related symptoms. The highest risk of TA, compared with natural hair, occurred when traction was added to relaxed hair (odds ratio 3.47 [P < .001, 95% confidence interval 1.94-6.20]). Only 18.9% of patients with TA had never had symptoms related to hairdressing. TA severity was associated with age group, current hairstyle, and hairdressing symptoms. Participants with severe disease were too few to estimate determinants. There is a need for the validation of the Marginal TA Severity score with larger numbers and for future studies to include more participants with severe disease. Our findings suggest that avoiding both hairdressing symptoms and the addition of traction, especially to chemically processed hair, may reduce the risk of developing TA.

[Leber's hereditary optic neuropathy].

PubMed

Hilo, Wasseem; Jabaly-Habib, Haneen; Modi, Naftali; Briscoe, Daniel

2013-08-01

Lebers hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by subacute severe visual loss in both eyes, which usually manifests in young adulthood. The disease has maternal inheritance due to mitochondrial DNA mutation. The final diagnosis is genetic. There is still no proven treatment, but there is significant progress in developments on the genetics of the disease to reach gene therapy. In this article we review the latest literature relevant to this disease.

Vaccination against Lyme disease: Are we ready for it?

PubMed

Kaaijk, Patricia; Luytjes, Willem

2016-03-03

Lyme disease is the most common tick-borne illness in the Northern hemisphere and is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. A first sign of Borrelia infection is a circular skin rash, erythema migrans, but it can develop to more serious manifestations affecting skin, nervous system, joints, and/or heart. The marked increase in Lyme disease incidence over the past decades, the severity of the disease, and the associated high medical costs of, in particular, the persistent forms of Lyme disease requires adequate measures for control. Vaccination would be the most effective intervention for prevention, but at present no vaccine is available. In the 1990s, 2 vaccines against Lyme disease based on the OspA protein from the predominant Borrelia species of the US showed to be safe and effective in clinical phase III studies. However, failed public acceptance led to the demise of these monovalent OspA-based vaccines. Nowadays, public seem to be more aware of the serious health problems that Lyme disease can cause and seem more ready for the use of a broadly protective vaccine. This article discusses several aspects that should be considered to enable the development and implementation of a vaccine to prevent Lyme disease successfully.

Vaccination against Lyme disease: Are we ready for it?

PubMed Central

Kaaijk, Patricia; Luytjes, Willem

2016-01-01

Abstract Lyme disease is the most common tick-borne illness in the Northern hemisphere and is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. A first sign of Borrelia infection is a circular skin rash, erythema migrans, but it can develop to more serious manifestations affecting skin, nervous system, joints, and/or heart. The marked increase in Lyme disease incidence over the past decades, the severity of the disease, and the associated high medical costs of, in particular, the persistent forms of Lyme disease requires adequate measures for control. Vaccination would be the most effective intervention for prevention, but at present no vaccine is available. In the 1990s, 2 vaccines against Lyme disease based on the OspA protein from the predominant Borrelia species of the US showed to be safe and effective in clinical phase III studies. However, failed public acceptance led to the demise of these monovalent OspA-based vaccines. Nowadays, public seem to be more aware of the serious health problems that Lyme disease can cause and seem more ready for the use of a broadly protective vaccine. This article discusses several aspects that should be considered to enable the development and implementation of a vaccine to prevent Lyme disease successfully. PMID:26337648

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.

Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

PubMed Central

Gralinski, Lisa E.; Bankhead, Armand; Jeng, Sophia; Menachery, Vineet D.; Proll, Sean; Belisle, Sarah E.; Matzke, Melissa; Webb-Robertson, Bobbie-Jo M.; Luna, Maria L.; Shukla, Anil K.; Ferris, Martin T.; Bolles, Meagan; Chang, Jean; Aicher, Lauri; Waters, Katrina M.; Smith, Richard D.; Metz, Thomas O.; Law, G. Lynn; Katze, Michael G.; McWeeney, Shannon; Baric, Ralph S.

2013-01-01

ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. PMID:23919993

Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis

PubMed Central

Woehrl, Bianca; Brouwer, Matthijs C.; Murr, Carmen; Heckenberg, Sebastiaan G.B.; Baas, Frank; Pfister, Hans W.; Zwinderman, Aeilko H.; Morgan, B. Paul; Barnum, Scott R.; van der Ende, Arie; Koedel, Uwe; van de Beek, Diederik

2011-01-01

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor–deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis. PMID:21926466

The neuropathology of traumatic brain injury.

PubMed

Mckee, Ann C; Daneshvar, Daniel H

2015-01-01

Traumatic brain injury, a leading cause of mortality and morbidity, is divided into three grades of severity: mild, moderate, and severe, based on the Glasgow Coma Scale, the loss of consciousness, and the development of post-traumatic amnesia. Although mild traumatic brain injury, including concussion and subconcussion, is by far the most common, it is also the most difficult to diagnose and the least well understood. Proper recognition, management, and treatment of acute concussion and mild traumatic brain injury are the fundamentals of an emerging clinical discipline. It is also becoming increasingly clear that some mild traumatic brain injuries have persistent, and sometimes progressive, long-term debilitating effects. Evidence indicates that a single traumatic brain injury can precipitate or accelerate multiple age-related neurodegenerations, increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease, and that repetitive mild traumatic brain injuries can provoke the development of a tauopathy, chronic traumatic encephalopathy. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus, septal abnormalities, and abnormal deposits of hyperphosphorylated tau (τ) as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy frequently occurs as a sole diagnosis, but may be associated with other neurodegenerative disorders, including Alzheimer's disease, Lewy body disease, and motor neuron disease. Currently, chronic traumatic encephalopathy can be diagnosed only at autopsy; however, promising efforts to develop imaging, spinal fluid, and peripheral blood biomarkers are underway to diagnose and monitor the course of disease in living subjects. © 2015 Elsevier B.V. All rights reserved.

Reversible infantile mitochondrial diseases.

PubMed

Boczonadi, Veronika; Bansagi, Boglarka; Horvath, Rita

2015-05-01

Mitochondrial diseases are usually severe and progressive conditions; however, there are rare forms that show remarkable spontaneous recoveries. Two homoplasmic mitochondrial tRNA mutations (m.14674T>C/G in mt-tRNA(Glu)) have been reported to cause severe infantile mitochondrial myopathy in the first months of life. If these patients survive the first year of life by extensive life-sustaining measures they usually recover and develop normally. Another mitochondrial disease due to deficiency of the 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) causes severe liver failure in infancy, but similar to the reversible mitochondrial myopathy, within the first year of life these infants may also recover completely. Partial recovery has been noted in some other rare forms of mitochondrial disease due to deficiency of mitochondrial tRNA synthetases and mitochondrial tRNA modifying enzymes. Here we summarize the clinical presentation of these unique reversible mitochondrial diseases and discuss potential molecular mechanisms behind the reversibility. Understanding these mechanisms may provide the key to treatments of potential broader relevance in mitochondrial disease, where for the majority of the patients no effective treatment is currently available.

Significant elevation of the levels of B-cell activating factor (BAFF) in patients with sarcoidosis.

PubMed

Ando, Masaru; Goto, Akihiko; Takeno, Yukiko; Yamasue, Mari; Komiya, Kosaku; Umeki, Kenji; Nureki, Shin-Ichi; Miyazaki, Eishi; Kadota, Jun-Ichi

2018-06-23

B-cell activating factor (BAFF) plays an important role in the survival and differentiation of B-cells and production of antibodies. Recent studies show that the serum BAFF levels are elevated in patients with sarcoidosis; however, they have not studied the relationship of the finding with the clinical features of the disease. The purpose of the present study is to analyze the BAFF and to elucidate the relationship between BAFF levels and the disease activity or severity of sarcoidosis. Eighty-eight patients with sarcoidosis and 21 healthy volunteers were enrolled in the present study. The BAFF levels were measured by an enzyme-linked immunosorbent assay. To assess the disease severity, we examined the number of affected organs, Schadding stages, respiratory function impairment (RFI), and the scoring system developed by Wasfi et al. The serum BAFF levels in sarcoidosis patients were significantly higher than those in healthy volunteers (median 1553.0 vs 984.6 pg/ml, p < 0.001). There were positive correlations between the serum BAFF level and disease activity markers. In addition, there were positive correlations between the BAFF levels and the disease severity score in both the serum (R = 0.367, p < 0.001) and bronchoalveolar lavage fluid (BALF) (R = 0.376, p < 0.001). This study demonstrated that the BAFF levels in both the serum and BALF were positively correlated with the disease activity markers and disease severity. BAFF may be useful as an indicator of both the disease activity and severity.

TLR/MyD88-mediated Innate Immunity in Intestinal Graft-versus-Host Disease.

PubMed

Lee, Young-Kwan; Kang, Myungsoo; Choi, Eun Young

2017-06-01

Graft-versus-host disease (GHVD) is a severe complication after allogeneic hematopoietic stem cell transplantation. The degree of inflammation in the gastrointestinal tract, a major GVHD target organ, correlates with the disease severity. Intestinal inflammation is initiated by epithelial damage caused by pre-conditioning irradiation. In combination with damages caused by donor-derived T cells, such damage disrupts the epithelial barrier and exposes innate immune cells to pathogenic and commensal intestinal bacteria, which release ligands for Toll-like receptors (TLRs). Dysbiosis of intestinal microbiota and signaling through the TLR/myeloid differentiation primary response gene 88 (MyD88) pathways contribute to the development of intestinal GVHD. Understanding the changes in the microbial flora and the roles of TLR signaling in intestinal GVHD will facilitate the development of preventative and therapeutic strategies.

Naval Medical Research and Development News. Volume 7, Issue 11, November 2015

DTIC Science & Technology

2015-11-01

enteric diseases such as shigellosis and typhoid fever . The goal of the laboratory is to research, understand, and develop protective strategies...military or public health significance in the region, including malaria and dengue fever , yellow fever , viral encephalitis, leishmaniasis, and...a food and waterborne disease, is characterized by fever , cramps and sometimes severe bloody diarrhea,” said Cmdr. Christopher Duplessis, lead

Methodology and potential pitfalls in allergic diseases study designs: measurements for the assessment of the overall severity of atopic dermatitis--the four step severity score (FSSS), SCORAD-related, electronic system, for the simple and rapid evaluation of the skin and mucosal allergic inflammation.

PubMed

Mastrandrea, F; Pecora, S; Scatena, C; Cadario, G

2005-11-01

Medical statistics may contribute to ameliorate research by improving the design of studies and identifying the optimal method for the analysis of results. Sometimes, nevertheless, it could be misemployed flawing the benefit potential. Allergic diseases pathogenesis is recognized to be systemic but global initiatives such as GINA and ARIA documents define allergic asthma and rhinitis as organ diseases; such an asymmetrical view raises a set of known and unknown confounding that could influence the quality of the process of evidence-based decision-making (topic symptomatic therapeutic interventions versus systemic pathogenetic interventions). This article shows the first scoring system for the assessment of atopic dermatitis lesions developed in the allergy-area. A four-step severity score (FSSS) was chosen in agreement with those developed for asthma and rhinitis in global initiatives, to avoid any further differences in evaluating the severity of allergic diseases. FSSS relates each step with the objective signs of the SCORAD and rates the disease course as intermittent or persistent. A devoted electronic program has been also framed to allow a quick and simple contemporary evaluation of the SCORAD Index (Section I) and of the FSSS (Section II); the program furthermore foresees a third section named ESAS (Extra Skin Allergic Signs) (Section III) in which it is possible to check whether organs other than the skin are involved by the allergic inflammation. The limitations potential generated by a misemployment of medical statistics for clinical trials designed to establish benefits rising from specific immunotherapy for allergic diseases have been also discussed extensively.

Economics and financing of vaccines for diarrheal diseases.

PubMed

Bartsch, Sarah M; Lee, Bruce Y

2014-01-01

The considerable burden of infectious disease-caused diarrhea around the world has motivated the continuing development of a number of vaccine candidates over the past several decades with some reaching the market. As with all major public health interventions, understanding the economics and financing of vaccines against diarrheal diseases is essential to their development and implementation. This review focuses on each of the major infectious pathogens that commonly cause diarrhea, the current understanding of their economic burden, the status of vaccine development, and existing economic evaluations of the vaccines. While the literature on the economics and financing of vaccines against diarrhea diseases is growing, there is considerable room for more inquiry. Substantial gaps exist for many pathogens, circumstances, and effects. Economics and financing studies are integral to vaccine development and implementation.

Economics and financing of vaccines for diarrheal diseases

PubMed Central

Bartsch, Sarah M; Lee, Bruce Y

2014-01-01

The considerable burden of infectious disease-caused diarrhea around the world has motivated the continuing development of a number of vaccine candidates over the past several decades with some reaching the market. As with all major public health interventions, understanding the economics and financing of vaccines against diarrheal diseases is essential to their development and implementation. This review focuses on each of the major infectious pathogens that commonly cause diarrhea, the current understanding of their economic burden, the status of vaccine development, and existing economic evaluations of the vaccines. While the literature on the economics and financing of vaccines against diarrhea diseases is growing, there is considerable room for more inquiry. Substantial gaps exist for many pathogens, circumstances, and effects. Economics and financing studies are integral to vaccine development and implementation. PMID:24755623

Development and Validation of a Disease Severity Scoring Model for Pediatric Sepsis.

PubMed

Hu, Li; Zhu, Yimin; Chen, Mengshi; Li, Xun; Lu, Xiulan; Liang, Ying; Tan, Hongzhuan

2016-07-01

Multiple severity scoring systems have been devised and evaluated in adult sepsis, but a simplified scoring model for pediatric sepsis has not yet been developed. This study aimed to develop and validate a new scoring model to stratify the severity of pediatric sepsis, thus assisting the treatment of sepsis in children. Data from 634 consecutive patients who presented with sepsis at Children's hospital of Hunan province in China in 2011-2013 were analyzed, with 476 patients placed in training group and 158 patients in validation group. Stepwise discriminant analysis was used to develop the accurate discriminate model. A simplified scoring model was generated using weightings defined by the discriminate coefficients. The discriminant ability of the model was tested by receiver operating characteristic curves (ROC). The discriminant analysis showed that prothrombin time, D-dimer, total bilirubin, serum total protein, uric acid, PaO2/FiO2 ratio, myoglobin were associated with severity of sepsis. These seven variables were assigned with values of 4, 3, 3, 4, 3, 3, 3 respectively based on the standardized discriminant coefficients. Patients with higher scores had higher risk of severe sepsis. The areas under ROC (AROC) were 0.836 for accurate discriminate model, and 0.825 for simplified scoring model in validation group. The proposed disease severity scoring model for pediatric sepsis showed adequate discriminatory capacity and sufficient accuracy, which has important clinical significance in evaluating the severity of pediatric sepsis and predicting its progress.

Risk factors for severe outcomes among members of the United States military hospitalized with pneumonia and influenza, 2000–2012

PubMed Central

Van Kerkhove, Maria D; Cooper, Michael J.; Eick-Cost, Angelia A.; Sanchez, Jose L.; Riley, Steven

2016-01-01

Background The progression from hospitalization for a respiratory infection to requiring substantial supportive therapy is a key stage of the influenza severity pyramid. Respiratory infections are responsible for 300,000 to 400,000 medical encounters each year among US military personnel, some of which progress to severe acute respiratory infections. Methods We obtained data on 11,086 hospitalizations for pneumonia and influenza (P&I) among non-recruit US military service members during the period of 1 January 2000 through 31 December 2012. From these, we identified 512 P&I hospitalizations that progressed to severe episodes using standard case definitions. We evaluated the effect of demographic and occupational characteristics, comorbid conditions, and history of influenza vaccination on the risk of a hospitalized P&I case becoming a severe case. We also evaluated the risk of a severe outcome and the length of time since influenza vaccination (within 180, 60 and 30 days). Results The median age of subjects at the time of the P&I episode was 32 years (range, 28–40) and subjects were predominantly male (89.5%). In a univariate analysis, demographic risk factors for a severe episode included service in the US Air Force (RR=1.6 relative to US Army, 95%CI 1.3-2.1), US Coast Guard (RR=2.1, 1.2-3.7) or US Navy (RR=1.4, 1.1-1.8). Being born in the US and recent influenza vaccination (within 180 days of episode) were protective against developing severe disease. Among comorbid conditions, univariate risk factors for severe disease included chronic renal or liver disease (RR=4.98, 95%CI 4.1-6.1), diseases of the circulatory system (RR=3.1, 95%CI 2.6-3.7), diabetes mellitus (RR=2.3, 95%CI 1.5-3.6), obesity (RR=1.6, 95%CI 1.2-2.1), cancer (RR=1.6, 95%CI 1.3-2.0) and chronic obstructive pulmonary disease (RR=1.4, 95%CI 1.1-1.7). Although many of the risk factors found to be significant in univariate analysis were no longer significant under a multivariate analysis, receipt of any influenza vaccine within 180 days of episode remained protective (RR=0.81, 95%CI 0.67-0.99), while serving in the US Coast Guard (RR=1.9, 95%CI 1.1-3.4) or US Air Force (RR=1. 5, 95%CI 1.2-2.0), presence of renal or liver disease (RR=3.6, 95%CI 2.9-4.6) and diseases of the circulatory system (RR=2.2, 95%CI 1.8-2.8), remained significantly associated with a higher risk of developing severe disease. Conclusions In a large cohort, after adjusting for many possible risk factors, influenza vaccination was protective against severe episodes among P&I hospitalizations. The service-specific (US Coast Guard or US Air Force) increased risk may represent some differences in data (e.g., coding or reporting practices) as opposed to genuine differences in physiological outcome. Our findings suggest that renal and liver disease as well as diseases of the circulatory system may contribute to influenza severity in this population independently of age and other potential comorbidities. These findings provide additional evidence for the prioritization of specific risk groups within the US military for influenza vaccination. PMID:26494627

Triglyceride level affecting shared susceptibility genes in metabolic syndrome and coronary artery disease.

PubMed

Kisfali, P; Polgár, N; Sáfrány, E; Sümegi, K; Melegh, B I; Bene, J; Wéber, A; Hetyésy, K; Melegh, B

2010-01-01

Metabolic syndrome is characterized primarily by abdominal obesity, high triglyceride- and low HDL cholesterol levels, elevated blood pressure, and increased fasting glucose levels, which are often associated with coronary heart diseases. Several factors, such as physical inactivity, age, and several endocrine and genetic factors can increase the risk of the development of the disease. Gathered evidence shows, that metabolic syndrome is not only a risk factor for cardiovascular disease, but often both of them have the same shared susceptibility genes, as several genetic variants have shown a predisposition to both diseases. Due to the spread of robust genome wide association studies, the number of candidate genes in metabolic syndrome and coronary heart disease susceptibility increases very rapidly. From the growing spectrum of the genes influencing lipid metabolism (like the LPL; PPARA; APOE; APOAI/CIII/AIV genecluster and APOAS5), the current review focuses on shared susceptibility variants involved in triglyceride metabolism and consequently the effects on the circulating triglyceride levels. As the elevated levels of triglycerides can be associated with disease phenotypes, some of these SNPs can have susceptibility features in both metabolic syndrome and in coronary heart disease, thereby some of them can even represent a kind of susceptibility link between metabolic syndrome and coronary artery disease.

Early identification of patients at risk for acute respiratory distress syndrome among severe pneumonia: a retrospective cohort study

PubMed Central

Luo, Jian; Yu, He; Hu, Yue-Hong; Liu, Dan; Wang, Yi-Wei; Wang, Mao-Yun

2017-01-01

Background Severe pneumonia is the predominant cause for acute respiratory distress syndrome (ARDS). Identification of ARDS from patients with severe pneumonia remains a significant clinical problem due to the overlap of clinical presentations and symptoms. Early recognition of risks for ARDS from severe pneumonia is of great clinical value. Methods From April 2014 to December 2015, patients with severe pneumonia at admission were retrieved from the hospital database, of which ARDS developed within 7 days were further identified. We compared the demographic and clinical characteristics at admission between severe pneumonia patients with and without ARDS development, followed by analysis of potential predictors for ARDS development and mortality. Multivariate logistic regression and receiver operating characteristic (ROC) curves were performed to screen independent risk factors and identify their sensitivity in predicting ARDS development and prognosis. Results Compared with severe pneumonia without ARDS development, patients with ARDS development had shorter disease duration before admission, higher lung injury score (LIS), serum fibrinogen (FiB), and positive end-expiratory pressure (PEEP), lower Marshall score, sequential organ failure assessment score and proportion of cardiovascular and gastrointestinal diseases, but similar mortality. Serum FiB >5.15 g/L [adjusted odds ratio (OR) 1.893, 95% confidence interval (CI): 1.141–3.142, P=0.014] and PEEP >6.5 cmH2O (adjusted OR 1.651, 95% CI: 1.218–2.237, P=0.001) were independent predictors for ARDS development with a sensitivity of 58.3% and 87.5%, respectively, and pH <7.35 (adjusted OR 0.832, 95% CI: 0.702–0.985, P=0.033) was an independent risk factor for ARDS mortality with a sensitivity of 95.2%. Conclusions ARDS development risk could be early recognized by PEEP >6.5 cmH2O and serum FiB >5.15 g/L in severe pneumonia patients, and pH <7.35 is a reliable prognostic factor in predicting ARDS mortality risk. PMID:29268409

Biomarkers and Surrogate Endpoints in Uveitis: The Impact of Quantitative Imaging.

PubMed

Denniston, Alastair K; Keane, Pearse A; Srivastava, Sunil K

2017-05-01

Uveitis is a major cause of sight loss across the world. The reliable assessment of intraocular inflammation in uveitis ('disease activity') is essential in order to score disease severity and response to treatment. In this review, we describe how 'quantitative imaging', the approach of using automated analysis and measurement algorithms across both standard and emerging imaging modalities, can develop objective instrument-based measures of disease activity. This is a narrative review based on searches of the current world literature using terms related to quantitative imaging techniques in uveitis, supplemented by clinical trial registry data, and expert knowledge of surrogate endpoints and outcome measures in ophthalmology. Current measures of disease activity are largely based on subjective clinical estimation, and are relatively insensitive, with poor discrimination and reliability. The development of quantitative imaging in uveitis is most established in the use of optical coherence tomographic (OCT) measurement of central macular thickness (CMT) to measure severity of macular edema (ME). The transformative effect of CMT in clinical assessment of patients with ME provides a paradigm for the development and impact of other forms of quantitative imaging. Quantitative imaging approaches are now being developed and validated for other key inflammatory parameters such as anterior chamber cells, vitreous haze, retinovascular leakage, and chorioretinal infiltrates. As new forms of quantitative imaging in uveitis are proposed, the uveitis community will need to evaluate these tools against the current subjective clinical estimates and reach a new consensus for how disease activity in uveitis should be measured. The development, validation, and adoption of sensitive and discriminatory measures of disease activity is an unmet need that has the potential to transform both drug development and routine clinical care for the patient with uveitis.

Role of elevated plasma soluble ICAM-1 and bronchial lavage fluid IL-8 levels as markers of chronic lung disease in premature infants.

PubMed Central

Little, S.; Dean, T.; Bevin, S.; Hall, M.; Ashton, M.; Church, M.; Warner, J.; Shute, J.

1995-01-01

BACKGROUND--Pulmonary neutrophilia characterises both the relatively transient inflammation associated with infant respiratory distress syndrome (IRDS) and the persistent inflammation of chronic lung disease. The possibility that persistently raised markers of inflammation indicate the development of chronic lung disease in low birth weight (< 1730 g) preterm (< 31 weeks) infants was therefore investigated. METHODS--Soluble ICAM-1 (sICAM-1) levels in plasma, and interleukin (IL)-8 and myeloperoxidase (MPO) levels in bronchial lavage fluid (BLF) obtained from 17 infants on days 1, 5, and 14 following birth were measured and correlations with the number of neutrophils in BLF sought. Peripheral neutrophils were isolated on Polymorphoprep and chemotactic responsiveness to IL-8 was assessed using micro Boyden chambers. RESULTS--Sixteen infants developed IRDS and, of these, 10 infants subsequently developed chronic lung disease. Levels of IL-8 in BLF at 14 days of age correlated with the long term requirement for intermittent positive pressure ventilation (IPPV). Interleukin 8 levels in BLF correlated with neutrophil numbers and MPO concentration, suggesting both recruitment and activation in response to this cytokine. Antibody depletion studies showed that approximately 50% of total neutrophil chemotactic activity in BLF was due to IL-8. No difference in peripheral neutrophil chemotactic responsiveness at any age was observed for infants with IRDS or chronic lung disease. Plasma soluble intercellular adhesion molecule (sICAM-1) was higher at 14 days of age in infants who developed chronic lung disease than in those with resolving IRDS, and correlated with severity of disease, as indicated by duration of IPPV. CONCLUSIONS--The results indicate that high levels of plasma sICAM-1 and IL-8 in BLF at day 14 correlate with the development of chronic lung disease and indicate the severity of disease. PMID:7491556

Analysis of the New Zealand Black contribution to lupus-like renal disease

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

Drake, C.G.; Rozzo, S.J.; Hirschfeld, H.F.

1995-03-01

F{sub 1} progeny of New Zealand Black (NZB) and New Zealand White (NZW) mice spontaneously develop an autoimmune process remarkably similar to human systemic lupus erythematosus. Previous studies have implicated major genetic contributions from the NZW MHC and from a dominant NZB gene on chromosome 4. To identify additional NZB contributions to lupus-like disease, (NZB x SM/J)F{sub 1} x NZW backcross mice were followed for the development of severe renal disease and were comprehensively genotyped. Despite a 50% incidence of disease significant associations between the presence of the NZB genotype and disease were noted on chromosomes 1, 4, 7, 10,more » 13, and 19. The data indicated that multiple NZB genes, in different combinations, contribute to severe renal disease, and that no single gene is required. To further investigate this NZB contribution, NZB x SM/J (NXSM) recombinant inbred (RI) strains were crossed with NZW mice, and F{sub 1} progeny were analyzed for the presence of lupus-like renal disease. Interestingly, nearly all of the (RI x NZW)F{sub 1} cohorts studies expressed some level of disease. Five RI strains generated a high incidence of disease, similar to (NZB x NZW)F{sub 1} mice, and nearly one-half of the cohorts developed disease at intermediate levels. Only two cohorts demonstrated very little disease, supporting the conclusion that multiple genes are capable of disease induction. Experiments correlating the genotypes of these RI strains with their ability to generate disease revealed that none of the disease-associated loci defined by the backcross analysis were present in all five RI strains that generated disease at high levels. Overall, both the backcross data and RI analysis provide additional support for the genetic complexity of lupus nephritis and uphold the conclusion that heterogeneous combinations of contributing NZB genes seem to operate in a threshold manner to generate the disease phenotype. 31 refs., 3 figs., 2 tabs.« less

A new scoring system in Cystic Fibrosis: statistical tools for database analysis - a preliminary report.

PubMed

Hafen, G M; Hurst, C; Yearwood, J; Smith, J; Dzalilov, Z; Robinson, P J

2008-10-05

Cystic fibrosis is the most common fatal genetic disorder in the Caucasian population. Scoring systems for assessment of Cystic fibrosis disease severity have been used for almost 50 years, without being adapted to the milder phenotype of the disease in the 21st century. The aim of this current project is to develop a new scoring system using a database and employing various statistical tools. This study protocol reports the development of the statistical tools in order to create such a scoring system. The evaluation is based on the Cystic Fibrosis database from the cohort at the Royal Children's Hospital in Melbourne. Initially, unsupervised clustering of the all data records was performed using a range of clustering algorithms. In particular incremental clustering algorithms were used. The clusters obtained were characterised using rules from decision trees and the results examined by clinicians. In order to obtain a clearer definition of classes expert opinion of each individual's clinical severity was sought. After data preparation including expert-opinion of an individual's clinical severity on a 3 point-scale (mild, moderate and severe disease), two multivariate techniques were used throughout the analysis to establish a method that would have a better success in feature selection and model derivation: 'Canonical Analysis of Principal Coordinates' and 'Linear Discriminant Analysis'. A 3-step procedure was performed with (1) selection of features, (2) extracting 5 severity classes out of a 3 severity class as defined per expert-opinion and (3) establishment of calibration datasets. (1) Feature selection: CAP has a more effective "modelling" focus than DA.(2) Extraction of 5 severity classes: after variables were identified as important in discriminating contiguous CF severity groups on the 3-point scale as mild/moderate and moderate/severe, Discriminant Function (DF) was used to determine the new groups mild, intermediate moderate, moderate, intermediate severe and severe disease. (3) Generated confusion tables showed a misclassification rate of 19.1% for males and 16.5% for females, with a majority of misallocations into adjacent severity classes particularly for males. Our preliminary data show that using CAP for detection of selection features and Linear DA to derive the actual model in a CF database might be helpful in developing a scoring system. However, there are several limitations, particularly more data entry points are needed to finalize a score and the statistical tools have further to be refined and validated, with re-running the statistical methods in the larger dataset.

Treatment of severe generalized chronic periodontitis in a patient with Behçet's disease: A case report.

PubMed

Morikawa, Satoru; Ouchi, Takehito; Asoda, Seiji; Horie, Nobuyuki; Tsunoda, Kazuyuki; Kawana, Hiromasa; Nakagawa, Taneaki

2018-05-01

Behçet's disease is a systemic disorder of unknown etiology. It involves multiple organ systems and is characterized by recurring episodes of oral ulcers as well as ocular, genital, and skin lesions. Oral ulcers can affect tooth brushing and impair proper oral hygiene. As a result, a dental biofilm accumulates, and the condition of the teeth and periodontal tissue deteriorates. The aim of this case report is to highlight the efficacy of periodontal treatment for patients with Behçet's disease. A 51-year-old man with Behçet's disease presented with generalized severe periodontitis. After basic treatment of the periodontal tissues, periodontal surgery was performed at several sites with bony defects. However, the patient developed severe stomatitis in the oral mucosa and gingiva after periodontal surgery. Administration of the antimicrobial agent cefdinir had little effect on recovery; however, subsequent administration of sitafloxacin resulted in significant improvement of the stomatitis. This case demonstrates that periodontal therapy is very useful for alleviating the oral signs and symptoms of Behçet's disease. Systemic antibiotic treatment with sitafloxacin (but not cefdinir) and mechanical debridement were effective in preventing the recurrence of aphthous ulcer outbreaks after periodontal surgery.

Autoimmune diseases and vaccinations.

PubMed

Vial, Thierry; Descotes, Jacques

2004-01-01

The potential association between vaccination and autoimmune diseases has been largely questioned in the past few years, but this assumption has mostly been based on case reports. The available evidence derived from several negative epidemiological studies is reassuring and at least indicates that vaccines are not a major cause of autoimmune diseases. However, there are still uncertainties as to whether a susceptible subpopulation may be at a higher risk of developing an autoimmune disease without causing an overall increase in the disease incidence. Based on selected examples, this review highlights the difficulties in assessing this issue. We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines. Copyright John Libbey Eurotext 2003.

Is Pregnancy Associated with Severe Dengue? A Review of Data from the Rio de Janeiro Surveillance Information System

PubMed Central

Machado, Carolina Romero; Machado, Elizabeth Stankiewicz; Rohloff, Roger Denis; Azevedo, Marina; Campos, Dayse Pereira; de Oliveira, Robson Bruniera; Brasil, Patrícia

2013-01-01

Background Dengue is a reportable disease in Brazil; however, pregnancy has been included in the application form of the Brazilian notification information system only after 2006. To estimate the severity of maternal dengue infection, the available data that were compiled from January 2007 to December 2008 by the official surveillance information system of the city of Rio de Janeiro were reviewed. Methods and Principal Findings During the study period, 151,604 cases of suspected dengue infection were reported. Five hundred sixty-one women in their reproductive age (15–49 years) presented with dengue infection; 99 (18.1%) pregnant and 447 (81.9%) non-pregnant women were analyzed. Dengue cases were categorized using the 1997 WHO classification system, and DHF/DSS were considered severe disease. The Mann-Whitney test was used to compare maternal age, according to gestational period, and severity of disease. A chi-square test was utilized to evaluate the differences in the proportion of dengue severity between pregnant and non-pregnant women. Univariate analysis was performed to compare outcome variables (severe dengue and non-severe dengue) and explanatory variables (pregnancy, gestational age and trimester) using the Wald test. A multivariate analysis was performed to assess the independence of statistically significant variables in the univariate analysis. A p-value<0.05 was considered statistically significant. A higher percentage of severe dengue infection among pregnant women was found, p = 0.0001. Final analysis demonstrated that pregnant women are 3.4 times more prone to developing severe dengue (OR: 3.38; CI: 2.10–5.42). Mortality among pregnant women was superior to non-pregnant women. Conclusion Pregnant women have an increased risk of developing severe dengue infection and dying of dengue. PMID:23675548

Rotavirus vaccines: safety, efficacy and public health impact.

PubMed

Gray, J

2011-09-01

Rotaviruses are the cause of acute gastroenteritis, and disease is widespread amongst infants and young children throughout the world. Also, rotavirus is associated with significant mortality in developing countries with more than 500 000 children dying each year as a result of the severe dehydration associated with rotavirus disease. Efforts have been ongoing for more than 30 years to develop a safe and effective rotavirus vaccine. Currently, two vaccines, RotaRix and RotaTeq, have been licensed for use in many countries throughout the world following comprehensive safety and efficiency trials. Monitoring their effectiveness after licensure has confirmed that their incorporation into early childhood vaccination schedules can significantly prevent severe rotavirus diarrhoea, which would have resulted in hospitalizations, emergency room visits or increased diarrhoea-related mortality. Although the efficacy of both vaccines is lower at approximately 40-59% in developing countries, their use could significantly reduce the mortality associated with rotavirus disease that is concentrated in these countries. © 2011 The Association for the Publication of the Journal of Internal Medicine.

Risk factors for the development of severe typhoid fever in Vietnam.

PubMed

Parry, Christopher M; Thompson, Corinne; Vinh, Ha; Chinh, Nguyen Tran; Phuong, Le Thi; Ho, Vo Anh; Hien, Tran Tinh; Wain, John; Farrar, Jeremy J; Baker, Stephen

2014-02-10

Typhoid fever is a systemic infection caused by the bacterium Salmonella enterica serovar Typhi. Age, sex, prolonged duration of illness, and infection with an antimicrobial resistant organism have been proposed risk factors for the development of severe disease or fatality in typhoid fever. We analysed clinical data from 581 patients consecutively admitted with culture confirmed typhoid fever to two hospitals in Vietnam during two periods in 1993-1995 and 1997-1999. These periods spanned a change in the antimicrobial resistance phenotypes of the infecting organisms i.e. fully susceptible to standard antimicrobials, resistance to chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole (multidrug resistant, MDR), and intermediate susceptibility to ciprofloxacin (nalidixic acid resistant). Age, sex, duration of illness prior to admission, hospital location and the presence of MDR or intermediate ciprofloxacin susceptibility in the infecting organism were examined by logistic regression analysis to identify factors independently associated with severe typhoid at the time of hospital admission. The prevalence of severe typhoid was 15.5% (90/581) and included: gastrointestinal bleeding (43; 7.4%); hepatitis (29; 5.0%); encephalopathy (16; 2.8%); myocarditis (12; 2.1%); intestinal perforation (6; 1.0%); haemodynamic shock (5; 0.9%), and death (3; 0.5%). Severe disease was more common with increasing age, in those with a longer duration of illness and in patients infected with an organism exhibiting intermediate susceptibility to ciprofloxacin. Notably an MDR phenotype was not associated with severe disease. Severe disease was independently associated with infection with an organism with an intermediate susceptibility to ciprofloxacin (AOR 1.90; 95% CI 1.18-3.07; p = 0.009) and male sex (AOR 1.61 (1.00-2.57; p = 0.035). In this group of patients hospitalised with typhoid fever infection with an organism with intermediate susceptibility to ciprofloxacin was independently associated with disease severity. During this period many patients were being treated with fluoroquinolones prior to hospital admission. Ciprofloxacin and ofloxacin should be used with caution in patients infected with S. Typhi that have intermediate susceptibility to ciprofloxacin.

Risk factors for the development of severe typhoid fever in Vietnam

PubMed Central

2014-01-01

Background Typhoid fever is a systemic infection caused by the bacterium Salmonella enterica serovar Typhi. Age, sex, prolonged duration of illness, and infection with an antimicrobial resistant organism have been proposed risk factors for the development of severe disease or fatality in typhoid fever. Methods We analysed clinical data from 581 patients consecutively admitted with culture confirmed typhoid fever to two hospitals in Vietnam during two periods in 1993–1995 and 1997–1999. These periods spanned a change in the antimicrobial resistance phenotypes of the infecting organisms i.e. fully susceptible to standard antimicrobials, resistance to chloramphenicol, ampicillin and trimethoprim-sulphamethoxazole (multidrug resistant, MDR), and intermediate susceptibility to ciprofloxacin (nalidixic acid resistant). Age, sex, duration of illness prior to admission, hospital location and the presence of MDR or intermediate ciprofloxacin susceptibility in the infecting organism were examined by logistic regression analysis to identify factors independently associated with severe typhoid at the time of hospital admission. Results The prevalence of severe typhoid was 15.5% (90/581) and included: gastrointestinal bleeding (43; 7.4%); hepatitis (29; 5.0%); encephalopathy (16; 2.8%); myocarditis (12; 2.1%); intestinal perforation (6; 1.0%); haemodynamic shock (5; 0.9%), and death (3; 0.5%). Severe disease was more common with increasing age, in those with a longer duration of illness and in patients infected with an organism exhibiting intermediate susceptibility to ciprofloxacin. Notably an MDR phenotype was not associated with severe disease. Severe disease was independently associated with infection with an organism with an intermediate susceptibility to ciprofloxacin (AOR 1.90; 95% CI 1.18-3.07; p = 0.009) and male sex (AOR 1.61 (1.00-2.57; p = 0.035). Conclusions In this group of patients hospitalised with typhoid fever infection with an organism with intermediate susceptibility to ciprofloxacin was independently associated with disease severity. During this period many patients were being treated with fluoroquinolones prior to hospital admission. Ciprofloxacin and ofloxacin should be used with caution in patients infected with S. Typhi that have intermediate susceptibility to ciprofloxacin. PMID:24512443

An Evaluation of Recollection and Familiarity in Alzheimer's Disease and Mild Cognitive Impairment Using Receiver Operating Characteristics

ERIC Educational Resources Information Center

Ally, Brandon A.; Gold, Carl A.; Budson, Andrew E.

2009-01-01

There is a need to investigate exactly how memory breaks down in the course of Alzheimer's disease (AD). Examining what aspects of memorial processing remain relatively intact early in the disease process will allow us to develop behavioral interventions and possible drug therapies focused on these intact processes. Several recent studies have…

[Trichoma (Plica polonica) - a contemporary case with a historical disease].

PubMed

Wolf, Florian; Scherr, Martin; Scherthöffer, Dirk; Bäuml, Josef; Förstl, Hans

2008-01-01

We describe a 62-year-old patient with a chronic delusional disorder who presented with severely matted hair ("plica polonica"). Until the late 19th century such dreadlocks were considered as cause, consequence and treatment of mental disease. The historical development of "plica polonica" is briefly reviewed as an example of early and once popular psychiatric disease concepts.

Canine Models for Copper Homeostasis Disorders.

PubMed

Wu, Xiaoyan; Leegwater, Peter A J; Fieten, Hille

2016-02-04

Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted.

Canine Models for Copper Homeostasis Disorders

PubMed Central

Wu, Xiaoyan; Leegwater, Peter A. J.; Fieten, Hille

2016-01-01

Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted. PMID:26861285

Ivermectin: a complimentary weapon against the spread of malaria?

PubMed Central

Alout, Haoues; Foy, Brian

2017-01-01

Introduction Ivermectin has transformed the treatment of parasitic diseases and led to incommensurable benefits to humans and animals. Ivermectin is effective in treating several neglected infectious diseases and recently it has been shown to reduce malaria parasite transmission. Areas covered Malaria control strategies could benefit from the addition of ivermectin to interrupt the transmission cycle if it is a long lasting formulation or repeatedly administered. In turn, this will help also to control neglected infectious diseases where the elimination goal has been slower to achieve. Despite the relevance of using ivermectin for integrated and sustained disease control, there are still essential questions that remain to be addressed about safety and practicality. The efficacy in various malaria ecologies and the interaction between control tools, either drugs or insecticides, are also important to assess. Expert commentary Overlapping distribution of several infectious diseases reveals the benefit of integrating control programs against several infectious diseases into one strategy for cost effectiveness and to reach the elimination goals. The use of ivermectin to control malaria transmission will necessitate development and testing of long-lasting formulations or repeated treatments, and implementation of these treatments with other disease control tools may increase the chance of successful and sustained control. PMID:27960597

Inflammatory cells implicated in neoplasia development in idiopathic inflammatory bowel disease.

PubMed

Hashash, Jana G; Hartman, Douglas J

2017-11-10

The inflammatory mechanisms that lead to the clinical symptoms that are grouped under the term inflammatory bowel disease have not been fully characterized. Although a specific mechanism has not been identified, inflammatory bowel disease is believed to be related to an inability by the immune system to shut active inflammation within the intestine. Many contributing factors have been implicated in the disease process. Based on population studies, patients with inflammatory bowel disease have an increased risk for neoplastic development. Although no specific immune cell has been implicated in neoplastic development within this patient population, several immune cells have been implicated as possible etiologies in inflammatory bowel disease. In this review, we will review the clinical evidence about the risk for neoplastic development in inflammatory bowel disease and the current clinical guidelines to survey this patient population. We will also review the pathologic assessment of inflammation within this patient population as well the underlying immune cells and cytokines that have been implicated in the etiology of inflammatory bowel disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Metabonomics Research Progress on Liver Diseases.

PubMed

Yu, Mengqian; Zhu, Ying; Cong, Qingwei; Wu, Chunyan

2017-01-01

Metabolomics as the new omics technique develops after genomics, transcriptomics, and proteomics and has rapid development at present. Liver diseases are worldwide public health problems. In China, chronic hepatitis B and its secondary diseases are the common liver diseases. They can be diagnosed by the combination of history, virology, liver function, and medical imaging. However, some patients seldom have relevant physical examination, so the diagnosis may be delayed. Many other liver diseases, such as drug-induced liver injury (DILI), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases, still do not have definite diagnostic markers; the diagnosis consists of history, medical imaging, and the relevant score. As a result, the clinical work becomes very complex. So it has broad prospects to explore the specific and sensitive biomarkers of liver diseases with metabolomics. In this paper, there are several summaries which are related to the current research progress and application of metabolomics on biomarkers of liver diseases.

Occurrence of spontaneous periodontal disease in the SAMP1/YitFc murine model of Crohn disease.

PubMed

Pietropaoli, Davide; Del Pinto, Rita; Corridoni, Daniele; Rodriguez-Palacios, Alexander; Di Stefano, Gabriella; Monaco, Annalisa; Weinberg, Aaron; Cominelli, Fabio

2014-12-01

Oral involvement is often associated with inflammatory bowel disease (IBD). Recent evidence suggests a high incidence of periodontal disease in patients with Crohn disease (CD). To the best of the authors' knowledge, no animal model of IBD that displays associated periodontal disease was reported previously. The aim of this study is to investigate the occurrence and progression of periodontal disease in SAMP1/YitFc (SAMP) mice that spontaneously develop a CD-like ileitis. In addition, the temporal correlation between the onset and progression of periodontal disease and the onset of ileitis in SAMP mice was studied. At different time points, SAMP and parental AKR/J (AKR) control mice were sacrificed, and mandibles were prepared for stereomicroscopy and histology. Terminal ilea were collected for histologic assessment of inflammation score. Periodontal status, i.e., alveolar bone loss (ABL) and alveolar bone crest, was examined by stereomicroscopy and histomorphometry, respectively. ABL increased in both strains with age. SAMP mice showed greater ABL compared with AKR mice by 12 weeks of age, with maximal differences observed at 27 weeks of age. AKR control mice did not show the same severity of periodontal disease. Interestingly, a strong positive correlation was found between ileitis severity and ABL in SAMP mice, independent of age. The present results demonstrate the occurrence of periodontal disease in a mouse model of progressive CD-like ileitis. In addition, the severity of periodontitis strongly correlated with the severity of ileitis, independent of age, suggesting that common pathogenic mechanisms, such as abnormal immune response and dysbiosis, may be shared between these two phenotypes.

Role for NLRP3 Inflammasome-mediated, IL-1β-Dependent Responses in Severe, Steroid-Resistant Asthma.

PubMed

Kim, Richard Y; Pinkerton, James W; Essilfie, Ama T; Robertson, Avril A B; Baines, Katherine J; Brown, Alexandra C; Mayall, Jemma R; Ali, M Khadem; Starkey, Malcolm R; Hansbro, Nicole G; Hirota, Jeremy A; Wood, Lisa G; Simpson, Jodie L; Knight, Darryl A; Wark, Peter A; Gibson, Peter G; O'Neill, Luke A J; Cooper, Matthew A; Horvat, Jay C; Hansbro, Philip M

2017-08-01

Severe, steroid-resistant asthma is the major unmet need in asthma therapy. Disease heterogeneity and poor understanding of pathogenic mechanisms hampers the identification of therapeutic targets. Excessive nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome and concomitant IL-1β responses occur in chronic obstructive pulmonary disease, respiratory infections, and neutrophilic asthma. However, the direct contributions to pathogenesis, mechanisms involved, and potential for therapeutic targeting remain poorly understood, and are unknown in severe, steroid-resistant asthma. To investigate the roles and therapeutic targeting of the NLRP3 inflammasome and IL-1β in severe, steroid-resistant asthma. We developed mouse models of Chlamydia and Haemophilus respiratory infection-mediated, ovalbumin-induced severe, steroid-resistant allergic airway disease. These models share the hallmark features of human disease, including elevated airway neutrophils, and NLRP3 inflammasome and IL-1β responses. The roles and potential for targeting of NLRP3 inflammasome, caspase-1, and IL-1β responses in experimental severe, steroid-resistant asthma were examined using a highly selective NLRP3 inhibitor, MCC950; the specific caspase-1 inhibitor Ac-YVAD-cho; and neutralizing anti-IL-1β antibody. Roles for IL-1β-induced neutrophilic inflammation were examined using IL-1β and anti-Ly6G. Chlamydia and Haemophilus infections increase NLRP3, caspase-1, IL-1β responses that drive steroid-resistant neutrophilic inflammation and airway hyperresponsiveness. Neutrophilic airway inflammation, disease severity, and steroid resistance in human asthma correlate with NLRP3 and IL-1β expression. Treatment with anti-IL-1β, Ac-YVAD-cho, and MCC950 suppressed IL-1β responses and the important steroid-resistant features of disease in mice, whereas IL-1β administration recapitulated these features. Neutrophil depletion suppressed IL-1β-induced steroid-resistant airway hyperresponsiveness. NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.

Relative Contribution of Dengue IgG Antibodies Acquired during Gestation or Breastfeeding in Mediating Dengue Disease Enhancement and Protection in Type I Interferon Receptor-Deficient Mice.

PubMed

Lee, Pei Xuan; Ong, Li Ching; Libau, Eshele Anak; Alonso, Sylvie

2016-06-01

Dengue virus (DENV) causes a spectrum of diseases ranging from self-limiting dengue fever to severe conditions such as haemorrhagic fever and dengue shock syndrome. Antibody-dependent enhancement (ADE) is thought to explain the occurrence of severe dengue whereby pre-existing binding but non-neutralising antibodies enhance DENV infection. The ADE phenomenon is supported by epidemiological findings that infants that born to dengue immune mothers are at greater risk to develop severe dengue upon primary infection. The role of maternally acquired dengue-specific antibodies in disease enhancement was recently recapitulated in a mouse model where mice born to DENV1-immune mothers experienced enhanced disease severity upon DENV2 infection. Here, this study investigates the relative contribution of maternal dengue-specific antibodies acquired during gestation and breastfeeding in dengue disease. Using a surrogate breastfeeding mother experimental approach, we showed that majority of the maternal dengue-specific antibodies were acquired during breastfeeding and conferred an extended enhancement window. On the other hand, in the context of homologous infection, breastfeeding conferred protection. Furthermore, measurement of dengue-specific antibody titres over time in mice born to dengue immune mothers revealed a biphasic pattern of antibody decay as reported in humans. Our work provides evidence of the potential contribution of breast milk-acquired dengue-specific IgG antibodies in enhancement and protection against dengue. Should such contribution be established in humans as well, it may have important implications for the development of guidelines to dengue-immune breastfeeding mothers.

Visual Analysis for Detection and Quantification of Pseudomonas cichorii Disease Severity in Tomato Plants.

PubMed

Rajendran, Dhinesh Kumar; Park, Eunsoo; Nagendran, Rajalingam; Hung, Nguyen Bao; Cho, Byoung-Kwan; Kim, Kyung-Hwan; Lee, Yong Hoon

2016-08-01

Pathogen infection in plants induces complex responses ranging from gene expression to metabolic processes in infected plants. In spite of many studies on biotic stress-related changes in host plants, little is known about the metabolic and phenotypic responses of the host plants to Pseudomonas cichorii infection based on image-based analysis. To investigate alterations in tomato plants according to disease severity, we inoculated plants with different cell densities of P. cichorii using dipping and syringe infiltration methods. High-dose inocula (≥ 10(6) cfu/ml) induced evident necrotic lesions within one day that corresponded to bacterial growth in the infected tissues. Among the chlorophyll fluorescence parameters analyzed, changes in quantum yield of PSII (ΦPSII) and non-photochemical quenching (NPQ) preceded the appearance of visible symptoms, but maximum quantum efficiency of PSII (Fv/Fm) was altered well after symptom development. Visible/near infrared and chlorophyll fluorescence hyperspectral images detected changes before symptom appearance at low-density inoculation. The results of this study indicate that the P. cichorii infection severity can be detected by chlorophyll fluorescence assay and hyperspectral images prior to the onset of visible symptoms, indicating the feasibility of early detection of diseases. However, to detect disease development by hyperspectral imaging, more detailed protocols and analyses are necessary. Taken together, change in chlorophyll fluorescence is a good parameter for early detection of P. cichorii infection in tomato plants. In addition, image-based visualization of infection severity before visual damage appearance will contribute to effective management of plant diseases.

Relative Contribution of Dengue IgG Antibodies Acquired during Gestation or Breastfeeding in Mediating Dengue Disease Enhancement and Protection in Type I Interferon Receptor-Deficient Mice

PubMed Central

Lee, Pei Xuan; Ong, Li Ching; Libau, Eshele Anak; Alonso, Sylvie

2016-01-01

Dengue virus (DENV) causes a spectrum of diseases ranging from self-limiting dengue fever to severe conditions such as haemorrhagic fever and dengue shock syndrome. Antibody-dependent enhancement (ADE) is thought to explain the occurrence of severe dengue whereby pre-existing binding but non-neutralising antibodies enhance DENV infection. The ADE phenomenon is supported by epidemiological findings that infants that born to dengue immune mothers are at greater risk to develop severe dengue upon primary infection. The role of maternally acquired dengue-specific antibodies in disease enhancement was recently recapitulated in a mouse model where mice born to DENV1-immune mothers experienced enhanced disease severity upon DENV2 infection. Here, this study investigates the relative contribution of maternal dengue-specific antibodies acquired during gestation and breastfeeding in dengue disease. Using a surrogate breastfeeding mother experimental approach, we showed that majority of the maternal dengue-specific antibodies were acquired during breastfeeding and conferred an extended enhancement window. On the other hand, in the context of homologous infection, breastfeeding conferred protection. Furthermore, measurement of dengue-specific antibody titres over time in mice born to dengue immune mothers revealed a biphasic pattern of antibody decay as reported in humans. Our work provides evidence of the potential contribution of breast milk-acquired dengue-specific IgG antibodies in enhancement and protection against dengue. Should such contribution be established in humans as well, it may have important implications for the development of guidelines to dengue-immune breastfeeding mothers. PMID:27341339

Disease progression in Chinese chronic hepatitis C patients with persistently normal alanine aminotransaminase levels.

PubMed

Hui, C-K; Zhang, H-Y; Shek, T; Yao, H; Yueng, Y-H; Leung, K-W; Lai, S-T; Lai, J-Y; Leung, N; Lau, G K

2007-06-01

Although chronic hepatitis C virus-infected patients with persistently normal alanine aminotransaminase levels usually have mild liver disease, disease progression can still occur. However, it is uncertain which group of patients is at risk of disease progression. To examine the severity of liver disease on liver biopsy in Chinese patients with persistently normal alanine aminotransaminase levels, and their disease progression over time. Eighty-two patients with persistently normal alanine aminotransaminase levels were followed up longitudinally. The median time of follow-up was 8.1 years. Forty-seven of the 82 patients (57.3%) had a second liver biopsy. At the time of analysis, six of the 82 patients (7.3%) developed decompensated liver cirrhosis. Patients with an initial fibrosis stage F2 or F3 [6/23 (26.1%) vs. 0/59 (0%), P < 0.0001] or inflammatory grade A2 or A3 [5/40 (12.5%) vs. 1/42 (2.4%), P = 0.04] were more likely to develop decompensated liver cirrhosis. On multivariate analysis, initial fibrosis stage F2 or F3 was independently associated with progression to decompensated liver cirrhosis (relative risk 2.3, 95% confidence interval 0.03-2.5, P = 0.02). Chinese chronic hepatitis C virus patients with persistently normal alanine aminotransaminase levels with moderate to severe fibrosis at initial evaluation are more likely to develop decompensated liver cirrhosis.

Integrating gut microbiota immaturity and disease-discriminatory taxa to diagnose the initiation and severity of shrimp disease.

PubMed

Xiong, Jinbo; Zhu, Jinyong; Dai, Wenfang; Dong, Chunming; Qiu, Qiongfen; Li, Chenghua

2017-04-01

Increasing evidence has emerged a tight link among the gut microbiota, host age and health status. This osculating interplay impedes the definition of gut microbiome features associated with host health from that in developmental stages. Consequently, gut microbiota-based prediction of health status is promising yet not well established. Here we firstly tracked shrimp gut microbiota (N = 118) over an entire cycle of culture; shrimp either stayed healthy or progressively transitioned into severe disease. The results showed that the gut microbiota were significantly distinct over shrimp developmental stages and disease progression. Null model and phylogenetic-based mean nearest taxon distance (MNTD) analyses indicated that deterministic processes that governed gut community became less important as the shrimp aged and disease progressed. The predicted gut microbiota age (using the profiles of age-discriminatory bacterial species as independent variables) fitted well (r = 0.996; P < 0.001) with the age of healthy subjects, while this defined trend was disrupted by disease. Microbiota-for-age Z-scores (MAZ, here defined as immaturity) were relative stable among healthy shrimp, but sharply decreased when disease emerged. By distinguishing between age- and disease- discriminatory taxa, we developed a model, bacterial indicators of shrimp health status, to diagnose disease from healthy subjects with 91.5% accuracy. Notably, the relative abundances of the bacterial indicators were indicative for shrimp disease severity. These findings, in aggregate, add our understanding on the gut community assembly patterns over shrimp developmental stages and disease progression. In addition, shrimp disease initiation and severity can be accurately diagnosed using gut microbiota immaturity and bacterial indicators. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

Meningococcal conjugate vaccines: optimizing global impact

PubMed Central

Terranella, Andrew; Cohn, Amanda; Clark, Thomas

2011-01-01

Meningococcal conjugate vaccines have several advantages over polysaccharide vaccines, including the ability to induce greater antibody persistence, avidity, immunologic memory, and herd immunity. Since 1999, meningococcal conjugate vaccine programs have been established across the globe. Many of these vaccination programs have resulted in significant decline in meningococcal disease in several countries. Recent introduction of serogroup A conjugate vaccine in Africa offers the potential to eliminate meningococcal disease as a public health problem in Africa. However, the duration of immune response and the development of widespread herd immunity in the population remain important questions for meningococcal vaccine programs. Because of the unique epidemiology of meningococcal disease around the world, the optimal vaccination strategy for long-term disease prevention will vary by country. PMID:22114508

Environmentally-driven ensemble forecasts of dengue fever

NASA Astrophysics Data System (ADS)

Yamana, T. K.; Shaman, J. L.

2017-12-01

Dengue fever is a mosquito-borne viral disease prevalent in the tropics and subtropics, with an estimated 2.5 billion people at risk of transmission. In many areas where dengue is found, disease transmission is seasonal but prone to high inter-annual variability with occasional severe epidemics. Predicting and preparing for periods of higher than average transmission remains a significant public health challenge. Recently, we developed a framework for forecasting dengue incidence using an dynamical model of disease transmission coupled with observational data of dengue cases using data-assimilation methods. Here, we investigate the use of environmental data to drive the disease transmission model. We produce retrospective forecasts of the timing and severity of dengue outbreaks, and quantify forecast predictive accuracy.

Alcoholic Beverage Consumption and Chronic Diseases

PubMed Central

Zhou, Yue; Zheng, Jie; Li, Sha; Zhou, Tong; Zhang, Pei; Li, Hua-Bin

2016-01-01

Epidemiological and experimental studies have consistently linked alcoholic beverage consumption with the development of several chronic disorders, such as cancer, cardiovascular diseases, diabetes mellitus and obesity. The impact of drinking is usually dose-dependent, and light to moderate drinking tends to lower risks of certain diseases, while heavy drinking tends to increase the risks. Besides, other factors such as drinking frequency, genetic susceptibility, smoking, diet, and hormone status can modify the association. The amount of ethanol in alcoholic beverages is the determining factor in most cases, and beverage types could also make an influence. This review summarizes recent studies on alcoholic beverage consumption and several chronic diseases, trying to assess the effects of different drinking patterns, beverage types, interaction with other risk factors, and provide mechanistic explanations. PMID:27231920

Treatment resistance in potentially malignant disorders-'Nature' or 'Nurture'…?

PubMed

Thomson, P J; Goodson, M L; Smith, D R

2017-11-01

Contemporary potentially malignant disorder management is based upon provisional histological diagnosis followed by interventional surgery to excise or ablate 'high-risk' mucosal lesions. Although the majority of patients achieve disease-free status post-treatment, others develop further or persistent disease unresponsive to intervention. A detailed, retrospective clinico-pathological review of treatment resistant potentially malignant lesions, from a 590 patient cohort treated by CO 2 laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was determined at study census date (31 December 2014). A total of 87 patients (15%) exhibited PMD disease resistant to treatment: 34 (6%) became disease free following further treatment, whilst 53 (9%) had persistent disease despite intervention. Disease-free patients were younger, changed lesion appearance from erythroleukoplakia to leukoplakia (P = .004), developed further lesions at new sites, demonstrated reduction in dysplasia severity with time and required multiple treatments to achieve disease-free status (P = .0005). In contrast, persistent disease patients were older, male, often presented with proliferative verrucous leukoplakia (PVL) on gingival and alveolar sites, displayed less severe dysplasia initially and underwent laser ablation rather than excision (P = .027). Despite clinico-pathological profiling of treatment resistant patients, the precise inter-relationship between the inherent nature of potentially malignant disease and the external influence of treatment intervention remains obscure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Syrian hamster model of hantavirus pulmonary syndrome

PubMed Central

Safronetz, David; Ebihara, Hideki; Feldmann, Heinz; Hooper, Jay W.

2012-01-01

Hantavirus pulmonary syndrome (HPS) is a relatively rare, but frequently fatal disease associated with New World hantaviruses, most commonly Sin Nombre and Andes viruses in North and South America, respectively. It is characterized by fever and the sudden, rapid onset of severe respiratory distress and cardiogenic shock, which can be fatal in up to 50% of cases. Currently there are no approved antiviral therapies or vaccines for the treatment or prevention of HPS. A major obstacle in the development of effective medical countermeasures against highly pathogenic agents like the hantaviruses is recapitulating the human disease as closely as possible in an appropriate and reliable animal model. To date, the only animal model that resembles HPS in humans is the Syrian hamster model. Following infection with Andes virus, hamsters develop HPS-like disease which faithfully mimics the human condition with respect to incubation period and pathophysiology of disease. Perhaps most importantly, the sudden and rapid onset of severe respiratory distress observed in humans also occurs in hamsters. The last several years has seen an increase in studies utilizing the Andes virus hamster model which have provided unique insight into HPS pathogenesis as well as potential therapeutic and vaccine strategies to treat and prevent HPS. The purpose of this article is to review the current understanding of HPS disease progression in Syrian hamsters and discuss the suitability of utilizing this model to evaluate potential medical countermeasures against HPS. PMID:22705798

Pulmonary Hypertension in Congenital Heart Disease: Beyond Eisenmenger Syndrome.

PubMed

Krieger, Eric V; Leary, Peter J; Opotowsky, Alexander R

2015-11-01

Patients with adult congenital heart disease have an increased risk of developing pulmonary hypertension. There are several mechanisms of pulmonary hypertension in patients with adult congenital heart disease, and understanding them requires a systematic approach to define the patient's hemodynamics and physiology. This article reviews the updated classification of pulmonary hypertension in patients with adult congenital heart disease with a focus on pathophysiology, diagnostics, and the evaluation of pulmonary hypertension in special adult congenital heart disease populations. Copyright © 2015 Elsevier Inc. All rights reserved.

Therapeutic approach to Crohn disease: possible parallels with hidradenitis suppurativa.

PubMed

González Lama, Y; Marín-Jiménez, I

2016-09-01

The current controversy in the setting of dermatology surrounding the treatment of inflammatory diseases, and specifically hidradenitis suppurativa, bears strong similarities with the debate concerning inflammatory bowel disease (IBD) that took place several years ago. That debate led to new perspectives on this disease and, in particular, its treatment after the development of biological agents. Copyright © 2016 Elsevier España, S.L.U. y AEDV. All rights reserved.

Diverticular Disease: Traditional and Evolving Paradigms.

PubMed

Lamanna, Lenore; Moran, Patricia E

Diverticular disease includes diverticulosis, which are sac protrusions of the intestinal mucosa, and diverticulitis, inflammation of the diverticula. Diverticular disease is listed as one of the top 10 leading physician diagnoses for gastrointestinal disorders in outpatient clinic visits in the United States. There are several classifications of diverticular disease ranging from asymptomatic diverticulosis to diverticulitis with complications. Several theories are linked to the development of diverticula which includes the physiology of the colon itself, collagen cross-linking, and recently challenged, low-fiber intake. The differential diagnoses of lower abdominal pain in addition to diverticular disease have overlapping signs and symptoms, which can make a diagnosis challenging. Identification of the distinct signs and symptoms of each classification will assist the practitioner in making the correct diagnosis and lead to appropriate management. The findings from recent studies have changed the paradigm of diverticular disease. The purpose of this article is to discuss traditional dogma and evolving concepts in the pathophysiology, prevention, and management of diverticular disease. Practitioners must be knowledgeable about diverticular disease for improved outcomes.

Diabetes-associated dry eye syndrome in a new humanized transgenic model of type 1 diabetes.

PubMed

Imam, Shahnawaz; Elagin, Raya B; Jaume, Juan Carlos

2013-01-01

Patients with Type 1 Diabetes (T1D) are at high risk of developing lacrimal gland dysfunction. We have developed a new model of human T1D using double-transgenic mice carrying HLA-DQ8 diabetes-susceptibility haplotype instead of mouse MHC-class II and expressing the human beta cell autoantigen Glutamic Acid Decarboxylase in pancreatic beta cells. We report here the development of dry eye syndrome (DES) after diabetes induction in our humanized transgenic model. Double-transgenic mice were immunized with DNA encoding human GAD65, either naked or in adenoviral vectors, to induce T1D. Mice monitored for development of diabetes developed lacrimal gland dysfunction. Animals developed lacrimal gland disease (classically associated with diabetes in Non Obese Diabetic [NOD] mice and with T1D in humans) as they developed glucose intolerance and diabetes. Animals manifested obvious clinical signs of dry eye syndrome (DES), from corneal erosions to severe keratitis. Histological studies of peri-bulbar areas revealed lymphocytic infiltration of glandular structures. Indeed, infiltrative lesions were observed in lacrimal/Harderian glands within weeks following development of glucose intolerance. Lesions ranged from focal lymphocytic infiltration to complete acinar destruction. We observed a correlation between the severity of the pancreatic infiltration and the severity of the ocular disease. Our results demonstrate development of DES in association with antigen-specific insulitis and diabetes following immunization with clinically relevant human autoantigen concomitantly expressed in pancreatic beta cells of diabetes-susceptible mice. As in the NOD mouse model and as in human T1D, our animals developed diabetes-associated DES. This specific finding stresses the relevance of our model for studying these human diseases. We believe our model will facilitate studies to prevent/treat diabetes-associated DES as well as human diabetes.

Prevention and management of ovarian hyperstimulation syndrome.

PubMed

Nelson, Scott M

2017-03-01

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication of ovarian stimulation. It is feasible to identify patients at risk, modify stimulation strategies to ameliorate risk, and initiate out-patient treatments that alter disease pathophysiology to reduce disease severity. Mitigation of OHSS risk and severity, through innovative approaches prior to treatment, during treatment and after treatment should now be standard care. This review summarizes recent developments and provides recommendations on the prevention and treatment of OHSS. © 2017 Elsevier Ltd. All rights reserved.

Severe Graves' ophthalmopathy may be a risk factor for the development of postthyroidectomy hypocalcaemia.

PubMed

Hassan, I; Danila, R; Maurer, E; Osei-Agymang, T; Zielke, A

2008-11-01

The aim of this study was to compare the rate of hypocalcaemia after thyroid resection in patients with versus patients without Graves' Ophthalmopathy (GO). 153 patients following thyroid surgery for Grave's disease were studied. Patients were divided into three groups according to the severity of GO at the time of surgery using the NOSPECS classification. Subgroup I comprised of 70 patients without GO, subgroup II comprised of 63 patients with moderate GO and 20 patients with severe GO were assigned to Subgroup III. Association between severe ophthalmopathy and postoperative hypocalcaemia after thyroidectomy was investigated. 12/70 patients complained transient and 3/70 permanent hypocalcemia within subgroup I. 14/63 patients developed transient and 4/63 patients permanent hypocalcaemia within subgroup II. There were 7/20 patients with transient and 5/20 cases with permanent hypocalcaemia in the patient group with severe GO (subgroup III). The incidence of permanent postthyroidectomy hypocalcaemia was significantly higher in the subgroup III with severe GO when compared to the subgroup I without GO (p=0.004). Although postthyroidectomy hypocalcemia seems to be a multifactorial phenomenon, this study implicates unknown role of severe GO at time of surgery in the development of hypocalcaemia after thyroid surgery for Graves' disease. Therefore, patients with GO should be considered for surgery at high volume centres specialised in thyroid and parathyroid surgery.

Home monitoring of patients with Parkinson's disease via wearable technology and a web-based application.

PubMed

Patel, Shyamal; Chen, Bor-Rong; Buckley, Thomas; Rednic, Ramona; McClure, Doug; Tarsy, Daniel; Shih, Ludy; Dy, Jennifer; Welsh, Matt; Bonato, Paolo

2010-01-01

Objective long-term health monitoring can improve the clinical management of several medical conditions ranging from cardiopulmonary diseases to motor disorders. In this paper, we present our work toward the development of a home-monitoring system. The system is currently used to monitor patients with Parkinson's disease who experience severe motor fluctuations. Monitoring is achieved using wireless wearable sensors whose data are relayed to a remote clinical site via a web-based application. The work herein presented shows that wearable sensors combined with a web-based application provide reliable quantitative information that can be used for clinical decision making.

Liver and lung transplantation in cystic fibrosis: an adult cystic fibrosis centre's experience.

PubMed

Sivam, S; Al-Hindawi, Y; Di Michiel, J; Moriarty, C; Spratt, P; Jansz, P; Malouf, M; Plit, M; Pleass, H; Havryk, A; Bowen, D; Haber, P; Glanville, A R; Bye, P T P

2016-07-01

Liver disease develops in one-third of patients with cystic fibrosis (CF). It is rare for liver disease to have its onset after 20 years of age. Lung disease, however, is usually more severe in adulthood. A retrospective analysis was performed on nine patients. Three patients required lung transplantation approximately a decade after liver transplant, and another underwent combined liver and lung transplants. Four additional patients with liver transplants are awaiting assessment for lung transplants. One patient is awaiting combined liver and lung transplants. With increased survival in CF, several patients may require more than single organ transplantation. © 2016 Royal Australasian College of Physicians.

Ambulatory screening of diabetic neuropathy and predictors of its severity in outpatient settings.

PubMed

Qureshi, M S; Iqbal, M; Zahoor, S; Ali, J; Javed, M U

2017-04-01

Diabetic neuropathy is one of the most common causes of chronic neuropathic symptomatology and the most disabling and difficult-to-treat diabetic microangiopathic complication. The neuropathies associated with diabetes are typically classified into generalized, focal and multifocal varieties. There exists a scarcity of literature studying the correlation of different patient- and disease-related variables with severity of neuropathy. This study aims to delineate the prevalence of diabetic neuropathy in type 2 diabetes, describe its characteristics and find out predictors of its severity. Eight hundred consecutive diabetic patients presenting to outpatient department (OPD) of Khan Research Labs (KRL) General Hospital and Centre for Diabetes and Liver diseases, Islamabad, during March-June, 2015 were made to complete a self-administered questionnaire (Michigan Neuropathy Screening Instrument-MNSI) and underwent a thorough physical examination according to MNSI protocols. A score of >2 was considered to be diagnostic for DPN. Patient and disease variables were noted. MNSI score was used as an index of severity of diabetic peripheral neuropathy (DPN). Correlation of several patient- and disease-related variables with the severity of DPN was determined using multivariate regression. Out of a total 800 patients screened, 90 (11.25%) were found to have diabetic neuropathy. Of these 90, 45.5% were males, the median age was 54.47 ± 10.87 years and the median duration of diabetes was 11.12 ± 9.8 years. The most common symptom was found to be numbness (63.6%) followed by generalized body weakness (61.5%). The common findings on physical examination were dry skin/callus (38.7%) and deformities (14.7%). Duration of diabetes was found to be the strongest predictor for development and severity of diabetic neuropathy followed by glycemic controls (HbA1c values) and age. Duration of diabetes rather than diabetic controls predicts better the development and severity of diabetic neuropathy indicating a failure of intensive treatment to avert such complications.

Statistical Modeling of Disease Progression for Chronic Obstructive Pulmonary Disease Using Data from the ECLIPSE Study.

PubMed

Exuzides, Alex; Colby, Chris; Briggs, Andrew H; Lomas, David A; Rutten-van Mölken, Maureen P M H; Tabberer, Maggie; Chambers, Mike; Muellerova, Hana; Locantore, Nicholas; Risebrough, Nancy A; Ismaila, Afisi S; Gonzalez-McQuire, Sebastian

2017-05-01

To develop statistical models predicting disease progression and outcomes in chronic obstructive pulmonary disease (COPD), using data from ECLIPSE, a large, observational study of current and former smokers with COPD. Based on a conceptual model of COPD disease progression and data from 2164 patients, associations were made between baseline characteristics, COPD disease progression attributes (exacerbations, lung function, exercise capacity, and symptoms), health-related quality of life (HRQoL), and survival. Linear and nonlinear functional forms of random intercept models were used to characterize these relationships. Endogeneity was addressed by time-lagging variables in the regression models. At the 5% significance level, an exacerbation history in the year before baseline was associated with increased risk of future exacerbations (moderate: +125.8%; severe: +89.2%) and decline in lung function (forced expiratory volume in 1 second [FEV 1 ]) (-94.20 mL per year). Each 1% increase in FEV 1 % predicted was associated with decreased risk of exacerbations (moderate: -1.1%; severe: -3.0%) and increased 6-minute walk test distance (6MWD) (+1.5 m). Increases in baseline exercise capacity (6MWD, per meter) were associated with slightly increased risk of moderate exacerbations (+0.04%) and increased FEV 1 (+0.62 mL). Symptoms (dyspnea, cough, and/or sputum) were associated with an increased risk of moderate exacerbations (+13.4% to +31.1%), and baseline dyspnea (modified Medical Research Council score ≥2 v. <2) was associated with lower FEV 1 (-112.3 mL). A series of linked statistical regression equations have been developed to express associations between indicators of COPD disease severity and HRQoL and survival. These can be used to represent disease progression, for example, in new economic models of COPD.

Taxonomy of rare genetic metabolic bone disorders.

PubMed

Masi, L; Agnusdei, D; Bilezikian, J; Chappard, D; Chapurlat, R; Cianferotti, L; Devolgelaer, J-P; El Maghraoui, A; Ferrari, S; Javaid, M K; Kaufman, J-M; Liberman, U A; Lyritis, G; Miller, P; Napoli, N; Roldan, E; Papapoulos, S; Watts, N B; Brandi, M L

2015-10-01

This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

Mannose Binding Lectin Is Required for Alphavirus-Induced Arthritis/Myositis

PubMed Central

Whitmore, Alan C.; Blevins, Lance K.; Hueston, Linda; Fraser, Robert J.; Herrero, Lara J.; Ramirez, Ruben; Smith, Paul N.; Mahalingam, Suresh; Heise, Mark T.

2012-01-01

Mosquito-borne alphaviruses such as chikungunya virus and Ross River virus (RRV) are emerging pathogens capable of causing large-scale epidemics of virus-induced arthritis and myositis. The pathology of RRV-induced disease in both humans and mice is associated with induction of the host inflammatory response within the muscle and joints, and prior studies have demonstrated that the host complement system contributes to development of disease. In this study, we have used a mouse model of RRV-induced disease to identify and characterize which complement activation pathways mediate disease progression after infection, and we have identified the mannose binding lectin (MBL) pathway, but not the classical or alternative complement activation pathways, as essential for development of RRV-induced disease. MBL deposition was enhanced in RRV infected muscle tissue from wild type mice and RRV infected MBL deficient mice exhibited reduced disease, tissue damage, and complement deposition compared to wild-type mice. In contrast, mice deficient for key components of the classical or alternative complement activation pathways still developed severe RRV-induced disease. Further characterization of MBL deficient mice demonstrated that similar to C3−/− mice, viral replication and inflammatory cell recruitment were equivalent to wild type animals, suggesting that RRV-mediated induction of complement dependent immune pathology is largely MBL dependent. Consistent with these findings, human patients diagnosed with RRV disease had elevated serum MBL levels compared to healthy controls, and MBL levels in the serum and synovial fluid correlated with severity of disease. These findings demonstrate a role for MBL in promoting RRV-induced disease in both mice and humans and suggest that the MBL pathway of complement activation may be an effective target for therapeutic intervention for humans suffering from RRV-induced arthritis and myositis. PMID:22457620

Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice.

PubMed

Sumner, Charlotte J; Wee, Claribel D; Warsing, Leigh C; Choe, Dong W; Ng, Andrew S; Lutz, Cathleen; Wagner, Kathryn R

2009-09-01

There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-beta family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn(-/-)) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA.

Measuring patients' satisfaction with their anti-TNF treatment in severe Crohn's disease: scoring and psychometric validation of the Satisfaction for PAtients in Crohn's diseasE Questionnaire (SPACE-Q(©)).

PubMed

Gilet, Hélène; Arnould, Benoit; Fofana, Fatoumata; Clerson, Pierre; Colombel, Jean-Frédéric; D'Hondt, Olivier; Faure, Patrick; Hagège, Hervé; Nachury, Maria; Nahon, Stéphane; Tucat, Gilbert; Vandromme, Luc; Cazala-Telinge, Ines; Thibout, Emmanuel

2014-01-01

Severe Crohn's disease management includes anti-tumor necrosis factor (anti-TNF) drugs that differ from early-stage treatments regarding efficacy, safety, and convenience. This study aimed to finalize and psychometrically validate the Satisfaction for PAtients in Crohn's diseasE Questionnaire (SPACE-Q(©)), developed to measure satisfaction with anti-TNF treatment in patients with severe Crohn's disease. A total of 279 patients with severe Crohn's disease receiving anti-TNF therapy completed the SPACE-Q 62-item pilot version at inclusion and 12 and 13 weeks after first anti-TNF injection. The final SPACE-Q scoring was defined using multitrait and regression analyses and clinical relevance considerations. Psychometric validation included clinical validity against Harvey-Bradshaw score, concurrent validity against Treatment Satisfaction Questionnaire for Medication (TSQM), internal consistency reliability, test-retest reliability, and responsiveness against the patient global impression of change (PGIC). Quality of completion was good (55%-67% of patients completed all items). Four items were removed from the questionnaire. Eleven scores were defined within the final 58-item SPACE-Q: disease control; symptoms, anal symptoms, and quality of life transition scales; tolerability; convenience; expectation confirmation toward efficacy, side effects, and convenience; satisfaction with treatment; and motivation. Scores met standards for concurrent validity (correlation between SPACE-Q satisfaction with treatment and TSQM satisfaction scores =0.59), internal consistency reliability (Cronbach's α=0.67-0.93), test-retest reliability (intraclass correlations =0.62-0.91), and responsiveness (improvement in treatment experience assessed by the SPACE-Q for patients reporting improvement on the PGIC). Significantly different mean scores were observed between groups of patients with different Harvey-Bradshaw disease severity scores. The SPACE-Q is a valid, reliable, and responsive instrument to measure satisfaction with anti-TNF treatment in patients with severe Crohn's disease and for use in future studies.

Development of a quantitative assessment method of pigmentary skin disease using ultraviolet optical imaging.

PubMed

Lee, Onseok; Park, Sunup; Kim, Jaeyoung; Oh, Chilhwan

2017-11-01

The visual scoring method has been used as a subjective evaluation of pigmentary skin disorders. Severity of pigmentary skin disease, especially melasma, is evaluated using a visual scoring method, the MASI (melasma area severity index). This study differentiates between epidermal and dermal pigmented disease. The study was undertaken to determine methods to quantitatively measure the severity of pigmentary skin disorders under ultraviolet illumination. The optical imaging system consists of illumination (white LED, UV-A lamp) and image acquisition (DSLR camera, air cooling CMOS CCD camera). Each camera is equipped with a polarizing filter to remove glare. To analyze images of visible and UV light, images are divided into frontal, cheek, and chin regions of melasma patients. Each image must undergo image processing. To reduce the curvature error in facial contours, a gradient mask is used. The new method of segmentation of front and lateral facial images is more objective for face-area-measurement than the MASI score. Image analysis of darkness and homogeneity is adequate to quantify the conventional MASI score. Under visible light, active lesion margins appear in both epidermal and dermal melanin, whereas melanin is found in the epidermis under UV light. This study objectively analyzes severity of melasma and attempts to develop new methods of image analysis with ultraviolet optical imaging equipment. Based on the results of this study, our optical imaging system could be used as a valuable tool to assess the severity of pigmentary skin disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Prediction of Severe Disease in Children with Diarrhea in a Resource-Limited Setting

PubMed Central

Levine, Adam C.; Munyaneza, Richard M.; Glavis-Bloom, Justin; Redditt, Vanessa; Cockrell, Hannah C.; Kalimba, Bantu; Kabemba, Valentin; Musavuli, Juvenal; Gakwerere, Mathias; Umurungi, Jean Paul de Charles; Shah, Sachita P.; Drobac, Peter C.

2013-01-01

Objective To investigate the accuracy of three clinical scales for predicting severe disease (severe dehydration or death) in children with diarrhea in a resource-limited setting. Methods Participants included 178 children admitted to three Rwandan hospitals with diarrhea. A local physician or nurse assessed each child on arrival using the World Health Organization (WHO) severe dehydration scale and the Centers for Disease Control (CDC) scale. Children were weighed on arrival and daily until they achieved a stable weight, with a 10% increase between admission weight and stable weight considered severe dehydration. The Clinical Dehydration Scale was then constructed post-hoc using the data collected for the other two scales. Receiver Operator Characteristic (ROC) curves were constructed for each scale compared to the composite outcome of severe dehydration or death. Results The WHO severe dehydration scale, CDC scale, and Clinical Dehydration Scale had areas under the ROC curves (AUCs) of 0.72 (95% CI 0.60, 0.85), 0.73 (95% CI 0.62, 0.84), and 0.80 (95% CI 0.71, 0.89), respectively, in the full cohort. Only the Clinical Dehydration Scale was a significant predictor of severe disease when used in infants, with an AUC of 0.77 (95% CI 0.61, 0.93), and when used by nurses, with an AUC of 0.78 (95% CI 0.63, 0.93). Conclusions While all three scales were moderate predictors of severe disease in children with diarrhea, scale accuracy varied based on provider training and age of the child. Future research should focus on developing or validating clinical tools that can be used accurately by nurses and other less-skilled providers to assess all children with diarrhea in resource-limited settings. PMID:24349271

Severity indices in rheumatoid arthritis: A systematic review.

PubMed

Toledano, Esther; García de Yébenes, M Jesús; González-Álvaro, Isidoro; Carmona, Loreto

2017-08-11

To identify tools designed to evaluate the severity of patients with rheumatoid arthritis (RA) in order to use them in the investigation of prognostic markers in early arthritis. We conducted a systematic review of studies that developed/validated an index for RA disease severity. They were analyzed using the COSMIN checklist to assess their methodological quality. In addition, all the variables included were evaluated for their clarity of definition, feasibility and probability of being present in each outcome during the first 2 years of the disease course. To estimate redundancy, variables were grouped by domains. After reviewing 3,519 articles, 3 studies were included. The first study, the PAS, assessed whether current and lifetime treatment with disease-modifying antirheumatic drugs and/or biologics accurately predicted RA severity, as measured by the patient-reported PAS. Treatment variables did not fully distinguish patients in the highest and lowest quartiles of PAS scores. Another severity index, the Claims-Based Index for RA Severity (CIRAS), included the variables age, sex, Felty's syndrome, number of rehabilitation and rheumatology visits, test for inflammatory markers, number of chemistry panels/platelet counts ordered and rheumatoid factor test. The correlation was low (r=0.56) with an index previously validated by the same research group, the RA medical records-based index of severity (RARBIS), with Disease Activity Score-C-reactive protein (DAS28-PCR) (r=0.07) and Multidimensional Health Assessment Questionnaire (MD-HAQ) (r=0.008). Finally, the RARBIS, used to validate the CIRAS, was devised as an RA severity index based on medical records. It includes as domains surgery, radiology, extra-articular manifestations, clinical and laboratory variables, previously chosen by an expert panel. RARBIS had a weak correlation with treatment intensity (r=0.35) and with DAS28 (r=0.41). There is no index to assess the severity of RA based on the course of the first 2 years of follow-up that is adapted to the current strategy of therapeutic management of this disease. Therefore, we believe it is reasonable to develop a new ad hoc severity index for patients with early arthritis. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Delivering vaccines to the people who need them most

PubMed Central

Barocchi, Michèle Anne; Rappuoli, Rino

2015-01-01

Thanks to the Global Alliance for Vaccines and Immunization (GAVI), the Vaccine Fund and the Bill & Melinda Gates Foundation, the global health community has made enormous progress in providing already existing vaccines to developing countries. However, there still exists a gap to develop vaccines for which there is no market in the Western world, owing to low economic incentives for the private sector to justify the investments necessary for vaccine development. In many cases, industry has the technologies, but lacks the impetus to direct resources to develop these vaccine products. The present emergency with the Ebola vaccine provides us an excellent example where a vaccine was feasible several years ago, but the global health community waited for a humanitarian disaster to direct efforts and resources to develop this vaccine. In the beginning of 2015, the first large-scale trials of two experimental vaccines against Ebola virus disease have begun in West Africa. During the past few years, several institutions have dedicated efforts to the development of vaccines against diseases present only in low-income countries. These include the International Vaccine Institute, the Novartis Vaccines Institute for Global Health, the Hilleman Institute, the Sabin Vaccine Institute and the Infectious Disease Research Institute. Nevertheless, solving this problem requires a more significant global effort than that currently invested. These efforts include a clear policy, global coordination of funds dedicated to the development of neglected disease and an agreement on regulatory strategies and incentives for the private sector. PMID:25964460

The role of plant disease in the development of controlled ecological life support systems

NASA Technical Reports Server (NTRS)

Nelson, B.

1986-01-01

Plant diseases could be important factors affecting growth of higher plants in Closed Ecological Life Support Systems (CELSS). Disease control, therefore, will be needed to maintain healthy plants. The most important controls should be aimed at preventing the introduction, reproduction and spread of pathogens and preventing plant infection. An integrared ease control program will maximize that approach. In the design and operation of CELSS, plant disease should be considered an important aspect of plant growth. The effects of plant diseases are reviewed and several disease control measures are discussed.

Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development.

PubMed

Brown, Traci Ann; Holian, Andrij; Pinkerton, Kent E; Lee, Joong Won; Cho, Yoon Hee

2016-07-01

Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual's lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development.

Challenges and opportunities for pediatric severe TBI-review of the evidence and exploring a way forward.

PubMed

Bell, Michael J; Adelson, P David; Wisniewski, Stephen R

2017-10-01

Traumatic brain injury (TBI) is a leading killer of children in the developed and developing world. Despite evidence-based guidelines and several recent clinical trials, the progress in developing best practices for children with severe TBI has been slow. This article describes (i) the burden of the disease, (ii) the inadequacies of the evidence-based guidelines, (iii) the failure of the largest clinical trials to prove their primary hypotheses, and (iv) possible advances from an observational cohort study called the Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial that has recently completed enrollment.

POMICS: A Simulation Disease Model for Timing Fungicide Applications in Management of Powdery Mildew of Cucurbits.

PubMed

Sapak, Z; Salam, M U; Minchinton, E J; MacManus, G P V; Joyce, D C; Galea, V J

2017-09-01

A weather-based simulation model, called Powdery Mildew of Cucurbits Simulation (POMICS), was constructed to predict fungicide application scheduling to manage powdery mildew of cucurbits. The model was developed on the principle that conditions favorable for Podosphaera xanthii, a causal pathogen of this crop disease, generate a number of infection cycles in a single growing season. The model consists of two components that (i) simulate the disease progression of P. xanthii in secondary infection cycles under natural conditions and (ii) predict the disease severity with application of fungicides at any recurrent disease cycles. The underlying environmental factors associated with P. xanthii infection were quantified from laboratory and field studies, and also gathered from literature. The performance of the POMICS model when validated with two datasets of uncontrolled natural infection was good (the mean difference between simulated and observed disease severity on a scale of 0 to 5 was 0.02 and 0.05). In simulations, POMICS was able to predict high- and low-risk disease alerts. Furthermore, the predicted disease severity was responsive to the number of fungicide applications. Such responsiveness indicates that the model has the potential to be used as a tool to guide the scheduling of judicious fungicide applications.

Gut Microbiome and the Development of Food Allergy and Allergic Disease

PubMed Central

Prince, Benjamin T.; Mandel, Mark J.; Nadeau, Kari; Singh, Anne Marie

2015-01-01

The prevalence of food allergy and other allergic diseases continues to rise within the industrialized world, yet the cause of this epidemic remains elusive. Environmental factors such as microbial exposures have more recently been implicated as one possible driving factor behind the increasing burden of allergic disease. The impact of gut microbiome on human development, nutritional needs, and disease has become evident with advances in our ability to study these complex communities of microorganisms, and there is a growing appreciation for the role of the microbiome in immune regulation. Several studies have examined associations between changes in the commensal microbiota and the development of asthma, allergic rhinitis, and asthma, but far less have evaluated the impact of the microbiome on the development of food allergy. In this article we review the human gastrointestinal microbiome, focusing on the theory and evidence for its role in the development of IgE-mediated food allergy and other allergic diseases. PMID:26456445

Bioactive lipids in osteoarthritis: risk or benefit?

PubMed

Ioan-Facsinay, Andreea; Kloppenburg, Margreet

2018-01-01

Lipids are bioactive molecules that can affect several biological functions. Technological developments allowing identification of novel lipid species and the study of their function have led to a significant advance in our understanding of lipid biology and their involvement in various diseases. This is particularly relevant for diseases associated with obesity in which lipid accumulation could be involved in pathogenesis. Here, we focus on osteoarthritis, a chronic joint disease aggravated by obesity, and will present the latest findings regarding the involvement of lipids in disease development and progression. Recent studies indicate a possible involvement of n-3 poly-unsaturated fatty acid and their anti-inflammatory and proresolving derivatives in osteoarthritis. These lipids were identified in the osteoarthritis joint, were found to have beneficial effects on cartilage in vitro and reduced pain in humans and animal models. Moreover, increased levels of cholesterol transport molecules, such as LDL particles, were recently associated with a higher risk of developing hand osteoarthritis in women and with more severe inflammation and osteophyte formation in osteoarthritis animal models. Together, these findings indicate that lipids are a promising target for future therapeutic intervention in osteoarthritis and open exciting possibilities for future research.

Modifications of Gait as Predictors of Natural Osteoarthritis Progression in STR/Ort Mice

PubMed Central

Poulet, Blandine; de Souza, Roberto; Knights, Chancie B; Gentry, Clive; Wilson, Alan M; Bevan, Stuart; Chang, Yu-Mei; Pitsillides, Andrew A

2014-01-01

Objective Osteoarthritis (OA) is a common chronic disease for which disease-modifying therapies are not currently available. Studies to seek new targets for slowing the progress of OA rely on mouse models, but these do not allow for longitudinal monitoring of disease development. This study was undertaken to determine whether gait can be used to measure disease severity in the STR/Ort mouse model of spontaneous OA and whether gait changes are related to OA joint pain. Methods Gait was monitored using a treadmill-based video system. Correlations between OA severity and gait at 3 treadmill speeds were assessed in STR/Ort mice. Gait and pain behaviors of STR/Ort mice and control CBA mice were analyzed longitudinally, with monthly assessments. Results The best speed to identify paw area changes associated with OA severity in STR/Ort mice was found to be 17 cm · seconds−1. Paw area was modified with age in CBA and STR/Ort mice, but this began earlier in STR/Ort mice and correlated with the onset of OA at 20 weeks of age. In addition, task noncompliance appeared at 20 weeks. Surprisingly, STR/Ort mice did not show any signs of pain with OA development, even when treated with the opioid antagonist naloxone, but did exhibit normal pain behaviors in response to complete Freund's adjuvant–induced arthritis. Conclusion The present results identify an animal model in which OA severity and OA pain can be studied in isolation from one another. The findings suggest that paw area and treadmill noncompliance may be useful tools to longitudinally monitor nonpainful OA development in STR/Ort mice. This will help in providing a noninvasive means of assessing new therapies to slow the progression of OA. PMID:24623711

Update on pathogenesis and clinical management of acute pancreatitis

PubMed Central

Cruz-Santamaría, Dulce M; Taxonera, Carlos; Giner, Manuel

2012-01-01

Acute pancreatitis (AP), defined as the acute nonbacterial inflammatory condition of the pancreas, is derived from the early activation of digestive enzymes found inside the acinar cells, with variable compromise of the gland itself, nearby tissues and other organs. So, it is an event that begins with pancreatic injury, elicits an acute inflammatory response, encompasses a variety of complications and generally resolves over time. Different conditions are known to induce this disorder, although the innermost mechanisms and how they act to develop the disease are still unknown. We summarize some well established aspects. A phase sequence has been proposed: etiology factors generate other conditions inside acinar cells that favor the AP development with some systemic events; genetic factors could be involved as susceptibility and modifying elements. AP is a disease with extremely different clinical expressions. Most patients suffer a mild and limited disease, but about one fifth of cases develop multi organ failure, accompanied by high mortality. This great variability in presentation, clinical course and complications has given rise to the confusion related to AP related terminology. However, consensus meetings have provided uniform definitions, including the severity of the illness. The clinical management is mainly based on the disease´s severity and must be directed to correct the underlying predisposing factors and control the inflammatory process itself. The first step is to determine if it is mild or severe. We review the principal aspects to be considered in this treatment, as reflected in several clinical practice guidelines. For the last 25 years, there has been a global increase in incidence of AP, along with many advances in diagnosis and treatment. However, progress in knowledge of its pathogenesis is scarce. PMID:22737590

Diet Influences Expression of Autoimmune Associated Genes and Disease Severity By Epigenetic Mechanisms in a Transgenic Lupus Model

PubMed Central

Strickland, Faith M.; Hewagama, Anura; Wu, Ailing; Sawalha, Amr H.; Delaney, Colin; Hoeltzel, Mark F.; Yung, Raymond; Johnson, Kent; Mickelson, Barbara; Richardson, Bruce C.

2013-01-01

Objective Lupus flares when genetically predisposed people encounter appropriate environmental agents. Current evidence indicates that the environment contributes by inhibiting T cell DNA methylation, causing overexpression of normally silenced genes. DNA methylation depends on both dietary transmethylation micronutrients and Erk-regulated DNA methyltransferase 1 (Dnmt1) levels. We used transgenic mice to study interactions between diet, Dnmt1 levels and genetic predisposition on the development and severity of lupus. Methods A doxycycline-inducible Erk defect was bred into lupus-resistant (C57BL/6) or lupus-susceptible (C57BL/6xSJL) mouse strains. Doxycycline treated mice were fed a standard commercial diet for eighteen weeks then switched to diets supplemented(MS) or restricted(MR) intransmethylation micronutrients. Disease severity was assessed by anti-dsDNA antibodies, proteinuria, hematuria and histopathology of kidney tissues. Pyrosequencing was used to determine micronutrient effects on DNA methylation. Results Doxycycline induced modest levels of anti-dsDNA antibodies in C57BL/6 mice and higher levels in C57BL/6xSJL mice. Doxycycline-treated C57BL/6xSJL mice developed hematuria and glomerulonephritis on the MR and standard but not the MS diet. In contrast C57BL/6 mice developed kidney disease only on the MR diet. Decreasing Erk signaling and methyl donors also caused demethylation and overexpression of the CD40lg gene in female mice, consistent with demethylation of the second X chromosome. Both the dietary methyl donor content and duration of treatment influenced methylation and expression of the CD40lg gene. Conclusions Dietary micronutrients that affect DNA methylation can exacerbate or ameliorate SLE disease in this transgenic murine lupus model, and contribute to lupus susceptibility and severity through genetic/epigenetic interactions. PMID:23576011

Women's health providers: don't forget about polycystic ovary syndrome.

PubMed

Farrell-Turner, Kristen A

2015-01-01

Comments on an article by Poleshuck and Woods (see record 2014-16756-003). The recent article by Poleshuck and Woods covered several areas of women's health that are defined, preceded, and/or followed by adverse psychosocial functioning. In a well-written and otherwise thorough summary of several women's health issues that are pertinent to mental health professionals, they neglected to mention polycystic ovary syndrome (PCOS), which is a very common disorder (8% to 17% prevalence; March et al., 2010) that is associated with several interrelated physiological and psychological disorders. The current author is submitting this comment because it is important that mental health professionals are familiar with the diagnostic criteria for PCOS, its impact on mental health functioning and on the development of several increasingly common chronic diseases, and how mental health professionals can play a role in reducing psychosocial disturbances and development of chronic disease among women with PCOS. PsycINFO Database Record (c) 2015 APA, all rights reserved.

Two cases of rickets presenting with poor growth, hypotonia, and respiratory problems.

PubMed

Wouters, E; Wojciechowski, M; de Vries, E

2015-06-01

Rickets is a rare disease in developed countries. In children, it is a disease which affects growing bone. Depending on the severity, it can present with a wide variety of symptoms. Because it is such a rare disease in developed countries, symptoms suggesting rickets are often not easily recognized. This can cause a delay in diagnosing and treating rickets. Often unnecessary and sometimes invasive investigations are performed. First leading clues to rickets on physical examination are poor growth, especially length, thickening of wrists, bow legs, and craniotabes. At further examination, special attention should be paid to osteopenia and cupping and fraying at the metaphyses on X-rays. Laboratory results suggestive for rickets are elevated alkaline phosphatase and disturbances in calcium and phosphate homeostasis. In this report, we present two cases presenting with poor growth, severe pain, and respiratory problems secondary to calcipenic rickets.

Translational study of microRNAs and its application in kidney disease and hypertension research

PubMed Central

KRIEGEL, Alison J.; MLADINOV, Domagoj; LIANG, Mingyu

2015-01-01

MicroRNA research in humans and mammalian model organisms is in a crucial stage of development. Diagnostic and therapeutic values of microRNAs appear promising, but remain to be established. The physiological and pathophysiological significance of microRNAs is generally recognized, but much better understood in some organ systems and disease areas than others. In the present paper, we review several translational studies of microRNAs, including those showing the potential value of therapeutic agents targeting microRNAs and diagnostic or prognostic microRNA markers detectable in body fluids. We discuss the lessons learned and the experience gained from these studies. Several recent studies have begun to explore translational microRNA research in kidney disease and hypertension. Translational research of microRNAs in the kidney faces unique challenges, but provides many opportunities to develop and apply new methods, and to merge complementary basic and clinical approaches. PMID:22283365

DNA vaccines in veterinary use

PubMed Central

Redding, Laurel; Werner, David B

2015-01-01

DNA vaccines represent a new frontier in vaccine technology. One important application of this technology is in the veterinary arena. DNA vaccines have already gained a foothold in certain fields of veterinary medicine. However, several important questions must be addressed when developing DNA vaccines for animals, including whether or not the vaccine is efficacious and cost effective compared with currently available options. Another important question to consider is how to apply this developing technology in a wide range of different situations, from the domestic pet to individual fish in fisheries with several thousand animals, to wildlife programs for disease control. In some cases, DNA vaccines represent an interesting option for vaccination, while in others, currently available options are sufficient. This review will examine a number of diseases of veterinary importance and the progress being made in DNA vaccine technology relevant to these diseases, and we compare these with the conventional treatment options available. PMID:19722897

Proteomic Discovery and Development of a Multiplexed Targeted MRM-LC-MS/MS Assay for Urine Biomarkers of Extracellular Matrix Disruption in Mucopolysaccharidoses I, II, and VI.

PubMed

Heywood, Wendy E; Camuzeaux, Stephane; Doykov, Ivan; Patel, Nina; Preece, Rhian-Lauren; Footitt, Emma; Cleary, Maureen; Clayton, Peter; Grunewald, Stephanie; Abulhoul, Lara; Chakrapani, Anupam; Sebire, Neil J; Hindmarsh, Peter; de Koning, Tom J; Heales, Simon; Burke, Derek; Gissen, Paul; Mills, Kevin

2015-12-15

The mucopolysaccharidoses (MPS) are lysosomal storage disorders that result from defects in the catabolism of glycosaminoglycans. Impaired muscle, bone, and connective tissue are typical clinical features of MPS due to disruption of the extracellular matrix. Markers of MPS disease pathology are needed to determine disease severity and monitor effects of existing and emerging new treatments on disease mechanisms. Urine samples from a small cohort of MPS-I, -II, and -VI patients (n = 12) were analyzed using label-free quantative proteomics. Fifty-three proteins including many associated with extracellular matrix organization were differently expressed. A targeted multiplexed peptide MRM LC-MS/MS assay was used on a larger validation cohort of patient samples (MPS-I n = 18, MPS-II n = 12, MPS-VI n = 6, control n = 20). MPS-I and -II groups were further subdivided according to disease severity. None of the markers assessed were altered significantly in the mild disease groups compared to controls. β-galactosidase, a lysosomal protein, was elevated 3.6-5.7-fold significantly (p < 0.05) in all disease groups apart from mild MPS-I and -II. Collagen type Iα, fatty-acid-binding-protein 5, nidogen-1, cartilage oligomeric matrix protein, and insulin-like growth factor binding protein 7 concentrations were elevated in severe MPS I and II groups. Cartilage oligomeric matrix protein, insulin-like growth factor binding protein 7, and β-galactosidase were able to distinguish the severe neurological form of MPS-II from the milder non-neurological form. Protein Heg1 was significantly raised only in MPS-VI. This work describes the discovery of new biomarkers of MPS that represent disease pathology and allows the stratification of MPS-II patients according to disease severity.

GLIS1-3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases.

PubMed

Jetten, Anton M

2018-05-19

Krüppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-similar 1-3 (GLIS1-3) constitute a subfamily of Krüppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1-3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while a little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases.

Cirrhosis in children and adolescents: An overview

PubMed Central

Pinto, Raquel Borges; Schneider, Ana Claudia Reis; da Silveira, Themis Reverbel

2015-01-01

Several conditions, especially chronic liver diseases, can lead to cirrhosis in children and adolescents. Most cases in clinical practice are caused by similar etiologies. In infants, cirrhosis is most often caused by biliary atresia and genetic-metabolic diseases, while in older children, it tends to result from autoimmune hepatitis, Wilson’s disease, alpha-1-antitrypsin deficiency and primary sclerosing cholangitis. The symptoms of cirrhosis in children and adolescents are similar to those of adults. However, in pediatric patients, the first sign of cirrhosis is often poor weight gain. The complications of pediatric cirrhosis are similar to those observed in adult patients, and include gastrointestinal bleeding caused by gastroesophageal varices, ascites and spontaneous bacterial peritonitis. In pediatric patients, special attention should be paid to the nutritional alterations caused by cirrhosis, since children and adolescents have higher nutritional requirements for growth and development. Children and adolescents with chronic cholestasis are at risk for several nutritional deficiencies. Malnutrition can have severe consequences for both pre- and post-liver transplant patients. The treatment of cirrhosis-induced portal hypertension in children and adolescents is mostly based on methods developed for adults. The present article will review the diagnostic and differential diagnostic aspects of end-stage liver disease in children, as well as the major treatment options for this condition. PMID:25848466

77 FR 45363 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-31

... in laboratory animal models of Parkinson's disease and protects several types of neurons in the brain... novel peptides that was found to be reduced in human middle temporal gyrus of Alzheimer's disease brains... role in neuroprotective effects of GDNF in human brain. The NIDA inventors have also developed antibody...

Factors associated with current and severe physical side-effects after prostate cancer treatment: What men report.

PubMed

Steentjes, L; Siesling, S; Drummond, F J; van Manen, J G; Sharp, L; Gavin, A

2018-01-01

We identified patient and disease characteristics associated with (1) "current" physical side-effects of any severity; and (2) "severe" physical side-effects "ever" experienced by 3,348 (54%) prostate cancer (PCa) survivors in Ireland diagnosed 2-18 years previously. Postal questionnaires collected symptoms at diagnosis, post-biopsy complications, comorbidities, primary treatments and physical side-effects post-treatment (urinary incontinence, erectile dysfunction, libido loss, bowel problems, breast changes, hot flushes, and fatigue, "ever" and "current" at time of questionnaire completion). Men were grouped by "early" (localised) and "late" (locally advanced/advanced) disease at diagnosis. Multivariable logistic regression analysis identified patient and disease-related factors associated with post-treatment side-effects. Complications post-biopsy were associated with higher risk of "current" libido loss and impotence. Radical prostatectomy was associated with higher risk of "current" and "severe" incontinence, libido loss and impotence in both early and late disease. In early disease, brachytherapy was associated with lower risk of "current" fatigue and "severe" impotence. Comorbidities were associated with higher risk of "current" experience of four side-effects (incontinence, libido loss, bowel problems, fatigue). Men on active surveillance/watchful-waiting reported lower risk of sexual dysfunction. These findings could inform development of tailored information on side-effects, which, in turn, could inform treatment decision-making and post-treatment monitoring. © 2016 John Wiley & Sons Ltd.

Progress in mind: focus on alcohol use disorders, an elsevier resource centre.

PubMed

Nutt, D J; Rehm, J; van den Brink, W; Gorwood, P; Buchsbaum, M S

2015-04-30

Harmful use of alcohol is one of the top five risks for burden of disease globally and in Europe; in 2012, 3.3 million net deaths (approximately 6% of all global deaths) were attributable to this risk factor. It is also linked to the development of a wide spectrum of alcohol use disorders, ranging from mild manifestations to a severe disease known as alcohol dependence. Alcohol dependence is a progressive, chronic, and relapsing brain disease resulting from the prolonged effects of alcohol on the brain. Alcohol dependence imposes a significant societal burden, with indirect societal costs reaching up to 0.64% of European countries׳ annual gross domestic product. With these facts in mind, it is important to recognize and manage alcohol dependence. Although the biological mechanisms behind the development of alcohol dependence are not fully known, factors that have been shown to influence its development include genetic predisposition, psychological problems, and social interactions. Alcohol use has also been linked to the development of hypertension, liver cirrhosis, chronic pancreatitis, multiple types of cancer, and psychiatric comorbidities such as depression and anxiety disorders. With such severe effects on both individuals and society, it is important to recognize the characteristic signs and symptoms of alcohol dependence and explore new ways to better manage patients with this brain disease. Effective treatment approaches for alcohol dependence include biological, behavioral, and social components addressing the multiple aspects of this disease. Comprehensive, educational platforms in which to explore the many facets of this disease such as the Progress in Mind: Focus on Alcohol Use Disorders Resource Centre, will provide clinicians with the tools necessary for recognizing patients with alcohol dependence and managing their disease along with related comorbidities. Online Access: http://progressinmind.elsevierresource.com. Copyright © 2015. Published by Elsevier Ireland Ltd.

Biallelic mutations in IRF8 impair human NK cell maturation and function

PubMed Central

Mace, Emily M.; Gunesch, Justin T.; Chinn, Ivan K.; Angelo, Laura S.; Maisuria, Sheetal; Keller, Michael D.; Togi, Sumihito; Watkin, Levi B.; LaRosa, David F.; Jhangiani, Shalini N.; Muzny, Donna M.; Stray-Pedersen, Asbjørg; Coban Akdemir, Zeynep; Smith, Jansen B.; Hernández-Sanabria, Mayra; Le, Duy T.; Hogg, Graham D.; Cao, Tram N.; Freud, Aharon G.; Szymanski, Eva P.; Collin, Matthew; Cant, Andrew J.; Gibbs, Richard A.; Holland, Steven M.; Caligiuri, Michael A.; Ozato, Keiko; Paust, Silke; Doody, Gina M.; Lupski, James R.; Orange, Jordan S.

2016-01-01

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8–/–, but not Irf8+/–, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense. PMID:27893462

Biallelic mutations in IRF8 impair human NK cell maturation and function.

PubMed

Mace, Emily M; Bigley, Venetia; Gunesch, Justin T; Chinn, Ivan K; Angelo, Laura S; Care, Matthew A; Maisuria, Sheetal; Keller, Michael D; Togi, Sumihito; Watkin, Levi B; LaRosa, David F; Jhangiani, Shalini N; Muzny, Donna M; Stray-Pedersen, Asbjørg; Coban Akdemir, Zeynep; Smith, Jansen B; Hernández-Sanabria, Mayra; Le, Duy T; Hogg, Graham D; Cao, Tram N; Freud, Aharon G; Szymanski, Eva P; Savic, Sinisa; Collin, Matthew; Cant, Andrew J; Gibbs, Richard A; Holland, Steven M; Caligiuri, Michael A; Ozato, Keiko; Paust, Silke; Doody, Gina M; Lupski, James R; Orange, Jordan S

2017-01-03

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8-/-, but not Irf8+/-, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense.

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications

PubMed Central

Pohl, Calvin S.; Medland, Julia E.

2015-01-01

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. PMID:26451004

Refeeding syndrome in children in developing countries who have celiac disease.

PubMed

Agarwal, Jaya; Poddar, Ujjal; Yachha, Surender K; Srivastava, Anshu

2012-04-01

The clinical presentations of celiac crisis and refeeding syndrome in celiac disease are almost similar, but information about refeeding syndrome is scarce. We are reporting for the first time 5 cases of refeeding syndrome in children with celiac disease that could have otherwise been labeled as celiac crisis. From January to December 2010, a chart review of hospital records of all celiac disease cases was performed, and refeeding syndrome was ascribed in those celiac patients who deteriorated clinically after initiation of a gluten-free diet and had biochemical parameters suggestive of refeeding syndrome such as hypophosphatemia, hypokalemia, hypocalcemia, and hypoalbuminemia. Of the total 35 celiac disease patients, 5 (median age 6.5 [range 2.2-10] years, 3 boys) were identified as having refeeding syndrome. All 5 children were severely malnourished (body mass index <14 kg/m) and all of them had anemia, hypophosphatemia, hypokalemia, hypoalbuminemia, and hypocalcemia, meaning that they had the perfect setting for developing refeeding syndrome. At the same time, their clinical features fulfilled the criteria for celiac crisis except that their symptoms have worsened after the introduction of a gluten-free diet. Nevertheless, instead of using steroids, they were managed as refeeding syndrome in terms of correction of electrolytes and gradual feeding, and that led to a successful outcome in all of them. Severely malnourished patients with celiac disease are at risk of developing potentially life-threatening refeeding syndrome, which may mimic celiac crisis, especially in developing countries. Early recognition and appropriate treatment are the keys to a successful outcome.

Fetal-onset Congenital Dyserythropoietic Anemia Type 1 due to a Novel Mutation With Severe Iron Overload and Severe Cholestatic Liver Disease.

PubMed

Chin, Hui-Lin; Lee, Le Ye; Koh, Pei Lin

2018-04-17

We report a rare case of severe congenital dyserythropoietic anemia type 1 with fetal onset. Our patient presented with fetal hydrops from 19 weeks of gestation, requiring multiple intrauterine transfusions. At birth, she had severe hemolytic anemia with severe jaundice, and was subsequently transfusion dependent. She eventually developed severe iron overload and fulminant liver failure before her demise at 5 months of age. Genetic testing revealed a novel mutation in CDAN1.

Inpatient management of atopic dermatitis.

PubMed

Cathcart, Shelley D; Theos, Amy

2011-01-01

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that is generally managed on an outpatient basis. However, a significant percentage of patients may develop complications severe enough to require inpatient treatment. The most common complications of AD that may require hospital admission include erythroderma, eczema herpeticum, and systemic bacterial infection. Hospital admission can also be useful for chronic and severe disease that has not responded to standard therapy or in situations where nonadherence is suspected as the cause of treatment failure. In these cases, inpatient treatment can offer an opportunity for caretaker education and allow for an objective evaluation of a patient's response to a structured treatment plan. This article will review the indications for inpatient management of AD and the therapies that can be used to acutely manage severe disease and associated complications. © 2011 Wiley Periodicals, Inc.

Pulmonary Foreign Body Granulomatosis in Dental Technician.

PubMed

Chung, Sung Jun; Koo, Gun Woo; Park, Dong Won; Kwak, Hyun Jung; Yhi, Ji Young; Moon, Ji-Yong; Kim, Sang-Heon; Sohn, Jang Won; Yoon, Ho Joo; Shin, Dong Ho; Park, Sung Soo; Pyo, Ju Yeon; Oh, Young-Ha; Kim, Tae-Hyung

2015-10-01

Occupational lung diseases are caused by several toxic substances including heavy metals; however, the exact pathologic mechanisms remain unknown. In the workplace, dental technicians are often exposed to heavy metals such as cobalt, nickel, or beryllium and occasionally develop occupational lung diseases. We described a case of occupational lung disease in a patient who was employed as a dental technician for over a decade. A 31-year-old, non-smoking woman presented with productive cough and shortness of breath of several weeks duration. Chest computed tomography revealed a large number of scattered, bilateral small pulmonary nodules throughout the lung field, and multiple mediastinal lymph nodes enlargement. Percutaneous needle biopsy showed multifocal small granulomas with foreign body type giant cells suggestive of heavy metals inhalation. The patient's condition improved on simple avoidance strategy for several months. This case highlighted the importance of proper workplace safety.

Effect of solar radiation on severity of soybean rust.

PubMed

Young, Heather M; George, Sheeja; Narváez, Dario F; Srivastava, Pratibha; Schuerger, Andrew C; Wright, David L; Marois, James J

2012-08-01

Soybean rust (SBR), caused by Phakopsora pachyrhizi, is a damaging fungal disease of soybean (Glycine max). Although solar radiation can reduce SBR urediniospore survival, limited information is available on how solar radiation affects SBR progress within soybean canopies. Such information can aid in developing accurate SBR prediction models. To manipulate light penetration into soybean canopies, structures of shade cloth attenuating 30, 40, and 60% sunlight were constructed over soybean plots. In each plot, weekly evaluations of severity in lower, middle, and upper canopies, and daily temperature and relative humidity were recorded. Final plant height and leaf area index were also recorded for each plot. The correlation between amount of epicuticular wax and susceptibility of leaves in the lower, middle, and upper canopies was assessed with a detached leaf assay. Final disease severity was 46 to 150% greater in the lower canopy of all plots and in the middle canopy of 40 and 60% shaded plots. While daytime temperature within the canopy of nonshaded soybean was greater than shaded soybean by 2 to 3°C, temperatures recorded throughout typical evenings and mornings of the growing season in all treatments were within the range (10 to 28.5°C) for SBR development as was relative humidity. This indicates temperature and relative humidity were not limiting factors in this experiment. Epicuticular wax and disease severity in detached leaf assays from the upper canopy had significant negative correlation (P = 0.009, R = -0.84) regardless of shade treatment. In laboratory experiments, increasing simulated total solar radiation (UVA, UVB, and PAR) from 0.15 to 11.66 MJ m(-2) increased mortality of urediniospores from 2 to 91%. Variability in disease development across canopy heights in early planted soybean may be attributed to the effects of solar radiation not only on urediniospore viability, but also on plant height, leaf area index, and epicuticular wax, which influence disease development of SBR. These results provide an understanding of the effect solar radiation has on the progression of SBR within the soybean canopy.

Treatment of leprosy/Hansen's disease in the early 21st century.

PubMed

Worobec, Sophie M

2009-01-01

Leprosy, or Hansen's disease (HD), is caused by Mycobacterium leprae, a slowly dividing mycobacterium that has evolved to be an intracellular parasite, causing skin lesions and nerve damage. Less than 5% of people exposed to M. leprae develop clinical disease. Host cell-mediated resistance determines whether an individual will develop paucibacillary or multibacillary disease. Hansen's disease is a worldwide disease with about 150 new cases reported annually in the United States. Effective anti-mycobacterial treatments are available, and many patients experience severe reversal and erythema nodosum leprosum reactions that also require treatment. Leprosy has been the target of a World Health Organization multiple drug therapy campaign to eliminate it as a national public health problem in member countries, but endemic regions persist. In the United States, the National Hansen's Disease Program has primary responsibility for medical care, research, and information.

Increased Nucleosomes and Neutrophil Activation Link to Disease Progression in Patients with Scrub Typhus but Not Murine Typhus in Laos.

PubMed

Paris, Daniel H; Stephan, Femke; Bulder, Ingrid; Wouters, Diana; van der Poll, Tom; Newton, Paul N; Day, Nicholas P J; Zeerleder, Sacha

2015-01-01

Cell-mediated immunity is essential in protection against rickettsial illnesses, but the role of neutrophils in these intracellular vasculotropic infections remains unclear. This study analyzed the plasma levels of nucleosomes, FSAP-activation (nucleosome-releasing factor), and neutrophil activation, as evidenced by neutrophil-elastase (ELA) complexes, in sympatric Lao patients with scrub typhus and murine typhus. In acute scrub typhus elevated nucleosome levels correlated with lower GCS scores, raised respiratory rate, jaundice and impaired liver function, whereas neutrophil activation correlated with fibrinolysis and high IL-8 plasma levels, a recently identified predictor of severe disease and mortality. Nucleosome and ELA complex levels were associated with a 4.8-fold and 4-fold increased risk of developing severe scrub typhus, beyond cut off values of 1,040 U/ml for nucleosomes and 275 U/ml for ELA complexes respectively. In murine typhus, nucleosome levels associated with pro-inflammatory cytokines and the duration of illness, while ELA complexes correlated strongly with inflammation markers, jaundice and increased respiratory rates. This study found strong correlations between circulating nucleosomes and neutrophil activation in patients with scrub typhus, but not murine typhus, providing indirect evidence that nucleosomes could originate from neutrophil extracellular trap (NET) degradation. High circulating plasma nucleosomes and ELA complexes represent independent risk factors for developing severe complications in scrub typhus. As nucleosomes and histones exposed on NETs are highly cytotoxic to endothelial cells and are strongly pro-coagulant, neutrophil-derived nucleosomes could contribute to vascular damage, the pro-coagulant state and exacerbation of disease in scrub typhus, thus indicating a detrimental role of neutrophil activation. The data suggest that increased neutrophil activation relates to disease progression and severe complications, and increased plasma levels of nucleosomes and ELA complexes represent independent risk factors for developing severe scrub typhus.

Increased Nucleosomes and Neutrophil Activation Link to Disease Progression in Patients with Scrub Typhus but Not Murine Typhus in Laos

PubMed Central

Paris, Daniel H.; Stephan, Femke; Bulder, Ingrid; Wouters, Diana; van der Poll, Tom; Newton, Paul N.; Day, Nicholas P. J.; Zeerleder, Sacha

2015-01-01

Cell-mediated immunity is essential in protection against rickettsial illnesses, but the role of neutrophils in these intracellular vasculotropic infections remains unclear. This study analyzed the plasma levels of nucleosomes, FSAP-activation (nucleosome-releasing factor), and neutrophil activation, as evidenced by neutrophil-elastase (ELA) complexes, in sympatric Lao patients with scrub typhus and murine typhus. In acute scrub typhus elevated nucleosome levels correlated with lower GCS scores, raised respiratory rate, jaundice and impaired liver function, whereas neutrophil activation correlated with fibrinolysis and high IL-8 plasma levels, a recently identified predictor of severe disease and mortality. Nucleosome and ELA complex levels were associated with a 4.8-fold and 4-fold increased risk of developing severe scrub typhus, beyond cut off values of 1,040 U/ml for nucleosomes and 275 U/ml for ELA complexes respectively. In murine typhus, nucleosome levels associated with pro-inflammatory cytokines and the duration of illness, while ELA complexes correlated strongly with inflammation markers, jaundice and increased respiratory rates. This study found strong correlations between circulating nucleosomes and neutrophil activation in patients with scrub typhus, but not murine typhus, providing indirect evidence that nucleosomes could originate from neutrophil extracellular trap (NET) degradation. High circulating plasma nucleosomes and ELA complexes represent independent risk factors for developing severe complications in scrub typhus. As nucleosomes and histones exposed on NETs are highly cytotoxic to endothelial cells and are strongly pro-coagulant, neutrophil-derived nucleosomes could contribute to vascular damage, the pro-coagulant state and exacerbation of disease in scrub typhus, thus indicating a detrimental role of neutrophil activation. The data suggest that increased neutrophil activation relates to disease progression and severe complications, and increased plasma levels of nucleosomes and ELA complexes represent independent risk factors for developing severe scrub typhus. PMID:26317419

Vedolizumab as a Treatment for Crohn's Disease and Ulcerative Colitis.

PubMed

Ha, Christina; Kornbluth, Asher

2014-12-01

The management of Crohn's disease and ulcerative colitis has become increasingly complex. With the current utilization of immunosuppressive therapies earlier in the disease course for patients presenting with moderate to severe disease, there is a great need for additional biologic agents targeting inflammatory mediators other than anti-tumor necrosis factor-α (anti-TNF) agents. Although anti-TNF agents have positively impacted the treatment of inflammatory bowel disease, many patients can lose their response or develop intolerance to these agents over time through the formation of antidrug antibodies. Furthermore, a sizeable percentage of patients are primary nonresponders to anti-TNF drugs. Vedolizumab (Entyvio, Takeda Pharmaceuticals), a monoclonal antibody to the α4β7 integrin, inhibits gut lymphocyte trafficking and has been demonstrated to be an effective and safe agent for the treatment of both Crohn's disease and ulcerative colitis. This article reviews the clinical trial evidence and rationale for the use of vedolizumab in moderate to severe Crohn's disease and ulcerative colitis.

Vedolizumab as a Treatment for Crohn’s Disease and Ulcerative Colitis

PubMed Central

Ha, Christina

2014-01-01

The management of Crohn’s disease and ulcerative colitis has become increasingly complex. With the current utilization of immunosuppressive therapies earlier in the disease course for patients presenting with moderate to severe disease, there is a great need for additional biologic agents targeting inflammatory mediators other than anti-tumor necrosis factor-α (anti-TNF) agents. Although anti-TNF agents have positively impacted the treatment of inflammatory bowel disease, many patients can lose their response or develop intolerance to these agents over time through the formation of antidrug antibodies. Furthermore, a sizeable percentage of patients are primary nonresponders to anti-TNF drugs. Vedolizumab (Entyvio, Takeda Pharmaceuticals), a monoclonal antibody to the α4β7 integrin, inhibits gut lymphocyte trafficking and has been demonstrated to be an effective and safe agent for the treatment of both Crohn’s disease and ulcerative colitis. This article reviews the clinical trial evidence and rationale for the use of vedolizumab in moderate to severe Crohn’s disease and ulcerative colitis. PMID:27524947

Group B Streptococcus vaccine: state of the art

PubMed Central

Nuccitelli, Annalisa; Rinaudo, C. Daniela

2015-01-01

Group B Streptococcus (GBS) is cause of neonatal invasive diseases as well as of severe infections in the elderly and immune-compromised patients. Despite significant advances in the prevention and treatment of neonatal disease, sepsis and meningitis caused by GBS still represent a significant public health care concern globally and additional prevention and therapeutic strategies against infection are highly desirable. The introduction of national recommended guidelines in several countries to screen pregnant women for GBS carriage and the use of antibiotics during delivery significantly reduced disease occurring within the first hours of life (early-onset disease), but it has had no effect on the late-onset diseases occurring after the first week and is not feasible in most countries. Availability of an effective vaccine against GBS would provide an effective means of controlling GBS disease. This review provides an overview of the burden of invasive disease caused by GBS in infants and adults, and highlights the strategies for the development of an effective vaccine against GBS infections. PMID:26288735

Inflammatory bowel disease in India - Past, present and future

PubMed Central

Ray, Gautam

2016-01-01

There is rising incidence and prevalence of inflammatory bowel disease (IBD) in India topping the Southeast Asian (SEA) countries. The common genes implicated in disease pathogenesis in the West are not causal in Indian patients and the role of “hygiene hypothesis” is unclear. There appears to be a North-South divide with more ulcerative colitis (UC) in north and Crohn’s disease (CD) in south India. IBD in second generation Indian migrants to the West takes the early onset and more severe form of the West whereas it retains the nature of its country of origin in migrants to SEA countries. The clinical presentation is much like other SEA countries (similar age and sex profile, low positive family history and effect of smoking, roughly similar disease location, use of aminosalicylates for CD, low use of biologics and similar surgical rates) with some differences (higher incidence of inflammatory CD, lower perianal disease, higher use of aminosalicylates and azathioprine and lower current use of corticosteroids). UC presents more with extensive disease not paralleled in severity clinically or histologically, follows benign course with easy medical control and low incidence of fulminant disease, cancer, complications, and surgery. UC related colorectal cancer develop in an unpredictable manner with respect to disease duration and site questioning the validity of strict screening protocol. About a third of CD patients get antituberculosis drugs and a significant number presents with small intestinal bleed which is predominantly afflicted by aggressive inflammation. Biomarkers have inadequate diagnostic sensitivity and specificity for both. Pediatric IBD tends to be more severe than adult. Population based studies are needed to address the lacunae in epidemiology and definition of etiological factors. Newer biomarkers and advanced diagnostic techniques (in the field of gastrointestinal endoscopy, molecular pathology and genetics) needs to be developed for proper disease definition and treatment. PMID:27688654

Cost effectiveness of a targeted age-based West Nile virus vaccination program.

PubMed

Shankar, Manjunath B; Staples, J Erin; Meltzer, Martin I; Fischer, Marc

2017-05-25

West Nile virus (WNV) is the leading cause of domestically-acquired arboviral disease in the United States. Several WNV vaccines are in various stages of development. We estimate the cost-effectiveness of WNV vaccination programs targeting groups at increased risk for severe WNV disease. We used a mathematical model to estimate costs and health outcomes of vaccination with WNV vaccine compared to no vaccination among seven cohorts, spaced at 10year intervals from ages 10 to 70years, each followed until 90-years-old. U.S. surveillance data were used to estimate WNV neuroinvasive disease incidence. Data for WNV seroprevalence, acute and long-term care costs of WNV disease patients, quality-adjusted life-years (QALYs), and vaccine characteristics were obtained from published reports. We assumed vaccine efficacy to either last lifelong or for 10years with booster doses given every 10years. There was a statistically significant difference in cost-effectiveness ratios across cohorts in both models and all outcomes assessed (Kruskal-Wallis test p<0.0001). The 60-year-cohort had a mean cost per neuroinvasive disease case prevented of $664,000 and disability averted of $1,421,000 in lifelong model and $882,000 and $1,887,000, respectively in 10-year immunity model; these costs were statistically significantly lower than costs for other cohorts (p<0.0001). Vaccinating 70-year-olds had the lowest cost per death averted in both models at around $4.7 million (95%CI $2-$8 million). Cost per disease case averted was lowest among 40- and 50-year-old cohorts and cost per QALY saved lowest among 60-year cohorts in lifelong immunity model. The models were most sensitive to disease incidence, vaccine cost, and proportion of persons developing disease among infected. Age-based WNV vaccination program targeting those at higher risk for severe disease is more cost-effective than universal vaccination. Annual variation in WNV disease incidence, QALY weights, and vaccine costs impact the cost effectiveness ratios. Published by Elsevier Ltd.

Dairy cow disability weights.

PubMed

McConnel, Craig S; McNeil, Ashleigh A; Hadrich, Joleen C; Lombard, Jason E; Garry, Franklyn B; Heller, Jane

2017-08-01

Over the past 175 years, data related to human disease and death have progressed to a summary measure of population health, the Disability-Adjusted Life Year (DALY). As dairies have intensified there has been no equivalent measure of the impact of disease on the productive life and well-being of animals. The development of a disease-adjusted metric requires a consistent set of disability weights that reflect the relative severity of important diseases. The objective of this study was to use an international survey of dairy authorities to derive disability weights for primary disease categories recorded on dairies. National and international dairy health and management authorities were contacted through professional organizations, dairy industry publications and conferences, and industry contacts. Estimates of minimum, most likely, and maximum disability weights were derived for 12 common dairy cow diseases. Survey participants were asked to estimate the impact of each disease on overall health and milk production. Diseases were classified from 1 (minimal adverse effects) to 10 (death). The data was modelled using BetaPERT distributions to demonstrate the variation in these dynamic disease processes, and to identify the most likely aggregated disability weights for each disease classification. A single disability weight was assigned to each disease using the average of the combined medians for the minimum, most likely, and maximum severity scores. A total of 96 respondents provided estimates of disability weights. The final disability weight values resulted in the following order from least to most severe: retained placenta, diarrhea, ketosis, metritis, mastitis, milk fever, lame (hoof only), calving trauma, left displaced abomasum, pneumonia, musculoskeletal injury (leg, hip, back), and right displaced abomasum. The peaks of the probability density functions indicated that for certain disease states such as retained placenta there was a relatively narrow range of expected impact whereas other diseases elicited a wider breadth of impact. This was particularly apparent with respect to calving trauma, lameness and musculoskeletal injury, all of which could be redefined using gradients of severity or accounting for sequelae. These disability weight distributions serve as an initial step in the development of the disease-adjusted lactation (DALact) metric. They will be used to assess the time lost due to dynamic phases of dairy cow diseases and injuries. Prioritizing health interventions based on time expands the discussion of animal health to view profits and losses in light of the quality and length of life. Copyright © 2017 Elsevier B.V. All rights reserved.

Self-reported physical activity correlates in Swedish adults with multiple sclerosis: a cross-sectional study.

PubMed

Anens, Elisabeth; Zetterberg, Lena; Urell, Charlotte; Emtner, Margareta; Hellström, Karin

2017-12-01

The benefits of physical activity in persons with Multiple Sclerosis (MS) are considerable. Knowledge about factors that correlate to physical activity is helpful in order to develop successful strategies to increase physical activity in persons with MS. Previous studies have focused on correlates to physical activity in MS, however falls self-efficacy, social support and enjoyment of physical activity are not much studied, as well as if the correlates differ with regard to disease severity. The aim of the study was to examine associations between physical activity and age, gender, employment, having children living at home, education, disease type, disease severity, fatigue, self-efficacy for physical activity, falls self-efficacy, social support and enjoyment of physical activity in a sample of persons with MS and in subgroups with regard to disease severity. This is a cross-sectional survey study including Swedish community living adults with MS, 287 persons, response rate 58.2%. The survey included standardized self-reported scales measuring physical activity, disease severity, fatigue, self-efficacy for physical activity, falls self-efficacy, and social support. Physical activity was measured by the Physical Activity Disability Survey - Revised. Multiple regression analyzes showed that 59% (F(6,3) = 64.9, p = 0.000) of the variation in physical activity was explained by having less severe disease (β = -0.30), being employed (β = 0.26), having high falls self-efficacy (β = 0.20), having high self-efficacy for physical activity (β = 0.17), and enjoying physical activity (β = 0.11). In persons with moderate/severe MS, self-efficacy for physical activity explained physical activity. Consistent with previous research in persons with MS in other countries this study shows that disease severity, employment and self-efficacy for physical activity are important for physical activity. Additional important factors were falls self-efficacy and enjoyment. More research is needed to confirm this and the subgroup differences.

Pathophysiology of Autoimmune Bullous Diseases: Nature Versus Nurture.

PubMed

Patel, Forum; Wilken, Reason; Patel, Falin B; Sultani, Hawa; Bustos, Itzel; Duong, Christopher; Zone, John J; Raychaudhuri, Siba P; Maverakis, Emanual

2017-01-01

Pemphigus and pemphigoid are the prototypical immunobullous diseases. Although it has been well established that they are caused by deposition of autoreactive antibodies directed against adherence proteins within the skin, the specific genetic and environmental factors leading to development of these diseases continue to be an area of investigation. Herein, we discuss several of the potential environmental triggers that may induce patients to develop immunobullous diseases including medications, viral infections, UV exposure or other radiation injury and dietary factors. In addition, the potential genetic and immunologic mechanisms contributing to the pathogenesis of pemphigus and pemphigoid will be reviewed. The multifactorial nature of these diseases contributes to their complexity and highlights the importance of a detailed personal and family history when caring for these patients.

Pathophysiology of Autoimmune Bullous Diseases: Nature Versus Nurture

PubMed Central

Patel, Forum; Wilken, Reason; Patel, Falin B; Sultani, Hawa; Bustos, Itzel; Duong, Christopher; Zone, John J; Raychaudhuri, Siba P; Maverakis, Emanual

2017-01-01

Pemphigus and pemphigoid are the prototypical immunobullous diseases. Although it has been well established that they are caused by deposition of autoreactive antibodies directed against adherence proteins within the skin, the specific genetic and environmental factors leading to development of these diseases continue to be an area of investigation. Herein, we discuss several of the potential environmental triggers that may induce patients to develop immunobullous diseases including medications, viral infections, UV exposure or other radiation injury and dietary factors. In addition, the potential genetic and immunologic mechanisms contributing to the pathogenesis of pemphigus and pemphigoid will be reviewed. The multifactorial nature of these diseases contributes to their complexity and highlights the importance of a detailed personal and family history when caring for these patients. PMID:28584368

Quantitative analysis of formal caregivers' use of communication strategies while assisting individuals with moderate and severe Alzheimer's disease during oral care.

PubMed

Wilson, Rozanne; Rochon, Elizabeth; Mihailidis, Alex; Leonard, Carol

2013-01-01

This cross-sectional observational study examined formal caregivers' use of task-focused and social communication strategies while assisting individuals with moderate and severe Alzheimer's disease residing in a long-term care facility during a basic activity of daily living: toothbrushing. Thirteen formal caregiver-resident dyads were observed during a total of 78 separate toothbrushing sessions. All caregiver utterances occurring during the task were transcribed and coded for type of communication strategy utilizing a multidimensional observational coding scheme, which was developed a priori. Overall, the majority of residents, irrespective of disease severity, successfully completed toothbrushing with the support of caregiver assistance. Caregivers assisting residents with moderate and severe AD were found to use a variety of communication strategies, with task-focused strategies accounting for the majority of use. For the most part, the communicative strategies employed did not differ across disease severity. However, some differences were identified including the use of one proposition, paraphrased repetition, using the resident's name, and provision of full assistance, with these strategies being used more often when assisting individuals with severe AD. This study adds to the emerging literature supporting the use of specific communication strategies while assisting residents with AD during the completion of daily tasks. From reviewing this study, readers will be able to identify a variety of communication strategies, both task-focused and relational, that formal caregivers utilize while assisting residents with moderate and severe Alzheimer's disease (AD) during a basic activity of daily living. Furthermore, the reader will be able to distinguish between communication strategies that are optimal when assisting individuals with moderate AD as compared to assisting individuals with severe AD. Copyright © 2013 Elsevier Inc. All rights reserved.

Spotlight on ixekizumab for the treatment of moderate-to-severe plaque psoriasis: design, development, and use in therapy.

PubMed

Giunta, Alessandro; Ventura, Alessandra; Chimenti, Maria Sole; Bianchi, Luca; Esposito, Maria

2017-01-01

Psoriasis is a chronic inflammatory disease affecting up to 3% of the general population, associated with discomfort and impaired quality of life. In recent years, the pathogenic cytokine network of psoriasis has been extensively studied leading to the development of new treatments that provide greater efficacy. Interleukin 17A (IL-17A) has been recognized as a crucial cytokine that mediates immunopathogenesis of psoriasis. Ixekizumab - indicated for the treatment of adults with moderate-to-severe plaque psoriasis - is a subcutaneously administered humanized monoclonal antibody that targets IL-17A. A large percentage of patients affected by psoriasis achieved consistent benefits in terms of disease control and rapid onset of action during clinical trials. Overall, ixekizumab brought clinical improvement and a favorable safety profile in phase III trials. Ixekizumab is characterized by consistent efficacy and rapid onset of response; it is not influenced by previous exposure to biologics and has shown good results in areas that are difficult to treat and in severe clinical variants of psoriasis. Ixekizumab has shown significant improvements in the activity of the disease and in those physical functions that inhibit radiographic progression in patients with concomitant involvement of joints. Our data support ixekizumab as a successful therapeutic option for patients affected by moderate-to-severe plaque-type psoriasis.

[Severe Legionnaire's disease revealing an invasive aspergillosis in an apparently immunocompetent patient].

PubMed

Vergne, S; Lathuile, D; Bénosa, B; Fragnier, F; Destrac, S; Avedan, M; Alzieu, M; Campistron, J

2003-10-18

Invasive aspergillosis, a sever disease, usually occurs in immuno-depressed patients. However, it may also develop in presumably immuno-competent patients. A 54-year-old man, smoker, was hospitalised for hypoxemia of the right lung and septic shock, rapidly requiring mechanical ventilation combined with administration of vasopressors, and followed by dialysis because of the rapid worsening of an acute kidney failure. The diagnosis of pulmonary Legionnaire's disease was made on the second day in view of the positivity of the urinary legionella antigen. The progression of the disease was marked by the discovery of a histologically documented gastric aspergillosis and three abscessed intracerebral lesions within the context of a strongly positive aspergillus antigenemia. The disease worsened and the patient died on D 17, despite the antibiotic and anti-aspergillus treatments, haemodynamic support and dialysis. To our knowledge, the association of invasive aspergillosis and severe Legionnaire's disease has never been described in an presumably immunocompetent patient. This clinical case suggests the existence, other than the usual risk factors of invasive aspergillosis that characterise profound states of immunodepression, of more subtle alterations in the immune system that may enhance this type of infection.

Autoimmune Addison disease: pathophysiology and genetic complexity.

PubMed

Mitchell, Anna L; Pearce, Simon H S

2012-01-31

Autoimmune Addison disease is a rare autoimmune disorder with symptoms that typically develop over months or years. Following the development of serum autoantibodies to the key steroidogenic enzyme, 21-hydroxylase, patients have a period of compensated or preclinical disease, characterized by elevations in adrenocortocotropic hormone and renin, before overt, symptomatic adrenal failure develops. We propose that local failure of steroidogenesis, causing breakdown of tolerance to adrenal antigens, might be a key factor in disease progression. The etiology of autoimmune Addison disease has a strong genetic component in man, and several dog breeds are also susceptible. Allelic variants of genes encoding molecules of both the adaptive and innate immune systems have now been implicated, with a focus on the immunological synapse and downstream participants in T lymphocyte antigen-receptor signaling. With the exception of MHC alleles, which contribute to susceptibility in both human and canine Addison disease, no major or highly penetrant disease alleles have been found to date. Future research into autoimmune Addison disease, making use of genome-wide association studies and next-generation sequencing technology, will address the gaps in our understanding of the etiology of this disease.

Influenza pathogenicity during pregnancy in women and animal models.

PubMed

van Riel, Debby; Mittrücker, Hans-Willi; Engels, Geraldine; Klingel, Karin; Markert, Udo R; Gabriel, Gülsah

2016-11-01

Pregnant women are at the highest risk to develop severe and even fatal influenza. The high vulnerability of women against influenza A virus infections during pregnancy was repeatedly highlighted during influenza pandemics including the pandemic of this century. In 2009, mortality rates were particularly high among otherwise healthy pregnant women. However, our current understanding of the molecular mechanisms involved in severe disease development during pregnancy is still very limited. In this review, we summarize the knowledge on the clinical observations in influenza A virus-infected pregnant women. In addition, knowledge obtained from few existing experimental infections in pregnant animal models is discussed. Since clinical data do not provide in-depth information on the pathogenesis of severe influenza during pregnancy, adequate animal models are urgently required that mimic clinical findings. Studies in pregnant animal models will allow the dissection of involved molecular disease pathways that are key to improve patient management and care.

Severe Sepsis and Acute Myocardial Dysfunction in an Adolescent with Chlamydia Trachomatis Pelvic Inflammatory Disease: A Case Report.

PubMed

Morgan, Ashley M; Roden, R Claire; Matson, Steven C; Wallace, Grant M; Lange, Hannah L H; Bonny, Andrea E

2018-04-01

Although generally asymptomatic, severe Chlamydia trachomatis (C. trachomatis) infections have been documented. C. trachomatis has been associated with myocarditis as well as sepsis. A 19-year-old girl with type 1 diabetes mellitus developed sudden-onset mental status change and shock after resolution of diabetic ketoacidosis. Abdominal and pelvic imaging showed uterine and adnexal inflammation, and pelvic examination confirmed a diagnosis of pelvic inflammatory disease. The patient was intubated, required vasopressor support, and developed severe biventricular myocardial dysfunction. Infectious myocarditis workup was negative. Nucleic acid amplification testing from vaginal discharge was positive for C. trachomatis and Trichomonas vaginalis and negative for Neisseria gonorrhoeae. C. trachomatis should be considered in the workup of septic shock, particularly in populations at high risk for sexually transmitted infections. Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

Dopamine-Independent Locomotor Actions of Amphetamines in a Novel Acute Mouse Model of Parkinson Disease

PubMed Central

Sotnikova, Tatyana D; Beaulieu, Jean-Martin; Barak, Larry S; Wetsel, William C; Gainetdinov, Raul R

2005-01-01

Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs. PMID:16050778

Immunotherapy of Malignant Disease Using Chimeric Antigen Receptor Engrafted T Cells

PubMed Central

Maher, John

2012-01-01

Chimeric antigen receptor- (CAR-) based immunotherapy has been under development for almost 25 years, over which period it has progressed from a new but cumbersome technology to an emerging therapeutic modality for malignant disease. The approach involves the genetic engineering of fusion receptors (CARs) that couple the HLA-independent binding of cell surface target molecules to the delivery of a tailored activating signal to host immune cells. Engineered CARs are delivered most commonly to peripheral blood T cells using a range of vector systems, most commonly integrating viral vectors. Preclinical refinement of this approach has proceeded over several years to the point that clinical testing is now being undertaken at several centres, using increasingly sophisticated and therapeutically successful genetic payloads. This paper considers several aspects of the pre-clinical and clinical development of CAR-based immunotherapy and how this technology is acquiring an increasing niche in the treatment of both solid and haematological malignancies. PMID:23304553

Disease progression of acute pancreatitis in pediatric patients.

PubMed

Hao, Fabao; Guo, Hongjie; Luo, Qianfu; Guo, Chunbao

2016-05-15

Approximately 10% of patients with acute pancreatitis (AP) progress to chronic pancreatitis. Little is known about the factors that affect recurrence of pancreatitis after an initial episode. We retrospectively investigated patients with AP, focusing on their outcomes and the predictors for disease progression. Between July 2003 and June 2015, we retrospectively enrolled first-time AP patients with medical records on disease etiology, severity (according to the Atlanta classifications), and recurrence of AP. Independent predictors of recurrent AP (RAP) and chronic pancreatitis were identified using the logistic regression model. Of the total 159 patients, 45 (28.3%) developed RAP, including two episodes of RAP in 19 patients, and 9 (5.7%) developed chronic pancreatitis. The median duration from the time of AP to the onset of RAP was 5.6 ± 2.3 months. RAP patients were identified as more common among patients with idiopathic first-time AP. The presence of severe ascites, pancreatic necrosis, and systemic complications was independent predictors of RAP in pediatric patients. Experiencing over two RAP episodes was the predictor for developing chronic pancreatitis. No influence of age or number of AP episodes was found on the occurrence of abdominal pain, pain severity, and the prevalence of any pain. Severity of first-time AP and idiopathic first-time AP are related to RAP. Recurrence increases risk for progression to chronic pancreatitis. The risk of recurrence increased with increasing numbers of AP episodes. Copyright © 2016 Elsevier Inc. All rights reserved.

Abatacept therapy and safety management.

PubMed

Pham, Thao; Bachelez, Hervé; Berthelot, Jean-Marie; Blacher, Jacques; Claudepierre, Pascal; Constantin, Arnaud; Fautrel, Bruno; Gaujoux-Viala, Cécile; Goëb, Vincent; Gossec, Laure; Goupille, Philippe; Guillaume-Czitrom, Séverine; Hachulla, Eric; Lequerré, Thierry; Marolleau, Jean-Pierre; Martinez, Valérie; Masson, Charles; Mouthon, Luc; Puéchal, Xavier; Richette, Pascal; Saraux, Alain; Schaeverbeke, Thierry; Soubrier, Martin; Viguier, Manuelle; Vittecoq, Olivier; Wendling, Daniel; Mariette, Xavier; Sibilia, Jean

2012-03-01

To develop and/or update fact sheets about abatacept treatment, in order to assist physicians in the management of patients with inflammatory joint disease. 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable 2. identification and review of publications relevant to each topic 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields (dermatologist, cardiologist, pediatric rheumatologist, endocrinologist, hematologist, immunologist, infectiologist), and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid arthritis (RA). They were members of the CRI (Club Rhumatismes et Inflammation), a section of the French Rheumatology Society (Societe Francaise de Rhumatologie). Each fact sheet was revised by several experts and the overall process was coordinated by three experts. Several topics of major interest were selected: contraindications of abatacept treatment; management of adverse effects and concomitant diseases that may develop during abatacept treatment; and management of common situations such as pregnancy, surgery, patient older than 75 years of age, and patients with co-morbidities (such as dialysis, hemoglobinopathy, or splenectomy). After a review of the literature and discussion among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA, initiation and monitoring of the abatacept treatment, management of patients with specific past histories, and specific clinical situations such as pregnancy 2. diseases other than RA, such as juvenile idiopathic arthritis, spondylarthropathies, or autoimmune diseases (systemic lupus erythematosus and other systemic autoimmune diseases) 3. models of letters for informing the rheumatologist and general practitioner 4. patient information about the use of abatacept in RA 5. and data on the new abatacept formulation for subcutaneous administration (approved by the FDA in August 2011 for patients with moderate-to-severe RA). These fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on abatacept. They will be available continuously on www.cri-net.com and will be updated at appropriate intervals. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

USSR Report, Life Sciences, Biomedical and Behavioral Sciences

DTIC Science & Technology

1985-01-29

land, and when wild vegetation was burned out they migrated to grain fields, where they inflicted damage more often on the periphery of the fields...or potato gangrene. Small ulcers or necrosis appear on the tubers; when there is severe develop- ment of the disease, the ulcers grow deeper, and as... exposing a dark powdery mass. The tubers grow susceptible to other diseases. Powdery scab develops throughout the storage period. Silvery scab

Noonan syndrome

PubMed Central

Roberts, Amy E; Allanson, Judith E; Tartaglia, Marco; Gelb, Bruce D

2014-01-01

Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS–MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype–phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments. PMID:23312968

Quantitative Evaluation of the Use of Actigraphy for Neurological and Psychiatric Disorders

PubMed Central

Song, Yu; Kwak, Shin; Yoshida, Sohei; Yamamoto, Yoshiharu

2014-01-01

Quantitative and objective evaluation of disease severity and/or drug effect is necessary in clinical practice. Wearable accelerometers such as an actigraph enable long-term recording of a patient's movement during activities and they can be used for quantitative assessment of symptoms due to various diseases. We reviewed some applications of actigraphy with analytical methods that are sufficiently sensitive and reliable to determine the severity of diseases and disorders such as motor and nonmotor disorders like Parkinson's disease, sleep disorders, depression, behavioral and psychological symptoms of dementia (BPSD) for vascular dementia (VD), seasonal affective disorder (SAD), and stroke, as well as the effects of drugs used to treat them. We believe it is possible to develop analytical methods to assess more neurological or psychopathic disorders using actigraphy records. PMID:25214709

Future of chronic obstructive pulmonary disease management.

PubMed

D'Urzo, Anthony; Vogelmeier, Claus

2012-06-01

Bronchodilators play a pivotal role in the management of symptomatic chronic obstructive pulmonary disease. Inhaled short-acting bronchodilators are used for all stages of chronic obstructive pulmonary disease, primarily for the immediate relief of symptoms; inhaled long-acting bronchodilators are recommended for maintenance therapy in patients with moderate-to-very severe disease and those with daily symptoms. When symptoms are not adequately controlled by a single bronchodilator, combining bronchodilators of different classes may prove effective. Several long-acting β(2)-agonists and long-acting muscarinic antagonists with 24-h duration of action and inhalers combining different classes of long-acting, once-daily bronchodilators are in development. The place of these agents in the treatment algorithm will be determined by their efficacy and safety profiles and their long-term impact on relevant clinical outcomes.

Generic Substitution of Orphan Drugs for the Treatment of Rare Diseases: Exploring the Potential Challenges.

PubMed

Di Paolo, Antonello; Arrigoni, Elena

2018-03-01

Generic drugs are important components of measures introduced by healthcare regulatory authorities to reduce treatment costs. In most patients and conditions the switch from a branded drug to its generic counterpart is performed with no major complications. However, evidence from complex diseases suggests that generic substitution requires careful evaluation in some settings and that current bioequivalence criteria may not always be adequate for establishing the interchangeability of branded and generic products. Rare diseases, also called orphan diseases, are a group of heterogeneous diseases that share important characteristics: in addition to their scarcity, most are severe, chronic, highly debilitating, and often present in early childhood. Finding a treatment for a rare disease is challenging. Thanks to incentives that encourage research and development programs in rare diseases, several orphan drugs are currently available. The elevated cost of orphan drugs is a highly debated issue and a cause of limited access to treatment for many patients. As patent protection and the exclusivity period of several orphan drugs will expire soon, generic versions of orphan drugs should reach the market shortly, with great expectations about their impact on the economic burden of rare diseases. However, consistent with other complex diseases, generic substitution may require thoughtful considerations and may be even contraindicated in some rare conditions. This article provides an overview of rare disease characteristics, reviews reports of problematic generic substitution, and discusses why generic substitution of orphan drugs may be challenging and should be undertaken carefully in rare disease patients.

Post-thrombotic syndrome and venous disease-specific quality of life in patients with vascular Behçet's disease.

PubMed

Alibaz-Oner, Fatma; Aldag, Belgin; Aldag, Mustafa; Unal, A Ugur; Mutiş, Aydan; Toptas, Tayfur; Ergun, Tulin; Direskeneli, Haner

2016-07-01

Deep venous thrombosis (DVT) is the most common form of vascular involvement in Behçet's disease (BD). Chronic post-thrombotic syndrome (PTS) develops in up to one-half of patients with DVT and is associated with impaired quality of life (QoL). There are no data on the severity of DVT-related PTS and its effect on QoL in patients with vascular BD (VBD). We aimed to evaluate PTS and venous disease-specific QoL in patients with VBD. This study included 50 patients (41 men, nine women) with VBD and 31 individuals matched for age and gender (22 men, nine women) with DVT associated with non-BD causes. The Villalta scale was used to assess PTS. The Venous Disability Score and the Venous Clinical Severity Score were used for the assessment of venous disease. Venous disease-specific QoL was measured through Venous Insufficiency Epidemiological and Economic Study Quality of Life/Symptom (VEINES-QoL/Sym) questionnaire. The Behçet Syndrome Activity Score (BSAS) questionnaire was used to assess disease activity. We observed a significantly lower risk of PTS together with significantly better VEINES-QoL/Sym, and Venous Disability Score in the VBD group compared with the non-BD group. When VBD patients with PTS were compared with patients without PTS, VEINES-QoL/Sym, and Venous Clinical Severity Score were significantly worse. BSAS was also significantly higher in patients with PTS. An inverse correlation was found between the VEINES-QoL and the BSAS in multivariate analysis. There were no differences between anticoagulant users and nonusers regarding the presence of PTS and scores of all of the venous assessment tools. We found lower PTS risk and better venous disease-specific QoL, symptom severity, and venous disability scores in VBD patients compared with the non-BD group. Venous disease-specific QoL negatively correlated with disease activity. Effective control of vascular inflammation through treatment in VBD might explain lower rates of PTS and better venous QoL outcomes in VBD patients. Our results suggest that successful control of BD activity might decrease the development of PTS, improve venous disease-specific QoL, and prevent relapses in VBD. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Quantitative Contrast-Enhanced Ultrasound Parameters in Crohn Disease: Their Role in Disease Activity Determination With Ultrasound.

PubMed

Medellin-Kowalewski, Alexandra; Wilkens, Rune; Wilson, Alexandra; Ruan, Ji; Wilson, Stephanie R

2016-01-01

The primary objective of our study was to examine the association between contrast-enhanced ultrasound (CEUS) parameters and established gray-scale ultrasound with color Doppler imaging (CDI) for the determination of disease activity in patients with Crohn disease. Our secondary objective was to develop quantitative time-signal intensity curve thresholds for disease activity. One hundred twenty-seven patients with Crohn disease underwent ultrasound with CDI and CEUS. Reviewers graded wall thickness, inflammatory fat, and mural blood flow as showing remission or inflammation (mild, moderate, or severe). If both gray-scale ultrasound and CDI predicted equal levels of disease activity, the studies were considered concordant. If ultrasound images suggested active disease not supported by CDI findings, the ultrasound results for disease activity were indeterminate. Time-signal intensity curves from CEUS were acquired with calculation of peak enhancement (PE), and AUCs. Interobserver variation and associations between PE and ultrasound parameters were examined. Multiclass ROC analysis was used to develop CEUS thresholds for activity. Ninety-six (76%) studies were concordant, 19 of which showed severe disease, and 31 (24%) studies were indeterminate. Kappa analyses revealed good interobserver agreement on grades for CDI (κ = 0.76) and ultrasound (κ = 0.80) assessments. PE values on CEUS and wall thickness showed good association with the Spearman rank correlation coefficient for the entire population (ρ = 0.62, p < 0.01) and for the concordant group (ρ = 0.70, p < 0.01). Multiclass ROC analyses of the concordant group using wall thickness alone as the reference standard showed cutoff points of 18.2 dB for differentiating mild versus moderate activity (sensitivity, 89.0% and specificity, 87.0%) and 23.0 dB for differentiating moderate versus severe (sensitivity, 90% and specificity, 86.8%). Almost identical cutoff points were observed when using ultrasound global assessment as the reference standard: using 18.2 dB to differentiate mild versus moderate activity yielded sensitivity of 89.2% and specificity of 90.9% and using 22.9 dB to differentiate moderate versus severe activity yielded sensitivity of 89.5% and specificity of 83.1%. Quantitative CEUS parameters integrated into inflammatory assessments with ultrasound reduce indeterminate results and improve disease activity level determinations.

[Brief history of percutaneous coronary intervention].

PubMed

Song, Zhi-yuan; Zhang, Zhi-ying; Xu, Ze-sheng

2010-05-01

Percutaneous coronary intervention (PCI) is that delivering balloon catheter and/or equipment such as a stent to the target coronary artery bypass peripheral artery, at the same time, expanding and opening the stenosis of coronary artery. Through several decades of development, PCI has become a most effective way to rescue patients with coronary heart disease and become one of the biggest advances in the field of heart disease. Because of the development of PCI, more lives have been saved in patients with coronary heart disease. However, PCI does not meet the point of perfection, still has a lot of issues remain to be further resolved. Through a review the development of PCI, we may be able to get some insights to perfect the treatment technique for the patients of coronary heart disease.

ViralEpi v1.0: a high-throughput spectrum of viral epigenomic methylation profiles from diverse diseases.

PubMed

Khan, Mohd Shoaib; Gupta, Amit Kumar; Kumar, Manoj

2016-01-01

To develop a computational resource for viral epigenomic methylation profiles from diverse diseases. Methylation patterns of Epstein-Barr virus and hepatitis B virus genomic regions are provided as web platform developed using open source Linux-Apache-MySQL-PHP (LAMP) bundle: programming and scripting languages, that is, HTML, JavaScript and PERL. A comprehensive and integrated web resource ViralEpi v1.0 is developed providing well-organized compendium of methylation events and statistical analysis associated with several diseases. Additionally, it also facilitates 'Viral EpiGenome Browser' for user-affable browsing experience using JavaScript-based JBrowse. This web resource would be helpful for research community engaged in studying epigenetic biomarkers for appropriate prognosis and diagnosis of diseases and its various stages.

Proposal for a functional classification system of heart failure in patients with end-stage renal disease: proceedings of the acute dialysis quality initiative (ADQI) XI workgroup.

PubMed

Chawla, Lakhmir S; Herzog, Charles A; Costanzo, Maria Rosa; Tumlin, James; Kellum, John A; McCullough, Peter A; Ronco, Claudio

2014-04-08

Structural heart disease is highly prevalent in patients with chronic kidney disease requiring dialysis. More than 80% of patients with end-stage renal disease (ESRD) are reported to have cardiovascular disease. This observation has enormous clinical relevance because the leading causes of death for patients with ESRD are of cardiovascular disease etiology, including heart failure, myocardial infarction, and sudden cardiac death. The 2 systems most commonly used to classify the severity of heart failure are the New York Heart Association (NYHA) functional classification and the American Heart Association (AHA)/American College of Cardiology (ACC) staging system. With rare exceptions, patients with ESRD who do not receive renal replacement therapy (RRT) develop signs and symptoms of heart failure, including dyspnea and edema due to inability of the severely diseased kidneys to excrete sodium and water. Thus, by definition, nearly all patients with ESRD develop a symptomatology consistent with heart failure if fluid removal by RRT is delayed. Neither the AHA/ACC heart failure staging nor the NYHA functional classification system identifies the variable symptomatology that patients with ESRD experience depending upon whether evaluation occurs before or after fluid removal by RRT. Consequently, the incidence, severity, and outcomes of heart failure in patients with ESRD are poorly characterized. The 11th Acute Dialysis Quality Initiative has identified this issue as a critical unmet need for the proper evaluation and treatment of heart failure in patients with ESRD. We propose a classification schema based on patient-reported dyspnea assessed both pre- and post-ultrafiltration, in conjunction with echocardiography. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

The Bordetella bronchiseptica Type III Secretion System Is Required for Persistence and Disease Severity but Not Transmission in Swine

PubMed Central

Brockmeier, Susan L.; Loving, Crystal L.; Register, Karen B.; Kehrli, Marcus E.; Shore, Sarah M.

2014-01-01

Bordetella bronchiseptica is pervasive in swine populations and plays multiple roles in respiratory disease. Most studies addressing virulence factors of B. bronchiseptica utilize isolates derived from hosts other than pigs in conjunction with rodent infection models. Based on previous in vivo mouse studies, we hypothesized that the B. bronchiseptica type III secretion system (T3SS) would be required for maximal disease severity and persistence in the swine lower respiratory tract. To examine the contribution of the T3SS to the pathogenesis of B. bronchiseptica in swine, we compared the abilities of a virulent swine isolate and an isogenic T3SS mutant to colonize, cause disease, and be transmitted from host to host. We found that the T3SS is required for maximal persistence throughout the lower swine respiratory tract and contributed significantly to the development of nasal lesions and pneumonia. However, the T3SS mutant and the wild-type parent are equally capable of transmission among swine by both direct and indirect routes, demonstrating that transmission can occur even with attenuated disease. Our data further suggest that the T3SS skews the adaptive immune response in swine by hindering the development of serum anti-Bordetella antibody levels and inducing an interleukin-10 (IL-10) cell-mediated response, likely contributing to the persistence of B. bronchiseptica in the respiratory tract. Overall, our results demonstrate that the Bordetella T3SS is required for maximal persistence and disease severity in pigs, but not for transmission. PMID:24366249

Zone 1 retinopathy of prematurity in a transitional economy: a cautionary note.

PubMed

Carden, Susan M; Lan, Luu Ngoc; Huynh, Tess

2006-06-01

To describe three low risk infants in whom severe retinopathy of prematurity developed. A prospective, observational case series. setting: National Hospital of Pediatrics, Hanoi, Vietnam. study population: Premature infants in the neonatal ward. observation procedure: Eye examinations. Severe retinopathy of prematurity occurred in three infants. All had zone 1 disease and other unusually severe findings, such as neovascularization of the disk. These infants would not be at risk for the development of such severe retinopathy of prematurity in countries with a developed economy. Unusual characteristics of retinopathy of prematurity may be occurring in countries with transitional economies. Screening programs should be implemented and should take into consideration the possibility that retinopathy of prematurity may occur in infants who fall outside the screening guidelines that are used in the developed world.

Tick-borne encephalitis in patients vaccinated against this disease.

PubMed

Lotrič-Furlan, S; Bogovič, P; Avšič-Županc, T; Jelovšek, M; Lusa, L; Strle, F

2017-08-01

Information on tick-borne encephalitis (TBE) in patients already vaccinated against the disease is limited. To compare the course and outcome in patients with vaccination breakthrough TBE with findings in patients who developed TBE without previous vaccination. All adult patients diagnosed with TBE at a single medical centre during a 16-year period and who had received at least two doses of TBE vaccine before the onset of illness qualified for the study. For each patient with breakthrough TBE, two unvaccinated sex- and age-matched patients, diagnosed with TBE in the same year, were included for comparison. Amongst 2332 patients diagnosed with TBE in the period 2000-2015, 39 (1.7%) had been vaccinated against the disease. Their median age was 59 (20-83) years; 22 of 39 (56.4%) were male. In comparison with unvaccinated patients with TBE, those with breakthrough disease more often experienced a monophasic course of illness (P = 0.006), had a higher CSF leucocyte count (P = 0.005), more often had urine retention (P = 0.012), more often needed ICU treatment (P = 0.009), were hospitalized for longer (P = 0.002) and had more severe acute illness (P = 0.004 for simple clinical assessment, P = 0.001 for severity score). In addition to several findings corroborating previous results in patients with vaccination breakthrough TBE, such as older age and the presence of a particular specific serum antibody pattern indicating anamnestic response, findings in this study indicate that the acute illness in patients with breakthrough TBE is more severe than in unvaccinated sex- and age-matched patients who develop the disease. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease

PubMed Central

Kash, John C.; Walters, Kathie-Anne; Kindrachuk, Jason; Baxter, David; Scherler, Kelsey; Janosko, Krisztina B.; Adams, Rick D.; Herbert, Andrew S.; James, Rebekah M.; Stonier, Spencer W.; Memoli, Matthew J.; Dye, John M.; Davey, Richard T.; Chertow, Daniel S.; Taubenberger, Jeffery K.

2017-01-01

The 2013–2015 outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was unprecedented in the number of documented cases, but there have been few published reports on immune responses in clinical cases and their relationships with the course of illness and severity of Ebola virus disease. Symptoms of Ebola virus disease can include severe headache, myalgia, asthenia, fever, fatigue, diarrhea, vomiting, abdominal pain, and hemorrhage. Although experimental treatments are in development, there are no current U.S. Food and Drug Administration–approved vaccines or therapies. We report a detailed study of host gene expression as measured by microarray in daily peripheral blood samples collected from a patient with severe Ebola virus disease. This individual was provided with supportive care without experimental therapies at the National Institutes of Health Clinical Center from before onset of critical illness to recovery. Pearson analysis of daily gene expression signatures revealed marked gene expression changes in peripheral blood leukocytes that correlated with changes in serum and peripheral blood leukocytes, viral load, antibody responses, coagulopathy, multiple organ dysfunction, and then recovery. This study revealed marked shifts in immune and antiviral responses that preceded changes in medical condition, indicating that clearance of replicating Ebola virus from peripheral blood leukocytes is likely important for systemic viral clearance. PMID:28404864

White-Nose Syndrome Disease Severity and a Comparison of Diagnostic Methods.

PubMed

McGuire, Liam P; Turner, James M; Warnecke, Lisa; McGregor, Glenna; Bollinger, Trent K; Misra, Vikram; Foster, Jeffrey T; Frick, Winifred F; Kilpatrick, A Marm; Willis, Craig K R

2016-03-01

White-nose syndrome is caused by the fungus Pseudogymnoascus destructans and has killed millions of hibernating bats in North America but the pathophysiology of the disease remains poorly understood. Our objectives were to (1) assess non-destructive diagnostic methods for P. destructans infection compared to histopathology, the current gold-standard, and (2) to evaluate potential metrics of disease severity. We used data from three captive inoculation experiments involving 181 little brown bats (Myotis lucifugus) to compare histopathology, quantitative PCR (qPCR), and ultraviolet fluorescence as diagnostic methods of P. destructans infection. To assess disease severity, we considered two histology metrics (wing area with fungal hyphae, area of dermal necrosis), P. destructans fungal load (qPCR), ultraviolet fluorescence, and blood chemistry (hematocrit, sodium, glucose, pCO2, and bicarbonate). Quantitative PCR was most effective for early detection of P. destructans, while all three methods were comparable in severe infections. Correlations among hyphae and necrosis scores, qPCR, ultraviolet fluorescence, blood chemistry, and hibernation duration indicate a multi-stage pattern of disease. Disruptions of homeostasis occurred rapidly in late hibernation. Our results provide valuable information about the use of non-destructive techniques for monitoring, and provide novel insight into the pathophysiology of white-nose syndrome, with implications for developing and implementing potential mitigation strategies.

New insights into the epigenetics of inflammatory rheumatic diseases.

PubMed

Ballestar, Esteban; Li, Tianlu

2017-10-01

Over the past decade, awareness of the importance of epigenetic alterations in the pathogenesis of rheumatic diseases has grown in parallel with a general recognition of the fundamental role of epigenetics in the regulation of gene expression. Large-scale efforts to generate genome-wide maps of epigenetic modifications in different cell types, as well as in physiological and pathological contexts, illustrate the increasing recognition of the relevance of epigenetics. To date, although several reports have demonstrated the occurrence of epigenetic alterations in a wide range of inflammatory rheumatic conditions, epigenomic information is rarely used in a clinical setting. By contrast, several epigenetic biomarkers and treatments are currently in use for personalized therapies in patients with cancer. This Review highlights advances from the past 5 years in the field of epigenetics and their application to inflammatory rheumatic diseases, delineating the future lines of development for a rational use of epigenetic information in clinical settings and in personalized medicine. These advances include the identification of epipolymorphisms associated with clinical outcomes, DNA methylation as a contributor to disease susceptibility in rheumatic conditions, the discovery of novel epigenetic mechanisms that modulate disease susceptibility and the development of new epigenetic therapies.

Cross inoculation of anthracnose pathogens infecting various tropical fruits

NASA Astrophysics Data System (ADS)

Suparman; Rahmiyah, M.; Pujiastuti, Y.; Gunawan, B.; Arsi

2018-01-01

Anthracnose disease is very important disease of tropical fruits causing significant yield losses. The disease is caused by Colletotrichum spp. and infects almost all tropical fruit species, especially the succulent ones. Various species of Colletotrichum infect various tropical fruits and there are possibilities for cross inoculation to occur among tropical fruits which might cause severe infection. An experimental research was conducted to examine the effect of cross inoculation of anthracnose pathogen among papaya, eggplant, chili and common bean on the infection development and severity of the disease on each inoculated fruit species. Colletotrichum spp. were isolated from naturally infected papaya, eggplant, chili and common bean. Each fungal isolate was purified and identified to determine the species name. The spores of each isolate were then used to separately inoculate healthy and sterilized papaya, eggplant, chili and common bean. The results showed that cross infection developed on chili, eggplant and papaya but not on bean. Chili showed the highest susceptibility to all Colletotrichum isolates and significantly different from eggplant and papaya. The anthracnose pathogen isolated from common bean showed no pathogenicity to other hosts and might be used as cross protection inoculant to the disease in the other hosts.

A Look to Future Directions in Gene Therapy Research for Monogenic Diseases

PubMed Central

Porteus, Matthew H; Connelly, Jon P; Pruett, Shondra M

2006-01-01

The concept of gene therapy has long appealed to biomedical researchers and clinicians because it promised to treat certain diseases at their origins. In the last several years, there have been several trials in which patients have benefited from gene therapy protocols. This progress, however, has revealed important problems, including the problem of insertional oncogenesis. In this review, which focuses on monogenic diseases, we discuss the problem of insertional oncogenesis and identify areas for future research, such as developing more quantitative assays for risk and efficacy, and ways of minimizing the genotoxic effects of gene therapy protocols, which will be important if gene therapy is to fulfill its conceptual promise. PMID:17009872

Successful Single-Lung Transplant for Severe Lung Graft-Versus-Host Disease Two Years After Sibling Allograft for Acute Lymphoblastic Leukemia: A Case Report.

PubMed

Irhimeh, M R; Musk, M; Cooney, J P

2016-11-01

Bone marrow transplantation (BMT) has been performed as a successful life-saving treatment for hematological and neoplastic diseases. Despite the predictable long-term survival rates in BMT, pulmonary complications reduce the survival rates significantly mainly because of chronic graft-versus-host disease (GVHD). This report briefly discusses a successful lung transplantation case for severe lung GVHD after allograft for acute lymphoblastic leukemia. This case report supports the scarce evidence in the literature for the importance of lung transplantation as a therapeutic option for patients who develop respiratory failure secondary to BMT. Copyright © 2016. Published by Elsevier Inc.

[NEUROPSYCHIATRIC MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS].

PubMed

Stryjer, Rafael; Shriki Tal, Liron; Gizunterman, Alex; Amital, Daniela; Amital, Howard; Kotler, Moshe

2017-12-01

This review deals with the neuropsychiatric disorders resulting from systemic lupus erythematosus (SLE). SLE is a chronic autoimmune disease that impacts all systems in the human body, including the central nervous system. Neuropsychiatric symptoms in SLE are a common complication of the disease. This complication has significant implications for the severity of the illness. In most cases no thorough psychiatric assessment is performed during initial evaluation of the disease and no protocol or clear guidelines for treating the psychiatric symptoms in SLE are available. Early diagnosis of the psychiatric symptoms in SLE is critical since absence of treatment may result in severe psychiatric complications. Clinical pharmacological studies are needed in order to develop guidelines for treating psychiatric symptoms in SLE.

Amyloid beta peptide immunotherapy in Alzheimer disease.

PubMed

Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

2014-12-01

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease.

PubMed

Ilus, T; Kaukinen, K; Virta, L J; Huhtala, H; Mäki, M; Kurppa, K; Heikkinen, M; Heikura, M; Hirsi, E; Jantunen, K; Moilanen, V; Nielsen, C; Puhto, M; Pölkki, H; Vihriälä, I; Collin, P

2014-02-01

Refractory coeliac disease (RCD) is thought to be a rare disorder, but the accurate prevalence is unknown. We aimed to identify the prevalence of and the risk factors for developing RCD in a Finnish population where the clinical detection rate of coeliac disease is high. The study involved 11 hospital districts in Finland where the number of treated RCD patients (n = 44), clinically diagnosed coeliac disease patients (n = 12 243) and adult inhabitants (n = 1.7 million) was known. Clinical characteristics at diagnosis of coeliac disease between the RCD patients and patients with uncomplicated disease were compared. The prevalence of RCD was 0.31% among diagnosed coeliac disease patients and 0.002% in the general population. Of the enrolled 44 RCD patients, 68% had type I and 23% type II; in 9% the type was undetermined. Comparing 886 patients with uncomplicated coeliac disease with these 44 patients that developed RCD later in life, the latter were significantly older (median 56 vs 44 years, P < 0.001), more often males (41% vs. 24%, P = 0.012) and seronegative (30% vs. 5%, P < 0.001) at the diagnosis of coeliac disease. Patients with evolving RCD had more severe symptoms at the diagnosis of coeliac disease, including weight loss in 36% (vs. 16%, P = 0.001) and diarrhoea in 54% (vs. 38%, P = 0.050). Refractory coeliac disease is very rare in the general population. Patients of male gender, older age, severe symptoms or seronegativity at the diagnosis of coeliac disease are at risk of future refractory coeliac disease and should be followed up carefully. © 2014 John Wiley & Sons Ltd.

[Hypochondriac symptoms in late-onset depression: the relationship between hypochondria and somatic state of patients].

PubMed

Ivanets, N N; Avdeeva, T I; Kinkul'kina, M A

2013-01-01

Authors studied 276 women with late-onset depression. Concomitant chronic somatic diseases were identified in 90%. The presence of disease and its nosological definition did not impact on the development of hypochondriac symptoms in patients with late-onset depression. Patients with hypochondriac late-onset depression more often had disability pension due to somatic disease because they more often referred to internists in case of similar objective severity of somatic pathology. It was singled out three variants of the relationship between hypochondria and somatic state: hypernosognostic (a complete coincidence of hypochondria content with actual somatic pathology; anosognostic (a lack of coincidence) and disharmonic (a partial coincidence). The themes of hypochondria in late-nset depressions were correlated with a total number of somatic diseases and their severity. At the same time, there was no correlation between the content of hypochondria and the character of somatic disease.

Agrochemicals against malaria, sleeping sickness, leishmaniasis and Chagas disease.

PubMed

Witschel, Matthias; Rottmann, Matthias; Kaiser, Marcel; Brun, Reto

2012-01-01

In tropical regions, protozoan parasites can cause severe diseases with malaria, leishmaniasis, sleeping sickness, and Chagas disease standing in the forefront. Many of the drugs currently being used to treat these diseases have been developed more than 50 years ago and can cause severe adverse effects. Above all, resistance to existing drugs is widespread and has become a serious problem threatening the success of control measures. In order to identify new antiprotozoal agents, more than 600 commercial agrochemicals have been tested on the pathogens causing the above mentioned diseases. For all of the pathogens, compounds were identified with similar or even higher activities than the currently used drugs in applied in vitro assays. Furthermore, in vivo activity was observed for the fungicide/oomyceticide azoxystrobin, and the insecticide hydramethylnon in the Plasmodium berghei mouse model, and for the oomyceticide zoxamide in the Trypanosoma brucei rhodesiense STIB900 mouse model, respectively.

Agrochemicals against Malaria, Sleeping Sickness, Leishmaniasis and Chagas Disease

PubMed Central

Witschel, Matthias; Rottmann, Matthias; Kaiser, Marcel; Brun, Reto

2012-01-01

In tropical regions, protozoan parasites can cause severe diseases with malaria, leishmaniasis, sleeping sickness, and Chagas disease standing in the forefront. Many of the drugs currently being used to treat these diseases have been developed more than 50 years ago and can cause severe adverse effects. Above all, resistance to existing drugs is widespread and has become a serious problem threatening the success of control measures. In order to identify new antiprotozoal agents, more than 600 commercial agrochemicals have been tested on the pathogens causing the above mentioned diseases. For all of the pathogens, compounds were identified with similar or even higher activities than the currently used drugs in applied in vitro assays. Furthermore, in vivo activity was observed for the fungicide/oomyceticide azoxystrobin, and the insecticide hydramethylnon in the Plasmodium berghei mouse model, and for the oomyceticide zoxamide in the Trypanosoma brucei rhodesiense STIB900 mouse model, respectively. PMID:23145187

Modeling ALS and FTD with iPSC-derived Neurons

PubMed Central

Lee, Sebum; Huang, Eric J.

2015-01-01

Recent advances in genetics and neuropathology support the idea that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTD) are two ends of a disease spectrum. Although several animal models have been developed to investigate the pathogenesis and disease progression in ALS and FTD, there are significant limitations that hamper our ability to connect these models with the neurodegenerative processes in human diseases. With the technical breakthrough in reprogramming biology, it is now possible to generate patient-specific induced pluripotent stem cells (iPSCs) and disease-relevant neuron subtypes. This review provides a comprehensive summary of studies that use iPSC-derived neurons to model ALS and FTD. We discuss the unique capabilities of iPSC-derived neurons that capture some key features of ALS and FTD, and underscore their potential roles in drug discovery. There are, however, several critical caveats that require improvements before iPSC-derived neurons can become highly effective disease models. PMID:26462653

Computerized scheme for detection of diffuse lung diseases on CR chest images

NASA Astrophysics Data System (ADS)

Pereira, Roberto R., Jr.; Shiraishi, Junji; Li, Feng; Li, Qiang; Doi, Kunio

2008-03-01

We have developed a new computer-aided diagnostic (CAD) scheme for detection of diffuse lung disease in computed radiographic (CR) chest images. One hundred ninety-four chest images (56 normals and 138 abnormals with diffuse lung diseases) were used. The 138 abnormal cases were classified into three levels of severity (34 mild, 60 moderate, and 44 severe) by an experienced chest radiologist with use of five different patterns, i.e., reticular, reticulonodular, nodular, air-space opacity, and emphysema. In our computerized scheme, the first moment of the power spectrum, the root-mean-square variation, and the average pixel value were determined for each region of interest (ROI), which was selected automatically in the lung fields. The average pixel value and its dependence on the location of the ROI were employed for identifying abnormal patterns due to air-space opacity or emphysema. A rule-based method was used for determining three levels of abnormality for each ROI (0: normal, 1: mild, 2: moderate, and 3: severe). The distinction between normal lungs and abnormal lungs with diffuse lung disease was determined based on the fractional number of abnormal ROIs by taking into account the severity of abnormalities. Preliminary results indicated that the area under the ROC curve was 0.889 for the 44 severe cases, 0.825 for the 104 severe and moderate cases, and 0.794 for all cases. We have identified a number of problems and reasons causing false positives on normal cases, and also false negatives on abnormal cases. In addition, we have discussed potential approaches for improvement of our CAD scheme. In conclusion, the CAD scheme for detection of diffuse lung diseases based on texture features extracted from CR chest images has the potential to assist radiologists in their interpretation of diffuse lung diseases.

Health Care Workers and Researchers Traveling to Developing-World Clinical Settings: Disease Transmission Risk and Mitigation

DTIC Science & Technology

2010-01-01

viruses can be transmitted by needlestick, such as dengue virus and other hemorrhagic fever viruses. Other potential disease risks include syphilis...Infectious Dis- eases [ 11]. All hemorrhagic fever viruses except dengue virus are known to infect via artificially produced aerosols in a laboratory en...specific health care-related risks (needlestick, hemorrhagic fever viruses, severe viral respiratory disease, and tuberculosis), with suggestions

Global Health Summary of Conference on Immunization in Developing Countries

DTIC Science & Technology

2000-03-01

incidence of specific vaccine - preventable diseases, the efficacy of vaccines in preventing these diseases, and the performance of the national...8217 Efficacy trials involve the administration of new vaccines to test populations as a means of establishing their effectiveness in preventing disease...Hib vaccines in the region. 12For example, a vaccine against rotavirus , which causes the most severe forms of diarrhea, was introduced in the United

Deciphering the transcriptomic response of Fusarium verticillioides in relation to nitrogen availability and the development of sugarcane pokkah boeng disease

NASA Astrophysics Data System (ADS)

Lin, Zhenyue; Wang, Jihua; Bao, Yixue; Guo, Qiang; Powell, Charles A.; Xu, Shiqiang; Chen, Baoshan; Zhang, Muqing

2016-07-01

Pokkah boeng, caused by Fusarium verticillioides, is a serious disease in sugarcane industry. The disease severity is related to the sugarcane genotype as well as environmental considerations, such as nitrogen application. The impact of the nitrogen source (ammonium sulfate, urea, or sodium nitrate) on sugarcane pokkah boeng disease and its pathogen was investigated in planta and fungal growth and sporulation production was measured in vitro. The results showed that ammonium and nitrate were beneficial to fungal mycelium growth, cell densities, and sporulation, which enhanced the disease symptoms of sugarcane pokkah boeng compared to urea fertilization. A total of 1,779 transcripts out of 13,999 annotated genes identified from global transcriptomic analysis were differentially expressed in F. verticillioides CNO-1 grown in the different sources of nitrogen. These were found to be involved in nitrogen metabolism, transport, and assimilation. Many of these genes were also associated with pathogenicity based on the PHI-base database. Several transcription factors were found to be associated with specific biological processes related to nitrogen utilization. Our results further demonstrated that nitrogen availability might play an important role in disease development by increasing fungal cell growth as well as influencing the expression of genes required for successful pathogenesis.

All Is Not Lost: Positive Behaviors in Alzheimer's Disease and Behavioral-Variant Frontotemporal Dementia with Disease Severity.

PubMed

Midorikawa, Akira; Leyton, Cristian E; Foxe, David; Landin-Romero, Ramon; Hodges, John R; Piguet, Olivier

2016-09-06

Anecdotal evidence indicates that some patients with dementia exhibit novel or increased positive behaviors, such as painting or singing, after the disease onset. Due to the lack of objective measures, however, the frequency and nature of these changes has not been formally investigated. This study aimed to systematically identify changes in these behaviors in the two most common younger-onset dementia syndromes: Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). Sixty-three caregivers of patients with dementia (32 caregivers of AD patients and 31 caregivers of bvFTD patients) participated in the study. Caregivers rated the presence and frequency of positive and negative behavior changes after the onset of dementia using the Hypersensory and Social/Emotional Scale (HSS) questionnaire, focusing on three domains: sensory processing, cognitive skills, and social/emotional processing. Six composites scores were obtained reflecting these three domains (two composite scores for each domain). Differences across scores and ratios of increased and decreased behaviors were analyzed between AD and bvFTD, at different disease severity levels. After disease onset, significant changes in the sensory processing domain were observed across disease severity levels, particularly in AD. Composite scores of the other domains did not change significantly. Importantly, however, some novel or increased positive behaviors were present in between 10% (Music activities) and 70% (Hypersensitivity) of AD and bvFTD patients, regardless of disease severity. We provide the first systematic investigation of positive behaviors in AD and bvFTD. The newly developed HSS questionnaire is a valid measure to characterize changes and progression of positive behaviors in patients with dementia.

Multidimensional Assessment of Life Satisfaction in Southern Appalachia

ERIC Educational Resources Information Center

Bardi, Massimo

2009-01-01

People living in Southern Appalachia have been burdened by lack of resources, economic disparity, gender issues, and an increased probability to develop chronic disease linked to stress and anxiety. These problems can severely affect the individual's evaluation of the quality of life. In this study we assessed several predictors of life…

Group 2 Pulmonary Hypertension: Pulmonary Venous Hypertension: Epidemiology and Pathophysiology.

PubMed

Clark, Craig B; Horn, Evelyn M

2016-08-01

Pulmonary hypertension from left heart disease (PH-LHD) is the most common form of PH, defined as mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure ≥15 mm Hg. PH-LHD development is associated with more severe left-sided disease and its presence portends a poor prognosis, particularly once right ventricular failure develops. Treatment remains focused on the underlying LHD and despite initial enthusiasm for PH-specific therapies, most studies have been disappointing and their routine clinical use cannot be recommended. More work is urgently needed to better understand the pathophysiology underlying this disease and to develop effective therapeutic strategies. Copyright © 2016 Elsevier Inc. All rights reserved.

[Obesity, a disease].

PubMed

Basdevant, Arnaud; Ciangura, Cécile

2010-01-01

Obesity has been considered as a disease by the World Health Organisation since 1997. It was previously considered a simple risk factor and a manifestation of consumer society. This recognition was based on several developments, including epidemiological data showing the worldwide spread of the disease; the increasing health expenditure due to the obesity-related increase in type 2 diabetes; and progress in pathophysiological concepts. Obesity is a chronic and progressive disease. Management approaches range from prevention to surgery, and must be adapted to the individual situation.

Cat scratch disease in an immunosuppressed patient with systemic lupus erythematosus.

PubMed

Vargas-Hitos, J A; Sabio, J M; Navarrete-Navarrete, N; Arenas-Miras, M del M; Zamora-Pasadas, M; Jiménez-Alonso, J

2016-03-01

Cat scratch disease is an infectious disorder transmitted by cats that typically affects children and young adults. Immunosuppression is a well-known risk factor for the development of severe and atypical forms of the disease; hence it is under-diagnosed in patients with compromised immunity. We are reporting the first case of cat scratch disease, which presented as fever and fatigue, in a patient with systemic lupus erythematosus while receiving immunosuppressant therapy after a kidney transplant. © The Author(s) 2015.

The Syrian hamster model of hantavirus pulmonary syndrome.

PubMed

Safronetz, David; Ebihara, Hideki; Feldmann, Heinz; Hooper, Jay W

2012-09-01

Hantavirus pulmonary syndrome (HPS) is a relatively rare, but frequently fatal disease associated with New World hantaviruses, most commonly Sin Nombre and Andes viruses in North and South America, respectively. It is characterized by fever and the sudden, rapid onset of severe respiratory distress and cardiogenic shock, which can be fatal in up to 50% of cases. Currently there are no approved antiviral therapies or vaccines for the treatment or prevention of HPS. A major obstacle in the development of effective medical countermeasures against highly pathogenic agents like the hantaviruses is recapitulating the human disease as closely as possible in an appropriate and reliable animal model. To date, the only animal model that resembles HPS in humans is the Syrian hamster model. Following infection with Andes virus, hamsters develop HPS-like disease which faithfully mimics the human condition with respect to incubation period and pathophysiology of disease. Perhaps most importantly, the sudden and rapid onset of severe respiratory distress observed in humans also occurs in hamsters. The last several years has seen an increase in studies utilizing the Andes virus hamster model which have provided unique insight into HPS pathogenesis as well as potential therapeutic and vaccine strategies to treat and prevent HPS. The purpose of this article is to review the current understanding of HPS disease progression in Syrian hamsters and discuss the suitability of utilizing this model to evaluate potential medical countermeasures against HPS. Copyright © 2012 Elsevier B.V. All rights reserved.

Huntington disease in subjects from an Israeli Karaite community carrying alleles of intermediate and expanded CAG repeats in the HTT gene: Huntington disease or phenocopy?

PubMed

Herishanu, Yuval O; Parvari, Ruti; Pollack, Yaakov; Shelef, Ilan; Marom, Batia; Martino, Tiziana; Cannella, Milena; Squitieri, Ferdinando

2009-02-15

We report a cluster of patients from a Karaite Jew community with a movement disorder suggestive of Huntington disease (HD), in some cases associated with repeat lengths below the edge of 36 CAG repeats. The study describes the clinical and genetic features of four patients who were followed over several years. Patients belonged to an inbred family in whom progressive chorea, manifesting predominantly with dystonia and cerebellar features, developed during middle age. Although severe psychiatric symptoms ultimately developed in two of the four patients, cognitive function remained reasonably well preserved in all of them even after several disease years. Moderate cognitive deficits were limited to the visuomotor organization and abstract thinking subtests in three of the four patients. Qualitative brain imaging showed atrophy of brain predominantly involving cortex and cerebellum. Genetic testing revealed a variable mutation penetrance among family members, some affected members showing an upper allele size ranging from 34 to 49, whereas others remained unaffected despite the presence of the full mutation beyond 40 CAG repeats. Co-morbidity with recessive hereditary inclusion body myopathy was found in two subjects from one family. Although the main diagnosis of HD remains to be confirmed by further neuropathological studies, these cases may suggest that HD could manifest with as few as 34 CAG repeats, in some geographic areas, the disease phenotype most probably being influenced by additional, as yet unidentified, genes.

Mitochondrial DNA disease—molecular insights and potential routes to a cure

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

Russell, Oliver; Turnbull, Doug, E-mail: doug.turnbull@newcastle.ac.uk

2014-07-01

Mitochondrial DNA diseases are common neurological conditions caused by mutations in the mitochondrial genome or nuclear genes responsible for its maintenance. Current treatments for these disorders are focussed on the management of the symptoms, rather than the correction of biochemical defects caused by the mutation. This review focuses on the molecular effects of mutations, the symptoms they cause and current work focusing on the development of targeted treatments for mitochondrial DNA disease. - Highlights: • We discuss several common disease causing mtDNA mutations. • We highlight recent work linking pathogenicity to deletion size and heteroplasmy. • We discuss recent advancesmore » in the development of targeted mtDNA disease treatments.« less

Obesity in Older Adults: Epidemiology and Implications for Disability and Disease

PubMed Central

Samper-Ternent, Rafael; Al Snih, Soham

2012-01-01

Summary Obesity is a worldwide problem with increasing prevalence and incidence in both developed and developing countries. In older adults, excess weight is associated with a higher prevalence of cardiovascular disease, metabolic disease, several important cancers, and numerous other medical conditions. Obesity has been also associated with increased functional limitations, disability, and poorer quality of life. Additionally, obesity has been independently associated with all-cause mortality. The obesity epidemic has important social and economic implications, representing an important source of increased public health care costs. The aim of this review is to report the epidemiology of obesity world-wide and the implications of obesity on disability and chronic diseases. PMID:22345902

Rapid, portable, multiplexed detection of bacterial pathogens directly from clinical sample matrices

DOE PAGES

Phaneuf, Christopher R.; Mangadu, Betty Lou Bosano; Piccini, Matthew E.; ...

2016-09-23

Enteric and diarrheal diseases are a major cause of childhood illness and death in countries with developing economies. Each year, more than half of a million children under the age of five die from these diseases. We have developed a portable, microfluidic platform capable of simultaneous, multiplexed detection of several of the bacterial pathogens that cause these diseases. Furthermore, this platform can perform fast, sensitive immunoassays directly from relevant, complex clinical matrices such as stool without extensive sample cleanup or preparation. Using only 1 µL of sample per assay, we demonstrate simultaneous multiplexed detection of four bacterial pathogens implicated inmore » diarrheal and enteric diseases in less than 20 min.« less

Rapid, portable, multiplexed detection of bacterial pathogens directly from clinical sample matrices

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

Phaneuf, Christopher R.; Mangadu, Betty Lou Bosano; Piccini, Matthew E.

Enteric and diarrheal diseases are a major cause of childhood illness and death in countries with developing economies. Each year, more than half of a million children under the age of five die from these diseases. We have developed a portable, microfluidic platform capable of simultaneous, multiplexed detection of several of the bacterial pathogens that cause these diseases. Furthermore, this platform can perform fast, sensitive immunoassays directly from relevant, complex clinical matrices such as stool without extensive sample cleanup or preparation. Using only 1 µL of sample per assay, we demonstrate simultaneous multiplexed detection of four bacterial pathogens implicated inmore » diarrheal and enteric diseases in less than 20 min.« less

Lack of association between HLA-A, -B and -DRB1 alleles and the development of SARS: a cohort of 95 SARS-recovered individuals in a population of Guangdong, southern China.

PubMed

Xiong, P; Zeng, X; Song, M S; Jia, S W; Zhong, M H; Xiao, L L; Lan, W; Cai, C; Wu, X W; Gong, F L; Wang, W

2008-02-01

Severe acute respiratory syndrome (SARS), caused by infection with a novel coronavirus (SARS-CoV), was the first major novel infectious disease at the beginning of the 21st century, with China especially affected. SARS was characterized by high infectivity, morbidity and mortality, and the confined pattern of the disease spreading among the countries of South-East and East Asia suggested the existence of susceptible factor(s) in these populations. Studies in the populations of Hong Kong and Taiwan showed an association of human leucocyte antigen (HLA) polymorphisms with the development and/or severity of SARS, respectively. The aim of the present study was to define the genotypic patterns of HLA-A, -B and -DRB1 loci in SARS patients and a co-resident population of Guangdong province, southern China, where the first SARS case was reported. The samples comprised 95 cases of recovered SARS patients and 403 unrelated healthy controls. HLA -A, -B and -DRB1 alleles were genotyped using polymerase chain reaction with sequence-specific primers. The severity of the disease was assessed according to the history of lung infiltration, usage of assisted ventilation and occurrence of lymphocytopenia. Although the allelic frequencies of A23, A34, B60, DRB1*12 in the SARS group were slightly higher, and A33, -B58 and -B61 were lower than in the controls, no statistical significance was found when the Pc value was considered. Similarly, no association of HLA alleles with the severity of the disease was detected. Thus, variations in the major histocompatibility complex are unlikely to have contributed significantly to either the susceptibility or the severity of SARS in the population of Guangdong.

ACUTE PANCREATITIS GRAVITY PREDICTIVE FACTORS: WHICH AND WHEN TO USE THEM?

PubMed Central

FERREIRA, Alexandre de Figueiredo; BARTELEGA, Janaina Alves; URBANO, Hugo Corrêa de Andrade; de SOUZA, Iure Kalinine Ferraz

2015-01-01

Introduction: Acute pancreatitis has as its main causes lithiasic biliary disease and alcohol abuse. Most of the time, the disease shows a self-limiting course, with a rapid recovery, only with supportive treatment. However, in a significant percentage of cases, it runs with important local and systemic complications associated with high mortality rates. Aim: To present the current state of the use of these prognostic factors (predictive scores) of gravity, as the time of application, complexity and specificity. Method: A non-systematic literature review through 28 papers, with emphasis on 13 articles published in indexed journals between 2008 and 2013 using Lilacs, Medline, Pubmed. Results: Several clinical, laboratory analysis, molecular and image variables can predict the development of severe acute pancreatitis. Some of them by themselves can be determinant to the progression of the disease to a more severe form, such as obesity, hematocrit, age and smoking. Hematocrit with a value lower than 44% and serum urea lower than 20 mg/dl, both at admission, appear as risk factors for pancreatic necrosis. But the PCR differentiates mild cases of serious ones in the first 24 h. Multifactorial scores measured on admission and during the first 48 h of hospitalization have been used in intensive care units, being the most ones used: Ranson, Apache II, Glasgow, Iget and Saps II. Conclusion: Acute pancreatitis is a disease in which several prognostic factors are employed being useful in predicting mortality and on the development of the severe form. It is suggested that the association of a multifactorial score, especially the Saps II associated with Iget, may increase the prognosis accuracy. However, the professional's preferences, the experience on the service as well as the available tools, are factors that have determined the choice of the most suitable predictive score. PMID:26537149

Attenuation and efficacy of live-attenuated Rift Valley fever virus vaccine candidates in non-human primates.

PubMed

Smith, Darci R; Johnston, Sara C; Piper, Ashley; Botto, Miriam; Donnelly, Ginger; Shamblin, Joshua; Albariño, César G; Hensley, Lisa E; Schmaljohn, Connie; Nichol, Stuart T; Bird, Brian H

2018-05-09

Rift Valley fever virus (RVFV) is an important mosquito-borne veterinary and human pathogen that has caused large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Currently, no licensed vaccine or therapeutics exists to treat this potentially deadly disease. The explosive nature of RVFV outbreaks and the severe consequences of its accidental or intentional introduction into RVFV-free areas provide the impetus for the development of novel vaccine candidates for use in both livestock and humans. Rationally designed vaccine candidates using reverse genetics have been used to develop deletion mutants of two known RVFV virulence factors, the NSs and NSm genes. These recombinant viruses were demonstrated to be protective and immunogenic in rats, mice, and sheep, without producing clinical illness in these animals. Here, we expand upon those findings and evaluate the single deletion mutant (ΔNSs rRVFV) and double deletion mutant (ΔNSs-ΔNSm rRVFV) vaccine candidates in the common marmoset (Callithrix jacchus), a non-human primate (NHP) model resembling severe human RVF disease. We demonstrate that both the ΔNSs and ΔNSs-ΔNSm rRVFV vaccine candidates were found to be safe and immunogenic in the current study. The vaccinated animals received a single dose of vaccine that led to the development of a robust antibody response. No vaccine-induced adverse reactions, signs of clinical illness or infectious virus were detected in the vaccinated marmosets. All vaccinated animals that were subsequently challenged with RVFV were protected against viremia and liver disease. In summary, our results provide the basis for further development of the ΔNSs and ΔNSs-ΔNSm rRVFV as safe and effective human RVFV vaccines for this significant public health threat.

Severely Crusted Cheilitis as an Initial Presentation of Systemic Lupus Erythematosus.

PubMed

Chan, Wai Man Mandy; Pang, Shiu Ming; Ng, See Ket

2017-01-01

Lupus erythematosus (LE) is an autoimmune disease which may initially present solely with lip lesions. Due to a wide spectrum of presentation, these features may initially be misdiagnosed as other oral diseases such as lichen planus, erythema multiforme (EM), and actinic cheilitis, leading to a delay in diagnosis and treatment. We discuss a case of severely crusted cheilitis which was initially diagnosed as EM, with subsequent development of subacute cutaneous LE, and progression to systemic LE. We will discuss the clinical and histological features of lupus cheilitis.

Newly diagnosed T1 diabetes presenting with hypoglycemia due to simultaneous co-existence of Addison disease.

PubMed

Glynn, Nigel; Bashir, Mohammed; Smith, Diarmuid; Thompson, Christopher J

2014-09-01

Type 1 diabetes mellitus (TIDM) classically presents with symptomatic hyperglycemia and many patients develop diabetic ketoacidosis prior to their diagnosis. However, non-classical presentation or co-presentation with associated diseases may delay diagnosis or lead to challenges in acute, clinical management. An 18-yr-old girl presented to hospital with severe, symptomatic hypoglycemia. Clinical history and serum electrolyte concentrations suggested a diagnosis of adrenal insufficiency. She remained hypoglycemic until glucocorticoid replacement was commenced, at which point she developed persistent hyperglycemia requiring insulin therapy. Subsequent follow up confirmed the diagnosis of Addison's disease (AD), the treatment of which unmasked co-existing type 1 diabetes. Autoimmune diseases often cluster together in affected patients and first-degree relatives. Approximately 1 in 200 patients with T1DM develop AD. However, months or more commonly years usually elapse between the presentation of different autoimmune conditions. The co-diagnosis T1DM and AD in the acute setting is rare. Moreover, the first presentation of T1DM with severe hypoglycemia is even more exceptional. This case highlights the need for vigilance during the acute, emergency management of patients with autoimmune conditions and, in particular, to consider the possibility of concurrent antibody-mediated diseases which may need to be addressed during resuscitation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Impact of yellow fever on the developing world.

PubMed

Tomori, O

1999-01-01

Yellow fever (YF) has remained a disease of public health importance since it was first described in the fifteenth century. At different periods in human history, YF has caused untold hardship and indescribable misery among populations in the Americas, Europe, and Africa. It brought economic disaster in its wake, constituting a stumbling block to development. Yellow fever is an arboviral infection with three epidemiological transmission cycles between monkeys, mosquitoes, and humans. It is an acute infectious disease characterized by sudden onset, with two phases of development separated by a short period of remission. The clinical spectrum of YF varies from a very mild, nonspecific, febrile illness to a fulminating, sometimes fatal disease with pathognomonic features. In severe cases, jaundice and bleeding diathesis with hepatorenal involvement are common. The fatality rate of severe YF is 50% or higher. Despite landmark achievements in the understanding of the epidemiology of YF and the availability of a safe, efficacious vaccine, YF remains a major public health problem in both Africa and South America, where annually the disease affects an estimated 200,000 persons, causing an estimated 30,000 deaths. Since the 1980s epidemics of YF in Africa have affected predominantly children under the age of 15 years. The failure to control YF arises from a misapplication of public health strategies and insufficient political commitment by governments in YF endemic areas, especially in Africa, to control the disease.

Modeling AEC—New Approaches to Study Rare Genetic Disorders

PubMed Central

Koch, Peter J.; Dinella, Jason; Fete, Mary; Siegfried, Elaine C.; Koster, Maranke I.

2015-01-01

Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare monogenetic disorder that is characterized by severe abnormalities in ectoderm-derived tissues, such as skin and its appendages. A major cause of morbidity among affected infants is severe and chronic skin erosions. Currently, supportive care is the only available treatment option for AEC patients. Mutations in TP63, a gene that encodes key regulators of epidermal development, are the genetic cause of AEC. However, it is currently not clear how mutations in TP63 lead to the various defects seen in the patients’ skin. In this review, we will discuss current knowledge of the AEC disease mechanism obtained by studying patient tissue and genetically engineered mouse models designed to mimic aspects of the disorder. We will then focus on new approaches to model AEC, including the use of patient cells and stem cell technology to replicate the disease in a human tissue culture model. The latter approach will advance our understanding of the disease and will allow for the development of new in vitro systems to identify drugs for the treatment of skin erosions in AEC patients. Further, the use of stem cell technology, in particular induced pluripotent stem cells (iPSC), will enable researchers to develop new therapeutic approaches to treat the disease using the patient’s own cells (autologous keratinocyte transplantation) after correction of the disease-causing mutations. PMID:24665072

Pertussis vaccination and whooping cough: and now what?

PubMed

Guiso, Nicole

2014-10-01

Pertussis or whooping cough is a respiratory disease caused by Bordetella pertussis or Bordetella parapertussis that are only known to infect humans. This severe and acute respiratory disease presents epidemic cycles and became a vaccine-preventable disease in the 1940s/1950s when developed countries introduced vaccination. The first type of vaccine developed against this disease was a whole-cell pertussis (wP) vaccine containing inactivated B. pertussis bacteria. Most developed countries produced their own vaccine and given the pediatric nature of the disease at the time of licensure, infants and toddlers were the primary targets and were thus massively vaccinated. The characterization of few virulence factors produced by B. pertussis enabled the development of second-generation pertussis vaccines called the acellular pertussis (aP) vaccines. These only contain 1-5 purified, detoxified B. pertussis proteins and were first introduced in Japan around 30 years ago. Australia, Europe and North America introduced aP vaccines approximately 15 years later, which replaced wP vaccines since then.

[Diabetes mellitus in children and adolescents: chronic complications and associated diseases].

PubMed

Rubio Cabezas, O; Argente Oliver, J

2007-03-01

Diabetes is one of the most common chronic diseases. Type 1, or autoimmune, diabetes accounts for more than 95 % of cases in children and adolescents. Chronic hyperglycemia per se is responsible for the development of several microvascular (retinopathy, nephropathy, neuropathy) and macrovascular complications (ischemic heart disease, cerebrovascular disease, and peripheral vascular disease). Other autoimmune diseases are also more frequent in type 1 diabetic patients. The present review aims to provide an update on some recent advances in this field to aid early detection of these complications and prevent or delay their progression through improved metabolic control.

Development of Enzyme-Linked Immunosorbent Assays Using Expressed Proteins of Rift Valley Fever Virus

USDA-ARS?s Scientific Manuscript database

Rift Valley fever virus (RVFV) is a member of the genus Phlebovirus, family Bunyaviridae that can cause severe disease in both humans and animals. The disease is enzootic in sub-Saharan Africa and RVFV epidemics/epizootics occur periodically, primarily in eastern and southern Africa. Since the virus...

Oral contraceptive pills induced hemichorea in an adolescent female with polycystic ovarian disease.

PubMed

Sharmila, Vijayan; Babu, Thirunavukkarasu Arun

2015-01-01

Chorea is a neurological adverse effect of oral contraceptive pills (OCPs). The onset of chorea following OCPs usage varies widely from few weeks to several years. We report a rare case of chorea which developed within a week of starting OCPs in an adolescent girl with polycystic ovarian disease.

Molecular detection and characterization of theileria spp infecting cattle in Sennar State, Sudan

USDA-ARS?s Scientific Manuscript database

Theileriosis is a serious animal disease transmitted by tick vectors. The agents of theileriosis are obligate intracellular parasites that cause mild to severe disease in the mammalian host. Tropical theileriosis has been recognized as a burden to the development of the dairy industry in Sudan and c...

Relation of antioxidant status at admission and disease severity and outcome in dogs naturally infected with Babesia canis canis.

PubMed

Crnogaj, Martina; Cerón, José Joaquin; Šmit, Iva; Kiš, Ivana; Gotić, Jelena; Brkljačić, Mirna; Matijatko, Vesna; Rubio, Camila Peres; Kučer, Nada; Mrljak, Vladimir

2017-04-24

Canine babesiosis is caused by species of the Babesia genus and has become an emerging disease worldwide. To the authors' knowledge there are no reports in which antioxidants have been analyzed in different presentations of canine babesiosis or in which the prognostic value of antioxidants has been studied. The aim of this study was to evaluate whether oxidative stress could be related to the severity and outcome of canine babesiosis. For this purpose a profile consisting of four antioxidant biomarkers (superoxide dismutase - SOD, glutathione peroxidase - GPx, catalase, total antioxidant status - TAS) and malondialdehyde - MDA as an oxidant biomarker (previously evaluated, here studied for comparative purposes) were evaluated in dogs with canine babesiosis of different clinical severity and outcomes. The study was conducted with a sample of 40 dogs suffering from babesiosis (further divided into uncomplicated, one complication and multiple organ dysfunction syndrome - MODS group) and 30 healthy dogs (control group). Additionally, the babesiosis group was divided according to the anaemia into non-anaemic, mildly anaemic, moderately anaemic and severely anaemic dogs. The results of our study showed significantly decreased SOD, catalase and TAS values in diseased dogs compared to controls, while there were no significant differences in GPx between these groups. Dogs that developed MODS showed lower activities of SOD and GPx and higher MDA values compared to dogs with uncomplicated babesiosis as well as with dogs that developed one complication. Superoxide dismutase, catalase and GPx were negatively correlated whereas MDA was positively correlated with the lethal outcome of the disease. Furthermore, this study detected more pronounced decrease in antioxidant biomarkers (SOD, GPx and catalase) in dogs with moderate anaemia compared to those with mild anaemia. The results of this study showed changes in biomarkers related to the antioxidant status of dogs naturally infected with B. canis canis. These biomarkers could be used as indicators of disease severity and outcome in dogs suffering from babesiosis.

Applying an artificial neural network model for developing a severity score for patients with hereditary amyloid polyneuropathy.

PubMed

Novis, Shenia; Machado, Felipe; Costa, Victor B; Foguel, Debora; Cruz, Marcia W; de Seixas, José Manoel

2017-09-01

Hereditary (familial) amyloid polyneuropathy (FAP) is a systemic disease that includes a sensorimotor polyneuropathy related to transthyretin (TTR) mutations. So far, a scale designed to classify the severity of this disease has not yet been validated. This work proposes the implementation of an artificial neural network (ANN) in order to develop a severity scale for monitoring the disease progression in FAP patients. In order to achieve this goal, relevant symptoms and laboratory findings were collected from 98 Brazilian patients included in THAOS - the Transthyretin Amyloidosis Outcomes Survey. Ninety-three percent of them bore Val30Met, the most prevalent variant of TTR worldwide; 63 were symptomatic and 35 were asymptomatic. These data were numerically codified for the purpose of constructing a Self-Organizing Map (SOM), which maps data onto a grid of artificial neurons. Mapped data could be clustered by similarity into five groups, based on increasing FAP severity (from Groups 1 to 5). Most symptoms were virtually absent from patients who mapped to Group 1, which also includes the asymptomatic patients. Group 2 encompasses the patients bearing symptoms considered to be initial markers of FAP, such as first signs of walking disabilities and lack of sensitivity to temperature and pain. Interestingly, the patients with cardiac symptoms, which also carry cardiac-associated mutations of the TTR gene (such as Val112Ile and Ala19Asp), were concentrated in Group 3. Symptoms such as urinary and fecal incontinence and diarrhea characterized particularly Groups 4 and 5. Renal impairment was found almost exclusively in Group 5. Model validation was accomplished by considering the symptoms from a sample with 48 additional Brazilian patients. The severity scores proposed here not only identify the current stage of a patient's disease but also offer to the physician an easy-to-read, 2D map that makes it possible to track disease progression.

Genetic susceptibility to Grave's disease.

PubMed

Li, Hong; Chen, Qiuying

2013-06-01

The variety of clinical presentations of eye changes in patients with Graves' disease (GD) suggests that complex interactions between genetic, environmental, endogenous and local factors influence the severity of Graves' ophthalmopathy (GO). It is thought that the development of GO might be influenced by genetic factors and environmental factors, such as cigarette smoking. At present, however, the role of genetic factors in the development of GO is not known. On the basis of studies with candidate genes and other genetic approaches, several susceptibility loci in GO have been proposed, including immunological genes, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), regulatory T-cell genes and thyroid-specific genes. This review gives a brief overview of the current range of major susceptibility genes found for GD.

Current approaches to the management of new-onset ulcerative colitis

PubMed Central

Marchioni Beery, Renée; Kane, Sunanda

2014-01-01

Ulcerative colitis (UC) is an idiopathic, inflammatory gastrointestinal disease of the colon. As a chronic condition, UC follows a relapsing and remitting course with medical maintenance during periods of quiescent disease and appropriate escalation of therapy during times of flare. Initial treatment strategies must not only take into account current clinical presentation (with specific regard for extent and severity of disease activity) but must also take into consideration treatment options for the long-term. The following review offers an approach to new-onset UC with a focus on early treatment strategies. An introduction to the disease entity is provided along with an approach to initial diagnosis. Stratification of patients based on clinical parameters, disease extent, and severity of illness is paramount to determining course of therapy. Frequent assessments are required to determine clinical response, and treatment intensification may be warranted if expected improvement goals are not appropriately reached. Mild-to- moderate UC can be managed with aminosalicylates, mesalamine, and topical corticosteroids with oral corticosteroids reserved for unresponsive cases. Moderate-to-severe UC generally requires oral or intravenous corticosteroids in the short-term with consideration of long-term management options such as biologic agents (as initial therapy or in transition from steroids) or thiopurines (as bridging therapy). Patients with severe or fulminant UC who are recalcitrant to medical therapy or who develop disease complications (such as toxic megacolon) should be considered for colectomy. Early surgical referral in severe or refractory UC is crucial, and colectomy may be a life-saving procedure. The authors provide a comprehensive evidence-based approach to current treatment options for new-onset UC with discussion of long-term therapeutic efficacy and safety, patient-centered perspectives including quality of life and medication compliance, and future directions in related inflammatory bowel disease care. PMID:24872716

Development and characterization of targeted poly(NIPAm) nanoparticles for delivery of anti-inflammatory peptides in peripheral artery disease and osteoarthritis

NASA Astrophysics Data System (ADS)

McMasters, James F.

Inflammation is the underlying cause of several severe diseases including cardiovascular disease and osteoarthritis. Peripheral artery disease (PAD) is characterized by atherosclerotic occlusions within the peripheral vasculature. Current treatment for severe PAD involves mechanical widening of the artery via percutaneous transluminal angioplasty. Unfortunately, deployment of the balloon damages the endothelial layer, exposing the underlying collagenous matrix. Circulating platelets can bind to this collagen and become activated, releasing proinflammatory cytokines that promote proliferation of local smooth muscle cells. These proliferating cells eventually reocclude the vessel, resulting in restenosis and necessitating the need for a second procedure to reopen the vessel. Current treatments for moderate osteoarthritis include local injection of anti-inflammatory compounds such as glucocorticoids. Unfortunately, prolonged treatment carries with it significant side effects including osteoporosis, and cardiovascular complications. Our lab has developed an anti-inflammatory cell-penetrating peptide that inhibits mitogen-activated protein kinase activated protein kinase 2 (MK2). MK2 is implicated in the inflammatory cascade of atherosclerosis and osteoarthritis, making it a potentially effective strategy for reducing inflammation in both disease states. Unfortunately, these peptides are untargeted and quickly degraded in the presence of serum proteases, making the development of an effective delivery system of paramount importance. The overall goal of the research presented here is to detail the development of a poly(N-isopropylacrylamide) nanoparticle that is able to effectively load and release anti-inflammatory peptides for the treatment of these inflammatory diseases. In this dissertation, I will discuss the development of a collagen-binding nanoparticle that is able to inhibit platelet binding following angioplasty, thereby halting the initial inflammatory cascade. Additionally, these particles demonstrate the ability to reduce inflammation by through the loading and release of MK2-inhibiting cell-penetrating peptides. Additionally, I will cover the development of a hollow nanoparticle system that is designed to load increased quantities of these anti-inflammatory peptides for the treatment of osteoarthritis. This particle demonstrated increased macrophage uptake and prolonged drug release, resulting in a progressive inhibition of osteoarthritic inflammation over 8 days. The results presented here advance our understanding of these nanoparticle platforms, and suggest that they may serve at effective platforms for the treatment of restenosis following angioplasty, as well as osteoarthritis.

Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development

PubMed Central

Brown, Traci A.; Holian, Andrij; Pinkerton, Kent E.; Lee, Joong Won; Cho, Yoon Hee

2016-01-01

Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual’s lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development. PMID:27138493

Delivering vaccines to the people who need them most.

PubMed

Barocchi, Michèle Anne; Rappuoli, Rino

2015-06-19

Thanks to the Global Alliance for Vaccines and Immunization (GAVI), the Vaccine Fund and the Bill & Melinda Gates Foundation, the global health community has made enormous progress in providing already existing vaccines to developing countries. However, there still exists a gap to develop vaccines for which there is no market in the Western world, owing to low economic incentives for the private sector to justify the investments necessary for vaccine development. In many cases, industry has the technologies, but lacks the impetus to direct resources to develop these vaccine products. The present emergency with the Ebola vaccine provides us an excellent example where a vaccine was feasible several years ago, but the global health community waited for a humanitarian disaster to direct efforts and resources to develop this vaccine. In the beginning of 2015, the first large-scale trials of two experimental vaccines against Ebola virus disease have begun in West Africa. During the past few years, several institutions have dedicated efforts to the development of vaccines against diseases present only in low-income countries. These include the International Vaccine Institute, the Novartis Vaccines Institute for Global Health, the Hilleman Institute, the Sabin Vaccine Institute and the Infectious Disease Research Institute. Nevertheless, solving this problem requires a more significant global effort than that currently invested. These efforts include a clear policy, global coordination of funds dedicated to the development of neglected disease and an agreement on regulatory strategies and incentives for the private sector. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Benefit-harm analysis and charts for individualized and preference-sensitive prevention: example of low dose aspirin for primary prevention of cardiovascular disease and cancer.

PubMed

Puhan, Milo A; Yu, Tsung; Stegeman, Inge; Varadhan, Ravi; Singh, Sonal; Boyd, Cynthia M

2015-10-01

Clinical practice guidelines provide separate recommendations for different diseases that may be prevented or treated by the same intervention. Also, they commonly provide recommendations for entire populations but not for individuals. To address these two limitations, our aim was to conduct benefit-harm analyses for a wide range of individuals using the example of low dose aspirin for primary prevention of cardiovascular disease and cancer and to develop Benefit-Harm Charts that show the overall benefit-harm balance for individuals. We used quantitative benefit-harm modeling that included 16 outcomes to estimate the probability that low dose aspirin provides more benefits than harms for a wide range of men and women between 45 and 84 years of age and without a previous myocardial infarction, severe ischemic stroke, or cancer. We repeated the quantitative benefit-harm modeling for different combinations of age, sex, and outcome risks for severe ischemic and hemorrhagic stroke, myocardial infarction, cancers, and severe gastrointestinal bleeds. The analyses considered weights for the outcomes, statistical uncertainty of the effects of aspirin, and death as a competing risk. We constructed Benefit-Harm Charts that show the benefit-harm balance for different combinations of outcome risks. The Benefit-Harm Charts ( http://www.benefit-harm-balance.com ) we have created show that the benefit-harm balance differs largely across a primary prevention population. Low dose aspirin is likely to provide more benefits than harms in men, elderly people, and in those at low risk for severe gastrointestinal bleeds. Individual preferences have a major impact on the benefit-harm balance. If, for example, it is a high priority for individuals to prevent stroke and severe cancers while severe gastrointestinal bleeds are deemed to be of little importance, the benefit-harm balance is likely to favor low dose aspirin for most individuals. Instead, if severe gastrointestinal bleeds are judged to be similarly important compared to the benefit outcomes, low dose aspirin is unlikely to provide more benefits than harms. Benefit-Harm Charts support individualized benefit-harm assessments and decision making. Similarly, individualized benefit-harm assessments may allow guideline developers to issue more finely granulated recommendations that reduce the risk of over- and underuse of interventions. The example of low dose aspirin for primary prevention of cardiovascular disease and cancer shows that it may be time for guideline developers to provide combined recommendations for different diseases that may be prevented or treated by the same intervention.

Role of Reactive Oxygen Species in Neonatal Pulmonary Vascular Disease

PubMed Central

Steinhorn, Robin H.

2014-01-01

Abstract Significance: Abnormal lung development in the perinatal period can result in severe neonatal complications, including persistent pulmonary hypertension (PH) of the newborn and bronchopulmonary dysplasia. Reactive oxygen species (ROS) play a substantive role in the development of PH associated with these diseases. ROS impair the normal pulmonary artery (PA) relaxation in response to vasodilators, and ROS are also implicated in pulmonary arterial remodeling, both of which can increase the severity of PH. Recent Advances: PA ROS levels are elevated when endogenous ROS-generating enzymes are activated and/or when endogenous ROS scavengers are inactivated. Animal models have provided valuable insights into ROS generators and scavengers that are dysregulated in different forms of neonatal PH, thus identifying potential therapeutic targets. Critical Issues: General antioxidant therapy has proved ineffective in reversing PH, suggesting that it is necessary to target specific signaling pathways for successful therapy. Future Directions: Development of novel selective pharmacologic inhibitors along with nonantioxidant therapies may improve the treatment outcomes of patients with PH, while further investigation of the underlying mechanisms may enable earlier detection of the disease. Antioxid. Redox Signal. 21, 1926–1942. PMID:24350610

Cow milk induced allergies (CMA) and asthma in new born.

PubMed

Wang, W; Wu, H-W; Liu, J-F

2016-01-01

The prevalence of asthma and allergic diseases in childhood has increased in several industrialized countries since the second half of the twentieth century. In some countries, the prevalence is still rising, although in others it seems to have plateaued or even decreased. It has been suggested that environmental factors operating prenatally and in early life affect the development of asthma and allergic diseases. Particularly changes in microbial exposure are proposed to play an important role in the development and maturation of the immune system. Thus, the factors that affect microbial exposure, such as mode of delivery and the use of antibiotics, may influence the development of asthma and allergic diseases. Several studies have explored the associations between perinatal factors and children's use of antibiotics and the risk of asthma, with inconsistent findings. The present review article will be focused on the important findings related with factors responsible for above allergic reactions along with asthma in young infants. Also, the influence of cow milk intake will also be taken in account to cover the aspect of cow milk induced allergies and asthma in infants.

The development of biomarkers for degenerative musculoskeletal conditions.

PubMed

Jayabalan, Prakash; Sowa, Gwendolyn A

2014-02-01

With an aging population, degenerative musculoskeletal conditions will become more prevalent with significantly increasing costs to society over the next several decades. The majority of these conditions are diagnosed radiographically, at which point the disease process is often more advanced and challenging to treat. The commonly available radiographic studies also do not adequately provide information as to the exact pain generator and findings often do not correlate either to patient symptoms or function. Personalized medicine involves formulating treatments based on a patient's own biology. The development of biological markers (biomarkers) pertaining to disease is a rapidly growing area within this field of medicine. For degenerative musculoskeletal conditions, biomarkers have the potential to provide an early non-invasive method of assessing the location and severity of tissue damage and presence of inflammation. By outlining mechanisms of disease they could allow the formulation of further treatment targets and through sub-categorizing patients into different groups based on their biomarker profile, one could provide more efficacious treatments for patients. The present article is a review of the development of biomarkers for these purposes specifically as they pertain to degenerative musculoskeletal conditions.

Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers.

PubMed

Cohen, Jeffrey I; Dropulic, Lesia; Hsu, Amy P; Zerbe, Christa S; Krogmann, Tammy; Dowdell, Kennichi; Hornung, Ronald L; Lovell, Jana; Hardy, Nancy; Hickstein, Dennis; Cowen, Edward W; Calvo, Katherine R; Pittaluga, Stefania; Holland, Steven M

2016-07-01

Most patients infected with Epstein-Barr virus (EBV) are asymptomatic, have nonspecific symptoms, or have self-limiting infectious mononucleosis. EBV, however, may result in severe primary disease or cancer. We report EBV diseases associated with GATA2 deficiency at one institution and describe the hematology, virology, and cytokine findings. Seven patients with GATA2 deficiency developed severe EBV disease. Three presented with EBV infectious mononucleosis requiring hospitalization, 1 had chronic active EBV disease (B-cell type), 1 had EBV-associated hydroa vacciniforme-like lymphoma with hemophagocytic lymphohistiocytosis, and 2 had EBV-positive smooth muscle tumors. Four of the 7 patients had severe warts and 3 had disseminated nontuberculous mycobacterial infections. All of the patients had low numbers of monocytes, B cells, CD4 T cells, and natural killer cells. All had elevated levels of EBV in the blood; 2 of 3 patients tested had expression of the EBV major immediate-early gene in the blood indicative of active EBV lytic infection. Mean plasma levels of tumor necrosis factor α, interferon γ, and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls. GATA2 is the first gene associated with EBV hydroa vacciniforme-like lymphoma. GATA2 deficiency should be considered in patients with severe primary EBV infection or EBV-associated cancer, especially in those with disseminated nontuberculous mycobacterial disease and warts. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

A Practical Green Synthesis and Biological Evaluation of Benzimidazoles Against Two Neglected Tropical Diseases: Chagas and Leishmaniasis.

PubMed

Bandyopadhyay, Debashis; Samano, Selina; Villalobos-Rocha, Juan Carlos; Sanchez-Torres, Luvia Enid; Nogueda-Torres, Benjamin; Rivera, Gildardo; Banik, Bimal K

2017-01-01

Antimicrobial resistance is an ever-increasing problem throughout the world and has already reached severe proportions. Two very common neglected tropical diseases are Chagas' disease and leishmaniasis. Chagas' disease is a severe health problem, mainly in Latin America, causing approximately 50000 deaths a year and millions of people are infected. About 25-30% of the patients infected with Trypanosoma cruzi develop the chronic form of the disease. On the other hand, Leishmaniasis represents complex diseases with an important clinical and epidemiological diversity. It is endemic in 88 countries 72 of which are developing countries and it has been estimated that are 12 million people infected and 350 million are in areas with infection risk. On this basis, research on organic compounds that can be used against these two diseases is an important target. A very simple, green, and efficient protocol is developed in which bismuth nitrate pentahydrate is employed as a Lewis acid catalyst in aqueous media under microwave irradiation for the synthesis of various 2-aryl substituted benzimidazoles from aldehydes and o-phenylenediamine. Other salient features of this protocol include milder conditions, atom-economy, easy extraction, and no wastes. Nine 1H-benzimidazole derivatives (1-9) with substituents at positions 2 and 5 were synthesized and the structure of the compounds was elucidated by spectroscopic methods. The compounds were screened to identify whether they posses pharmacological activity against Chagas' disease and leishmaniasis. Compound 8 showed better activity than the control Nifurtimox against INC-5 Trypanosoma cruzi strain whereas compounds 3 and 9 have demonstrated potent leshmanicidal activity. A systematic green synthetic procedure and in vitro biological evaluation of nine 1H-benzimidazoles are described. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Stalking The Silent Killers.

ERIC Educational Resources Information Center

DeYoung, H. Garrett

1983-01-01

New technologies have been developed to diagnose such disorders as cancer, heart disease, and defects of the newborn in presymptomatic stages. Several technologies, including amniocentesis, radioimmunoassay, enzyme immunoassay, multichannel analysis and others are discussed. Development of these technologies and issues related to their use are…

Risk factors for the development and severity of juvenile-onset recurrent respiratory papillomatosis: a systematic review.

PubMed

Niyibizi, Joseph; Rodier, Caroline; Wassef, Maggy; Trottier, Helen

2014-02-01

Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare yet aggressive disease caused by human papillomavirus (HPV). Although many newborns are likely exposed to HPV, few develop JoRRP and the clinical course of the disease varies from one child to another. This systematic review seeks to provide an up-to-date understanding of the risk factors for acquisition and severity. We conducted a comprehensive literature search in EMBASE, MEDLINE and EBMR databases using various combinations of keywords related to JoRRP etiology, risk factors and severity. We also searched Google Scholar and the reference lists of eligible studies. Our search was limited to original studies published in French or English between 1995 and July 2012 and to patients under 20 years of age. Of 1362 citations, we retrieved 102 articles and found 14 additional studies. We retained 32 studies meeting inclusion criteria. All were observational and together included 2296 JoRRP cases. Risk factors could be classified mainly as maternal and birth history, viral genotype, and host factors. A history of genital warts during pregnancy and delivery was strongly linked to the development of JoRRP. Depending on ethnicity, specific human leukocyte antigen class II alleles and immune response factors were important determinants of JoRRP acquisition and severity. HPV-11 genotype and younger age at onset of JoRRP were important predictors of severity. Genetic and immunological profiles underlying the acquisition and clinical course are not readily modifiable. Thus, preventing condylomas in women of childbearing age could reduce the burden of this life-threatening disease. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease.

PubMed

Smith, R E; Reyes, N J; Khandelwal, P; Schlereth, S L; Lee, H S; Masli, S; Saban, D R

2016-08-01

Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity. © Society for Leukocyte Biology.

Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease

PubMed Central

Smith, R. E.; Reyes, N. J.; Khandelwal, P.; Schlereth, S. L.; Lee, H. S.; Masli, S.; Saban, D. R.

2016-01-01

Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity. PMID:26856994

Early-life stress origins of gastrointestinal disease: animal models, intestinal pathophysiology, and translational implications.

PubMed

Pohl, Calvin S; Medland, Julia E; Moeser, Adam J

2015-12-15

Early-life stress and adversity are major risk factors in the onset and severity of gastrointestinal (GI) disease in humans later in life. The mechanisms by which early-life stress leads to increased GI disease susceptibility in adult life remain poorly understood. Animal models of early-life stress have provided a foundation from which to gain a more fundamental understanding of this important GI disease paradigm. This review focuses on animal models of early-life stress-induced GI disease, with a specific emphasis on translational aspects of each model to specific human GI disease states. Early postnatal development of major GI systems and the consequences of stress on their development are discussed in detail. Relevant translational differences between species and models are highlighted. Copyright © 2015 the American Physiological Society.

The Global Burden of Occupational Disease.

PubMed

Rushton, Lesley

2017-09-01

Burden of occupational disease estimation contributes to understanding of both magnitude and relative importance of different occupational hazards and provides essential information for targeting risk reduction. This review summarises recent key findings and discusses their impact on occupational regulation and practice. New methods have been developed to estimate burden of occupational disease that take account of the latency of many chronic diseases and allow for exposure trends and workforce turnover. Results from these studies have shown in several countries and globally that, in spite of improvements in workplace technology, practices and exposures over the last decades, occupational hazards remain an important cause of ill health and mortality worldwide. Major data gaps have been identified particularly regarding exposure information. Reliable data on employment and disease are also lacking especially in developing countries. Burden of occupational disease estimates form an important part of decision-making processes.

Genetic Susceptibility to Chagas Disease: An Overview about the Infection and about the Association between Disease and the Immune Response Genes

PubMed Central

Ayo, Christiane Maria; Dalalio, Márcia Machado de Oliveira; Visentainer, Jeane Eliete Laguila; Reis, Pâmela Guimarães; Jarduli, Luciana Ribeiro; Alves, Hugo Vicentin; Sell, Ana Maria

2013-01-01

Chagas disease, which is caused by the flagellate parasite Trypanosoma cruzi, affects 8–10 million people in Latin America. The disease is endemic and is characterised by acute and chronic phases that develop in the indeterminate, cardiac, and/or gastrointestinal forms. The immune response during human T. cruzi infection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Polymorphisms in genes involved in the innate and specific immune response are being widely studied in order to clarify their possible role in the occurrence or severity of disease. Here we review the role of classic and nonclassic MHC, KIR, and cytokine host genetic factors on the infection by T. cruzi and the clinical course of Chagas disease. PMID:24069594

Primary biliary cirrhosis associated with Graves' disease in a male patient.

PubMed

Suzuki, Yuji; Ishida, Kazuyuki; Takahashi, Hiroshi; Koeda, Norihiko; Kakisaka, Keisuke; Miyamoto, Yasuhiro; Suzuki, Akiko; Takikawa, Yasuhiro

2016-04-01

Primary biliary cirrhosis (PBC), which predominantly affects women, has been associated with various autoimmune diseases. Although hypothyroidism accompanying PBC is well documented, the concomitance of PBC and hyperthyroidism is rare. Herein, we report the case of a 62-year-old man who was diagnosed with PBC several years after the development of Graves' disease. This is the first case of a male patient developing PBC with Graves' disease. Both serum alanine aminotransferase levels and serum thyroid hormone levels were normalized after the administration of thiamazole for Graves' disease. However, the cholestatic liver enzyme abnormalities continued, indicating that the PBC was actualized by the administration of thiamazole. After starting ursodeoxycholic acid treatment, cholestatic liver enzyme abnormalities improved. Taken together, when a cholestatic pattern of liver enzymes is observed during follow-up for Graves' disease, an association between Graves' disease and PBC should be considered as a differential diagnosis.

Leptin, cardiovascular diseases and type 2 diabetes mellitus.

PubMed

Katsiki, Niki; Mikhailidis, Dimitri P; Banach, Maciej

2018-06-07

Leptin, an adipokine that is implicated in the control of food intake via appetite suppression, may also stimulate oxidative stress, inflammation, thrombosis, arterial stiffness, angiogenesis and atherogenesis. These leptin-induced effects may predispose to the development of cardiovascular diseases. In the present review we discuss the evidence linking leptin levels with the presence, severity and/or prognosis of both coronary artery disease and non-cardiac vascular diseases such as stroke, carotid artery disease, peripheral artery disease (PAD) and abdominal aortic aneurysms (AAA) as well as with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Leptin levels have been positively associated with the presence, severity, extent and lesion complexity of coronary atherosclerosis as well as with the presence, severity and poor clinical outcomes of both ischemic and hemorrhagic strokes. But conflicting results also exist. Furthermore, leptin was reported to independently predict common carotid intima-media thickness and carotid plaque instability. A link between hyperleptinemia and PAD has been reported, whereas limited data were available on the potential association between leptin and AAA. Elevated leptin concentrations have also been related to CKD incidence and progression as well as with insulin resistance, T2DM, micro- and macrovascular diabetic complications. Statins and antidiabetic drugs (including sitagliptin, metformin, pioglitazone, liraglutide and empagliflozin) may affect leptin levels. Further research is needed to establish the potential use (if any) of leptin as a therapeutic target in these diseases.

Oral-Fluid Thiol-Detection Test Identifies Underlying Active Periodontal Disease Not Detected by the Visual Awake Examination.

PubMed

Queck, Katherine E; Chapman, Angela; Herzog, Leslie J; Shell-Martin, Tamara; Burgess-Cassler, Anthony; McClure, George David

Periodontal disease in dogs is highly prevalent but can only be accurately diagnosed by performing an anesthetized oral examination with periodontal probing and dental radiography. In this study, 114 dogs had a visual awake examination of the oral cavity and were administered an oral-fluid thiol-detection test prior to undergoing a a full-mouth anesthetized oral examination and digital dental radiographs. The results show the visual awake examination underestimated the presence and severity of active periodontal disease. The thiol-detection test was superior to the visual awake examination at detecting the presence and severity of active periodontal disease and was an indicator of progression toward alveolar bone loss. The thiol-detection test detected active periodontal disease at early stages of development, before any visual cues were present, indicating the need for intervention to prevent periodontal bone loss. Early detection is important because without intervention, dogs with gingivitis (active periodontal disease) progress to irreversible periodontal bone loss (stage 2+). As suggested in the current AAHA guidelines, a thiol-detection test administered in conjunction with the visual awake examination during routine wellness examinations facilitates veterinarian-client communication and mitigates under-diagnosis of periodontal disease and underutilization of dental services. The thiol-detection test can be used to monitor the periodontal health status of the conscious patient during follow-up examinations based on disease severity.

Personalized medicine in interstitial lung diseases.

PubMed

Spagnolo, Paolo; Oldham, Justin M; Jones, Mark G; Lee, Joyce S

2017-05-01

A number of recent studies have explored the possibility to apply personalized medicine to interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF), the most common and deadly of the idiopathic interstitial pneumonias. In our review, we summarize and discuss the most recent literature on personalized medicine in IPF as well as hypersensitivity pneumonitis and sarcoidosis, with emphasis on patient subgroups for which a personalized approach to disease prognostication and management may become a reality in the near future. Most of the studies that have explored the applicability of personalized medicine to ILDs have been conducted in patients with IPF. Such studies have suggested the existence of several distinct disease subgroups defined by similar genetic profiles, molecular pathways, exposures and individual lifestyles. Personalized medicine in hypersensitivity pneumonitis is in its infancy. The development and applicability of personalized medicine to sarcoidosis, on the other hand, remains problematic for several reasons, including the lack of a diagnostic gold standard, the highly variable and unpredictable disease course, particularly across patients of different ethnicities, the poor correlation between disease activity and disease severity and the lack of a validated management algorithm. A number of distinct patient subgroups have been identified in ILDs. Although available data need to be validated longitudinally, the possibility to study homogeneous groups of patients may allow prediction of disease behavior and response to treatment with dramatic clinical implications.

Hepatotoxicosis in dogs consuming a diet of camel meat contaminated with indospicine.

PubMed

FitzGerald, L M; Fletcher, M T; Paul, A E H; Mansfield, C S; O'Hara, A J

2011-03-01

Four dogs presented with clinical signs of severe hepatic disease after consuming a commercial camel meat diet. Laboratory investigation revealed evidence of severe liver disease, including markedly increased serum alanine aminotransferase (ALT) activity and total bilirubin concentration, and prolonged clotting times. Two dogs deteriorated despite supportive therapy and were euthanased. Histologically, both livers appeared similar, with the main lesion being extensive periacinar necrosis and haemorrhage. Indospicine, a toxic amino acid of plant origin, was detected in the serum and/or plasma from all four dogs, as well as in tissues of a dog that was necropsied and in a sample of the camel meat fed to this animal. Serum biochemistry tests using blood samples collected from 15 additional dogs identified as having eaten the diet detected indospicine was in the serum of 14 and 3 had increased ALT activity. One of the latter dogs subsequently developed clinical signs of severe liver disease and was euthanased. To the authors' knowledge, this is the first published report of the detection of indospicine residues in camel meat and the occurrence of severe, sometimes fatal, liver disease in dogs that consumed this contaminated meat. © 2011 The Authors. Australian Veterinary Journal © 2011 Australian Veterinary Association.

Severe acute interstitial lung disease in a patient with anaplastic lymphoma kinase rearrangement-positive non-small cell lung cancer treated with alectinib.

PubMed

Yamamoto, Yuzo; Okamoto, Isamu; Otsubo, Kohei; Iwama, Eiji; Hamada, Naoki; Harada, Taishi; Takayama, Koichi; Nakanishi, Yoichi

2015-10-01

Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was therefore diagnosed with interstitial lung disease induced by alectinib. Her CT findings and respiratory condition improved after steroid pulse therapy. As far as we are aware, this is the first reported case of alectinib-induced severe interstitial lung disease (ILD). We should be aware of the possibility of such a severe adverse event and should therefore carefully monitor patients treated with this drug.

Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice

PubMed Central

Sumner, Charlotte J.; Wee, Claribel D.; Warsing, Leigh C.; Choe, Dong W.; Ng, Andrew S.; Lutz, Cathleen; Wagner, Kathryn R.

2009-01-01

There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-β family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn−/−) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA. PMID:19477958

Relationship between human papillomavirus and penile cancer—implications for prevention and treatment

PubMed Central

Kidd, Laura C.; Chaing, Sharon; Chipollini, Juan; Spiess, Philippe E.

2017-01-01

Penile cancer is a rare disease in the United States, but rates are increasing, causing concern. Several risk factors have been associated with the disease, including human papillomavirus (HPV) infection. Knowledge of HPV pathogenesis has led to the development of a vaccine, which has proven instrumental in reducing the incidence of female HPV-related cancers, but results in men have yet to be elucidated. Fortunately, rates of vaccination are up-trending in both males and females in the past several years. In addition, targeted therapies are the focus of several ongoing research efforts. Some of these therapeutics are currently in use, while several are in trials. With continued patient education and research, both treatment and prevention of HPV-related pre-malignant lesions and penile cancer will likely diminish. PMID:29184775

Developing new treatments for Alzheimer’s disease

PubMed Central

Lyketsos, Constantine G.; Szekely, Christine A.; Mielke, Michelle M.; Rosenberg, Paul B.; Zandi, Peter P.

2008-01-01

This synthetic review presents an approach to the use of biomarkers for the development of new treatments for Alzheimer’s disease (AD). After reviewing the process of translation as applied to AD, the paper provides a general update on what is known about the biology of the disease, and highlights currently available treatments. This is followed by a discussion of future drug development for AD emphasizing the roles that biomarkers are likely to play in this process: (1) Define patients who are going to progress rapidly for the purpose of trial enrichment; (2) Differentiate disease and therapeutically relevant AD subtypes; (3) Assess the potential activity of specific therapies in vivo or ex vivo; and (4) Measure the underlying disease state, so as to (a) detect disease and assess drug response in asymptomatic patients, (b) serve as a secondary outcome measures in clinical trials of symptomatic patients, (c) decide if further development of a treatment should be stopped as it is not likely to be effective. Several examples are used to illustrate each biomarker utility in the AD context. PMID:18498669

Development of imaging techniques to study the pathogenesis of biosafety level 2/3 infectious agents

PubMed Central

Rella, Courtney E.; Ruel, Nancy; Eugenin, Eliseo A.

2015-01-01

Despite significant advances in microbiology and molecular biology over the last decades, several infectious diseases remain global concerns, resulting in the death of millions of people worldwide each year. According to the Center for Disease Control (CDC) in 2012, there were 34 million people infected with HIV, 8.7 million new cases of tuberculosis, 500 million cases of hepatitis, and 50–100 million people infected with dengue. Several of these pathogens, despite high incidence, do not have reliable clinical detection methods. New or improved protocols have been generated to enhance detection and quantitation of several pathogens using high-end microscopy (light, confocal, and STORM microscopy) and imaging software. In the current manuscript, we discuss these approaches and the theories behind these methodologies. Thus, advances in imaging techniques will open new possibilities to discover therapeutic interventions to reduce or eliminate the devastating consequences of infectious diseases. PMID:24990818

[Postoperative recurrence of Crohn's disease, and its prevention].

PubMed

Lakatos, László; Lakatos, Péter László

2010-05-23

Crohn's disease is a chronic, progressive disabling condition ultimately leading to stricturing and/or penetrating complications. The need for surgery may be as high as 70% in patients with severe active disease or complications. However, relapse may develop in a significant proportion of the patients after surgery leading to frequent re-operations. Despite emerging data, postoperative prevention is still controversial. After careful evaluation of the individual risk a tailored therapy should be considered. In patients with small risk for relapse mesalazine or in selected cases no-treatment may be an option. In patients with a moderate-to-high risk azathioprine should be considered together with metronidazole in the three months. Follow-up ileocolonoscopy 6-12 months after the surgery is helpful in the determination of endoscopic severity and may assist in the optimization of the therapy. In most severe cases anti-TNF agents may be appropriate for postoperative prevention and therapy.

Global gene expression and Ingenuity biological functions analysis on PCBs 153 and 138 induced human PBMC in vitro reveals differential mode(s) of action in developing toxicities.

PubMed

Ghosh, Somiranjan; Zang, Shizhu; Mitra, Partha S; Ghimbovschi, Svetlana; Hoffman, Eric P; Dutta, Sisir K

2011-07-01

Several reports have indicated that low level of polychlorinated biphenyl (PCB) exposure can adversely affect a multitude of physiological disorders and diseases in in vitro, in vivo, and as reported in epidemiological studies. This investigation is focused on the possible contribution of two most prevalent PCB congeners in vitro in developing toxicities. We used PCBs 138 and 153 at the human equivalence level as model agents to test their specificity in developing toxicities. We chose a global approach using oligonucleotide microarray technology to investigate modulated gene expression for biological effects, upon exposure of PCBs, followed by Ingenuity Pathway Analysis (IPA), to understand the underlying consequence in developing disease and disorders. We performed in vitro studies with human peripheral blood mononuclear cells (PBMC), where PBMC cells were exposed to respective PCBs for 48 h. Overall, our observation on gene expression indicated that PCB produces a unique signature affecting different pathways, specific for each congener. While analyzing these data through IPA, the prominent and interesting disease and disorders were neurological disease, cancer, cardiovascular disease, respiratory disease, as well as endocrine system disorders, genetic disorders, and reproductive system disease. They showed strong resemblances with in vitro, in vivo, and in the epidemiological studies. A distinct difference was observed in renal and urological diseases, organisimal injury and abnormalities, dental disease, ophthalmic disease, and psychological disorders, which are only revealed by PCB 138 exposure, but not in PCB 153. The present study emphasizes the challenges of global gene expression in vitro and was correlated with the results of exposed human population. The microarray results give a molecular mechanistic insight and functional effects, following PCB exposure. The extent of changes in genes related to several possible mode(s) of action highlights the changes in cellular functions and signaling pathways that play major roles. In addition to understanding the pathways related to mode of action for chemicals, these data could lead to the identification of genomic signatures that could be used for screening of chemicals for their potential to cause disease and developmental disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Measuring severe maternal morbidity: validation of potential measures.

PubMed

Main, Elliott K; Abreo, Anisha; McNulty, Jennifer; Gilbert, William; McNally, Colleen; Poeltler, Debra; Lanner-Cusin, Katarina; Fenton, Douglas; Gipps, Theresa; Melsop, Kathryn; Greene, Naomi; Gould, Jeffrey B; Kilpatrick, Sarah

2016-05-01

Both maternal mortality rate and severe maternal morbidity rate have risen significantly in the United Sates. Recently, the Centers for Disease Control and Prevention introduced International Classification of Diseases, 9th revision, criteria for defining severe maternal morbidity with the use of administrative data sources; however, those criteria have not been validated with the use of chart reviews. The primary aim of the current study was to validate the Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria for the identification of severe maternal morbidity. This analysis initially required the development of a reproducible set of clinical conditions that were judged to be consistent with severe maternal morbidity to be used as the clinical gold standard for validation. Alternative criteria for severe maternal morbidity were also examined. The 67,468 deliveries that occurred during a 12-month period from 16 participating California hospitals were screened initially for severe maternal morbidity with the presence of any of 4 criteria: (1) Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, diagnosis and procedure codes; (2) prolonged postpartum length of stay (>3 standard deviations beyond the mean length of stay for the California population); (3) any maternal intensive care unit admissions (with the use of hospital billing sources); and (4) the administration of any blood product (with the use of transfusion service data). Complete medical records for all screen-positive cases were examined to determine whether they satisfied the criteria for the clinical gold standard (determined by 4 rounds of a modified Delphi technique). Descriptive and statistical analyses that included area under the receiver operating characteristic curve and C-statistic were performed. The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria had a reasonably high sensitivity of 0.77 and a positive predictive value of 0.44 with a C-statistic of 0.87. The most important source of false-positive cases were mothers whose only criterion was 1-2 units of blood products. The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria screen rate ranged from 0.51-2.45% among hospitals. True positive severe maternal morbidity ranged from 0.05-1.13%. When hospitals were grouped by their neonatal intensive care unit level of care, severe maternal morbidity rates were statistically lower at facilities with lower level neonatal intensive care units (P < .0001). The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria can serve as a reasonable administrative metric for measuring severe maternal morbidity at population levels. Caution should be used with the use of these criteria for individual hospitals, because case-mix effects appear to be strong. Copyright © 2016 Elsevier Inc. All rights reserved.

Hydrogen sulfide production from subgingival plaque samples.

PubMed

Basic, A; Dahlén, G

2015-10-01

Periodontitis is a polymicrobial anaerobe infection. Little is known about the dysbiotic microbiota and the role of bacterial metabolites in the disease process. It is suggested that the production of certain waste products in the proteolytic metabolism may work as markers for disease severity. Hydrogen sulfide (H2S) is a gas produced by degradation of proteins in the subgingival pocket. It is highly toxic and believed to have pro-inflammatory properties. We aimed to study H2S production from subgingival plaque samples in relation to disease severity in subjects with natural development of the disease, using a colorimetric method based on bismuth precipitation. In remote areas of northern Thailand, adults with poor oral hygiene habits and a natural development of periodontal disease were examined for their oral health status. H2S production was measured with the bismuth method and subgingival plaque samples were analyzed for the presence of 20 bacterial species with the checkerboard DNA-DNA hybridization technique. In total, 43 subjects were examined (age 40-60 years, mean PI 95 ± 6.6%). Fifty-six percent had moderate periodontal breakdown (CAL > 3 < 7 mm) and 35% had severe periodontal breakdown (CAL > 7 mm) on at least one site. Parvimonas micra, Filifactor alocis, Porphyromonas endodontalis and Fusobacterium nucleatum were frequently detected. H2S production could not be correlated to periodontal disease severity (PPD or CAL at sampled sites) or to a specific bacterial composition. Site 21 had statistically lower production of H2S (p = 0.02) compared to 16 and 46. Betel nut chewers had statistically significant lower H2S production (p = 0.01) than non-chewers. Rapid detection and estimation of subgingival H2S production capacity was easily and reliably tested by the colorimetric bismuth sulfide precipitation method. H2S may be a valuable clinical marker for degradation of proteins in the subgingival pocket. Copyright © 2014 Elsevier Ltd. All rights reserved.

Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse.

PubMed

Droz, Brian A; Sneed, Bria L; Jackson, Charles V; Zimmerman, Karen M; Michael, M Dodson; Emmerson, Paul J; Coskun, Tamer; Peterson, Richard G

2017-01-01

Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia. Since many clinical studies have established a close link between higher body weight and the development of type 2 diabetes, we investigated whether time to progression to type 2 diabetes or disease severity in FATZO mice was dependent on weight gain in young animals. Our results indicate that lighter animals developed metabolic disturbances much slower and to a lesser magnitude than their heavier counterparts. Consumption of a diet containing high fat, accelerated weight gain in parallel with disease progression. A naturally occurring and significant variation in the body weight of FATZO offspring enables these mice to be identified as low, mid and high body weight groups at a young age. These weight groups remain into adulthood and correspond to slow, medium and accelerated development of type 2 diabetes. Thus, body weight inclusion criteria can optimize the FATZO model for studies of prevention, stabilization or treatment of type 2 diabetes.

Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse

PubMed Central

Droz, Brian A.; Sneed, Bria L.; Jackson, Charles V.; Zimmerman, Karen M.; Michael, M. Dodson; Emmerson, Paul J.; Coskun, Tamer

2017-01-01

Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia. Since many clinical studies have established a close link between higher body weight and the development of type 2 diabetes, we investigated whether time to progression to type 2 diabetes or disease severity in FATZO mice was dependent on weight gain in young animals. Our results indicate that lighter animals developed metabolic disturbances much slower and to a lesser magnitude than their heavier counterparts. Consumption of a diet containing high fat, accelerated weight gain in parallel with disease progression. A naturally occurring and significant variation in the body weight of FATZO offspring enables these mice to be identified as low, mid and high body weight groups at a young age. These weight groups remain into adulthood and correspond to slow, medium and accelerated development of type 2 diabetes. Thus, body weight inclusion criteria can optimize the FATZO model for studies of prevention, stabilization or treatment of type 2 diabetes. PMID:28640904

Vedolizumab: first global approval.

PubMed

Poole, Raewyn M

2014-07-01

Vedolizumab [Entyvio(®) (US, Europe)], a humanized monoclonal antibody α4β7 integrin receptor antagonist, has been developed by Millennium Pharmaceuticals (d/b/a Takeda Pharmaceuticals International) for the treatment of ulcerative colitis and Crohn's disease. Vedolizumab has received its first global approval for the treatment of ulcerative colitis and Crohn's disease in the US, for use in adult patients with moderate-to-severe disease who have had an inadequate response, loss of response or intolerance to one or more standard therapies (corticosteroids, immunomodulators or tumour necrosis factor-α inhibitor) or demonstrated dependence on corticosteroids. Vedolizumab has since been approved for ulcerative colitis and Crohn's disease in the EU, Norway, Iceland and Liechtenstein. This article summarizes the milestones in the development of vedolizumab leading to its first approval for the treatment of ulcerative colitis and Crohn's disease.

Delayed-onset dementia after stroke or transient ischemic attack.

PubMed

Mok, Vincent C T; Lam, Bonnie Y K; Wang, Zhaolu; Liu, Wenyan; Au, Lisa; Leung, Eric Y L; Chen, Sirong; Yang, Jie; Chu, Winnie C W; Lau, Alexander Y L; Chan, Anne Y Y; Shi, Lin; Fan, Florence; Ma, Sze H; Ip, Vincent; Soo, Yannie O Y; Leung, Thomas W H; Kwok, Timothy C Y; Ho, Chi L; Wong, Lawrence K S; Wong, Adrian

2016-11-01

Patients surviving stroke without immediate dementia are at high risk of delayed-onset dementia. Mechanisms underlying delayed-onset dementia are complex and may involve vascular and/or neurodegenerative diseases. Dementia-free patients with stroke and/or transient ischemic attack (TIA; n = 919) were studied for 3 years prospectively, excluding those who developed dementia 3 to 6 months after stroke and/or TIA. Forty subjects (4.4%) developed dementia during the study period. Imaging markers of severe small vessel disease (SVD), namely presence of ≥3 lacunes and confluent white matter changes; history of hypertension and diabetes mellitus independently predicted delayed-onset dementia after adjustment for age, gender, and education. Only 6 of 31 (19.4%) subjects with delayed cognitive decline harbored Alzheimer's disease-like Pittsburg compound B (PiB) retention. Most PiB cases (16/25, 64%) had evidence of severe SVD. Severe SVD contributes importantly to delayed-onset dementia after stroke and/or TIA. Future clinical trials aiming to prevent delayed-onset dementia after stroke and/or TIA should target this high-risk group. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Inflammatory bowel disease therapy: blockade of cytokines and cytokine signaling pathways.

PubMed

Yamamoto-Furusho, Jesus K

2018-07-01

Treatment of inflammatory bowel disease (IBD) patients can vary depending on the degree of response, lack of response or intolerance to conventional or biological agents aimed at blocking various cytokines or integrins. Recent therapies targeting several cytokines were reviewed to evaluate efficacy in IBD patients. Ustekinumab is an interleukin inhibitor which blocks the p40 subunit of IL-12 and IL-23 axis and is already approved for the treatment of Crohn's disease patients, specially those who had inadequate response or intolerance to conventional treatment with anti-TNF-α agents. Several treatments have been developed that are focused on the blockade of specific cytokines such as IL-6, IL-12, IL-13, IL-17, IL-23 and a chemokine named IFN-γ-inducible protein-10 as well as some oral small-molecule inhibitors of intracellular cytoplasmic tyrosine kinases like tofacitinib, filgotinib and upadacitinib. Several biologics blocking different and specific cytokines and oral small molecule agents have been and are being evaluated in IBD patients. A comprehensive understanding of the underlying immunological mechanisms will allow to develop effective and safe agents that inhibit one or more cytokines to improve the outcome in patients with IBD.

The immunopathogenesis of celiac disease reveals possible therapies beyond the gluten-free diet.

PubMed

McAllister, Christopher S; Kagnoff, Martin F

2012-07-01

Celiac disease is a T cell-mediated autoimmune inflammatory disease of the small intestine that is activated by gluten. The diagnosis of celiac disease is challenging as patients display a wide range of symptoms and some are asymptomatic. A lifelong gluten-free diet is the only currently approved treatment of celiac disease. Although the diet is safe and effective, the compliance rates and patient acceptance vary. Furthermore, many patients treated with a gluten-free diet continue to be mildly to severely symptomatic with persistent histological abnormalities, and a small number of patients develop refractory celiac disease. New therapeutic adjuncts and potential alternatives to the gluten-free diet could improve the treatment options for these patients. Advances in understanding the immunopathogenesis of celiac disease have suggested several types of therapeutic strategies that may augment or supplant the gluten-free diet. Some of these strategies attempt to decrease the immunogenicity of gluten-containing grains by manipulating the grain itself or by using oral enzymes to break down immunogenic peptides that normally remain intact during digestion. Other strategies focus on preventing the absorption of these peptides, preventing tissue transglutaminase from rendering gluten peptides more immunogenic, or inhibiting their binding to celiac disease-specific antigen-presenting molecules. Strategies that limit T cell migration to the small intestine or that reestablish mucosal homeostasis and tolerance to gluten antigens are also being explored. Additionally, it is vital to develop new therapeutic options for refractory celiac disease patients. This review highlights therapeutic strategies that may ultimately improve the health and well-being of individuals with celiac disease.

Clinical guidelines for management of dry eye associated with Sjögren disease.

PubMed

Foulks, Gary N; Forstot, S Lance; Donshik, Peter C; Forstot, Joseph Z; Goldstein, Michael H; Lemp, Michael A; Nelson, J Daniel; Nichols, Kelly K; Pflugfelder, Stephen C; Tanzer, Jason M; Asbell, Penny; Hammitt, Katherine; Jacobs, Deborah S

2015-04-01

To provide a consensus clinical guideline for management of dry eye disease associated with Sjögren disease by evaluating published treatments and recommending management options. Consensus panel evaluation of reported treatments for dry eye disease. Using the 2007 Report of the International Workshop on Dry Eye (DEWS) as a starting point, a panel of eye care providers and consultants evaluated peer-reviewed publications and developed recommendations for evaluation and management of dry eye disease associated with Sjögren disease. Publications were graded according to the American Academy of Ophthalmology Preferred Practice Pattern guidelines for level of evidence. Strength of recommendation was according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. The recommendations of the panel are briefly summarized herein. Evaluation should include symptoms of both discomfort and visual disturbance as well as determination of the relative contribution of aqueous production deficiency and evaporative loss of tear volume. Objective parameters of tear film stability, tear osmolarity, degree of lid margin disease, and ocular surface damage should be used to stage severity of dry eye disease to assist in selecting appropriate treatment options. Patient education with regard to the nature of the problem, aggravating factors, and goals of treatment is critical to successful management. Tear supplementation and stabilization, control of inflammation of the lacrimal glands and ocular surface, and possible stimulation of tear production are treatment options that are used according to the character and severity of dry eye disease. Management guidelines for dry eye associated with Sjögren's disease are presented. Copyright © 2015 Elsevier Inc. All rights reserved.

Metabolic network failures in Alzheimer’s disease: A biochemical road map

PubMed Central

Toledo, Jon B.; Arnold, Matthias; Kastenmüuller, Gabi; Chang, Rui; Baillie, Rebecca A.; Han, Xianlin; Thambisetty, Madhav; Tenenbaum, Jessica D.; Suhre, Karsten; Thompson, J. Will; St. John-Williams, Lisa; MahmoudianDehkordi, Siamak; Rotroff, Daniel M.; Jack, John R.; Motsinger-Reif, Alison; Risacher, Shannon L.; Blach, Colette; Lucas, Joseph E.; Massaro, Tyler; Louie, Gregory; Zhu, Hongjie; Dallmann, Guido; Klavins, Kristaps; Koal, Therese; Kim, Sungeun; Nho, Kwangsik; Shen, Li; Casanova, Ramon; Varma, Sudhir; Legido-Quigley, Cristina; Moseley, M. Arthur; Zhu, Kuixi; Henrion, Marc Y. R.; van der Lee, Sven J.; Harms, Amy C.; Demirkan, Ayse; Hankemeier, Thomas; van Duijn, Cornelia M.; Trojanowski, John Q.; Shaw, Leslie M.; Saykin, Andrew J.; Weiner, Michael W.; Doraiswamy, P. Murali; Kaddurah-Daouk, Rima

2018-01-01

Introduction The Alzheimer’s Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer’s disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. Methods Fasting serum samples from the Alzheimer’s Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1–42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. Discussion Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. PMID:28341160

Predictors of Aggressive Inflammatory Bowel Disease

PubMed Central

Yarur, Andres J.; Strobel, Sebastian G.; Deshpande, Amar R.

2011-01-01

Inflammatory bowel disease comprises a group of conditions characterized by idiopathic inflammation of the gastrointestinal tract. The natural course of disease can range from an indolent course with prolonged periods of remission to aggressive, incapacitating disease. Predicting which patients are more susceptible to developing severe disease is important, especially when choosing therapeutic agents and treatment strategies. This paper reviews current evidence on the main demographic, clinical, endoscopic, histologic, serologic, and genetic markers that predict aggressive inflammatory bowel disease. In ulcerative colitis, we considered disease to be aggressive when patients had a high relapse rate, need for admission and/or surgery, development of colon cancer, or extraintestinal manifestations. We defined aggressive Crohn's disease as having a high relapse rate, development of penetrating disease, need for repeat surgery, or multiple admissions for flares. In Crohn's disease, involvement of the upper gastrointestinal tract and ileum, penetrating disease, early age at diagnosis, smoking, extensive ulceration of the mucosa, high titers of serum antibodies, and mutations of the NOD2 gene are markers of aggressive disease. In ulcerative colitis, patients with more extensive involvement of the colon (pancolitis) have more symptomatology and are at higher risk for needing a colectomy and developing colon cancer. Also, plasmocytic infiltration of the colonic mucosa and crypt atrophy predict treatment failure. As with diagnosis, no single method can predict disease aggressiveness. Multiple serologic and genetic tests are being developed to refine the accuracy of prediction. Endoscopic findings can also predict the future course of disease. At present, clinical manifestations are the most useful way to make therapeutic decisions. PMID:22298958

A discussion on disease severity index values: using the disease severity index for null hypothesis testing

USDA-ARS?s Scientific Manuscript database

A disease severity index (DSI) is a single number for summarizing a large amount of information on disease severity. It has been used to indicate the performance of a cultivar in regard to disease resistance at a particular location, to relate disease severity to yield loss, to determine the effecti...

[Analysis of heavy-metal-mediated disease and development of a novel remediation system based on fieldwork and experimental research].

PubMed

Yajima, Ichiro; Zou, Cunchao; Li, Xiang; Nakano, Chizuru; Omata, Yasuhiro; Kumasaka, Mayuko Y

2015-01-01

Heavy-metal pollution occurs in various environments, including water, air and soil, and has serious effects on human health. Since heavy-metal pollution in drinking water causes various diseases including skin cancer, it has become a global problem worldwide. However, there is limited information on the mechanism of development of heavy-metal-mediated disease. We performed both fieldwork and experimental studies to elucidate the levels of heavy-metal pollution and mechanisms of development of heavy-metal-related disease and to develop a novel remediation system. Our fieldwork in Bangladesh, Vietnam and Malaysia demonstrated that drinking well water in these countries was polluted with high concentrations of several heavy metals including arsenic, barium, iron and manganese. Our experimental studies based on the data from our fieldwork demonstrated that these heavy metals caused skin cancer and hearing loss. Further experimental studies resulted in the development of a novel remediation system with which toxic heavy metals were absorbed from polluted drinking water. Implementation of both fieldwork and experimental studies is important for prediction, prevention and therapy of heavy-metal-mediated diseases.

Compulsive behaviors in patients with Parkinson's disease.

PubMed

Kenangil, Gülay; Ozekmekçi, Sibel; Sohtaoglu, Melis; Erginöz, Ethem

2010-05-01

Several impulse control disorders (ICDs) may develop in patients with Parkinson's disease (PD). We aimed to identify the frequency and phenomenology of ICDs in our PD population. Among 554 PD patients examined in a 3-year period, we identified 33 patients with ICDs. Disease duration, gender, and age-matched 65 PD patients without ICDs were selected as controls. We noted age-at-onset, duration, and severity of PD, dose and types of dopaminergic treatment, as well as presence of motor complications in both groups. Of 554 patients, 33 (5.9%) had ICDs, of whom, 27 were men (81%), mean age-at onset of PD was 48 and disease duration 8 years. While all patients with ICDs were on dopamine agonist drugs (+/- an adjuvant), all but 2 of controls were on dopamine agonists. Punding was the most frequent behavioral problem (57%), 42% exhibited aggressive hypersexuality, 27% compulsive eating, 24% pathologic shopping, and 21% compulsive medication. Severity of PD, presence of l-Dopa-induced motor complications, l-Dopa equivalent doses of dopamine agonists administered were not statistically different between 2 groups. In this study performed in a tertiary clinic for movement disorders in Turkey, several ICDs occurred in a small group of PD patients, mostly in men with young-onset disease, similar to the previous reported series. However, in contrast to the Western series, the number of gamblers was quite low because gambling is illegal in our country. We did not find any association between ICDs and severity of PD as well as doses of dopaminergic agents.

Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers

PubMed Central

Cohen, Jeffrey I.; Dropulic, Lesia; Hsu, Amy P.; Zerbe, Christa S.; Krogmann, Tammy; Dowdell, Kennichi; Hornung, Ronald L.; Lovell, Jana; Hardy, Nancy; Hickstein, Dennis; Cowen, Edward W.; Calvo, Katherine R.; Pittaluga, Stefania; Holland, Steven M.

2016-01-01

Background. Most patients infected with Epstein-Barr virus (EBV) are asymptomatic, have nonspecific symptoms, or have self-limiting infectious mononucleosis. EBV, however, may result in severe primary disease or cancer. Methods. We report EBV diseases associated with GATA2 deficiency at one institution and describe the hematology, virology, and cytokine findings. Results. Seven patients with GATA2 deficiency developed severe EBV disease. Three presented with EBV infectious mononucleosis requiring hospitalization, 1 had chronic active EBV disease (B-cell type), 1 had EBV-associated hydroa vacciniforme–like lymphoma with hemophagocytic lymphohistiocytosis, and 2 had EBV-positive smooth muscle tumors. Four of the 7 patients had severe warts and 3 had disseminated nontuberculous mycobacterial infections. All of the patients had low numbers of monocytes, B cells, CD4 T cells, and natural killer cells. All had elevated levels of EBV in the blood; 2 of 3 patients tested had expression of the EBV major immediate-early gene in the blood indicative of active EBV lytic infection. Mean plasma levels of tumor necrosis factor α, interferon γ, and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls. Conclusions. GATA2 is the first gene associated with EBV hydroa vacciniforme–like lymphoma. GATA2 deficiency should be considered in patients with severe primary EBV infection or EBV-associated cancer, especially in those with disseminated nontuberculous mycobacterial disease and warts. PMID:27169477

Osteonecrosis of the femoral head in sickle cell disease: prevalence, comorbidities, and surgical outcomes in California.

PubMed

Adesina, Oyebimpe; Brunson, Ann; Keegan, Theresa H M; Wun, Ted

2017-07-11

Osteonecrosis of the femoral head (ONFH) is a prevalent complication of sickle cell disease (SCD) that has not been well described in population-based cohort studies. Using California's Office of Statewide Planning and Development discharge databases (1991-2013), we estimated the cumulative incidence of ONFH after accounting for the competing risk of death and used a multivariable Cox proportional hazards regression to identify factors associated with ONFH diagnosis. We also calculated rates of readmissions to the hospital or emergency department within 30 to 90 days of hip replacement surgery. Of the 6237 patients in our SCD cohort, 22% (n = 1356) developed ONFH at a median age of 27 years, and 23% (n = 308) of the patients with ONFH underwent hip replacement surgery at a median age of 36 years. The cumulative incidence of ONFH to age 30 years was higher among SCD patients with more severe disease (24%; vs 8% in less severe) and those with antecedent acute chest syndrome (ACS) (18%; vs 8% without prior history of ACS). From 2003 to 2013, SCD patients with more severe disease (hazard ratio [HR], 2.77; 95% confidence interval [CI], 2.38-3.23) or with antecedent ACS (HR, 1.61; CI, 1.35-1.91) were more likely to develop ONFH. Twenty-seven percent of post-hip surgery patients were readmitted within 30 days, mostly for painful vaso-occlusive crises. ONFH is a common SCD complication that increases with age; ongoing studies into prevention and effective nonsurgical interventions for SCD-induced osteonecrosis must remain a high research priority.

Osteonecrosis of the femoral head in sickle cell disease: prevalence, comorbidities, and surgical outcomes in California

PubMed Central

Brunson, Ann; Keegan, Theresa H. M.

2017-01-01

Osteonecrosis of the femoral head (ONFH) is a prevalent complication of sickle cell disease (SCD) that has not been well described in population-based cohort studies. Using California’s Office of Statewide Planning and Development discharge databases (1991-2013), we estimated the cumulative incidence of ONFH after accounting for the competing risk of death and used a multivariable Cox proportional hazards regression to identify factors associated with ONFH diagnosis. We also calculated rates of readmissions to the hospital or emergency department within 30 to 90 days of hip replacement surgery. Of the 6237 patients in our SCD cohort, 22% (n = 1356) developed ONFH at a median age of 27 years, and 23% (n = 308) of the patients with ONFH underwent hip replacement surgery at a median age of 36 years. The cumulative incidence of ONFH to age 30 years was higher among SCD patients with more severe disease (24%; vs 8% in less severe) and those with antecedent acute chest syndrome (ACS) (18%; vs 8% without prior history of ACS). From 2003 to 2013, SCD patients with more severe disease (hazard ratio [HR], 2.77; 95% confidence interval [CI], 2.38-3.23) or with antecedent ACS (HR, 1.61; CI, 1.35-1.91) were more likely to develop ONFH. Twenty-seven percent of post–hip surgery patients were readmitted within 30 days, mostly for painful vaso-occlusive crises. ONFH is a common SCD complication that increases with age; ongoing studies into prevention and effective nonsurgical interventions for SCD-induced osteonecrosis must remain a high research priority. PMID:29296770

Distinct antibody responses of patients with mild and severe leptospirosis determined by whole proteome microarray analysis

PubMed Central

Lessa-Aquino, Carolina; Lindow, Janet C.; Randall, Arlo; Wunder, Elsio; Pablo, Jozelyn; Nakajima, Rie; Jasinskas, Algis; Cruz, Jaqueline S.; Damião, Alcineia O.; Nery, Nívison; Ribeiro, Guilherme S.; Costa, Federico; Hagan, José E.; Reis, Mitermayer Galvão; Ko, Albert I.; Medeiros, Marco Alberto; Felgner, Philip L.

2017-01-01

Background Leptospirosis is an important zoonotic disease worldwide. Humans usually present a mild non-specific febrile illness, but a proportion of them develop more severe outcomes, such as multi-organ failure, lung hemorrhage and death. Such complications are thought to depend on several factors, including the host immunity. Protective immunity is associated with humoral immune response, but little is known about the immune response mounted during naturally-acquired Leptospira infection. Methods and principal findings Here, we used protein microarray chip to profile the antibody responses of patients with severe and mild leptospirosis against the complete Leptospira interrogans serovar Copenhageni predicted ORFeome. We discovered a limited number of immunodominant antigens, with 36 antigens specific to patients, of which 11 were potential serodiagnostic antigens, identified at acute phase, and 33 were potential subunit vaccine targets, detected after recovery. Moreover, we found distinct antibody profiles in patients with different clinical outcomes: in the severe group, overall IgM responses do not change and IgG responses increase over time, while both IgM and IgG responses remain stable in the mild patient group. Analyses of individual patients’ responses showed that >74% of patients in the severe group had significant IgG increases over time compared to 29% of patients in the mild group. Additionally, 90% of IgM responses did not change over time in the mild group, compared to ~51% in the severe group. Conclusions In the present study, we detected antibody profiles associated with disease severity and speculate that patients with mild disease were protected from severe outcomes due to pre-existing antibodies, while patients with severe leptospirosis demonstrated an antibody profile typical of first exposure. Our findings represent a significant advance in the understanding of the humoral immune response to Leptospira infection, and we have identified new targets for the development of subunit vaccines and diagnostic tests. PMID:28141801

Extracorporeal virus elimination for the treatment of severe Ebola virus disease--first experience with lectin affinity plasmapheresis.

PubMed

Büttner, Stefan; Koch, Benjamin; Dolnik, Olga; Eickmann, Markus; Freiwald, Tilo; Rudolf, Sarah; Engel, Jürgen; Becker, Stephan; Ronco, Claudio; Geiger, Helmut

2014-01-01

Therapeutic options for Ebola virus disease (EVD) are currently limited to (1) best supportive care, and (2) evolving virus-specific therapies, resulting from decades of analyzing one of the world's deadliest diseases. Supportive care ranges from oral or intravenous rehydration therapy and anti-emetics in developing countries to much more extensive life-support interventions in resource-rich countries. Current EVD-specific therapies attempt to either interfere with the earliest steps of viral replication or to elicit a strong immune response against the virus. An entirely new approach is the extracorporeal elimination of viruses and viral glycoproteins by lectin affinity plasmapheresis. Herein, we report for the first time the successful and safe use of lectin affinity plasmapheresis in a patient with severe Ebola virus disease. © 2015 S. Karger AG, Basel.

Identification and assessment of COPD exacerbations.

PubMed

Oliveira, A S; Munhá, J; Bugalho, A; Guimarães, M; Reis, G; Marques, A

2017-12-24

Chronic Obstructive Pulmonary Disease (COPD) exacerbations play a central role in the disease natural history of the disease, affecting its overall severity, decreasing pulmonary function, worsening underlying co-morbidities, impairing quality of life (QoL) and leading to severe morbidity and mortality. Therefore, identification and correct assessment of COPD exacerbations is paramount, given it will strongly influence therapy success. For the identification of exacerbations, several questionnaires exist, with varying degrees of complexity. However, most questionnaires remain of limited clinical utility, and symptom scales seem to be more useful in clinical practice. In the assessment of exacerbations, the type and degree of severity should be ascertained in order to define the management setting and optimize treatment options. Still, a consensual and universal classification system to assess the severity and type of an exacerbation is lacking, and there are no established criteria for less severely ill patients not requiring hospital assessment. This might lead to under-reporting of minor to moderate exacerbations, which has an impact on patients' health status. There is a clear unmet need to develop clinically useful questionnaires and a comprehensive system to evaluate the severity of exacerbations that can be used in all settings, from primary health care to general hospitals. Copyright © 2017. Published by Elsevier España, S.L.U.

Pulmonary manifestations of rheumatologic diseases.

PubMed

Cidon, Michal; Bansal, Manvi; Hartl, Dominik

2017-06-01

The present review intends to provide an overview of the diversity and complexity of pulmonary manifestations of rheumatologic diseases and gaps in knowledge to effectively manage them. Diffuse lung disease in children with rheumatologic diseases represents a heterogeneous group of autoimmune disorders. Despite their significant morbidity and mortality, we have limited understanding about their pathogenesis. Here, we provide an overview of the pathophysiology and current management approach of these disorders, highlighting tools which assist with diagnosis, risk stratification and therapy. In this context, we address the need to develop a standardized approach to diagnose at-risk patients with rheumatologic disease and to predict their progression and the need to develop robust studies which evaluate the factors and interventions that influence pulmonary disease outcome. Diffuse lung disease in children with rheumatologic diseases represents a heterogeneous group of severe autoimmune disorders. By adopting a collaborative research approach among multicenters to help diagnose, risk stratify, and understand disease progression, effective management decisions can be optimized to improve clinical outcome.

Relation between mast cells concentration and serotonin expression in chagasic megacolon development.

PubMed

Freitas, M A R; Segatto, N; Tischler, N; de Oliveira, E C; Brehmer, A; da Silveira, A B M

2017-03-01

Chagas' disease is still reaching about 10 million people in the world. In South America, one of the most severe forms of this disease is the megacolon, characterized by severe constipation, dilated sigmoid colon and rectum and severe malnutrition. Previous data suggested that mast cells and serotonin (5-hydroxytryptamine [5-HT]) expression could be involved in intestinal homeostasis control, avoiding the chagasic megacolon development. The aim at this study was to characterize the presence of mast cells and expression of serotonin in chagasic patients with and without megacolon and evaluate the relation between mast cells, serotonin and megacolon development. Our results demonstrated that patients without megacolon feature a large amount of serotonin and few mast cells, while patients with megacolon feature low serotonin expression and a lot of mast cells. We believe that serotonin may be involved in the inflammatory process control, triggered by mast cells, and the presence of this substance in large quantities of the intestine could represent a mechanism of megacolon prevention. © 2017 John Wiley & Sons Ltd.

Models of acute and chronic pancreatitis.

PubMed

Lerch, Markus M; Gorelick, Fred S

2013-06-01

Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Follow-up study of children with cerebral coordination disturbance (CCD, Vojta).

PubMed

Imamura, S; Sakuma, K; Takahashi, T

1983-01-01

713 children (from newborn to 12-month-old) with delayed motor development were carefully examined and classified into normal, very light cerebral coordination disturbance (CCD, Vojta), light CCD, moderate CCD, severe CCD, suspected cerebral palsy (CP) and other diseases at their first visit, and were followed up carefully. Finally, 89.0% of very light CCD, 71.4% of light CCD, 56.0% of moderate CCD and 30.0% of severe CCD developed into normal. 59.5% of moderate CCD and 45.5% of severe CCD among children who were given Vojta's physiotherapy developed into normal. The classification of cases with delayed motor development into very light, light, moderate and severe CCD based on the extent of abnormality in their postural reflexes is useful and well correlated with their prognosis. Treatment by Vojta's method seems to be efficient and helpful for young children with delayed motor development.

Ebola vaccine and treatment.

PubMed

Takada, Ayato

2015-01-01

Filoviruses (Ebola and Marburg viruses) cause severe hemorrhagic fever in humans and nonhuman primates. No effective prophylaxis or treatment for filovirus diseases is yet commercially available. The recent outbreak of Ebola virus disease in West Africa has accelerated efforts to develop anti-Ebola virus prophylaxis and treatment, and unapproved drugs were indeed used for the treatment of patients during the outbreak. This article reviews previous researches and the latest topics on vaccine and therapy for Ebola virus disease.

Adaptive pathway development for Fabry disease: a clinical approach.

PubMed

Schuller, Yvonne; Arends, Maarten; Körver, Simon; Langeveld, Mirjam; Hollak, Carla E M

2018-06-01

Fabry disease (FD) is a rare X-chromosome-linked lysosomal storage disorder. Although initial expectations of enzyme replacement therapy (ERT) were high, it is now clear that real-world effectiveness is disappointing and evidence gathering has been inadequate. In retrospect, development of ERT for FD had several shortcomings. Little convincing evidence on the effectiveness existed at time of authorization. Also, post-marketing evaluation failed to generate sufficient and relevant data for adequate evaluation on effectiveness. Adaptive pathways might have benefitted ERT development by: (i) involving healthcare professionals, patients, health technology assessment bodies and payers in the development process; (ii) iterative development, starting with initial authorization in classical males; (iii) a clear real-world data collection plan; (iv) an independent disease registry; and (v) prescription control. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Early Detection of Chronic Obstructive Pulmonary Disease in Apparently Healthy Attendants of Tertiary Care Hospital and Assessment of its Severity.

PubMed

Zubair, Tahira; Abbassi, Amanullah; Khan, Osama Ahsan

2017-05-01

Early detection of Chronic Obstructive Pulmonary Disease in apparently healthy attendants of tertiary care hospital and assessment of its severity. Cross-sectional, observational study. Study was conducted from January 2015 to July 2015 at Dow University Hospital, Ojha campus. Ascreening method was designed for apparently healthy individuals including attendants of patients, hospital staff, faculty and students, belonging to age group 18-60 years after excluding severe obesity and already diagnosed respiratory and cardiovascular diseases by means of history. Each participant performed pulmonary function tests via spirometer after filling a questionnaire based on various risk factors and symptoms of chronic obstructive pulmonary disease (COPD). Data was entered and analysed by SPSS-20. Out of the 517 participants, 122 (23.6%) were found to have COPD diagnosed by means of spirometry. Out of these, 23 (4.4%) had COPD stage I, 42 (8.1%) had COPD II, 34 (6.6%) had COPD III, and 23 (4.4%) had COPD IV. Exposure to smoking, wooden stoves, pesticides, biomass fuel, aerosol sprays, gas grill and vehicle exhaust were found to be statistically significant factors in relation to development of COPD. Apparently healthy individuals may have underlying COPD and active screening by means of spirometry plays vital role in early detection of COPD. Smoking and exposure to certain hazardous environmental pollutants are responsible for the development and progression of COPD.

Biologics that inhibit the Th17 pathway and related cytokines to treat inflammatory disorders.

PubMed

Balato, Anna; Scala, Emanuele; Balato, Nicola; Caiazzo, Giuseppina; Di Caprio, Roberta; Monfrecola, Giuseppe; Raimondo, Annunziata; Lembo, Serena; Ayala, Fabio

2017-11-01

Advances in the understanding of TNF-α and IL-17 synergistic functions have recently led to the concept that patients who do not respond or who respond inadequately to TNF-α inhibitors may have IL-17-driven diseases, opening up the way for a new class of therapeutic development: Th17-inhibitors. Areas covered: In this review, the authors discuss the central role that the IL-23/Th17 axis plays in the pathogenesis of several inflammatory diseases, such as psoriasis, highlighting its position as a relevant therapeutic target. In particular, the authors start by giving a brief historical excursus on biologic agent development up until the success of TNF-α inhibitors, and continue with an overview of IL12/23 pathway inhibition. Next, they describe Th17 cell biology, focusing on the role of IL-17 in host defense and in human immune-inflammatory diseases, discussing the use and side effects of IL-17 inhibitors. Expert opinion: The IL-23/Th17 signaling pathway plays a central role in the pathogenesis of several inflammatory diseases, such as psoriasis. Recent data has demonstrated that biologics neutralizing IL-17 (ixekizumab, secukinumab) or its receptor (brodalumab) are highly effective with a positive safety profile in treating moderate to severe psoriasis, offering new treatment possibilities, especially for patients who do not respond adequately to anti-TNF-α therapies.

Pathway mapping and development of disease-specific biomarkers: protein-based network biomarkers

PubMed Central

Chen, Hao; Zhu, Zhitu; Zhu, Yichun; Wang, Jian; Mei, Yunqing; Cheng, Yunfeng

2015-01-01

It is known that a disease is rarely a consequence of an abnormality of a single gene, but reflects the interactions of various processes in a complex network. Annotated molecular networks offer new opportunities to understand diseases within a systems biology framework and provide an excellent substrate for network-based identification of biomarkers. The network biomarkers and dynamic network biomarkers (DNBs) represent new types of biomarkers with protein–protein or gene–gene interactions that can be monitored and evaluated at different stages and time-points during development of disease. Clinical bioinformatics as a new way to combine clinical measurements and signs with human tissue-generated bioinformatics is crucial to translate biomarkers into clinical application, validate the disease specificity, and understand the role of biomarkers in clinical settings. In this article, the recent advances and developments on network biomarkers and DNBs are comprehensively reviewed. How network biomarkers help a better understanding of molecular mechanism of diseases, the advantages and constraints of network biomarkers for clinical application, clinical bioinformatics as a bridge to the development of diseases-specific, stage-specific, severity-specific and therapy predictive biomarkers, and the potentials of network biomarkers are also discussed. PMID:25560835

Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.

PubMed

Li, Rui; Sun, Le; Fang, Ai; Li, Peng; Wu, Qian; Wang, Xiaoqun

2017-11-01

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

Microbiota and Metatranscriptome Changes Accompanying the Onset of Gingivitis

PubMed Central

2018-01-01

ABSTRACT Over half of adults experience gingivitis, a mild yet treatable form of periodontal disease caused by the overgrowth of oral microbes. Left untreated, gingivitis can progress to a more severe and irreversible disease, most commonly chronic periodontitis. While periodontal diseases are associated with a shift in the oral microbiota composition, it remains unclear how this shift impacts microbiota function early in disease progression. Here, we analyzed the transition from health to gingivitis through both 16S v4-v5 rRNA amplicon and metatranscriptome sequencing of subgingival plaque samples from individuals undergoing an experimental gingivitis treatment. Beta-diversity analysis of 16S rRNA reveals that samples cluster based on disease severity and patient but not by oral hygiene status. Significant shifts in the abundance of several genera occurred during disease transition, suggesting a dysbiosis due to development of gingivitis. Comparing taxonomic abundance with transcriptomic activity revealed concordance of bacterial diversity composition between the two quantification assays in samples originating from both healthy and diseased teeth. Metatranscriptome sequencing analysis indicates that during the early stages of transition to gingivitis, a number of virulence-related transcripts were significantly differentially expressed in individual and across pooled patient samples. Upregulated genes include those involved in proteolytic and nucleolytic processes, while expression levels of those involved in surface structure assembly and other general virulence functions leading to colonization or adaptation within the host are more dynamic. These findings help characterize the transition from health to periodontal disease and identify genes associated with early disease. PMID:29666288

Vertebral degenerative disc disease severity evaluation using random forest classification

NASA Astrophysics Data System (ADS)

Munoz, Hector E.; Yao, Jianhua; Burns, Joseph E.; Pham, Yasuyuki; Stieger, James; Summers, Ronald M.

2014-03-01

Degenerative disc disease (DDD) develops in the spine as vertebral discs degenerate and osseous excrescences or outgrowths naturally form to restabilize unstable segments of the spine. These osseous excrescences, or osteophytes, may progress or stabilize in size as the spine reaches a new equilibrium point. We have previously created a CAD system that detects DDD. This paper presents a new system to determine the severity of DDD of individual vertebral levels. This will be useful to monitor the progress of developing DDD, as rapid growth may indicate that there is a greater stabilization problem that should be addressed. The existing DDD CAD system extracts the spine from CT images and segments the cortical shell of individual levels with a dual-surface model. The cortical shell is unwrapped, and is analyzed to detect the hyperdense regions of DDD. Three radiologists scored the severity of DDD of each disc space of 46 CT scans. Radiologists' scores and features generated from CAD detections were used to train a random forest classifier. The classifier then assessed the severity of DDD at each vertebral disc level. The agreement between the computer severity score and the average radiologist's score had a quadratic weighted Cohen's kappa of 0.64.

Programming of endocrine mechanisms of cardiovascular control and growth.

PubMed

Green, L R

2001-01-01

Several epidemiologic studies have linked size at birth to health in adult life. One school of thought centers on the part that periconceptual or intrauterine events play in this relationship. The idea is that an event, or several events, during critical periods of development can program, or permanently alter, fetal physiology resulting in altered size at birth and subsequent adult disease, including that of the cardiovascular system. Maternal diet or body composition at the time of conception can influence placental development and subsequent transfer of nutrients and substrates to the fetus. Alterations to the maternal diet or body composition throughout gestation are then seen as challenges that are superimposed on this backdrop of periconceptual events. One task is to find an animal model that replicates the major features of the epidemiologic data: for adult cardiovascular disease this would be altered fetal size and the development of postnatal hypertension. In addition, a critical issue is to investigate the mechanisms underlying this Fetal Origins of Adult Disease hypothesis. The multiple mechanisms that constitute fetal cardiovascular responses to hypoxia in late gestation at neuronal, endocrine, and local tissue levels have been studied extensively, and there is evidence from several different experimental paradigms that these control mechanisms can be programmed by intrauterine challenges. This review synthesizes the current knowledge in this area and considers how the programming of cardiovascular control relates to fetal growth.

Toxin-Induced Experimental Models of Learning and Memory Impairment

PubMed Central

More, Sandeep Vasant; Kumar, Hemant; Cho, Duk-Yeon; Yun, Yo-Sep; Choi, Dong-Kug

2016-01-01

Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson’s disease dementia and Alzheimer’s disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders. PMID:27598124

Toxin-Induced Experimental Models of Learning and Memory Impairment.

PubMed

More, Sandeep Vasant; Kumar, Hemant; Cho, Duk-Yeon; Yun, Yo-Sep; Choi, Dong-Kug

2016-09-01

Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson's disease dementia and Alzheimer's disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders.

Ideotype Development in Southern Pines: Rationale and Strategies for Overcoming Scale-Related Obstacles

Treesearch

Timothy A. Martin; Kurt H. Johnsen; Timothy L. White

2001-01-01

Indirect genetic selection for early growth and disease resistance of southern pines has proven remarkably successful over the past several decades. However, several benefits could be derived for southern pine breeding programs by incorporating ideotypes, conceptual models which explicitly describe plant phenotypic characteristics that are hypothesized to produce...

Development of a Rift Valley fever virus viremia challenge model in sheep and goats

USDA-ARS?s Scientific Manuscript database

Rift valley fever virus (RVFV), a member of the family Bunyaviridae, causes severe to fatal disease in newborn ruminants, as well as abortions in pregnant animals; both preventable by vaccination. Availability of a challenge model is a pre-requisite for vaccine efficacy trials. Several modes of ino...

Severity of Chagasic Cardiomyopathy Is Associated With Response To A Novel Rapid Diagnostic Test For Trypanosoma cruzi TcII/V/VI.

PubMed

Bhattacharyya, Tapan; Messenger, Louisa A; Bern, Caryn; Mertens, Pascal; Gilleman, Quentin; Zeippen, Nicolas; Bremer Hinckel, Bruno C; Murphy, Niamh; Gilman, Robert H; Miles, Michael A

2018-02-09

Trypanosoma cruzi causes Chagas disease in the Americas. Outcome of infection ranges from lifelong asymptomatic status to severe disease. Understanding how history of T. cruzi lineage (TcI-TcVI) infection relates to clinical prognosis is challenging. We previously described peptide-based lineage-specific ELISA with Trypomastigote Small Surface Antigen (TSSA). A novel rapid diagnostic test (Chagas Sero K-SeT) incorporating a peptide corresponding to the TSSA-II/V/VI common epitope was developed, and validated by comparison with ELISA. Patients from Bolivia and Peru were then tested by Chagas Sero K-SeT, including individuals with varying cardiac pathology, and matched mothers and neonates. Chagas Sero K-SeT and ELISAs, with a Bolivian subset of cardiac patients, mothers and neonates, were in accord. In adult chronic infections (n = 121), comparison of severity class A (no evidence of Chagas cardiomyopathy) against classes B (ECG suggestive of Chagas cardiomyopathy) and C/D (moderate/severe Chagas cardiomyopathy) revealed statistically significant increase in Chagas Sero K-SeT reactivity with increasing severity (Chi Square for trend 7.39; p = 0.007). In Peru, where TcII/V/VI lineages are rarely reported, Chagas Sero K SeT detected sporadic infections. We develop a novel, low-cost, point-of-care, rapid test and demonstrate that it can replace ELISA for identification of lineage-specific TSSA II/V/VI IgG. Most importantly, we show that response to the TSSA II/V/VI epitope in this RDT is associated with severity of Chagas cardiomyopathy, and thus may have prognostic value. Repeated challenge with T. cruzi infection may both exacerbate disease progression and boost the immune response to the TSSApep-II/V/VI epitope. © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

The drug and vaccine landscape for neglected diseases (2000-11): a systematic assessment.

PubMed

Pedrique, Belen; Strub-Wourgaft, Nathalie; Some, Claudette; Olliaro, Piero; Trouiller, Patrice; Ford, Nathan; Pécoul, Bernard; Bradol, Jean-Hervé

2013-12-01

In 1975-99, only 1·1% of new therapeutic products had been developed for neglected diseases. Since then, several public and private initiatives have attempted to mitigate this imbalance. We analysed the research and development pipeline of drugs and vaccines for neglected diseases from 2000 to 2011. We searched databases of drug regulatory authorities, WHO, and clinical trial registries for entries made between Jan 1, 2000, and Dec 31, 2011. We defined neglected diseases as malaria, tuberculosis, diarrhoeal diseases, neglected tropical diseases (NTDs; WHO definition), and other diseases of poverty according to common definitions. Of the 850 new therapeutic products registered in 2000-11, 37 (4%) were indicated for neglected diseases, comprising 25 products with a new indication or formulation and eight vaccines or biological products. Only four new chemical entities were approved for neglected diseases (three for malaria, one for diarrhoeal disease), accounting for 1% of the 336 new chemical entities approved during the study period. Of 148,445 clinical trials registered in Dec 31, 2011, only 2016 (1%) were for neglected diseases. Our findings show a persistent insufficiency in drug and vaccine development for neglected diseases. Nevertheless, these and other data show a slight improvement during the past 12 years in new therapeutics development and registration. However, for many neglected diseases, new therapeutic products urgently need to be developed and delivered to improve control and potentially achieve elimination. None. Copyright © 2013 Pedrique et al. Open Access article distributed under the terms of CC BY-NC-SA. Published by .. All rights reserved.

[Severity assessment strategies based on administrative data using stroke as an example].

PubMed

Schubert, Ingrid; Hammer, Antje; Köster, Ingrid

2017-10-01

Information on disease severity is relevant for many studies with claims data in health service research, but only limited information is available in routine data. Stroke serves as an example to analyse whether the combination of different information in claims data can provide insight into the severity of a disease. As a first step, a literature search was conducted. Strategies to assess the severity of a disease by means of routine data were examined with regard to approval and applicability to German sickness fund data. In order to apply and extend the identified procedures, the statutory health insurance sample AOK Hessen/KV Hessen (VSH) served as data source. It is an 18.75 % random sample of persons insured by the AOK Hessen, with 2013 being the most recent year. Stroke patients were identified by the ICD-10 GM code I63 and I64. Patients with said diagnoses being coded as a hospital discharge diagnosis in 2012 were included due to an acute event in 2012 (n=944). The follow-up time was one year. Ten studies covering seven different methods to assess stroke severity were identified. Codes for coma (4.2 % of stroke patients in the SHI sample) as well as coma and/or the application of a PEG tube (9.8 % of the stroke patients) were applied as a proxy for disease severity of acute cases. Taking age, sex and comorbidity into consideration, patients in a coma show a significantly increased risk of mortality compared to those without coma. Three operationalisations were chosen as possible proxies for disease severity of stroke in the further course of disease: i) sequelae (hemiplegia, neurological neglect), ii) duration of the index inpatient stay, and iii) nursing care/ care level 3 for the first time after stroke. The latter proxy has the highest explanatory value for SHI costs. The studies identified use many variables mainly based on hospital information in order to describe disease severity. With the exception of coma, these proxies were neither validated nor did the authors provide more detailed grounds for their use. An identified score for stroke severity could not be applied to SHI data. To develop a comparable score requires a linkage of clinical and administrative data. Since routine data include information from all sectors of care, it should be explored whether these data (for example, the patients' care needs) are suitable to assess disease severity. For validation, separate databases and, optimally, primary patient data are necessary. Copyright © 2017. Published by Elsevier GmbH.

Intestinal Pathogenic Escherichia coli: Insights for Vaccine Development

PubMed Central

Rojas-Lopez, Maricarmen; Monterio, Ricardo; Pizza, Mariagrazia; Desvaux, Mickaël; Rosini, Roberto

2018-01-01

Diarrheal diseases are one of the major causes of mortality among children under five years old and intestinal pathogenic Escherichia coli (InPEC) plays a role as one of the large causative groups of these infections worldwide. InPECs contribute significantly to the burden of intestinal diseases, which are a critical issue in low- and middle-income countries (Asia, Africa and Latin America). Intestinal pathotypes such as enteropathogenic E. coli (EPEC) and enterotoxigenic E. coli (ETEC) are mainly endemic in developing countries, while ETEC strains are the major cause of diarrhea in travelers to these countries. On the other hand, enterohemorrhagic E. coli (EHEC) are the cause of large outbreaks around the world, mainly affecting developed countries and responsible for not only diarrheal disease but also severe clinical complications like hemorrhagic colitis and hemolytic uremic syndrome (HUS). Overall, the emergence of antibiotic resistant strains, the annual cost increase in the health care system, the high incidence of traveler diarrhea and the increased number of HUS episodes have raised the need for effective preventive treatments. Although the use of antibiotics is still important in treating such infections, non-antibiotic strategies are either a crucial option to limit the increase in antibiotic resistant strains or absolutely necessary for diseases such as those caused by EHEC infections, for which antibiotic therapies are not recommended. Among non-antibiotic therapies, vaccine development is a strategy of choice but, to date, there is no effective licensed vaccine against InPEC infections. For several years, there has been a sustained effort to identify efficacious vaccine candidates able to reduce the burden of diarrheal disease. The aim of this review is to summarize recent milestones and insights in vaccine development against InPECs. PMID:29615989

Characterization of a spontaneous disease of white leghorn chickens resembling progressive systemic sclerosis (scleroderma)

PubMed Central

1981-01-01

University of California, Davis (UCD) line 200 White Leghorn Chickens spontaneously develop a syndrome that has many analogous features to human progressive systemic sclerosis. This syndrome is characterized by progressive involution of comb, dermal fibrosis, and distal polyarthritis. These three features occur within 6 wk after hatching, and are accompanied by a 40% mortality as a result of vaso-occlusive disease, with development of secondary infection of peripheral gangrenous lesions. Birds that survive greater than 2 mo after hatching progressively develop fibrosis of the esophagous and mononuclear infiltration of heart and kidney, with prominent occlusion of small and medium sized blood vessels. In addition, line 200 chickens develop rheumatoid factors, antinuclear antibodies, and antibodies to collagen, but do not have antibodies to thymocytes, DNA, or extractable nuclear antigens. Moreover, antinuclear antibodies when studied using HEp-2 cells as substrate demonstrate predominantly a speckled pattern. This syndrome of line 200 chickens is not detectable in F1 crosses to several UCD inbred lines. F1 X parental line BC1 backcrosses have an approximately 50% incidence of disease, suggesting that this syndrome is inherited as autosomal recessive. However, only 4% of F2 generation birds show abnormal symptoms, suggesting the presence of modifying genes. There is no appearance of IgG deposition, as determined by immunofluorescence, in either skin, blood vessels, esophagus, or heart. However, approximately 20% of chickens have a glomerulonephritis; this feature appears to be a terminal event and does not appear clinically significant. Although this syndrome of line 200 chickens has several features that are in sharp distinction to human scleroderma, the presence of common immunologic and pathologic denominators suggest that this spontaneous disease may be an appropriate model to develop a better understanding of autoimmune connective tissue diseases. PMID:7252423

Commentary: A Historical Review of Centers for Disease Control and Prevention Antiviral Treatment and Postexposure Chemoprophylaxis Guidance for Human Infections With Novel Influenza A Viruses Associated With Severe Human Disease.

PubMed

Havers, Fiona P; Campbell, Angela P; Uyeki, Timothy M; Fry, Alicia M

2017-09-15

Human infections with novel influenza A viruses are of global public health concern, and antiviral medications have a potentially important role in treatment and prevention of human illness. Initial guidance was developed by the U.S. Centers for Disease Control and Prevention after the emergence of human infections with avian influenza A(H5N1) and has evolved over time, with identification of influenza A(H7N9) virus infections in humans, as well as detection of avian influenza viruses in birds in the United States. This commentary describes the historical context and current guidance for the use of influenza antiviral medications for treatment and post-exposure chemoprophylaxis of human infections with novel influenza A viruses associated with severe human illness, or with the potential to cause severe human disease, and provides the scientific rationale behind current recommendations. Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease.

PubMed

Douglas, Madeline G; Kocher, Jacob F; Scobey, Trevor; Baric, Ralph S; Cockrell, Adam S

2018-04-01

We recently established a mouse model (288-330 +/+ ) that developed acute respiratory disease resembling human pathology following infection with a high dose (5 × 10 6 PFU) of mouse-adapted MERS-CoV (icMERSma1). Although this high dose conferred fatal respiratory disease in mice, achieving similar pathology at lower viral doses may more closely reflect naturally acquired infections. Through continued adaptive evolution of icMERSma1 we generated a novel mouse-adapted MERS-CoV (maM35c4) capable of achieving severe respiratory disease at doses between 10 3 and 10 5 PFU. Novel mutations were identified in the maM35c4 genome that may be responsible for eliciting etiologies of acute respiratory distress syndrome at 10-1000 fold lower viral doses. Importantly, comparative genetics of the two mouse-adapted MERS strains allowed us to identify specific mutations that remained fixed through an additional 20 cycles of adaptive evolution. Our data indicate that the extent of MERS-CoV adaptation determines the minimal infectious dose required to achieve severe respiratory disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-term cognitive follow-up in children treated for Maroteaux-Lamy syndrome.

PubMed

Ebbink, Berendine J; Brands, Marion M G; van den Hout, Johanna M P; Lequin, Maarten H; Coebergh van den Braak, Robert R J; van de Weitgraven, Rianne L; Plug, Iris; Aarsen, Femke K; van der Ploeg, Ans T

2016-03-01

It remains unclear to what extent the brain is affected by Maroteaux-Lamy syndrome (MPS VI), a progressive lysosomal storage disorder. While enzyme replacement therapy (ERT) elicits positive effects, the drug cannot cross the blood-brain barrier. We therefore studied cognitive development and brain abnormalities in the Dutch MPS VI patient population treated with ERT. In a series of 11 children with MPS VI (age 2 to 20 years), we assessed cognitive functioning and brain magnetic resonance imaging prospectively at the start of ERT and at regular times thereafter up to 4.8 years. We also assessed the children's clinical characteristics, their siblings' cognitive development, and their parents' educational levels. The patients' intelligence scores ranged from normal to mentally delayed (range test scores 52-131). In 90%, their scores remained fairly stable during follow-up, generally lying in the same range as their siblings' test scores (median for patients = 104, median for siblings = 88) and comparing well with the parental educational levels. Native-speaking patients had higher intelligence test scores than non-native-speaking patients. Two patients, both with high baseline glycosaminoglycan levels in their urine and severe mutations in the arylsulfatase B gene, scored clearly lower than expected. Patients with pY210C performed best. Brain abnormalities were aspecific, occurring more in patients with severe symptoms. Our study shows that cognitive development in MPS VI patients is determined not only by familial and social-background factors, but, in patients with a severe form of the disease, also by the disease itself. Therefore in patients with severe disease presentation cognition should be monitored carefully.

Cynomolgus Macaque as an Animal Model for Severe Acute Respiratory Syndrome

PubMed Central

Lawler, James V; Endy, Timothy P; Hensley, Lisa E; Garrison, Aura; Fritz, Elizabeth A; Lesar, May; Baric, Ralph S; Kulesh, David A; Norwood, David A; Wasieloski, Leonard P; Ulrich, Melanie P; Slezak, Tom R; Vitalis, Elizabeth; Huggins, John W; Jahrling, Peter B; Paragas, Jason

2006-01-01

Background The emergence of severe acute respiratory syndrome (SARS) in 2002 and 2003 affected global health and caused major economic disruption. Adequate animal models are required to study the underlying pathogenesis of SARS-associated coronavirus (SARS-CoV) infection and to develop effective vaccines and therapeutics. We report the first findings of measurable clinical disease in nonhuman primates (NHPs) infected with SARS-CoV. Methods and Findings In order to characterize clinically relevant parameters of SARS-CoV infection in NHPs, we infected cynomolgus macaques with SARS-CoV in three groups: Group I was infected in the nares and bronchus, group II in the nares and conjunctiva, and group III intravenously. Nonhuman primates in groups I and II developed mild to moderate symptomatic illness. All NHPs demonstrated evidence of viral replication and developed neutralizing antibodies. Chest radiographs from several animals in groups I and II revealed unifocal or multifocal pneumonia that peaked between days 8 and 10 postinfection. Clinical laboratory tests were not significantly changed. Overall, inoculation by a mucosal route produced more prominent disease than did intravenous inoculation. Half of the group I animals were infected with a recombinant infectious clone SARS-CoV derived from the SARS-CoV Urbani strain. This infectious clone produced disease indistinguishable from wild-type Urbani strain. Conclusions SARS-CoV infection of cynomolgus macaques did not reproduce the severe illness seen in the majority of adult human cases of SARS; however, our results suggest similarities to the milder syndrome of SARS-CoV infection characteristically seen in young children. PMID:16605302

Identification of cocoa trees combining high yield potential and resistance to diseases in segregating progenies In Ecuador

USDA-ARS?s Scientific Manuscript database

Diseases and low yielding planting material are the main factors limiting production of “fine” or “flavour” cocoa in Ecuador. This makes it necessary to develop modern varieties capable of overcoming these limitations. During the 1960s and 1970s INIAP tested several progenies from selected crosses...

Renovating Alzheimer's: "Constructive" Reflections on the New Clinical and Research Diagnostic Guidelines

ERIC Educational Resources Information Center

George, Daniel R.; Qualls, Sara H.; Camp, Cameron J.; Whitehouse, Peter J.

2013-01-01

The development of disease concepts for conditions such as Alzheimer's disease (AD) is an ongoing social process that evolves over time. The biomedical paradigm about AD that has informed our culture's understanding of brain aging for the past several decades is currently undergoing a major and timely renovation in the early 21st century. This…

Bioconjugated gold nanoparticles accelerate the growth of new blood vessels through redox signaling.

PubMed

Nethi, Susheel Kumar; Mukherjee, Sudip; Veeriah, Vimal; Barui, Ayan Kumar; Chatterjee, Suvro; Patra, Chitta Ranjan

2014-11-28

We have designed and developed novel pro-angiogenic bio-synthesized gold nanoconjugates (b-Au-HP) that make new blood vessels, as observed by several in vitro and in vivo assays, suggesting their future potential applications in alternative treatment strategies for wound healing, cardiovascular diseases (CVD) and ischemic diseases using a nanomedicine approach.

Development of Phytophthora fruit rot caused by Phytophthora capsici on resistant and susceptible watermelon fruit of different ages

USDA-ARS?s Scientific Manuscript database

Watermelon is an important crop grown in 44 states in the United States. Phytophthora fruit rot caused by Phytophthora capsici is a serious disease in the southeastern U.S., where over 50% of the watermelons are produced. The disease has resulted in severe losses to watermelon growers, especially in...