[Functional dependence and chronic disease in older Mexicans].

PubMed

Barrantes-Monge, Melba; García-Mayo, Emilio José; Gutiérrez-Robledo, Luis Miguel; Miguel-Jaimes, Alejandro

2007-01-01

The aim of this study is to determine the prevalence of functional dependence in older Mexicans and associated chronic conditions. The study was conducted between June and December 2004 in the Geriatric Department of the Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubiran, Mexico City. The data for the variables were obtained from the information in the National Study of Health and Aging in Mexico survey (ENASEM). The survey was based on the law for statistical and geographic information,Chapter V, Article 38. A total of 4,872 subjects from the national survey of aging and health in Mexico were asked about their need for help in basic activities of daily living (BADL) and instrumental activities of daily living (IADL). Presence of disease was obtained through self-reporting. Prevalence of functional dependence was 24 and 23% for BADL and IADL, respectively. Joint disease, cerebrovascular disease, cognitive impairment and depression were associated with dependency in BADL and IADL. The prevalence of functional dependence is high among Mexicans over 65 years old. This study shows the chronic conditions that are closely associated with functional dependence and provides a perspective in order to develop preventative measures.

Disruption of Fetal Hormonal Programming (Prenatal Stress) Implicates Shared Risk for Sex Differences in Depression and Cardiovascular Disease

PubMed Central

Goldstein, JM; Handa, RJ; Tobet, SA

2014-01-01

Comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) represents the fourth leading cause of morbidity and mortality worldwide, and women have a two times greater risk than men. Thus understanding the pathophysiology has widespread implications for attenuation and prevention of disease burden. We suggest that sex-dependent MDD-CVD comorbidity may result from alterations in fetal programming consequent to the prenatal maternal environments that produce excess glucocorticoids, which then drive sex-dependent developmental alterations of the fetal hypothalamic-pituitary-adrenal (HPA) axis circuitry impacting mood, stress regulation, autonomic nervous system (ANS), and the vasculature in adulthood. Evidence is consistent with the hypothesis that disruptions of pathways associated with gamma aminobutyric acid (GABA) in neuronal and vascular development and growth factors have critical roles in key developmental periods and adult responses to injury in heart and brain. Understanding the potential fetal origins of these sex differences will contribute to development of novel sex-dependent therapeutics. PMID:24355523

Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice.

PubMed

Uribe, Valeria; Wong, Bibiana K Y; Graham, Rona K; Cusack, Corey L; Skotte, Niels H; Pouladi, Mahmoud A; Xie, Yuanyun; Feinberg, Konstantin; Ou, Yimiao; Ouyang, Yingbin; Deng, Yu; Franciosi, Sonia; Bissada, Nagat; Spreeuw, Amanda; Zhang, Weining; Ehrnhoefer, Dagmar E; Vaid, Kuljeet; Miller, Freda D; Deshmukh, Mohanish; Howland, David; Hayden, Michael R

2012-05-01

Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6-/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6-/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD.

Epidemics in Adaptive Social Networks with Temporary Link Deactivation

NASA Astrophysics Data System (ADS)

Tunc, Ilker; Shkarayev, Maxim S.; Shaw, Leah B.

2013-04-01

Disease spread in a society depends on the topology of the network of social contacts. Moreover, individuals may respond to the epidemic by adapting their contacts to reduce the risk of infection, thus changing the network structure and affecting future disease spread. We propose an adaptation mechanism where healthy individuals may choose to temporarily deactivate their contacts with sick individuals, allowing reactivation once both individuals are healthy. We develop a mean-field description of this system and find two distinct regimes: slow network dynamics, where the adaptation mechanism simply reduces the effective number of contacts per individual, and fast network dynamics, where more efficient adaptation reduces the spread of disease by targeting dangerous connections. Analysis of the bifurcation structure is supported by numerical simulations of disease spread on an adaptive network. The system displays a single parameter-dependent stable steady state and non-monotonic dependence of connectivity on link deactivation rate.

Older women's perceptions of independence versus dependence in food-related work.

PubMed

Gustafsson, Kerstin; Andersson, Ingegerd; Andersson, Jenny; Fjellström, Christina; Sidenvall, Birgitta

2003-01-01

This qualitative study aims to explore the cultural meaning of accomplishing food-related work by older women, when disease has diminished their abilities and threatens to make them dependent. Seventy-two women with stroke, rheumatoid arthritis, and Parkinson's disease, as well as women without those diseases, were interviewed. All were living at home. Results showed that older women valued independence and feared dependence when declining ability threatened performance of food-related work. They also had strong beliefs about living a "normal life," managing by oneself as long as possible, and becoming their own masters again. To remain independent, participants used three kinds of strategies: Public Health Service Support, self-managing, and adaptation. Their beliefs about dependence included not becoming a burden, retaining self-determination, and maintaining order in life. Implications for nursing include supporting independent cooking, developing care plans with the care recipient, and demonstrating respect for the women's self-determination.

PRKAR1A mutation causing pituitary-dependent Cushing disease in a patient with Carney complex.

PubMed

Kiefer, Florian W; Winhofer, Yvonne; Iacovazzo, Donato; Korbonits, Márta; Wolfsberger, Stefan; Knosp, Engelbert; Trautinger, Franz; Höftberger, Romana; Krebs, Michael; Luger, Anton; Gessl, Alois

2017-08-01

Carney complex (CNC) is an autosomal dominant condition caused, in most cases, by an inactivating mutation of the PRKAR1A gene, which encodes for the type 1 alpha regulatory subunit of protein kinase A. CNC is characterized by the occurrence of endocrine overactivity, myxomas and typical skin manifestations. Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine disease observed in CNC. Here, we describe the first case of a patient with CNC and adrenocorticotropic hormone (ACTH)-dependent Cushing disease due to a pituitary corticotroph adenoma. Loss-of-heterozygosity analysis of the pituitary tumour revealed loss of the wild-type copy of PRKAR1A , suggesting a role of this gene in the pituitary adenoma development. PRKAR1A loss-of-function mutations can rarely lead to ACTH-secreting pituitary adenomas in CNC patients. Pituitary-dependent disease should be considered in the differential diagnosis of Cushing syndrome in CNC patients. © 2017 European Society of Endocrinology.

[Oxygen-dependent energy deficit as related to the problems of ontogenetic development disorders and human sociobiological adaptation (theoretical and applied aspects)].

PubMed

Ilyukhina, V A; Kataeva, G V; Korotkov, A D; Chernysheva, E M

2015-01-01

The review states and argues theoretical propositions on the pathogenetic role of pre- and perinatal hypoxic-ischemic brain damage in the formation of sustained oxygen-dependent energy deficit underlying in further ontogenesis the following neurobiological abnormalities: a) a decline in the level of health and compensatory-adaptive capacities of the organism, b) disorders of the psycho-speech development and adaptive behavior in children, c) early development of neuropsychic diseases, g) addition of other types of brain energy metabolism (including glucose metabolism) disorders in chronic polyetiologic diseases young and middle-aged individuals. We highlight and theoretically substantiate the integrated physiological parameters of the oxygen-dependent energy deficit types. We address the features of abnormalities in neuroreflectory and neurohumora regulatory mechanisms of the wakefulness level and its vegetative and hemodynamic provision in different types of energy deficit in children with DSMD, ADHD and school maladjustment. The use of the state-of-the-art neuroimaging techniques significantly increased the possibility of the disintegration of regulatory processes and cognitive functions in children with psycho-speech delays and in a wide range of chronic polyetiologic diseases.

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

Water-Related Parasitic Diseases in China

PubMed Central

Lv, Shan; Tian, Li-Guang; Liu, Qin; Qian, Men-Bao; Fu, Qing; Steinmann, Peter; Chen, Jia-Xu; Yang, Guo-Jing; Yang, Kun; Zhou, Xiao-Nong

2013-01-01

Water-related parasitic diseases are directly dependent on water bodies for their spread or as a habitat for indispensable intermediate or final hosts. Along with socioeconomic development and improvement of sanitation, overall prevalence is declining in the China. However, the heterogeneity in economic development and the inequity of access to public services result in considerable burden due to parasitic diseases in certain areas and populations across the country. In this review, we demonstrated three aspects of ten major water-related parasitic diseases, i.e., the biology and pathogenicity, epidemiology and recent advances in research in China. General measures for diseases control and special control strategies are summarized. PMID:23685826

A multivariate test of disease risk reveals conditions leading to disease amplification.

PubMed

Halliday, Fletcher W; Heckman, Robert W; Wilfahrt, Peter A; Mitchell, Charles E

2017-10-25

Theory predicts that increasing biodiversity will dilute the risk of infectious diseases under certain conditions and will amplify disease risk under others. Yet, few empirical studies demonstrate amplification. This contrast may occur because few studies have considered the multivariate nature of disease risk, which includes richness and abundance of parasites with different transmission modes. By combining a multivariate statistical model developed for biodiversity-ecosystem-multifunctionality with an extensive field manipulation of host (plant) richness, composition and resource supply to hosts, we reveal that (i) host richness alone could not explain most changes in disease risk, and (ii) shifting host composition allowed disease amplification, depending on parasite transmission mode. Specifically, as predicted from theory, the effect of host diversity on parasite abundance differed for microbes (more density-dependent transmission) and insects (more frequency-dependent transmission). Host diversity did not influence microbial parasite abundance, but nearly doubled insect parasite abundance, and this amplification effect was attributable to variation in host composition. Parasite richness was reduced by resource addition, but only in species-rich host communities. Overall, this study demonstrates that multiple drivers, related to both host community and parasite characteristics, can influence disease risk. Furthermore, it provides a framework for evaluating multivariate disease risk in other systems. © 2017 The Author(s).

Aldosterone and cardiovascular disease: the heart of the matter

PubMed Central

He, B. Julie; Anderson, Mark E.

2012-01-01

Aldosterone contributes to the endocrine basis of heart failure and studies on cardiac aldosterone signaling have reinforced its value as a therapeutic target. Recent focus has shifted to new roles of aldosterone that appear to depend on co-existing pathologic stimuli, cell type, and disease etiology. This review evaluates recent advances in mechanisms underlying aldosterone-induced cardiac disease and highlights the interplay between aldosterone and Ca2+ and calmodulin dependent protein kinase II, whose hyperactivity during heart failure contributes to disease progression. Increasing evidence implicates aldosterone in diastolic dysfunction, and there is need to develop more targeted therapeutics such as aldosterone synthase inhibitors and molecularly specific anti-oxidants. Despite accumulating knowledge, many questions still persist and will likely dictate areas of future research. PMID:23040074

[Hygienic aspects of the occurrence of ecology-dependent diseases in children and adolescents of the Primorsky Krai].

PubMed

Izmaylova, O A; Kiku, P F; Yarygina, M V; Moreva, V G; Ananev, V Yu; Kosolapov, A B

With the use of the methodology of the system approach there were obtained results of the evaluation of the occurrence of ecology-dependent diseases in children and adolescents in bioclimatic zones of the Primorsky Krai. Analysis of the prevalence of the main classes of ecologically dependent diseases according to the appealability (diseases of the respiratory system, diseases of digestive organs, diseases of blood and blood-forming organs, diseases of the circulatory system, diseases of the skin and subcutaneous tissue, diseases of the genitourinary system, neoplasms, congenital anomalies, infectious diseases) was performed with the use of official statistical report forms No. 12 (ICD-10) over the period of2000-2014. Informational Database of parameters of the environment was represented by the factor modules: 6 - sanitary, and 5-environmental ones). By means of the method of the regression analysis there was established the relationship between environmental factors and the prevalence of ecological-dependent diseases, there were calculated values of the factor loads influencing on the indices of the morbidity rate in children and adolescents. The analysis of morbidity according to classes showed that during the study period, in the total there was a gain in the indicator ecologically dependent morbidity rate in children by 33.3%, in adolescents - by 35.3%. In the children and adolescent population there are prevalent diseases of the respiratory system - 67.3% and 52.45%, respectively; further in children and adolescent groups diseases of the digestive system - 9.45% and 17.08% take place; then in the children cohort are infectious diseases, and in adolescents - diseases of the genitourinary system. The level of ecologically dependent morbidity rate is determined by the complex impact of environmental and hygienic factors, with a predominance of sanitary-hygienic component and related with it parameters of the environment of habitation, such as chemical pollution of urban areas (soil, air, water sources), nevertheless biotropic factors (temperature, humidity, fog, number of days with biologically active solar radiation) make a significant contribution. The revealed various degree of the response of children and adolescents through the prevalence rate level to the exposure of ecological and hygienic factors of environment should be taken into account in the development and carrying out medical-preventive measures.

[Modelling the effect of local climatic variability on dengue transmission in Medellin (Colombia) by means of time series analysis].

PubMed

Rúa-Uribe, Guillermo L; Suárez-Acosta, Carolina; Chauca, José; Ventosilla, Palmira; Almanza, Rita

2013-09-01

Dengue fever is a major impact on public health vector-borne disease, and its transmission is influenced by entomological, sociocultural and economic factors. Additionally, climate variability plays an important role in the transmission dynamics. A large scientific consensus has indicated that the strong association between climatic variables and disease could be used to develop models to explain the incidence of the disease. To develop a model that provides a better understanding of dengue transmission dynamics in Medellin and predicts increases in the incidence of the disease. The incidence of dengue fever was used as dependent variable, and weekly climatic factors (maximum, mean and minimum temperature, relative humidity and precipitation) as independent variables. Expert Modeler was used to develop a model to better explain the behavior of the disease. Climatic variables with significant association to the dependent variable were selected through ARIMA models. The model explains 34% of observed variability. Precipitation was the climatic variable showing statistically significant association with the incidence of dengue fever, but with a 20 weeks delay. In Medellin, the transmission of dengue fever was influenced by climate variability, especially precipitation. The strong association dengue fever/precipitation allowed the construction of a model to help understand dengue transmission dynamics. This information will be useful to develop appropriate and timely strategies for dengue control.

Non-transfusion Dependent Thalassemias: A Developing Country Perspective.

PubMed

Mukherjee, Somnath; Das, Rashmi R; Raghuwanshi, Babita

2015-01-01

Non-transfusion-dependent thalassemias (NTDT) encompass a group of hereditary chronic hemolytic anemia, which, as the name indicates, not require regular blood transfusion for survival. These include β-thalassemia intermedia, hemoglobin E/β-thalassemia, and Hemoglobin H disease (α- thalassemia intermedia). Individuals with structural variant of hemoglobin especially Hemoglobin S and Hemoglobin C associated with "α" or "β" thalassemia in heterozygous condition may also present with similar features of NTDT. NTDT patients are not immune to the development of transfusion unrelated complications in the long run. These hereditary chronic hemolytic anemias are still under-recognized in developing countries like India, where the disease burden might be high causing significant morbidity. The pathophysiologic hallmark that characterizes this group of disorders (ineffective erythropoiesis, hemolysis, chronic anemia) leads to a number of serious complications, similar to transfusion dependent thalassemia. So, timely diagnosis and institution of appropriate preventive/remedial measures as well as education of patient population can help decrease the morbidity to a significant extent. In the present review, focus will be on the pathophysiological mechanisms and available management options of NTDT from a developing country perspective like India.

To what degree does cognitive impairment in Alzheimer's disease predict dependence of patients on caregivers?

PubMed Central

Caro, Jaime; Ward, Alexandra; Ishak, Khajak; Migliaccio-Walle, Kristen; Getsios, Denis; Papadopoulos, George; Torfs, Koen

2002-01-01

Background Patients with Alzheimer's disease experience a progressive loss of cognitive function, and the ability to independently perform activities of daily life. Sometimes a dependent stage is reached quite early in the disease, when caregivers decide that the patients can no longer be left alone safely. This is an important aspect of Alzheimer's for patients, their families, and also health care providers. Understanding the relationship between a patient's current cognitive status and their need for care may assist clinicians when recommending an appropriate management plan. In this study, we investigated the relationship of cognitive function to dependence on caregivers before the patients reach a severe stage of the disease. Methods Data were obtained on 1,289 patients with mild-to-moderate Alzheimer's disease studied in two randomised clinical trials of galantamine (Reminyl®). Cognition was assessed using the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Mini-Mental State Examination (MMSE). Patients were considered dependent if they required >12 hours of supervision each day or had high care needs. The Disability Assessment for Dementia (DAD) scale was also used as a measure of dependence. Disability was predicted directly using MMSE and ADAS-cog and compared to predictions from converted scores. Results The odds ratio of dependence was significantly higher amongst the patients with worse cognitive impairment, adjusting for age, gender and antipsychotic medication use. For example, a 4-point difference in ADAS-cog score was associated with an increase of 17% (95% CI 11–23) in the adjusted odds for >12 hours of supervision, and of 35% (95% CI 28–43) for dependence. Disability predicted directly using actual ADAS-cog and scores converted from MMSE values had close agreement using the models developed. Conclusion In patients with mild-to-moderate Alzheimer's disease, even relatively small degrees of poorer cognitive function increased the risk of losing the ability to live independently. PMID:12184819

MCAT elements and the TEF-1 family of transcription factors in muscle development and disease.

PubMed

Yoshida, Tadashi

2008-01-01

MCAT elements are located in the promoter-enhancer regions of cardiac, smooth, and skeletal muscle-specific genes including cardiac troponin T, beta-myosin heavy chain, smooth muscle alpha-actin, and skeletal alpha-actin, and play a key role in the regulation of these genes during muscle development and disease. The binding factors of MCAT elements are members of the transcriptional enhancer factor-1 (TEF-1) family. However, it has not been fully understood how these transcription factors confer cell-specific expression in muscle, because their expression patterns are relatively broad. Results of recent studies revealed multiple mechanisms whereby TEF-1 family members control MCAT element-dependent muscle-specific gene expression, including posttranslational modifications of TEF-1 family members, the presence of muscle-selective TEF-1 cofactors, and cell-selective control of TEF-1 accessibility to MCAT elements. In addition, of particular interest, recent studies regarding MCAT element-dependent transcription of the myocardin gene and the smooth muscle alpha-actin gene in muscle provide evidence for the transcriptional diversity among distinct cell types and subtypes. This article summarizes the role of MCAT elements and the TEF-1 family of transcription factors in muscle development and disease, and reviews recent progress in our understanding of the transcriptional regulatory mechanisms involved in MCAT element-dependent muscle-specific gene expression.

Non-transfusion-dependent thalassemias

PubMed Central

Musallam, Khaled M.; Rivella, Stefano; Vichinsky, Elliott; Rachmilewitz, Eliezer A.

2013-01-01

Non-transfusion-dependent thalassemias include a variety of phenotypes that, unlike patients with beta (β)-thalassemia major, do not require regular transfusion therapy for survival. The most commonly investigated forms are β-thalassemia intermedia, hemoglobin E/β-thalassemia, and α-thalassemia intermedia (hemoglobin H disease). However, transfusion-independence in such patients is not without side effects. Ineffective erythropoiesis and peripheral hemolysis, the hallmarks of disease process, lead to a variety of subsequent pathophysiologies including iron overload and hypercoagulability that ultimately lead to a number of serious clinical morbidities. Thus, prompt and accurate diagnosis of non-transfusion-dependent thalassemia is essential to ensure early intervention. Although several management options are currently available, the need to develop more novel therapeutics is justified by recent advances in our understanding of the mechanisms of disease. Such efforts require wide international collaboration, especially since non-transfusion-dependent thalassemias are no longer bound to low- and middle-income countries but have spread to large multiethnic cities in Europe and the Americas due to continued migration. PMID:23729725

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

Characterization of a U.S. Sheep Scrapie Isolate with Short Incubation Time

USDA-ARS?s Scientific Manuscript database

Scrapie is a naturally occurring fatal neurodegenerative disease of sheep and goats. Susceptibility to the disease is partly dependent upon the genetic makeup of the host. In a previous study it was shown that sheep intracerebrally inoculated with US scrapie inoculum (No. 13-7) developed terminal di...

[Psychopathology and clinical features of oneiroid-catatonic conditions during endogenous diseases].

PubMed

Alekseeva, A G

2011-01-01

Psychopathology and clinical features of oneiroid-catatonic conditions during endogenous diseases remain a topical problem in modem psychiatry. The author describes psychopathologcal features of oneiroid depending on the form of the affect and presents new data on its relation to peculiarities of the development of attacks.

Role of renal urothelium in the development and progression of kidney disease.

PubMed

Carpenter, Ashley R; McHugh, Kirk M

2017-04-01

The clinical and financial impact of chronic kidney disease (CKD) is significant, while its progression and prognosis is variable and often poor. Studies using the megabladder (mgb -/- ) model of CKD show that renal urothelium plays a key role in modulating early injury responses following the development of congenital obstruction. The aim of this review is to examine the role that urothelium has in normal urinary tract development and pathogenesis. We discuss normal morphology of renal urothelium and then examine the role that uroplakins (Upks) play in its development. Histologic, biochemical, and molecular characterization of Upk1b RFP/RFP mice indicated Upk1b expression is essential for normal urinary tract development, apical plaque/asymmetric membrane unit (AUM) formation, and differentiation and functional integrity of the renal urothelium. Our studies provide the first evidence that Upk1b is directly associated with the development of congenital anomalies of the urinary tract (CAKUT), spontaneous age-dependent hydronephrosis, and dysplastic urothelia. These observations demonstrate the importance of proper urothelial differentiation in normal development and pathogenesis of the urinary tract and provide a unique working model to test the hypothesis that the complex etiology associated with CKD is dependent upon predetermined genetic susceptibilities that establish pathogenic thresholds for disease initiation and progression.

Role of Renal Urothelium in the Development and Progression of Kidney Disease

PubMed Central

Carpenter, Ashley R.; McHugh, Kirk M.

2016-01-01

The clinical and financial impact of chronic kidney disease (CKD) is significant, while the progression and prognosis of CKD is variable and often poor. Studies using the megabladder (mgb−/−) model of CKD have shown that renal urothelium plays a key role in modulating the early injury responses following the development of congenital obstruction. The aim of this review is to examine the role that urothelium has in normal urinary tract development and pathogenesis. We discuss normal morphology of renal urothelium and then examine the role that uroplakins (Upks) play in its development. Histologic, biochemical and molecular characterization of Upk1bRFP/RFP mice indicated Upk1b expression is essential for normal urinary tract development, apical plaque/AUM formation and differentiation and functional integrity of the renal urothelium. Our studies provide the first evidence Upk1b is directly associated with the development of congenital anomalies of the urinary tract (CAKUT), spontaneous age-dependent hydronephrosis and dysplastic urothelia. These observations demonstrate the importance of proper urothelial differentiation in the normal development and pathogenesis of the urinary tract, and provide a unique working model to test the hypothesis that the complex etiology associated with CKD is dependent upon predetermined genetic susceptibilities that establish pathogenic thresholds for disease initiation and progression. PMID:27115886

[Turpentine baths in rehabilitation of patients with chronic obstructive pulmonary disease].

PubMed

Aĭrapetova, N S; Polikanova, E B; Davydova, O B; Gosn, L D; Kulikova, O V; Ksenofontova, I V; Nikoda, N V; Rassulova, M A; Nitchenko, O V; Siziakova, L A; Doronina, Iu V; Derevnina, N A

2007-01-01

We have investigated effects of turpentine baths with white emultion, yellow solution and mixed on the course of inflammation, immunocompetent system, external respiration function, pulmonary cardiohemodynamics, physical performance in patients with chronic obstructive pulmonary disease. We developed differential indications for each bath variant depending on the features of a clinical picture of the disease, comorbid pathology and revealed contraindications to their administration.

Targeting oxidant-dependent mechanisms for the treatment of respiratory diseases and their comorbidities.

PubMed

Thomson, Neil C

2018-06-01

Oxidative stress is implicated in the pathogenesis of respiratory diseases, such as COPD and its comorbidities, asthma, idiopathic pulmonary fibrosis and radiation pneumonitis. Antioxidants drugs, such as small molecule thiols, nuclear erythroid-2 related factor 2 activators and catalytic enzyme mimetics have been developed to target oxidant-dependent mechanisms. The therapeutic effects of antioxidants have been generally disappointing. A small number of antioxidants are approved for clinical use, such as the small molecule thiol N-acetyl-l-cysteine for chronic obstructive pulmonary disease, and in the United States, the superoxide dismutase mimetic AEOL 10150 for severe radiation pneumonitis. The future use of antioxidants for the treatment of chronic respiratory diseases may require a precision medicine approach to identify responsive patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

TNFalpha and IL-10 gene polymorphisms in inflammatory bowel disease. Association of -1082 AA low producer IL-10 genotype with steroid dependency.

PubMed

Castro-Santos, Patricia; Suarez, Ana; López-Rivas, Laureano; Mozo, Lourdes; Gutierrez, Carmen

2006-05-01

An altered production of cytokines underlies inflammatory bowel disease (IBD) susceptibility. Various polymorphisms at the IL-10 and TNFalpha gene promoters control cytokine production levels. The influence of these polymorphisms on susceptibility to ulcerative colitis (UC) and Crohn's disease (CD) and their association with clinical features were analyzed. Genetic polymorphisms of TNFalpha (-308 G/A) and IL-10 (-1082 G/A, -812 C/T, and -592 C/A) were determined using the LightCycler system with hybridization probes matched with one sequence variant. The study population included 99 UC patients, 146 CD patients, and 343 matched controls. We did not find association between TNFalpha or IL-10 gene polymorphisms and UC or CD susceptibility, though a slight influence of -1082*G allele in UC appearance was observed. In a stratified analysis, a highly significant association between the -1082 AA IL-10 genotype and the steroid dependency was observed in IBD (p < 0.0001), contributing both UC (p = 0.004) and CD (p = 0.003) to this association. In contrast, TNFalpha genotypes did not influence steroid dependency in IBD. Further, the contribution of cytokine genotypes and of clinical features to the appearance of steroid-dependent status (dependent variable) was studied by multivariate analysis. The steroid-dependent phenotype correlated in UC with extensive disease (p = 0.010) and with the low producer -1082 AA IL-10 genotype (p = 0.002) and in CD with penetrating disease (p = 0.010), arthritis (p = 0.011), and the -1082 AA IL-10 genotype (p = 0.006). The main conclusion is that carriage of the -1082 AA IL-10 genotype (low producer) is a relevant risk factor for developing steroid-dependent IBD.

[New infectious diseases in Finland--caused by climate change?].

PubMed

Vapalahti, Olli; Ruuhela, Reija; Henttonen, Heikki

2012-01-01

Although the appearance and spreading of most new infectious diseases are likely to be due to globalization or socio-economic changes, the occurrence of tick-, insect- and rodent-borne infections is at least partially dependent on climate variability and change. Climate influences the distribution and life cycle of vectors of arthropod-borne viruses as well as viral evolution and efficacy of transmission. The natural circulation of many pathogens and the development of epidemics are dependent on complex ecological factors, such as biodiversity and predator-prey cycles that in turn are indirectly linked to climate.

Causes of childhood blindness in a developing country and an underdeveloped country.

PubMed

Santos-Bueso, E; Dorronzoro-Ramírez, E; Gegúndez-Fernández, J A; Vinuesa-Silva, J M; Vinuesa-Silva, I; García-Sánchez, J

2015-05-01

The causes of childhood blindness depend on factors such as geographic location or the human development index of the populations under study. The main causes in developed countries are genetic and hereditary diseases, while infectious and contagious diseases, together with nutritional and vitamin deficiencies, are the main causes in underdeveloped countries (UDCs). Study of the causes of blindness among children admitted to a regional centre in Nador, Morocco, and among children in Mekele, Ethiopia. The study was carried out in collaboration with two non-governmental organizations based in Madrid, Spain. First, we worked with Fudación Adelias in June 2010, and with Proyecto Visión in October 2012. The study comprised a total of 27 children in Morocco and 85 in Ethiopia. The average age of the children was 10.92 and 6.94 years, respectively. The main causes of blindness in Morocco were hereditary pathologies (25.92%) and refractive errors (14.82%), although trauma (7.40%) and corneal disease (7.40%) are relevant. Among the children from Ethiopia, corneal disease (27.05%) and trauma (20%) were the main causes of blindness, while congenital and hereditary diseases had a lower prevalence (4.70%). The causes of blindness depend on the human development index of the populations under study. While corneal disease and trauma are the main causes observed in UDCs like Ethiopia, hereditary pathologies and refractive errors are the main causes within the Moroccan population studied. A mixed form can be observed in this country, as the cause of blindness found in developed countries, such as congenital and hereditary pathologies which are present alongside the causes normally found in LDCs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Transcriptional atlas of cardiogenesis maps congenital heart disease interactome.

PubMed

Li, Xing; Martinez-Fernandez, Almudena; Hartjes, Katherine A; Kocher, Jean-Pierre A; Olson, Timothy M; Terzic, Andre; Nelson, Timothy J

2014-07-01

Mammalian heart development is built on highly conserved molecular mechanisms with polygenetic perturbations resulting in a spectrum of congenital heart diseases (CHD). However, knowledge of cardiogenic ontogeny that regulates proper cardiogenesis remains largely based on candidate-gene approaches. Mapping the dynamic transcriptional landscape of cardiogenesis from a genomic perspective is essential to integrate the knowledge of heart development into translational applications that accelerate disease discovery efforts toward mechanistic-based treatment strategies. Herein, we designed a time-course transcriptome analysis to investigate the genome-wide dynamic expression landscape of innate murine cardiogenesis ranging from embryonic stem cells to adult cardiac structures. This comprehensive analysis generated temporal and spatial expression profiles, revealed stage-specific gene functions, and mapped the dynamic transcriptome of cardiogenesis to curated pathways. Reconciling known genetic underpinnings of CHD, we deconstructed a disease-centric dynamic interactome encoded within this cardiogenic atlas to identify stage-specific developmental disturbances clustered on regulation of epithelial-to-mesenchymal transition (EMT), BMP signaling, NF-AT signaling, TGFb-dependent EMT, and Notch signaling. Collectively, this cardiogenic transcriptional landscape defines the time-dependent expression of cardiac ontogeny and prioritizes regulatory networks at the interface between health and disease. Copyright © 2014 the American Physiological Society.

Targeting Interferon Regulatory Factor for Cardiometabolic Diseases: Opportunities and Challenges.

PubMed

Zhang, Yaxing; Zhang, Xiao-Jing; Li, Hongliang

2017-01-01

The pathological activation of innate immune system may contribute to the development of cardiometabolic diseases. The interferon regulatory factor (IRF) family members, which are the major transcription factors in innate immune signaling, are implicated in cardiometabolic diseases. The aim of this review is to summary the current knowledge of the biological functions of IRFs in innate immune responses and immune cell development, and highlight our contemporary understanding of the functions and molecular mechanisms of IRFs in metabolic diseases, cardiovascular remodeling, and stroke. IRFs are the essential regulators of cardiometabolic diseases via immune-dependent and - independent manners. IRFs signaling is the promising target to manage the initiation and progression of cardiometabolic disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Kawasaki Disease

PubMed Central

2006-01-01

Kawasaki disease is an acute febrile, systemic vasculitic syndrome of an unknown etiology that primarily occurs in children younger than five years of age. The principal presentations of Kawasaki disease include fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary artery aneurysms or ectasia develops in 15% to 25% of untreated children with the disease, which may later lead to myocardial infarction, sudden death, or ischemic heart disease. Treatment with intravenous gamma globulin (IVIG) is effective, but the mode of action is still unclear. The development of a diagnostic test, a more specific therapy, and ultimately the prevention of this potentially fatal illness in children are all dependent upon the continued advances in determining the etiopathogenesis of this fascinating disorder. PMID:17191303

Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

USDA-ARS?s Scientific Manuscript database

Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been show...

Optimal sampling strategies for detecting zoonotic disease epidemics.

PubMed

Ferguson, Jake M; Langebrake, Jessica B; Cannataro, Vincent L; Garcia, Andres J; Hamman, Elizabeth A; Martcheva, Maia; Osenberg, Craig W

2014-06-01

The early detection of disease epidemics reduces the chance of successful introductions into new locales, minimizes the number of infections, and reduces the financial impact. We develop a framework to determine the optimal sampling strategy for disease detection in zoonotic host-vector epidemiological systems when a disease goes from below detectable levels to an epidemic. We find that if the time of disease introduction is known then the optimal sampling strategy can switch abruptly between sampling only from the vector population to sampling only from the host population. We also construct time-independent optimal sampling strategies when conducting periodic sampling that can involve sampling both the host and the vector populations simultaneously. Both time-dependent and -independent solutions can be useful for sampling design, depending on whether the time of introduction of the disease is known or not. We illustrate the approach with West Nile virus, a globally-spreading zoonotic arbovirus. Though our analytical results are based on a linearization of the dynamical systems, the sampling rules appear robust over a wide range of parameter space when compared to nonlinear simulation models. Our results suggest some simple rules that can be used by practitioners when developing surveillance programs. These rules require knowledge of transition rates between epidemiological compartments, which population was initially infected, and of the cost per sample for serological tests.

IL-22 is required for Th17 cell–mediated pathology in a mouse model of psoriasis-like skin inflammation

PubMed Central

Ma, Hak-Ling; Liang, Spencer; Li, Jing; Napierata, Lee; Brown, Tom; Benoit, Stephen; Senices, Mayra; Gill, Davinder; Dunussi-Joannopoulos, Kyriaki; Collins, Mary; Nickerson-Nutter, Cheryl; Fouser, Lynette A.; Young, Deborah A.

2008-01-01

Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4+CD45RBhiCD25– cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22–neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell–dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis. PMID:18202747

IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.

PubMed

Ma, Hak-Ling; Liang, Spencer; Li, Jing; Napierata, Lee; Brown, Tom; Benoit, Stephen; Senices, Mayra; Gill, Davinder; Dunussi-Joannopoulos, Kyriaki; Collins, Mary; Nickerson-Nutter, Cheryl; Fouser, Lynette A; Young, Deborah A

2008-02-01

Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4(+)CD45RB(hi)CD25(-) cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22-neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell-dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis.

Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia.

PubMed

Ataga, Kenneth I; Stocker, Jonathan

2009-02-01

Sickle cell disease (SCD) is characterized by hemolytic as well as vaso-occlusive complications. The development of treatments for this inherited disease is based on an understanding of its pathophysiology. Polymerization of sickle hemoglobin is dependent on several independent factors, including the intracellular hemoglobin concentration. The hydration state (and intracellular hemoglobin concentration) of the sickle erythrocyte depends on the loss of solute and osmotically obliged water through specific pathways. Senicapoc (also known as ICA-17043) is a potent blocker of the Gardos channel, a calcium-activated potassium channel of intermediate conductance, in the red blood cell. Preclinical studies and studies in transgenic models of SCD show that inhibition of potassium efflux through the Gardos channel is associated with an increased hemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hemoglobin and decreases in markers of hemolysis. Despite the lack of a reduction in the frequency of pain episodes, the increasing recognition that hemolysis contributes to the development of several SCD-related complications suggests that by decreasing hemolysis, senicapoc may yet prove to be beneficial in this disease.

Accelerated Age-Dependent Hippocampal Volume Loss in Parkinson Disease With Mild Cognitive Impairment.

PubMed

Schneider, Christine B; Donix, Markus; Linse, Katharina; Werner, Annett; Fauser, Mareike; Klingelhoefer, Lisa; Löhle, Matthias; von Kummer, Rüdiger; Reichmann, Heinz; Storch, Alexander

2017-09-01

Patients with Parkinson disease are at high risk of developing dementia. During the course of the disease, a substantial number of patients will experience a cognitive decline, indicating the dynamics of the underlying neuropathology. Magnetic resonance imaging (MRI) has become increasingly useful for identifying structural characteristics in radiological brain anatomy existing prior to clinical symptoms. Whether these changes reflect pathology, whether they are aging related, or both often remains unclear. We hypothesized that aging-associated brain structural changes would be more pronounced in the hippocampal region among patients with Parkinson disease having mild cognitive deficits relative to cognitively unimpaired patients. Using MRI, we investigated 30 cognitively healthy patients with Parkinson disease and 33 patients with nondemented Parkinson disease having mild cognitive impairment. All participants underwent structural MRI scanning and extensive clinical and neuropsychological assessments. Irrespective of the study participants' cognitive status, older age was associated with reduced cortical thickness in various neocortical regions. Having mild cognitive impairment was not associated with an increased rate of cortical thinning or volume loss in these regions, except in the hippocampus bilaterally. Patients with Parkinson disease having mild cognitive impairment show an accelerated age-dependent hippocampal volume loss when compared with cognitively healthy patients with Parkinson disease. This may indicate pathological processes in a key region for memory functioning in patients with Parkinson disease at risk of developing dementia. Structural MRI of the hippocampal region could potentially contribute to identifying patients who should receive early treatment aimed at delaying the clinical onset of dementia.

Drosophila Fragile X Mental Retardation Protein Developmentally Regulates Activity-Dependent Axon Pruning

PubMed Central

Tessier, Charles R.; Broadie, Kendal

2014-01-01

Summary Fragile X Syndrome (FraX) is a broad-spectrum neurological disorder with symptoms ranging from hyperexcitability to mental retardation and autism. Loss of the fragile X mental retardation 1 (fmr1) gene product, the mRNA-binding translational regulator FMRP, causes structural over-elaboration of dendritic and axonal processes as well as functional alterations in synaptic plasticity at maturity. It is unclear, however, whether FraX is primarily a disease of development, a disease of plasticity or both; a distinction vital for engineering intervention strategies. To address this critical issue, we have used the Drosophila FraX model to investigate the developmental roles of Drosophila FMRP (dFMRP). dFMRP expression and regulation of chickadee/profilin coincides with a transient window of late brain development. During this time, dFMRP is positively regulated by sensory input activity, and required to limit axon growth and for efficient activity-dependent pruning of axon branches in the Mushroom Body learning/memory center. These results demonstrate that dFMRP has a primary role in activity-dependent neural circuit refinement in late brain development. PMID:18321984

Oxidative stress signaling to chromatin in health and disease

PubMed Central

Kreuz, Sarah; Fischle, Wolfgang

2016-01-01

Oxidative stress has a significant impact on the development and progression of common human pathologies, including cancer, diabetes, hypertension and neurodegenerative diseases. Increasing evidence suggests that oxidative stress globally influences chromatin structure, DNA methylation, enzymatic and non-enzymatic post-translational modifications of histones and DNA-binding proteins. The effects of oxidative stress on these chromatin alterations mediate a number of cellular changes, including modulation of gene expression, cell death, cell survival and mutagenesis, which are disease-driving mechanisms in human pathologies. Targeting oxidative stress-dependent pathways is thus a promising strategy for the prevention and treatment of these diseases. We summarize recent research developments connecting oxidative stress and chromatin regulation. PMID:27319358

TARGETING POLYMER THERAPEUTICS TO BONE

PubMed Central

Low, Stewart; Kopeček, Jindřich

2012-01-01

An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides an unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems. PMID:22316530

Vaccines against viral hemorrhagic fevers: non-human primate models.

PubMed

Carrion, Ricardo; Patterson, Jean L

2011-06-01

Viral hemorrhagic fevers are a group of disease syndromes caused by infection with certain RNA viruses. The disease is marked by a febrile response, malaise, coagulopathy and vascular permeability culminating in death. Case fatality rates can reach 90% depending on the etiologic agent. Currently, there is no approved antiviral treatment. Because of the high case fatality, risk of importation and the potential to use these agents as biological weapons, development of countermeasures to these agents is a high priority. The sporadic nature of disease outbreaks and the ethical issues associated with conducting a human trial for such diseases make human studies impractical; therefore, development of countermeasures must occur in relevant animal models. Non-human primates are superior models to study infectious disease because their immune system is similar to humans and they are good predictors of efficacy in vaccine development and other intervention strategies. This review article summarizes viral hemorrhagic fever non-human primate models.

NetDecoder: a network biology platform that decodes context-specific biological networks and gene activities.

PubMed

da Rocha, Edroaldo Lummertz; Ung, Choong Yong; McGehee, Cordelia D; Correia, Cristina; Li, Hu

2016-06-02

The sequential chain of interactions altering the binary state of a biomolecule represents the 'information flow' within a cellular network that determines phenotypic properties. Given the lack of computational tools to dissect context-dependent networks and gene activities, we developed NetDecoder, a network biology platform that models context-dependent information flows using pairwise phenotypic comparative analyses of protein-protein interactions. Using breast cancer, dyslipidemia and Alzheimer's disease as case studies, we demonstrate NetDecoder dissects subnetworks to identify key players significantly impacting cell behaviour specific to a given disease context. We further show genes residing in disease-specific subnetworks are enriched in disease-related signalling pathways and information flow profiles, which drive the resulting disease phenotypes. We also devise a novel scoring scheme to quantify key genes-network routers, which influence many genes, key targets, which are influenced by many genes, and high impact genes, which experience a significant change in regulation. We show the robustness of our results against parameter changes. Our network biology platform includes freely available source code (http://www.NetDecoder.org) for researchers to explore genome-wide context-dependent information flow profiles and key genes, given a set of genes of particular interest and transcriptome data. More importantly, NetDecoder will enable researchers to uncover context-dependent drug targets. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Smoking status and response to thiopurines in steroid-dependent inflammatory bowel disease.

PubMed

Domènech, Eugeni; Carrión, Sílvia; Garcia-Planella, Esther; Mañosa, Míriam; Gordillo, Jordi; Concepción, Mar; Guarner, Carlos; Cabré, Eduard

2011-04-01

The influence of smoking on inflammatory bowel disease (IBD) susceptibility and on its clinical course is well known, but not its impact on drug efficacy. The aim of this study was to evaluate the response to thiopurines in patients with steroid-dependent IBD according to their smoking habits. The medical records of 163 IBD patients (103 Crohn's disease [CD], 60 ulcerative colitis [UC]) in whom thiopurines were started because of steroid-dependency were reviewed. Therapeutic response was defined by steroid-free clinical remission for at least 6 months after 12 months of starting thiopurines. Clinical data and smoking status at diagnosis, at the time thiopurines were started, and during the follow-up were registered. A therapeutic response was obtained in 72% of CD and 61% of UC patients. Smoking habits did not influence the rate of response to thiopurines, the need for rescue therapies, or the development of penetrating/stricturing complications (CD) or proximal progression (UC). However, CD responders who continued smoking required new courses of steroids more often during follow-up. No influence of smoking was found when these outcomes were analyzed depending on gender or disease location. In the multivariate analysis, smoking status was the only predictive factor of drug tolerance. Active smoking does not influence the response to thiopurines in steroid-dependent IBD, but may decrease the likelihood of drug tolerance. Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Development of a computational model of glucose toxicity in the progression of diabetes mellitus.

PubMed

Perez-Rivera, Danilo T; Torres-Torres, Veronica L; Torres-Colon, Abraham E; Cruz-Aponte, Maytee

2016-10-01

Diabetes mellitus is a disease characterized by a range of metabolic complications involving an individual's blood glucose levels, and its main regulator, insulin. These complications can vary largely from person to person depending on their current biophysical state. Biomedical research day-by-day makes strides to impact the lives of patients of a variety of diseases, including diabetes. One large stride that is being made is the generation of techniques to assist physicians to ``personalize medicine''. From available physiological data, biological understanding of the system, and dimensional analysis, a differential equation-based mathematical model was built in a sequential matter, to be able to elucidate clearly how each parameter correlates to the patient's current physiological state. We developed a simple mathematical model that accurately simulates the dynamics between glucose, insulin, and pancreatic $\\beta$-cells throughout disease progression with constraints to maintain biological relevance. The current framework is clearly capable of tracking the patient's current progress through the disease, dependent on factors such as latent insulin resistance or an attrite $\\beta$-cell population. Further interests would be to develop tools that allow the direct and feasible testing of how effective a given plan of treatment would be at returning the patient to a desirable biophysical state.

[Gender aspects of socioeconomic and psychosocial risk factors of cardiovascular diseases].

PubMed

Dorner, Thomas; Kiefer, Ingrid; Kunze, Michael; Rieder, Anita

2004-09-01

Socioeconomic and psychosocial factors exert influence on health as well as the development, the progression and the prevention of diseases. Social factors regarding cardiovascular diseases have been widely researched. Whilst characteristics of classic type A behaviour increase cardiovascular risk among men, characteristics of type B behaviour represent a protective value, especially among women. Depression--a disease that is particularly prevalent among women and is associated with socioeconomic factors--negatively influences the development of cardiovascular diseases, triggers cardiovascular events and influences rehabilitation. Lifestyle factors, which are positively or negatively correlated with cardiovascular disease, show a gender-specific prevalence and are related to psychosocial factors. More women than men report healthy nutrition, whereas more men report partaking in physical exercise. Obesity is--depending on the occupational group and the social level--more prevalent among women compared to men.

Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience-Dependent Cortical Plasticity

PubMed Central

Smith, Milo R.; Burman, Poromendro

2016-01-01

Throughout childhood and adolescence, periods of heightened neuroplasticity are critical for the development of healthy brain function and behavior. Given the high prevalence of neurodevelopmental disorders, such as autism, identifying disruptors of developmental plasticity represents an essential step for developing strategies for prevention and intervention. Applying a novel computational approach that systematically assessed connections between 436 transcriptional signatures of disease and multiple signatures of neuroplasticity, we identified inflammation as a common pathological process central to a diverse set of diseases predicted to dysregulate plasticity signatures. We tested the hypothesis that inflammation disrupts developmental cortical plasticity in vivo using the mouse ocular dominance model of experience-dependent plasticity in primary visual cortex. We found that the administration of systemic lipopolysaccharide suppressed plasticity during juvenile critical period with accompanying transcriptional changes in a particular set of molecular regulators within primary visual cortex. These findings suggest that inflammation may have unrecognized adverse consequences on the postnatal developmental trajectory and indicate that treating inflammation may reduce the burden of neurodevelopmental disorders. PMID:28101530

Korsakoff minus Wernicke syndrome.

PubMed

Blansjaar, B A; Van Dijk, J G

1992-07-01

It is commonly believed that Korsakoff's amnesic state in alcoholics is characteristically the sequel to Wernicke's disease. However, in a study of 44 Korsakoff patients it was found that 33 had developed serious memory impairment without having had alarming neurological symptoms. This insidious nature of the onset of the disease indicates that all alcohol-dependent patients should be treated with vitamin B.

PhylloLux technology for crop protection: alternative management of diseases and arthropods for strawberry production

USDA-ARS?s Scientific Manuscript database

A search for alternatives to synthetic fungicides for control of strawberry diseases has led us to the development of PhylloLux© technology that combines UV-C irradiation followed by a specific dark period (2-4 hr depending on pathogen) and application of microbial antagonists. This technology is s...

What is Your Risk of Contracting Alzheimer's Disease? A Telematics Tool Helps you to Predict it.

PubMed

Méndez-Sanz, Rodrigo; de la Torre-Díez, Isabel; López-Coronado, Miguel

2016-01-01

Alzheimer's disease (AD) is the most common dementia in developed countries. Between the identified risk factors, one of the most important is the age. Its prevalence reaches 24 % in men and 33 % in women over 85 years. Increase in life expectancy, making it a serious public health problem. Prevention of Alzheimer's disease represents a major challenge to health. Given that Alzheimer's disease is largely dependent on the genetics of each person and uninterrupted progress of the age, which is try to make people aware that there are other factors that can alter your chance of developing the Alzheimer disease and although currently not reduce, help is not increased in the near or distant future.The aim of this paper is to develop and evaluate a Web-Mobile application (Alzhe Alert) used to calculate the risk of Alzheimer's from a short questionnaire using a computer or mobile device, so that any user, without requiring computer skills, can access the website to estimate their risk of developing the disease in the coming years depending on their habits and daily basis activities. The users who have realized the questionnaire can to observe in a graph the result, and they will know which is at risk for Alzheimer's at present and over the next 50 years if they continue with the same habits and lifestyle. The objective is that the users can be aware of the risk they have different habits of life about their health. Currently, 243 users (84 women and 159 men) of white race have completed the questionnaire. 76 % of the users have got a risk below the average.

Vitamin D deficiency: infertility and neurodevelopmental diseases (attention deficit hyperactivity disorder, autism, and schizophrenia).

PubMed

Berridge, Michael J

2018-02-01

The process of development depends on a number of signaling systems that regulates the progressive sequence of developmental events. Infertility and neurodevelopmental diseases, such as attention deficit hyperactivity disorder, autism spectrum disorders, and schizophrenia, are caused by specific alterations in these signaling processes. Calcium signaling plays a prominent role throughout development beginning at fertilization and continuing through early development, implantation, and organ differentiation such as heart and brain development. Vitamin D plays a major role in regulating these signaling processes that control development. There is an increase in infertility and an onset of neurodevelopmental diseases when vitamin D is deficient. The way in which vitamin D deficiency acts to alter development is a major feature of this review. One of the primary functions of vitamin D is to maintain the phenotypic stability of both the Ca 2+ and redox signaling pathways that play such a key role throughout development.

The epidemiology, consequences and management of periodontal disease in older adults.

PubMed

Boehm, Tobias K; Scannapieco, Frank A

2007-09-01

This review summarizes the literature on periodontal disease (PD) in older adults. The authors focused on significant sequelae of PD and therapy in this population. The authors conducted a search on PubMed for human studies using the terms "periodontal disease OR periodontitis" and "older adults." They retrieved 649 articles and excluded studies that had poor experimental design. For each topic of the review, they selected one to three of the most recent studies or reviews for inclusion and cited classic articles where appropriate. PD is a common oral chronic inflammatory disease often found in older adults. In older patients, PD may lead to root caries, impaired eating and socialization. It also may increase patients' risk of developing systemic diseases such as diabetes mellitus, lung disease, heart disease and stroke. Treatment is not limited by chronological age but depends on the patient's medical and emotional status and the availability of financial resources. General dentists usually can treat the majority of older people with mild or moderate PD. For older adults who are medically compromised and dependent, the literature supports treatment that prevents PD progression.

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.

Chronic Wasting Disease: Transmission Mechanisms and the Possibility of Harvest Management

PubMed Central

Potapov, Alex; Merrill, Evelyn; Pybus, Margo; Lewis, Mark A.

2016-01-01

We develop a model of CWD management by nonselective deer harvest, currently the most feasible approach available for managing CWD in wild populations. We use the model to explore the effects of 6 common harvest strategies on disease prevalence and to identify potential optimal harvest policies for reducing disease prevalence without population collapse. The model includes 4 deer categories (juveniles, adult females, younger adult males, older adult males) that may be harvested at different rates, a food-based carrying capacity, which influences juvenile survival but not adult reproduction or survival, and seasonal force of infection terms for each deer category under differing frequency-dependent transmission dynamics resulting from environmental and direct contact mechanisms. Numerical experiments show that the interval of transmission coefficients β where the disease can be controlled is generally narrow and efficiency of a harvest policy to reduce disease prevalence depends crucially on the details of the disease transmission mechanism, in particular on the intensity of disease transmission to juveniles and the potential differences in the behavior of older and younger males that influence contact rates. Optimal harvest policy to minimize disease prevalence for each of the assumed transmission mechanisms is shown to depend on harvest intensity. Across mechanisms, a harvest that focuses on antlered deer, without distinguishing between age classes reduces disease prevalence most consistently, whereas distinguishing between young and older antlered deer produces higher uncertainty in the harvest effects on disease prevalence. Our results show that, despite uncertainties, a modelling approach can determine classes of harvest strategy that are most likely to be effective in combatting CWD. PMID:26963921

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.

A minimal model for multiple epidemics and immunity spreading.

PubMed

Sneppen, Kim; Trusina, Ala; Jensen, Mogens H; Bornholdt, Stefan

2010-10-18

Pathogens and parasites are ubiquitous in the living world, being limited only by availability of suitable hosts. The ability to transmit a particular disease depends on competing infections as well as on the status of host immunity. Multiple diseases compete for the same resource and their fate is coupled to each other. Such couplings have many facets, for example cross-immunization between related influenza strains, mutual inhibition by killing the host, or possible even a mutual catalytic effect if host immunity is impaired. We here introduce a minimal model for an unlimited number of unrelated pathogens whose interaction is simplified to simple mutual exclusion. The model incorporates an ongoing development of host immunity to past diseases, while leaving the system open for emergence of new diseases. The model exhibits a rich dynamical behavior with interacting infection waves, leaving broad trails of immunization in the host population. This obtained immunization pattern depends only on the system size and on the mutation rate that initiates new diseases.

Membrane traffic and muscle: lessons from human disease.

PubMed

Dowling, James J; Gibbs, Elizabeth M; Feldman, Eva L

2008-07-01

Like all mammalian tissues, skeletal muscle is dependent on membrane traffic for proper development and homeostasis. This fact is underscored by the observation that several human diseases of the skeletal muscle are caused by mutations in gene products of the membrane trafficking machinery. An examination of these diseases and the proteins that underlie them is instructive both in terms of determining disease pathogenesis and of understanding the normal aspects of muscle biology regulated by membrane traffic. This review highlights our current understanding of the trafficking genes responsible for human myopathies.

Diagnosis and treatment of cardiac iron overload in transfusion-dependent thalassemia patients.

PubMed

Siri-Angkul, Natthaphat; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2018-05-18

Thalassemia is among the most common genetic diseases. Patients with severe forms of the disease are transfusion-dependent, leading to iron overload. A condition which can eventually develop in the iron-loaded heart is iron overload cardiomyopathy, a debilitating disease that accounts for the majority of deaths in thalassemia patients. Areas covered: This review article provides a comprehensive summary of the diagnosis and treatment of cardiac iron overload in transfusion-dependent thalassemia patients, with discussion covering current weak points and potential improvements of the relevant diagnostic and therapeutic strategies. Expert commentary: Current limitations of various diagnostic techniques for iron overload cardiomyopathy include suboptimal accuracy, untimely detection, or inadequate accessibility, and novel modalities are required to overcome these shortcomings. Treatment should address key pathophysiologic mechanisms of iron overload cardiomyopathy, which include cardiac iron mishandling and iron-induced oxidative injury. Apart from the promotion of iron removal by chelators, prevention of cardiac iron deposition and attenuation of oxidative damage should also be rigorously investigated on a cell-to-bedside basis.

Impact of perinatal environmental tobacco smoke on the development of childhood allergic diseases.

PubMed

Yang, Hyeon-Jong

2016-08-01

Allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and food allergy, are most common chronic, noncommunicable diseases in childhood. In the past few decades, the prevalence has increased abruptly worldwide. There are 2 possible explanations for the rising prevalence of allergic diseases worldwide, that an increased disease-awareness of physician, patient, or caregivers, and an abrupt exposure to unknown hazards. Unfortunately, the underlying mechanisms remain largely unknown. Despite the continuing efforts worldwide, the etiologies and rising prevalence remain unclear. Thus, it is important to identify and control risk factors in the susceptible individual for the best prevention and management. Genetic susceptibility or environments may be a potential background for the development of allergic disease, however they alone cannot explain the rising prevalence worldwide. There is growing evidence that epigenetic change depends on the gene, environment, and their interactions, may induce a long-lasting altered gene expression and the consequent development of allergic diseases. In epigenetic mechanisms, environmental tobacco smoke (ETS) exposure during critical period (i.e., during pregnancy and early life) are considered as a potential cause of the development of childhood allergic diseases. However, the causal relationship is still unclear. This review aimed to highlight the impact of ETS exposure during the perinatal period on the development of childhood allergic diseases and to propose a future research direction.

Recent trends and perspectives of molecular markers against fungal diseases in wheat.

PubMed

Goutam, Umesh; Kukreja, Sarvjeet; Yadav, Rakesh; Salaria, Neha; Thakur, Kajal; Goyal, Aakash K

2015-01-01

Wheat accounts for 19% of the total production of major cereal crops in the world. In view of ever increasing population and demand for global food production, there is an imperative need of 40-60% increase in wheat production to meet the requirement of developing world in coming 40 years. However, both biotic and abiotic stresses are major hurdles for attaining the goal. Among the most important diseases in wheat, fungal diseases pose serious threat for widening the gap between actual and attainable yield. Fungal disease management, mainly, depends on the pathogen detection, genetic and pathological variability in population, development of resistant cultivars and deployment of effective resistant genes in different epidemiological regions. Wheat protection and breeding of resistant cultivars using conventional methods are time-consuming, intricate and slow processes. Molecular markers offer an excellent alternative in development of improved disease resistant cultivars that would lead to increase in crop yield. They are employed for tagging the important disease resistance genes and provide valuable assistance in increasing selection efficiency for valuable traits via marker assisted selection (MAS). Plant breeding strategies with known molecular markers for resistance and functional genomics enable a breeder for developing resistant cultivars of wheat against different fungal diseases.

A clinical approach to Lyme disease.

PubMed

Nadelman, R B; Wormser, G P

1990-05-01

Lyme disease (also known as Lyme borreliosis) is an emerging, newly described infectious disease with diverse clinical manifestations. The disease is caused by the spirochetal agent Borrelia burgdorferi, which is transmitted to humans by the bite of certain species of Ixodes ticks harboring the organism. The most readily identifiable clinical feature is the distinctive skin lesion, erythema migrans. If recently infected patients go untreated, approximately 15% will develop neurologic conditions (most commonly facial nerve palsy), 8% will develop myocarditis (typically with heart block), and 60% will develop migratory mono- or pauci-articular arthritis. Diagnosis depends on clinical suspicion, recognition of the characteristic signs and symptoms, and appropriate testing for antibody to B. burgdorferi. Serology for Lyme disease, although in need of better standardization, is most useful in diagnosing patients with manifestations of Lyme disease other than erythema migrans. All manifestations of Lyme disease are potentially treatable with either a beta-lactam antibiotic (for instance penicillin, amoxicillin, or ceftriaxone) or a tetracycline preparation. However, the optimal antimicrobial regimen, including choice of drug, drug dose, route of administration, and length of therapy, is unknown. Other important areas for future research include Ixodes biology and control, improved laboratory tests for diagnosis and for assessing response to therapy, and vaccine development.

Inference on cancer screening exam accuracy using population-level administrative data.

PubMed

Jiang, H; Brown, P E; Walter, S D

2016-01-15

This paper develops a model for cancer screening and cancer incidence data, accommodating the partially unobserved disease status, clustered data structures, general covariate effects, and dependence between exams. The true unobserved cancer and detection status of screening participants are treated as latent variables, and a Markov Chain Monte Carlo algorithm is used to estimate the Bayesian posterior distributions of the diagnostic error rates and disease prevalence. We show how the Bayesian approach can be used to draw inferences about screening exam properties and disease prevalence while allowing for the possibility of conditional dependence between two exams. The techniques are applied to the estimation of the diagnostic accuracy of mammography and clinical breast examination using data from the Ontario Breast Screening Program in Canada. Copyright © 2015 John Wiley & Sons, Ltd.

Impact of gastrointestinal disease states on oral drug absorption - implications for formulation design - a PEARRL review.

PubMed

Effinger, Angela; O'Driscoll, Caitriona M; McAllister, Mark; Fotaki, Nikoletta

2018-05-16

Drug product performance in patients with gastrointestinal (GI) diseases can be altered compared to healthy subjects due to pathophysiological changes. In this review, relevant differences in patients with inflammatory bowel diseases, coeliac disease, irritable bowel syndrome and short bowel syndrome are discussed and possible in vitro and in silico tools to predict drug product performance in this patient population are assessed. Drug product performance was altered in patients with GI diseases compared to healthy subjects, as assessed in a limited number of studies for some drugs. Underlying causes can be observed pathophysiological alterations such as the differences in GI transit time, the composition of the GI fluids and GI permeability. Additionally, alterations in the abundance of metabolising enzymes and transporter systems were observed. The effect of the GI diseases on each parameter is not always evident as it may depend on the location and the state of the disease. The impact of the pathophysiological change on drug bioavailability depends on the physicochemical characteristics of the drug, the pharmaceutical formulation and drug metabolism. In vitro and in silico methods to predict drug product performance in patients with GI diseases are currently limited but could be a useful tool to improve drug therapy. Development of suitable in vitro dissolution and in silico models for patients with GI diseases can improve their drug therapy. The likeliness of the models to provide accurate predictions depends on the knowledge of pathophysiological alterations, and thus, further assessment of physiological differences is essential. © 2018 Royal Pharmaceutical Society.

Chronic Obstructive Pulmonary Disease, Cognitive Impairment, and Development of Disability: The Health and Retirement Study

PubMed Central

Richardson, Caroline R.; Han, MeiLan K.; Cigolle, Christine T.

2014-01-01

Rationale: The relationship between chronic obstructive pulmonary disease (COPD) and cognitive impairment in leading to disability has not been characterized. Objectives: We aimed to investigate the prevalence and cumulative incidence of disability among adults with and without COPD and the association of COPD and cognitive impairment with disability. Methods: We analyzed 2006–2008 waves of the Health and Retirement Study, a nationally representative longitudinal health survey. COPD was self-reported. Prevalent disability was defined as baseline dependency in one or more activities of daily living (ADLs) and incident disability as one or more additional ADL dependencies. We used a validated performance-based measure of cognition to identify dementia and mild cognitive impairment. Covariates included seven chronic diseases, four geriatric syndromes, and sociodemographics. We used logistic regression to test associations between COPD, cognitive status, and prevalent/incident disability. Measurements and Main Results: Of 17,535 participants at least 53 years of age in wave 2006 (representing 77.7 million Americans), 9.5% reported COPD and 13.5% mild cognitive impairment; 17.5% of those with COPD had mild cognitive impairment. Prevalent disability for COPD was 12.8% (5.2% for no-COPD, P < 0.001). An additional 9.2% with COPD developed incident disability at 2 years (4.0% for no-COPD, P < 0.001). In adjusted models, COPD was associated with baseline (odds ratio, 2.0) and incident disability (odds ratio, 2.1; adjusted for baseline disability). Cognitive impairment had an additive effect to COPD. The COPD–disability association, prevalent/incident, was of similar or greater magnitude than that of other chronic diseases (e.g., stroke, diabetes). The associations were maintained in sensitivity analyses using alternative definitions of disability (dependency in two or more ADLs, dependency in instrumental ADLs), and in analysis excluding respondents with dementia. Conclusions: Both COPD and mild cognitive impairment increase the risk of disability. The risk conferred by COPD is significant and similar or higher than other chronic diseases. PMID:25285360

Current Guidelines, Common Clinical Pitfalls, and Future Directions for Laboratory Diagnosis of Lyme Disease, United States.

PubMed

Moore, Andrew; Nelson, Christina; Molins, Claudia; Mead, Paul; Schriefer, Martin

2016-07-01

In the United States, Lyme disease is caused by Borrelia burgdorferi and transmitted to humans by blacklegged ticks. Patients with an erythema migrans lesion and epidemiologic risk can receive a diagnosis without laboratory testing. For all other patients, laboratory testing is necessary to confirm the diagnosis, but proper interpretation depends on symptoms and timing of illness. The recommended laboratory test in the United States is 2-tiered serologic analysis consisting of an enzyme-linked immunoassay or immunofluorescence assay, followed by reflexive immunoblotting. Sensitivity of 2-tiered testing is low (30%-40%) during early infection while the antibody response is developing (window period). For disseminated Lyme disease, sensitivity is 70%-100%. Specificity is high (>95%) during all stages of disease. Use of other diagnostic tests for Lyme disease is limited. We review the rationale behind current US testing guidelines, appropriate use and interpretation of tests, and recent developments in Lyme disease diagnostics.

Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner

PubMed Central

Randolph, Matthew E; Luo, Qingwei; Ho, Justin; Vest, Katherine E; Sokoloff, Alan J; Pavlath, Grace K

2014-01-01

The inability to swallow, or dysphagia, is a debilitating and life-threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild-type mice depending on the particular muscle analysed. Furthermore, wild-type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild-type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild-type A10 PABPN1 was protective against age-related muscle atrophy in the laryngopharynx and prevented the development of age-related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region-dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia. PMID:25326455

Executive summary: biomarkers of nutrition for development: building a consensus

USDA-ARS?s Scientific Manuscript database

The ability to develop evidence-based clinical guidance and effective programs and policies to achieve global health promotion and disease prevention goals depends on the availability of valid and reliable data. With specific regard to the role of food and nutrition in achieving those goals, relevan...

Mediator complex dependent regulation of cardiac development and disease.

PubMed

Grueter, Chad E

2013-06-01

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality. The risk factors for CVD include environmental and genetic components. Human mutations in genes involved in most aspects of cardiovascular function have been identified, many of which are involved in transcriptional regulation. The Mediator complex serves as a pivotal transcriptional regulator that functions to integrate diverse cellular signals by multiple mechanisms including recruiting RNA polymerase II, chromatin modifying proteins and non-coding RNAs to promoters in a context dependent manner. This review discusses components of the Mediator complex and the contribution of the Mediator complex to normal and pathological cardiac development and function. Enhanced understanding of the role of this core transcriptional regulatory complex in the heart will help us gain further insights into CVD. Copyright © 2013. Production and hosting by Elsevier Ltd.

An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development.

PubMed

Pedros, Christophe; Gaud, Guillaume; Bernard, Isabelle; Kassem, Sahar; Chabod, Marianne; Lagrange, Dominique; Andréoletti, Olivier; Dejean, Anne S; Lesourne, Renaud; Fournié, Gilbert J; Saoudi, Abdelhadi

2015-08-15

The development of inflammatory diseases depends on complex interactions between several genes and various environmental factors. Discovering new genetic risk factors and understanding the mechanisms whereby they influence disease development is of paramount importance. We previously reported that deficiency in Themis1, a new actor of TCR signaling, impairs regulatory T cell (Treg) function and predisposes Brown-Norway (BN) rats to spontaneous inflammatory bowel disease (IBD). In this study, we reveal that the epistasis between Themis1 and Vav1 controls the occurrence of these phenotypes. Indeed, by contrast with BN rats, Themis1 deficiency in Lewis rats neither impairs Treg suppressive functions nor induces pathological manifestations. By using congenic lines on the BN genomic background, we show that the impact of Themis1 deficiency on Treg suppressive functions depends on a 117-kb interval coding for a R63W polymorphism that impacts Vav1 expression and functions. Indeed, the introduction of a 117-kb interval containing the Lewis Vav1-R63 variant restores Treg function and protects Themis1-deficient BN rats from spontaneous IBD development. We further show that Themis1 binds more efficiently to the BN Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT and to fully promote the activation of Erk kinases. Together, these results highlight the importance of the signaling pathway involving epistasis between Themis1 and Vav1 in the control of Treg suppressive function and susceptibility to IBD development. Copyright © 2015 by The American Association of Immunologists, Inc.

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

Alcohol consumption in late adolescence is associated with an increased risk of severe liver disease later in life.

PubMed

Hagström, Hannes; Hemmingsson, Tomas; Discacciati, Andrea; Andreasson, Anna

2018-03-01

High alcohol consumption is associated with an increased risk of severe liver disease. Current recommendations suggest it is safe for men to consume 30 grams of alcohol per day. We investigated the association between alcohol consumption early in life and later development of severe liver disease. We used data on alcohol consumption at conscription to military service from 43,296 men (18-20 years) in Sweden between 1969 and 1970. Outcomes were defined as incident diagnoses of severe liver disease from systematic national registration of clinical events until the end of 2009. A Cox regression model adjusted for body mass index, smoking, use of narcotics, cognitive ability and cardiovascular capacity was applied. During a mean follow-up of 37.8 years, 383 men developed severe liver disease. Alcohol consumption was associated with an increased risk of development of severe liver disease in a dose-response pattern (adjusted hazard ratio for every one gram/day increase 1.02; 95% CI 1.01-1.02). No evidence of a threshold effect was found. Importantly, a clear trend pointed towards an increased risk of severe liver disease in men who consumed less than 30 grams of alcohol per day. Alcohol consumption in young men is associated with an increased risk of severe liver disease, up to 39 years later in life. The risk was dose-dependent, with no sign of a threshold effect. Current guidelines for safe alcohol intake in men might have to be revised. We investigated more than 43,000 Swedish men in their late teens enlisted for conscription in 1969-1970. After almost 40 years of follow-up, we found that alcohol consumption was a significant risk factor for developing severe liver disease, independent of confounders. This risk was dose-dependent, and was most pronounced in men consuming two drinks per day or more. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Modelling the effect of urbanization on the transmission of an infectious disease.

PubMed

Zhang, Ping; Atkinson, Peter M

2008-01-01

This paper models the impact of urbanization on infectious disease transmission by integrating a CA land use development model, population projection matrix model and CA epidemic model in S-Plus. The innovative feature of this model lies in both its explicit treatment of spatial land use development, demographic changes, infectious disease transmission and their combination in a dynamic, stochastic model. Heuristically-defined transition rules in cellular automata (CA) were used to capture the processes of both land use development with urban sprawl and infectious disease transmission. A population surface model and dwelling distribution surface were used to bridge the gap between urbanization and infectious disease transmission. A case study is presented involving modelling influenza transmission in Southampton, a dynamically evolving city in the UK. The simulation results for Southampton over a 30-year period show that the pattern of the average number of infection cases per day can depend on land use and demographic changes. The modelling framework presents a useful tool that may be of use in planning applications.

ENVIRONMENTAL PCB EXPOSURE AND RISK OF ENDOMETRIOSIS

EPA Science Inventory

BACKGROUND: Hormonally active environmental agents recently have been associated with the development of endometriosis. METHODS: We undertook a study to assess the relation between endometriosis, an estrogen dependent gynecologic disease, and 62 individual polychlorinated biphe...

Loop mediated isothermal amplification: An innovative gene amplification technique for animal diseases.

PubMed

Sahoo, Pravas Ranjan; Sethy, Kamadev; Mohapatra, Swagat; Panda, Debasis

2016-05-01

India being a developing country mainly depends on livestock sector for its economy. However, nowadays, there is emergence and reemergence of more transboundary animal diseases. The existing diagnostic techniques are not so quick and with less specificity. To reduce the economy loss, there should be a development of rapid, reliable, robust diagnostic technique, which can work with high degree of sensitivity and specificity. Loop mediated isothermal amplification assay is a rapid gene amplification technique that amplifies nucleic acid under an isothermal condition with a set of designed primers spanning eight distinct sequences of the target. This assay can be used as an emerging powerful, innovative gene amplification diagnostic tool against various pathogens of livestock diseases. This review is to highlight the basic concept and methodology of this assay in livestock disease.

An Immuno-epidemiological Model of Paratuberculosis

NASA Astrophysics Data System (ADS)

Martcheva, M.

2011-11-01

The primary objective of this article is to introduce an immuno-epidemiological model of paratuberculosis (Johne's disease). To develop the immuno-epidemiological model, we first develop an immunological model and an epidemiological model. Then, we link the two models through time-since-infection structure and parameters of the epidemiological model. We use the nested approach to compose the immuno-epidemiological model. Our immunological model captures the switch between the T-cell immune response and the antibody response in Johne's disease. The epidemiological model is a time-since-infection model and captures the variability of transmission rate and the vertical transmission of the disease. We compute the immune-response-dependent epidemiological reproduction number. Our immuno-epidemiological model can be used for investigation of the impact of the immune response on the epidemiology of Johne's disease.

Polymorphism in the Helicobacter pylori CagA and VacA toxins and disease

PubMed Central

Bridge, Dacie R.; Merrell, D. Scott

2013-01-01

Half of the world’s population is infected with Helicobacter pylori and approximately 20% of infected individuals develop overt clinical disease such as ulcers and stomach cancer. Paradoxically, despite its classification as a class I carcinogen, H. pylori has been shown to be protective against development of asthma, allergy, and esophageal disease. Given these conflicting roles for H. pylori, researchers are attempting to define the environmental, host, and pathogen interactions that ultimately result in severe disease in some individuals. From the bacterial perspective, the toxins, CagA and VacA, have each been shown to be polymorphic and to contribute to disease in an allele-dependent manner. Based on the notable advances that have recently been made in the CagA field, herein we review recent studies that have begun to shed light on the role of CagA polymorphism in H. pylori disease. Moreover, we discuss the potential interaction of CagA and VacA as a mediator of gastric disease. PMID:23380646

Epstein-Barr Virus in Systemic Autoimmune Diseases

PubMed Central

Duus, Karen; Houen, Gunnar

2013-01-01

Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation. PMID:24062777

Epstein-Barr virus in systemic autoimmune diseases.

PubMed

Draborg, Anette Holck; Duus, Karen; Houen, Gunnar

2013-01-01

Systemic autoimmune diseases (SADs) are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV) with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS) and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation.

The oral administration of bacterial extracts prevents asthma via the recruitment of regulatory T cells to the airways.

PubMed

Navarro, S; Cossalter, G; Chiavaroli, C; Kanda, A; Fleury, S; Lazzari, A; Cazareth, J; Sparwasser, T; Dombrowicz, D; Glaichenhaus, N; Julia, V

2011-01-01

The prevalence of asthma has steadily increased during the last decade, probably as the result of changes in the environment, including reduced microbial exposure during infancy. Accordingly, experimental studies have shown that deliberate infections with live pathogens prevent the development of allergic airway diseases in mice. Bacterial extracts are currently used in children suffering from repeated upper respiratory tract infections. In the present study, we have investigated whether bacterial extracts, commercially available as Broncho-Vaxom (BV), could prevent allergic airway disease in mice. Oral treatment with BV suppressed airway inflammation through interleukin-10 (IL-10)-dependent and MyD88 (myeloid differentiation primary response gene (88))-dependent mechanisms and induced the conversion of FoxP3 (forkhead box P3)(-) T cells into FoxP3(+) regulatory T cells. Furthermore, CD4(+) T cells purified from the trachea of BV-treated mice conferred protection against airway inflammation when adoptively transferred into sensitized mice. Therefore, treatment with BV could possibly be a safe and efficient strategy to prevent the development of allergic diseases in children.

SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington’s Disease Mice

PubMed Central

Tulino, Raffaella; Benjamin, Agnesska C.; Jolinon, Nelly; Smith, Donna L.; Chini, Eduardo N.; Carnemolla, Alisia; Bates, Gillian P.

2016-01-01

Huntington’s disease (HD) is a neurodegenerative disorder for which there are no disease-modifying treatments. SIRT1 is a NAD+-dependent protein deacetylase that is implicated in maintaining neuronal health during development, differentiation and ageing. Previous studies suggested that the modulation of SIRT1 activity is neuroprotective in HD mouse models, however, the mechanisms controlling SIRT1 activity are unknown. We have identified a striatum-specific phosphorylation-dependent regulatory mechanism of SIRT1 induction under normal physiological conditions, which is impaired in HD. We demonstrate that SIRT1 activity is down-regulated in the brains of two complementary HD mouse models, which correlated with altered SIRT1 phosphorylation levels. This SIRT1 impairment could not be rescued by the ablation of DBC1, a negative regulator of SIRT1, but was linked to changes in the sub-cellular distribution of AMPK-α1, a positive regulator of SIRT1 function. This work provides insights into the regulation of SIRT1 activity with the potential for the development of novel therapeutic strategies. PMID:26815359

Host culling as an adaptive management tool for chronic wasting disease in white-tailed deer: a modelling study.

PubMed

Wasserberg, Gideon; Osnas, Erik E; Rolley, Robert E; Samuel, Michael D

2009-04-01

Emerging wildlife diseases pose a significant threat to natural and human systems. Because of real or perceived risks of delayed actions, disease management strategies such as culling are often implemented before thorough scientific knowledge of disease dynamics is available. Adaptive management is a valuable approach in addressing the uncertainty and complexity associated with wildlife disease problems and can be facilitated by using a formal model.We developed a multi-state computer simulation model using age, sex, infection-stage, and seasonality as a tool for scientific learning and managing chronic wasting disease (CWD) in white-tailed deer Odocoileus virginianus. Our matrix model used disease transmission parameters based on data collected through disease management activities. We used this model to evaluate management issues on density- (DD) and frequency-dependent (FD) transmission, time since disease introduction, and deer culling on the demographics, epizootiology, and management of CWD.Both DD and FD models fit the Wisconsin data for a harvested white-tailed deer population, but FD was slightly better. Time since disease introduction was estimated as 36 (95% CI, 24-50) and 188 (41->200) years for DD and FD transmission, respectively. Deer harvest using intermediate to high non-selective rates can be used to reduce uncertainty between DD and FD transmission and improve our prediction of long-term epidemic patterns and host population impacts. A higher harvest rate allows earlier detection of these differences, but substantially reduces deer abundance.Results showed that CWD has spread slowly within Wisconsin deer populations, and therefore, epidemics and disease management are expected to last for decades. Non-hunted deer populations can develop and sustain a high level of infection, generating a substantial risk of disease spread. In contrast, CWD prevalence remains lower in hunted deer populations, but at a higher prevalence the disease competes with recreational hunting to reduce deer abundance.Synthesis and applications. Uncertainty about density- or frequency-dependent transmission hinders predictions about the long-term impacts of chronic wasting disease on cervid populations and the development of appropriate management strategies. An adaptive management strategy using computer modelling coupled with experimental management and monitoring can be used to test model predictions, identify the likely mode of disease transmission, and evaluate the risks of alternative management responses.

Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases?

PubMed

Iida, Tomoya; Wagatsuma, Kohei; Hirayama, Daisuke; Nakase, Hiroshi

2017-12-21

Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.

Recent trends and perspectives of molecular markers against fungal diseases in wheat

PubMed Central

Goutam, Umesh; Kukreja, Sarvjeet; Yadav, Rakesh; Salaria, Neha; Thakur, Kajal; Goyal, Aakash K.

2015-01-01

Wheat accounts for 19% of the total production of major cereal crops in the world. In view of ever increasing population and demand for global food production, there is an imperative need of 40–60% increase in wheat production to meet the requirement of developing world in coming 40 years. However, both biotic and abiotic stresses are major hurdles for attaining the goal. Among the most important diseases in wheat, fungal diseases pose serious threat for widening the gap between actual and attainable yield. Fungal disease management, mainly, depends on the pathogen detection, genetic and pathological variability in population, development of resistant cultivars and deployment of effective resistant genes in different epidemiological regions. Wheat protection and breeding of resistant cultivars using conventional methods are time-consuming, intricate and slow processes. Molecular markers offer an excellent alternative in development of improved disease resistant cultivars that would lead to increase in crop yield. They are employed for tagging the important disease resistance genes and provide valuable assistance in increasing selection efficiency for valuable traits via marker assisted selection (MAS). Plant breeding strategies with known molecular markers for resistance and functional genomics enable a breeder for developing resistant cultivars of wheat against different fungal diseases. PMID:26379639

Blue fingerprint in spectrum of cancer change of biotissues

NASA Astrophysics Data System (ADS)

Yermolenko, Sergey B.

2010-11-01

This paper follows to combine optical and biochemical techniques for identification the cell membrane transformation in the dynamic of growth and development of experimental solid tumour. It is researched that in all the cases the linear dichroism appears in biotissues (the human esophagus, the muscle tissue of rats, prostate tissue) with the cancer disease the magnitude of which depends on the type of the tissue and on the time of the cancer process development. As the linear dichroism is lacking for healthy tissues, then the obtained results can have diagnostic values with the purpose of detection and estimation of the stage of the cancer disease development.

Spectropolarimetry features of biotissue's malignant changes

NASA Astrophysics Data System (ADS)

Gruia, I.; Yermolenko, S. B.; Gavrila, C.; Ivashko, P. V.; Gruia, M. I.

2010-11-01

This paper follows to combine optical and biochemical techniques for identification the cell membrane transformation in the dynamic of growth and development of experimental solid tumour. It is researched that in all the cases the linear dichroism appears in biotissues (the human esophagus, the muscle tissue of rats, prostate tissue) with the cancer disease the magnitude of which depends on the type of the tissue and on the time of the cancer process development. As the linear dichroism is lacking for healthy tissues, then the obtained results can have diagnostic values with the purpose of detection and estimation of the stage of the cancer disease development.

NEuro COgnitive REhabilitation for Disease of Addiction (NECOREDA) Program: From Development to Trial

PubMed Central

Rezapour, Tara; Hatami, Javad; Farhoudian, Ali; Sofuoglu, Mehmet; Noroozi, Alireza; Daneshmand, Reza; Samiei, Ahmadreza; Ekhtiari, Hamed

2015-01-01

Despite extensive evidence for cognitive deficits associated with drug use and multiple publications supporting the efficacy of cognitive rehabilitation treatment (CRT) services for drug addictions, there are a few well-structured tools and organized programs to improve cognitive abilities in substance users. Most published studies on cognitive rehabilitation for drug dependent patients used rehabilitation tools, which have been previously designed for other types of brain injuries such as schizophrenia or traumatic brain injuries and not specifically designed for drug dependent patients. These studies also suffer from small sample size, lack of follow-up period assessments and or comprehensive treatment outcome measures. To address these limitations, we decided to develop and investigate the efficacy of a paper and pencil cognitive rehabilitation package called NECOREDA (Neurocognitive Rehabilitation for Disease of Addiction) to improve neurocognitive deficits associated with drug dependence particularly caused by stimulants (e.g. amphetamine type stimulants and cocaine) and opiates. To evaluate the feasibility of NECOREDA program, we conducted a pilot study with 10 opiate and methamphetamine dependent patients for 3 months in outpatient setting. NECOREDA was revised based on qualitative comments received from clients and treatment providers. Final version of NECOREDA is composed of brain training exercises called “Brain Gym” and psychoeducational modules called “Brain Treasures” which is implemented in 16 training sessions interleaved with 16 review and practice sessions. NECOREDA will be evaluated as an add-on intervention to methadone maintenance treatment in a randomized clinical trial among opiate dependent patients starting from August 2015. We discuss methodological features of NECOREDA development and evaluation in this article. PMID:26649167

pHLIP®-Mediated Delivery of PEGylated Liposomes to Cancer Cells

PubMed Central

Yao, Lan; Daniels, Jennifer; Wijesinghe, Dayanjali; Andreev, Oleg A.; Reshetnyak, Yana K.

2013-01-01

We develop a method for pH-dependent fusion between liposomes and cellular membranes using pHLIP® (pH Low Insertion Peptide), which inserts into lipid bilayer of membrane only at low pH. Previously we establish the molecular mechanism of peptide action and show that pHLIP can target acidic diseased tissue. Here we investigate how coating of PEGylated liposomes with pHLIP might affect liposomal uptake by cells. The presence of pHLIP on the surface of PEGylated-liposomes enhanced membrane fusion and lipid exchange in a pH dependent fashion, leading to increase of cellular uptake and payload release, and inhibition of cell proliferation by liposomes containing ceramide. A novel type of pH-sensitive, “fusogenic” pHLIP-liposomes was developed, which could be used to selectively deliver various diagnostic and therapeutic agents to acidic diseased cells. PMID:23416366

A Pressing Need for Pharmacotherapy Development to Treat Drug Addiction: An Editorial from a Legal Perspective.

PubMed

Andraka-Christou, B

2016-01-01

Only three FDA-approved pharmacological treatments exist for treating opiate dependence, all of which are underprescribed and underused. No FDA-approved pharmacological treatments exist for cocaine or methamphetamine dependence. More evidence-based, FDA-approved treatments are needed for treating drug dependence, but pharmaceutical companies are unlikely to pursue such research without government incentives. Today pharmaceutical companies primarily conduct research and development (R&D) related to "blockbuster" and rare diseases; drug dependence does not fall into either category. Further compounding the problem, pharmaceutical companies have been recently slashing risky areas of research, rather than adopting new areas. Fortunately, the government has a number of options to incentivize pharmaceutical R&D relating to drug dependence treatment, including the following: market exclusivity for new medications, tax breaks, priority review vouchers, liability reduction, and an advanced market commitment. © 2016 Elsevier Inc. All rights reserved.

Overview of saxagliptin efficacy and safety in patients with type 2 diabetes and cardiovascular disease or risk factors for cardiovascular disease

PubMed Central

Toth, Peter P

2015-01-01

Most individuals with type 2 diabetes mellitus have or will develop multiple independent risk factors for cardiovascular disease, particularly coronary artery disease (CAD). CAD is the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus, and treating these patients is challenging. The risk of hypoglycemia, weight gain, or fluid retention with some diabetes medications should be considered when developing a treatment plan for individuals with a history of CAD or at risk for CAD. Dipeptidyl peptidase-4 inhibitors are oral antihyperglycemic agents that inhibit the breakdown of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, resulting in increased glucose-dependent insulin secretion and suppression of glucagon secretion. Saxagliptin is a potent and selective dipeptidyl peptidase-4 inhibitor that improves glycemic control and is generally well tolerated when used as monotherapy and as add-on therapy to other antihyperglycemic medications. This review summarizes findings from recently published post hoc analyses of saxagliptin clinical trials that have been conducted in patients with and without a history of cardiovascular disease and in patients with and without various risk factors for cardiovascular disease. The results show that saxagliptin was generally well tolerated and consistently improved glycemic control, as assessed by reductions from baseline in glycated hemoglobin, fasting plasma glucose concentration, and postprandial glucose concentration, regardless of the presence or absence of baseline cardiovascular disease, hypertension, statin use, number of cardiovascular risk factors, or high Framingham 10-year cardiovascular risk score. PMID:25565858

Women, drug dependency and consequences: a study from a developing country.

PubMed

Khajedaluee, Mohammad; Dadgarmoghaddam, Maliheh; Erfanian, Majidreza; Alipourtabrizi, Arash; Khadem-Rezaiyan, Majid

2015-01-01

Introduction. Addiction in women can expose them to malnutrition, high blood pressure, cancer, and some other dangerous diseases like hepatitis, AIDS, or other sexual transmitted diseases. The aim of this study was to assess illegal sexual relations in three groups of women. Methods. This is a cross-sectional study that was done on 236 girls and young women aged 16-25 years in 2012 in three groups: vulnerable women who have substance dependency (crimes that had made women incarcerated were considered as vulnerability in this study), invulnerable women who have substance dependency (substance dependent women without a history of incarceration), and a control group (women with no history of substance dependency or being in prison). Results. 43.8% of vulnerable women who have substance dependency had extramarital sexual relations; this percentage was 55.8% in invulnerable women who have substance dependency and 1.4% in the control group. Crystal and methamphetamine abuse was higher in addicts who had extramarital sexual relations and alcohol abuse was correlated with unsafe sexual intercourse (r = 0.36, P = 0.001). There was a statistically significant difference in extramarital sexual relation based on marital status (P < 0.001). Conclusions. Poverty, drug dependency, divorce, and alcohol consumption make women prone to other high risk behaviors that need more attention.

Preclinical Development of New Therapy for Glycogen Storage Diseases

PubMed Central

Sun, Baodong; Brooks, Elizabeth D.; Koeberl, Dwight D.

2015-01-01

Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of β2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available. PMID:26122079

Baclofen Toxicity in a Patient with Hemodialysis-Dependent End-Stage Renal Disease.

PubMed

Porter, Lauren M; Merrick, Stephanie S; Katz, Kenneth D

2017-04-01

Oral baclofen toxicity is extremely rare, but can affect patients with renal disease due to the drug's predominant renal clearance of approximately 69-85%. Patients with severely impaired renal function typically develop symptoms soon after initiating baclofen therapy, even at relatively low doses. A 69-year-old woman with a history of hemodialysis-dependent end-stage renal disease presented to the Emergency Department with encephalopathy, ataxia, and dystonia after the addition of a recent baclofen prescription for back pain (10 mg twice daily). She had been taking baclofen as prescribed for approximately 1 week when, the day prior to admission, she had increased her dose to a total of 40 mg. Diagnostic studies demonstrated the patient had chronic, end-stage renal disease and a supratherapeutic concentration of baclofen. Signs and symptoms resolved with hemodialysis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is of critical importance for emergency physicians to appreciate impaired baclofen clearance in those with underlying renal disease to obviate the potential for significant drug toxicity. Copyright © 2016 Elsevier Inc. All rights reserved.

Spreading of diseases through comorbidity networks across life and gender

NASA Astrophysics Data System (ADS)

Chmiel, Anna; Klimek, Peter; Thurner, Stefan

2014-11-01

The state of health of patients is typically not characterized by a single disease alone but by multiple (comorbid) medical conditions. These comorbidities may depend strongly on age and gender. We propose a specific phenomenological comorbidity network of human diseases that is based on medical claims data of the entire population of Austria. The network is constructed from a two-layer multiplex network, where in one layer the links represent the conditional probability for a comorbidity, and in the other the links contain the respective statistical significance. We show that the network undergoes dramatic structural changes across the lifetime of patients. Disease networks for children consist of a single, strongly interconnected cluster. During adolescence and adulthood further disease clusters emerge that are related to specific classes of diseases, such as circulatory, mental, or genitourinary disorders. For people over 65 these clusters start to merge, and highly connected hubs dominate the network. These hubs are related to hypertension, chronic ischemic heart diseases, and chronic obstructive pulmonary diseases. We introduce a simple diffusion model to understand the spreading of diseases on the disease network at the population level. For the first time we are able to show that patients predominantly develop diseases that are in close network proximity to disorders that they already suffer. The model explains more than 85% of the variance of all disease incidents in the population. The presented methodology could be of importance for anticipating age-dependent disease profiles for entire populations, and for design and validation of prevention strategies.

Kinetics of distribution of infections in networks

NASA Astrophysics Data System (ADS)

Avramov, I.

2007-06-01

SummaryWe develop a model for disease spreading in networks in a manner similar to the kinetics of crystallization of undercooled melts. The same kind of equations can be used in ecology and in sociology studies. For instance, they control the spread of gossip among the population. The time t dependence of the overall fraction α( t) of an infected network mass (individuals) affected by the disease is represented by an S-shaped curve. The derivative, i.e. the time dependence of intensity W( t) with which the epidemic evolves, is a bell-shaped curve. In essence, an analytical solution is offered describing the kinetics of spread of information along a ( d-dimensional) network.

Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling.

PubMed

Horn, Margaux A; Trafford, Andrew W

2016-04-01

Cardiovascular disease is a leading cause of death worldwide and there is a pressing need for new therapeutic strategies to treat such conditions. The risk of developing cardiovascular disease increases dramatically with age, yet the majority of experimental research is executed using young animals. The cardiac extracellular matrix (ECM), consisting predominantly of fibrillar collagen, preserves myocardial integrity, provides a means of force transmission and supports myocyte geometry. Disruptions to the finely balanced control of collagen synthesis, post-synthetic deposition, post-translational modification and degradation may have detrimental effects on myocardial functionality. It is now well established that the aged heart is characterized by fibrotic remodelling, but the mechanisms responsible for this are incompletely understood. Furthermore, studies using aged animal models suggest that interstitial remodelling with disease may be age-dependent. Thus with the identification of new therapeutic strategies targeting fibrotic remodelling, it may be necessary to consider age-dependent mechanisms. In this review, we discuss remodelling of the cardiac collagen matrix as a function of age, whilst highlighting potential novel mediators of age-dependent fibrotic pathways. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment

PubMed Central

LeBlanc, A C; Ramcharitar, J; Afonso, V; Hamel, E; Bennett, D A; Pakavathkumar, P; Albrecht, S

2014-01-01

Active Caspase-6 is abundant in the neuropil threads, neuritic plaques and neurofibrillary tangles of Alzheimer disease brains. However, its contribution to the pathophysiology of Alzheimer disease is unclear. Here, we show that higher levels of Caspase-6 activity in the CA1 region of aged human hippocampi correlate with lower cognitive performance. To determine whether Caspase-6 activity, in the absence of plaques and tangles, is sufficient to cause memory deficits, we generated a transgenic knock-in mouse that expresses a self-activated form of human Caspase-6 in the CA1. This Caspase-6 mouse develops age-dependent spatial and episodic memory impairment. Caspase-6 induces neuronal degeneration and inflammation. We conclude that Caspase-6 activation in mouse CA1 neurons is sufficient to induce neuronal degeneration and age-dependent memory impairment. These results indicate that Caspase-6 activity in CA1 could be responsible for the lower cognitive performance of aged humans. Consequently, preventing or inhibiting Caspase-6 activity in the aged may provide an efficient novel therapeutic approach against Alzheimer disease. PMID:24413155

Development of diet-induced insulin resistance in adult Drosophila melanogaster

PubMed Central

Morris, Siti Nur Sarah; Coogan, Claire; Chamseddin, Khalil; Fernandez-Kim, Sun Ok; Kolli, Santharam; Keller, Jeffrey N.; Bauer, Johannes H.

2013-01-01

The fruit fly Drosophila melanogaster is increasingly utilized as an alternative to costly rodent models to study human diseases. Fly models exist for a wide variety of human conditions, such as Alzheimer's and Parkinson’s Disease, or cardiac function. Advantages of the fly system are its rapid generation time and its low cost. However, the greatest strength of the fly system are the powerful genetic tools that allow for rapid dissection of molecular disease mechanisms. Here, we describe the diet-dependent development of metabolic phenotypes in adult fruit flies. Depending on the specific type of nutrient, as well as its relative quantity in the diet, flies show weight gain and changes in the levels of storage macromolecules. Furthermore, the activity of insulin-signaling in the major metabolic organ of the fly, the fat body, decreases upon overfeeding. This decrease in insulin-signaling activity in overfed flies is moreover observed when flies are challenged with an acute food stimulus, suggesting that overfeeding leads to insulin resistance. Similar changes were observed in aging flies, with the development of the insulin resistance-like phenotype beginning at early middle ages. Taken together, these data demonstrate that imbalanced diet disrupts metabolic homeostasis in adult D. melanogaster and promotes insulin-resistant phenotypes. Therefore, the fly system may be a useful alternative tool in the investigation of molecular mechanisms of insulin resistance and the development of pharmacologic treatment options. PMID:22542511

Prenatal programming of pulmonary hypertension induced by chronic hypoxia or ductal ligation in sheep.

PubMed

Papamatheakis, Demosthenes G; Chundu, Madalitso; Blood, Arlin B; Wilson, Sean M

2013-12-01

Pulmonary hypertension of the newborn is caused by a spectrum of functional and structural abnormalities of the cardiopulmonary circuit. The existence of multiple etiologies and an incomplete understanding of the mechanisms of disease progression have hindered the development of effective therapies. Animal models offer a means of gaining a better understanding of the fundamental basis of the disease. To that effect, a number of experimental animal models are being used to generate pulmonary hypertension in the fetus and newborn. In this review, we compare the mechanisms associated with pulmonary hypertension caused by two such models: in utero ligation of the ductus arteriosus and chronic perinatal hypoxia in sheep fetuses and newborns. In this manner, we make direct comparisons between ductal ligation and chronic hypoxia with respect to the associated mechanisms of disease, since multiple studies have been performed with both models in a single species. We present evidence that the mechanisms associated with pulmonary hypertension are dependent on the type of stress to which the fetus is subjected. Such an analysis allows for a more thorough evaluation of the disease etiology, which can help focus clinical treatments. The final part of the review provides a clinical appraisal of current treatment strategies and lays the foundation for developing individualized therapies that depend on the causative factors.

The Epimmunity Theory: The Single Cell Defenses against Infectious and Genetic Diseases.

PubMed

Barghouthi, Sameer A

2017-01-01

Single cell defense against diseases defines "epimmunity." Epimmunity is complementary to the immune system and can neither be substituted by innate nor by acquired immunity. Epimmunity, the proposed new branch of immunity, is further explored and analyzed for enucleated mature mammalian erythrocytes and nucleated erythrocytes of non-mammalian vertebrates leading to the development of "The Epimmunity Theory." Enucleation of mammalian erythroblast and inactivation of nuclei in erythrocytes of non-mammalian vertebrates are major contributors to the collective immunity: epimmunity, innate, and acquired. The fact that diseases of mature erythrocytes (MEs) are rare supports the notion that a single cell can resist microbial and genetic diseases; MEs are refractory to malaria and cancer. Nucleated cells, such as B-cells, T-cells, hepatocytes, and cell developmental stages are susceptible to genetic and specific microbial diseases depending on their nuclear activities and the receptors they express; such cells show lower epimmunity relative to MEs. Epimmunity is important as a disease insulator that prevents the spread of diseases from an infected tissue to the majority of other tissues. Breakdown of epimmunity may lead to disease development.

Redefining meaningful age groups in the context of disease.

PubMed

Geifman, Nophar; Cohen, Raphael; Rubin, Eitan

2013-12-01

Age is an important factor when considering phenotypic changes in health and disease. Currently, the use of age information in medicine is somewhat simplistic, with ages commonly being grouped into a small number of crude ranges reflecting the major stages of development and aging, such as childhood or adolescence. Here, we investigate the possibility of redefining age groups using the recently developed Age-Phenome Knowledge-base (APK) that holds over 35,000 literature-derived entries describing relationships between age and phenotype. Clustering of APK data suggests 13 new, partially overlapping, age groups. The diseases that define these groups suggest that the proposed divisions are biologically meaningful. We further show that the number of different age ranges that should be considered depends on the type of disease being evaluated. This finding was further strengthened by similar results obtained from clinical blood measurement data. The grouping of diseases that share a similar pattern of disease-related reports directly mirrors, in some cases, medical knowledge of disease-age relationships. In other cases, our results may be used to generate new and reasonable hypotheses regarding links between diseases.

Virus signaling and apoptosis in the central nervous system infection.

PubMed

Perkins, Dana

2005-09-01

Viruses target the central nervous system (CNS) incidentally, due to complications of systemic infection, or specifically, by ascending via the axons of peripheral and cranial nerves. In the CNS, viruses cause acute disease (viz. encephalitis), latent infections or neurodegenerative pathology. Causation of acute disease or immune-mediated pathology, and virus involvement in the etiology of chronic neurodegenerative diseases depends, at least in part, on the ability to commander signaling pathways. Better understanding of these virus-host cell interactions will help identify molecular targets for the development of improved therapeutic strategies.

Context Dependence of Protein Misfolding and Structural Strains in Neurodegenerative Diseases

PubMed Central

Mehta, Anil K.; Rosen, Rebecca F.; Childers, W. Seth; Gehman, John D.; Walker, Lary C.; Lynn, David G.

2014-01-01

Vast arrays of structural forms are accessible to simple amyloid peptides and environmental conditions can direct assembly into single phases. These insights are now being applied to the aggregation of the Aβ peptide of Alzheimer’s disease (AD) and the identification of causative phases. We extend use of the imaging agent Pittsburgh compound B (PiB) to discriminate among Aβ phases and begin to define conditions of relevance to the disease state. And we specifically highlight the development of methods for defining the structures of these more complex phases. PMID:23893572

Current Guidelines, Common Clinical Pitfalls, and Future Directions for Laboratory Diagnosis of Lyme Disease, United States

PubMed Central

Moore, Andrew; Nelson, Christina; Molins, Claudia; Mead, Paul

2016-01-01

In the United States, Lyme disease is caused by Borrelia burgdorferi and transmitted to humans by blacklegged ticks. Patients with an erythema migrans lesion and epidemiologic risk can receive a diagnosis without laboratory testing. For all other patients, laboratory testing is necessary to confirm the diagnosis, but proper interpretation depends on symptoms and timing of illness. The recommended laboratory test in the United States is 2-tiered serologic analysis consisting of an enzyme-linked immunoassay or immunofluorescence assay, followed by reflexive immunoblotting. Sensitivity of 2-tiered testing is low (30%–40%) during early infection while the antibody response is developing (window period). For disseminated Lyme disease, sensitivity is 70%–100%. Specificity is high (>95%) during all stages of disease. Use of other diagnostic tests for Lyme disease is limited. We review the rationale behind current US testing guidelines, appropriate use and interpretation of tests, and recent developments in Lyme disease diagnostics. PMID:27314832

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.

Postnatal airway growth in cystic fibrosis piglets.

PubMed

Adam, Ryan J; Abou Alaiwa, Mahmoud H; Bouzek, Drake C; Cook, Daniel P; Gansemer, Nicholas D; Taft, Peter J; Powers, Linda S; Stroik, Mallory R; Hoegger, Mark J; McMenimen, James D; Hoffman, Eric A; Zabner, Joseph; Welsh, Michael J; Meyerholz, David K; Stoltz, David A

2017-09-01

Mutations in the gene encoding the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) anion channel cause CF. The leading cause of death in the CF population is lung disease. Increasing evidence suggests that in utero airway development is CFTR-dependent and that developmental abnormalities may contribute to CF lung disease. However, relatively little is known about postnatal CF airway growth, largely because such studies are limited in humans. Therefore, we examined airway growth and lung volume in a porcine model of CF. We hypothesized that CF pigs would have abnormal postnatal airway growth. To test this hypothesis, we performed CT-based airway and lung volume measurements in 3-wk-old non-CF and CF pigs. We found that 3-wk-old CF pigs had tracheas of reduced caliber and irregular shape. Their bronchial lumens were reduced in size proximally but not distally, were irregularly shaped, and had reduced distensibility. Our data suggest that lack of CFTR results in aberrant postnatal airway growth and development, which could contribute to CF lung disease pathogenesis. NEW & NOTEWORTHY This CT scan-based study of airway morphometry in the cystic fibrosis (CF) postnatal period is unique, as analogous studies in humans are greatly limited for ethical and technical reasons. Findings such as reduced airway lumen area and irregular caliber suggest that airway growth and development are CF transmembrane conductance regulator-dependent and that airway growth defects may contribute to CF lung disease pathogenesis. Copyright © 2017 the American Physiological Society.

Systemic lupus erythematosus: Is it one disease?

PubMed

Rivas-Larrauri, Francisco; Yamazaki-Nakashimada, Marco Antonio

2016-01-01

Systemic lupus erythematosus (SLE) is a multisystemic disease with a variety of clinical presentations. Monogenic predisposing conditions to the development of this disease have been described. As examples, an impaired expression of interferon-α regulated genes or complement deficiencies have been reported in patients with SLE, with particular clinical presentations. Those defects present particular presentations and a different severity, making an argument that lupus is not a single disease but many. Treatment could be individualized depending on the underlying defect generating the subtype of the disease. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Concentration-dependent Cu(II) binding to prion protein

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Lu, Wenchang; Bernholc, Jerry

2008-03-01

The prion protein plays a causative role in several neurodegenerative diseases, including mad cow disease in cattle and Creutzfeldt-Jakob disease in humans. The normal function of the prion protein is unknown, but it has been linked to its ability to bind copper ions. Experimental evidence suggests that copper can be bound in three distinct modes depending on its concentration, but only one of those binding modes has been fully characterized experimentally. Using a newly developed hybrid DFT/DFT method [1], which combines Kohn-Sham DFT with orbital-free DFT, we have examined all the binding modes and obtained their detailed binding geometries and copper ion binding energies. Our results also provide explanation for experiments, which have found that when the copper concentration increases the copper binding mode changes, surprisingly, from a stronger to a weaker one. Overall, our results indicate that prion protein can function as a copper buffer. 1. Hodak, Lu, Bernholc, JCP, in press.

Managing malignant biliary obstruction in pancreas cancer: Choosing the appropriate strategy

PubMed Central

Boulay, Brian R; Parepally, Mayur

2014-01-01

Most patients with pancreatic cancer develop malignant biliary obstruction. Treatment of obstruction is generally indicated to relieve symptoms and improve morbidity and mortality. First-line therapy consists of endoscopic biliary stent placement. Recent data comparing plastic stents to self-expanding metallic stents (SEMS) has shown improved patency with SEMS. The decision of whether to treat obstruction and the means for doing so depends on the clinical scenario. For patients with resectable disease, preoperative biliary decompression is only indicated when surgery will be delayed or complications of jaundice exist. For patients with locally advanced disease, self-expanding metal stents are superior to plastic stents for long-term patency. For patients with advanced disease, the choice of metallic or plastic stent depends on life expectancy. When endoscopic stent placement fails, percutaneous or surgical treatments are appropriate. Endoscopic therapy or surgical approach can be used to treat concomitant duodenal and biliary obstruction. PMID:25071329

Pathways of cellular proteostasis in aging and disease.

PubMed

Klaips, Courtney L; Jayaraj, Gopal Gunanathan; Hartl, F Ulrich

2018-01-02

Ensuring cellular protein homeostasis, or proteostasis, requires precise control of protein synthesis, folding, conformational maintenance, and degradation. A complex and adaptive proteostasis network coordinates these processes with molecular chaperones of different classes and their regulators functioning as major players. This network serves to ensure that cells have the proteins they need while minimizing misfolding or aggregation events that are hallmarks of age-associated proteinopathies, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. It is now clear that the capacity of cells to maintain proteostasis undergoes a decline during aging, rendering the organism susceptible to these pathologies. Here we discuss the major proteostasis pathways in light of recent research suggesting that their age-dependent failure can both contribute to and result from disease. We consider different strategies to modulate proteostasis capacity, which may help develop urgently needed therapies for neurodegeneration and other age-dependent pathologies. © 2018 Klaips et al.

Dose-Dependent Lowering of Mutant Huntingtin Using Antisense Oligonucleotides in Huntington Disease Patients.

PubMed

van Roon-Mom, Willeke M C; Roos, Raymund A C; de Bot, Susanne T

2018-04-01

On December 11 of 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx Phase 1/2a study in Huntington disease (HD) patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the first trial targeting the cause of HD, namely the mutant huntingtin protein, using antisense oligonucleotides (ASOs). The press release also states that the primary endpoints of the study (safety and tolerability) were met, but does not contain data. This news follows the approval of another therapeutic ASO nusinersen (trade name Spinraza) for a neurological disease, spinal muscular atrophy, by the U.S. Food and Drug Administration and European Medicines Agency, in 2016 and 2017, respectively. Combined, this offers hope for the development of the HTTRx therapy for HD patients.

Humans as holobionts: implications for prevention and therapy.

PubMed

van de Guchte, Maarten; Blottière, Hervé M; Doré, Joël

2018-05-01

The human gut microbiota is increasingly recognized for its important or even decisive role in health. As it becomes clear that microbiota and host mutually affect and depend on each other in an intimate relationship, a holistic view of the gut microbiota-host association imposes itself. Ideally, a stable state of equilibrium, homeostasis, is maintained and serves health, but signs are that perturbation of this equilibrium beyond the limits of resilience can propel the system into an alternative stable state, a pre-disease state, more susceptible to the development of chronic diseases. The microbiota-host equilibrium of a large and growing proportion of individuals in Western society may represent such a pre-disease state and explain the explosive development of chronic diseases such as inflammatory bowel disease, obesity, and other inflammatory diseases. These diseases themselves represent other alternative stable states again and are therefore hard to cure. The holistic view of the microbiota-host association where feedback loops between microbiota and host are thought to maintain the system in a stable state-be it a healthy, pre-disease, or disease state-implies that integrated approaches, addressing host processes and microbiota, should be used to treat or prevent (pre-)disease.

Ambiguous roles of innate lymphoid cells in chronic development of liver diseases.

PubMed

Shen, Yue; Li, Jing; Wang, Si-Qi; Jiang, Wei

2018-05-14

Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets.

Ambiguous roles of innate lymphoid cells in chronic development of liver diseases

PubMed Central

Shen, Yue; Li, Jing; Wang, Si-Qi; Jiang, Wei

2018-01-01

Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets. PMID:29760540

Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia, and atherosclerosis.

PubMed

Russell, James C; Proctor, Spencer D

2006-01-01

Cardiovascular disease, the leading cause of death in much of the modern world, is the common symptomatic end stage of a number of distinct diseases and, therefore, is multifactorial and polygenetic in character. The two major underlying causes are disorders of lipid metabolism and metabolic syndrome. The ability to develop preventative and ameliorative treatments will depend on animal models that mimic human disease processes. The focus of this review is to identify suitable animal models and insights into cardiovascular disease achieved to date using such models. The ideal animal model of cardiovascular disease will mimic the human subject metabolically and pathophysiologically, will be large enough to permit physiological and metabolic studies, and will develop end-stage disease comparable to those in humans. Given the complex multifactorial nature of cardiovascular disease, no one species will be suitable for all studies. Potential larger animal models are problematic due to cost, ethical considerations, or poor pathophysiological comparability to humans. Rabbits require high-cholesterol diets to develop cardiovascular disease, and there are no rabbit models of metabolic syndrome. Spontaneous mutations in rats provide several complementary models of obesity, hyperlipidemia, insulin resistance, and type 2 diabetes, one of which spontaneously develops cardiovascular disease and ischemic lesions. The mouse, like normal rats, is characteristically resistant to cardiovascular disease, although genetically altered strains respond to cholesterol feeding with atherosclerosis, but not with end-stage ischemic lesions. The most useful and valid species/strains for the study of cardiovascular disease appear to be small rodents, rats, and mice. This fragmented field would benefit from a consensus on well-characterized appropriate models for the study of different aspects of cardiovascular disease and a renewed emphasis on the biology of underlying diseases.

Hodgkin's disease: thyroid dysfunction following external irradiation

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

Tamura, K.; Shimaoka, K.

1981-01-01

The thyroid gland is commonly included in the field of radiation therapy for patients with malignant lymphoma and with head and neck tumors. The radiation dose for malignant diseases varies considerably depending on the purpose of treatment and the institutional policies. A substantial number of these patients are developing subclinical and clinical hypothyroidism. The risk of developing hypothyroidism after a moderate radiation dose of 2000 to 4500 rads has been reported to be 10 to 20 percent. In addition, subclinical hypothyroidism is induced further in one third of the patients. There are also suggestions that external irradiation of the thyroidmore » gland in patients with malignant lymphomas, as well as internal irradiation with radioiodine of the normal and hyperthyroid human thyroid glands, would induce elevations of serum antithyroid autoantibody titers. However, only a few cases of Graves disease following irradiation to the thyroid gland have been reported. We encountered a young woman who received radiation therapy to the mantle field for her Hodgkin's disease and developed hypothyroxinemia without overt signs and symptoms of hypothyroidism, followed by appearance of nodular goiter and then full-blown Graves disease.« less

Environmental determinants of allergy and asthma in early life.

PubMed

Burbank, Allison J; Sood, Amika K; Kesic, Matthew J; Peden, David B; Hernandez, Michelle L

2017-07-01

Allergic disease prevalence has increased significantly in recent decades. Primary prevention efforts are being guided by study of the exposome (or collective environmental exposures beginning during the prenatal period) to identify modifiable factors that affect allergic disease risk. In this review we explore the evidence supporting a relationship between key components of the external exposome in the prenatal and early-life periods and their effect on atopy development focused on microbial, allergen, and air pollution exposures. The abundance and diversity of microbial exposures during the first months and years of life have been linked with risk of allergic sensitization and disease. Indoor environmental allergen exposure during early life can also affect disease development, depending on the allergen type, dose, and timing of exposure. Recent evidence supports the role of ambient air pollution in allergic disease inception. The lack of clarity in the literature surrounding the relationship between environment and atopy reflects the complex interplay between cumulative environmental factors and genetic susceptibility, such that no one factor dictates disease development in all subjects. Understanding the effect of the summation of environmental exposures throughout a child's development is needed to identify cost-effective interventions that reduce atopy risk in children. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Intrathoracic extrapulmonary hydatid cysts.

PubMed

Atoini, Fouad; Ouarssani, Aziz; Hachimi, Moulay Ahmed; Aitlhou, Fatima; Rguibi, Mustapha Idrissi; Hommadi, Abdelaziz

2012-01-01

Hydatid disease caused by echinococcus granulosus is still a serious problem in both underdeveloped and developing countries. Clinical signs of the disease are not specific. Most patients have a few symptoms when a hydatid cyst is discovered. Symptoms depend on its location, size and complications. Parasite can settle in every organ and tissue in the human body. We report two cases with intrathoracic extrapulmonary hydatid cyst with multiple cysts. Pathophysiology of the mode of dissemination, and surgery are discussed.

TEACH (Train to Enable/Achieve Culturally Sensitive Healthcare)

NASA Technical Reports Server (NTRS)

Maulitz, Russell; Santarelli, Thomas; Barnieu, Joanne; Rosenzweig, Larry; Yi, Na Yi; Zachary, Wayne; OConnor, Bonnie

2010-01-01

Personnel from diverse ethnic and demographic backgrounds come together in both civilian and military healthcare systems, facing diagnoses that at one level are equalizers: coronary disease is coronary disease, breast cancer is breast cancer. Yet the expression of disease in individuals from different backgrounds, individual patient experience of disease as a particular illness, and interactions between patients and providers occurring in any given disease scenario, all vary enormously depending on the fortuity of the equation of "which patient happens to arrive in whose exam room." Previously, providers' absorption of lessons-learned depended on learning as an apprentice would when exposed over time to multiple populations. As a result, and because providers are often thrown into situations where communications falter through inadequate direct patient experience, diversity in medicine remains a training challenge. The questions then become: Can simulation and virtual training environments (VTEs) be deployed to short-track and standardize this sort of random-walk problem? Can we overcome the unevenness of training caused by some providers obtaining the valuable exposure to diverse populations, whereas others are left to "sink or swim"? This paper summarizes developing a computer-based VTE called TEACH (Training to Enable/Achieve Culturally Sensitive Healthcare). TEACH was developed to enhance healthcare providers' skills in delivering culturally sensitive care to African-American women with breast cancer. With an authoring system under development to ensure extensibility, TEACH allows users to role-play in clinical oncology settings with virtual characters who interact on the basis of different combinations of African American sub-cultural beliefs regarding breast cancer. The paper reports on the roll-out and evaluation of the degree to which these interactions allow providers to acquire, practice, and refine culturally appropriate communication skills and to achieve cultural and individual personalization of healthcare in their clinical practices.

Bidirectional Regulation of Amyloid Precursor Protein-Induced Memory Defects by Nebula/DSCR1: A Protein Upregulated in Alzheimer's Disease and Down Syndrome

PubMed Central

Shaw, Jillian L.; Zhang, Shixing

2015-01-01

Aging individuals with Down syndrome (DS) have an increased risk of developing Alzheimer's disease (AD), a neurodegenerative disorder characterized by impaired memory. Memory problems in both DS and AD individuals usually develop slowly and progressively get worse with age, but the cause of this age-dependent memory impairment is not well understood. This study examines the functional interactions between Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. Using Drosophila as a model, we find that overexpression of nebula (fly homolog of DSCR1) initially protects against APP-induced memory defects by correcting calcineurin and cAMP signaling pathways but accelerates the rate of memory loss and exacerbates mitochondrial dysfunction in older animals. We report that transient upregulation of Nebula/DSCR1 or acute pharmacological inhibition of calcineurin in aged flies protected against APP-induced memory loss. Our data suggest that calcineurin dyshomeostasis underlies age-dependent memory impairments and further imply that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory impairments in AD in DS. SIGNIFICANCE STATEMENT Most Down syndrome (DS) individuals eventually develop Alzheimer's disease (AD)-like dementia, but mechanisms underlying this age-dependent memory impairment remain poorly understood. This study examines Nebula/Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. We uncover a previously unidentified role for Nebula/DSCR1 in modulating APP-induced memory defects during aging. We show that upregulation of Nebula/DSCR1, an inhibitor of calcineurin, rescues APP-induced memory defects in young flies but enhances memory loss of older flies. Excitingly, transient Nebula/DSCR1 overexpression or calcineurin inhibition in aged flies ameliorates APP-mediated memory problems. These results suggest that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory loss in DS and AD and points to correcting calcineurin signaling as a means to improve memory during aging. PMID:26269644

Bidirectional Regulation of Amyloid Precursor Protein-Induced Memory Defects by Nebula/DSCR1: A Protein Upregulated in Alzheimer's Disease and Down Syndrome.

PubMed

Shaw, Jillian L; Zhang, Shixing; Chang, Karen T

2015-08-12

Aging individuals with Down syndrome (DS) have an increased risk of developing Alzheimer's disease (AD), a neurodegenerative disorder characterized by impaired memory. Memory problems in both DS and AD individuals usually develop slowly and progressively get worse with age, but the cause of this age-dependent memory impairment is not well understood. This study examines the functional interactions between Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. Using Drosophila as a model, we find that overexpression of nebula (fly homolog of DSCR1) initially protects against APP-induced memory defects by correcting calcineurin and cAMP signaling pathways but accelerates the rate of memory loss and exacerbates mitochondrial dysfunction in older animals. We report that transient upregulation of Nebula/DSCR1 or acute pharmacological inhibition of calcineurin in aged flies protected against APP-induced memory loss. Our data suggest that calcineurin dyshomeostasis underlies age-dependent memory impairments and further imply that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory impairments in AD in DS. Most Down syndrome (DS) individuals eventually develop Alzheimer's disease (AD)-like dementia, but mechanisms underlying this age-dependent memory impairment remain poorly understood. This study examines Nebula/Down syndrome critical region 1 (DSCR1) and amyloid-precursor protein (APP), proteins upregulated in both DS and AD, in regulating memory. We uncover a previously unidentified role for Nebula/DSCR1 in modulating APP-induced memory defects during aging. We show that upregulation of Nebula/DSCR1, an inhibitor of calcineurin, rescues APP-induced memory defects in young flies but enhances memory loss of older flies. Excitingly, transient Nebula/DSCR1 overexpression or calcineurin inhibition in aged flies ameliorates APP-mediated memory problems. These results suggest that chronic Nebula/DSCR1 upregulation may contribute to age-dependent memory loss in DS and AD and points to correcting calcineurin signaling as a means to improve memory during aging. Copyright © 2015 the authors 0270-6474/15/3511374-10$15.00/0.

Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease

PubMed Central

George, Britta; Verma, Rakesh; Soofi, Abdulsalam A.; Garg, Puneet; Zhang, Jidong; Park, Tae-Ju; Giardino, Laura; Ryzhova, Larisa; Johnstone, Duncan B.; Wong, Hetty; Nihalani, Deepak; Salant, David J.; Hanks, Steven K.; Curran, Tom; Rastaldi, Maria Pia; Holzman, Lawrence B.

2012-01-01

The morphology of healthy podocyte foot processes is necessary for maintaining the characteristics of the kidney filtration barrier. In most forms of glomerular disease, abnormal filter barrier function results when podocytes undergo foot process spreading and retraction by remodeling their cytoskeletal architecture and intercellular junctions during a process known as effacement. The cell adhesion protein nephrin is necessary for establishing the morphology of the kidney podocyte in development by transducing from the specialized podocyte intercellular junction phosphorylation-mediated signals that regulate cytoskeletal dynamics. The present studies extend our understanding of nephrin function by showing that nephrin activation in cultured podocytes induced actin dynamics necessary for lamellipodial protrusion. This process required a PI3K-, Cas-, and Crk1/2-dependent signaling mechanism distinct from the previously described nephrin-Nck1/2 pathway necessary for assembly and polymerization of actin filaments. Our present findings also support the hypothesis that mechanisms governing lamellipodial protrusion in culture are similar to those used in vivo during foot process effacement in a subset of glomerular diseases. In mice, podocyte-specific deletion of Crk1/2 prevented foot process effacement in one model of podocyte injury and attenuated foot process effacement and associated proteinuria in a delayed fashion in a second model. In humans, focal adhesion kinase and Cas phosphorylation — markers of focal adhesion complex–mediated Crk-dependent signaling — was induced in minimal change disease and membranous nephropathy, but not focal segmental glomerulosclerosis. Together, these observations suggest that activation of a Cas-Crk1/2–dependent complex is necessary for foot process effacement observed in distinct subsets of human glomerular diseases. PMID:22251701

Deletion of chromosome 9p21 noncoding cardiovascular risk interval in mice alters Smad2 signaling and promotes vascular aneurysm.

PubMed

Loinard, Céline; Basatemur, Gemma; Masters, Leanne; Baker, Lauren; Harrison, James; Figg, Nichola; Vilar, José; Sage, Andrew P; Mallat, Ziad

2014-12-01

Vascular aneurysm is an abnormal local dilatation of an artery that can lead to vessel rupture and sudden death. The only treatment involves surgical or endovascular repair or exclusion. There is currently no approved medical therapy for this condition. Recent data established a strong association between genetic variants in the 9p21 chromosomal region in humans and the presence of cardiovascular diseases, including aneurysms. However, the mechanisms linking this 9p21 DNA variant to cardiovascular risk are still unknown. Here, we show that deletion of the orthologous 70-kb noncoding interval on mouse chromosome 4 (chr4(Δ70kb/Δ70kb) mice) is associated with reduced aortic expression of cyclin-dependent kinase inhibitor genes p19Arf and p15Inkb. Vascular smooth muscle cells from chr4(Δ70kb/Δ70kb) mice show reduced transforming growth factor-β-dependent canonical Smad2 signaling but increased cyclin-dependent kinase-dependent Smad2 phosphorylation at linker sites, a phenotype previously associated with tumor growth and consistent with the mechanistic link between reduced canonical transforming growth factor-β signaling and susceptibility to vascular diseases. We also show that targeted deletion of the 9p21 risk interval promotes susceptibility to aneurysm development and rupture when mice are subjected to a validated model of aneurysm formation. The vascular disease of chr4(Δ70kb/Δ70kb) mice is prevented by treatment with a cyclin-dependent kinase inhibitor. The results establish a direct mechanistic link between 9p21 noncoding risk interval and susceptibility to aneurysm and may have important implications for the understanding and treatment of vascular diseases. © 2014 American Heart Association, Inc.

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.

Substance dependence and non-dependence in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD): can an identical conceptualization be achieved?

PubMed

Saunders, John B

2006-09-01

This review summarizes the history of the development of diagnostic constructs that apply to repetitive substance use, and compares and contrasts the nature, psychometric performance and utility of the major diagnoses in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD) diagnostic systems. The available literature was reviewed with a particular focus on diagnostic concepts that are relevant for clinical and epidemiological practice, and so that research questions could be generated that might inform the development of the next generation of DSM and ICD diagnoses. The substance dependence syndrome is a psychometrically robust and clinically useful construct, which applies to a range of psychoactive substances. The differences between the DSM fourth edition (DSM-IV) and the ICD tenth edition (ICD-10) versions are minimal and could be resolved. DSM-IV substance abuse performs moderately well but, being defined essentially by social criteria, may be culture-dependent. ICD-10 harmful substance use performs poorly as a diagnostic entity. There are good prospects for resolving many of the differences between the DSM and ICD systems. A new non-dependence diagnosis is required. There would also be advantages in a subthreshold diagnosis of hazardous or risky substance use being incorporated into the two systems. Biomedical research can be drawn upon to define a psychophysiological 'driving force' which could underpin a broad spectrum of substance use disorders.

Malassezia species and seborrheic dermatitis.

PubMed

Zisova, Lilia G

2009-01-01

Malassezia spp. are medically important dimorphic, lipophilic yeasts that form part of the normal cutaneous microflora of human. Seborrheic dermatitis is a multifactor disease that needs endogenous and exogenous predisposing factors for its development. Presence of these factors leads to reproduction of the saprophytic opportunistic pathogen Malassezia spp. and development of a disease. The inflammatory reaction against the yeast Malassezia is considered basic in the etiology of the seborrheic dermatitis. The pathogenesis and exact mechanisms via which these yeasts cause inflammation are still not fully elucidated. They are rather complex and subject of controversy in literature. Most probably Malassezia spp. cause seborrheic dermatitis by involving and combining both nonummune and immune mechanisms (nonspecific and specific). Which of these mechanisms will dominate in any single case depends on the number and virulence of the yeasts as well as on the microorganism reactivity. In the recent years a great interest have been aroused by the epidemiological investigations. Depending on the geographical place of the countries different Malassezia species in seborrheic dermatitis dominate in the different countries. In view of the etiology and pathogenesis of the seborrheic dermatitis comprehensive antifungal preparations have been recently introduced and are nowadays the basic therapeutic resource in the treatment of this disease.

Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

PubMed Central

Corrado, Alessia; Donato, Paolo; Maccari, Silvia; Cecchi, Raffaella; Spadafina, Tiziana; Arcidiacono, Letizia; Tavarini, Simona; Sammicheli, Chiara; Laera, Donatello; Manetti, Andrea Guido Oreste; Ruggiero, Paolo; Galletti, Bruno; Nuti, Sandra; De Gregorio, Ennio; Bertholet, Sylvie; Seubert, Anja; Bagnoli, Fabio; Bensi, Giuliano; Chiarot, Emiliano

2016-01-01

Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans. Characterization of the local and systemic inflammatory and immune responses following bacterial infection brought to light specific signatures of disease. Immunization of mice with the vaccine formulation we have recently described (4C-Staph), induced a strong antibody response and specific CD4+ effector memory T cells, and resulted in reduced bacterial load in the knee joints, a milder general inflammatory state and protection against bacterial-mediated cellular toxicity. Possible correlates of protection are finally proposed, which might contribute to the development of an effective vaccine for human use. PMID:27901071

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.

A scalable lysyl hydroxylase 2 expression system and luciferase-based enzymatic activity assay

PubMed Central

Guo, Hou-Fu; Cho, Eun Jeong; Devkota, Ashwini K.; Chen, Yulong; Russell, William; Phillips, George N.; Yamauchi, Mitsuo; Dalby, Kevin; Kurie, Jonathan M.

2017-01-01

Hydroxylysine aldehyde-derived collagen cross-links (HLCCs) accumulate in fibrotic tissues and certain types of cancer and are thought to drive the progression of these diseases. HLCC formation is initiated by lysyl hydroxylase 2 (LH2), an Fe(II) and α-ketoglutarate (αKG)-dependent oxygenase that hydroxylates telopeptidyl lysine residues on collagen. Development of LH2 antagonists for the treatment of these diseases will require a reliable source of recombinant LH2 protein and a non-radioactive LH2 enzymatic activity assay that is amenable to high throughput screens of small molecule libraries. However, LH2 protein generated previously using E coli– or insect-based expression systems was either insoluble or enzymatically unstable, and LH2 enzymatic activity assays have measured radioactive CO2 released from 14C-labeled αKG during its conversion to succinate. To address these deficiencies, we have developed a scalable process to purify human LH2 protein from Chinese hamster ovary cell-derived conditioned media samples and a luciferase-based assay that quantifies LH2-dependent conversion of αKG to succinate. These methodologies may be applicable to other Fe(II) and αKG-dependent oxygenase systems. PMID:28216326

Persistent activation of an innate immune axis translates respiratory viral infection into chronic lung disease

PubMed Central

Kim, Edy Y.; Battaile, John T.; Patel, Anand C.; You, Yingjian; Agapov, Eugene; Grayson, Mitchell H.; Benoit, Loralyn A.; Byers, Derek E.; Alevy, Yael; Tucker, Jennifer; Swanson, Suzanne; Tidwell, Rose; Tyner, Jeffrey W.; Morton, Jeffrey D.; Castro, Mario; Polineni, Deepika; Patterson, G. Alexander; Schwendener, Reto A.; Allard, John D.; Peltz, Gary; Holtzman, Michael J.

2008-01-01

To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of a chronic lung disease that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after infection with a common type of respiratory virus is cleared to trace levels of noninfectious virus. Unexpectedly, the chronic inflammatory disease arises independently of an adaptive immune response and is driven by IL-13 produced by macrophages stimulated by CD1d-dependent TCR-invariant NKT cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a novel NKT cell-macrophage innate immune axis. PMID:18488036

Glyceollin I reverses epithelial to mesenchymal transition in letrozole resistance

USDA-ARS?s Scientific Manuscript database

Although aromatase inhibitors, such as letrozole; are standard endocrine therapy for postmenopausal women with early stage metastatic estrogen-dependent breast cancer, the major limitation in managing this disease is the development of drug resistance; therefore, a better understanding of this proce...

Measuring quality of life in opioid-dependent people: a systematic review of assessment instruments.

PubMed

Strada, Lisa; Vanderplasschen, Wouter; Buchholz, Angela; Schulte, Bernd; Muller, Ashley E; Verthein, Uwe; Reimer, Jens

2017-12-01

Opioid dependence is a chronic relapsing disorder. Despite increasing research on quality of life (QOL) in people with opioid dependence, little attention has been paid to the instruments used. This systematic review examines the suitability of QOL instruments for use in opioid-dependent populations and the instruments' quality. A systematic search was performed in the databases Medline, PsycInfo, The Cochrane Library, and CINAHL. Articles were eligible if they assessed QOL of opioid-dependent populations using a validated QOL instrument. Item content relevance to opioid-dependent people was evaluated by means of content analysis, and instrument properties were assessed using minimum standards for patient-reported outcome measures. Eighty-nine articles were retrieved, yielding sixteen QOL instruments, of which ten were assessed in this review. Of the ten instruments, six were disease specific, but none for opioid dependence. Two instruments had good item content relevance. The conceptual and measurement model were described in seven instruments. Four instruments were developed with input from the respective target population. Eight instruments had low respondent and administrator burden. Psychometric properties were either not assessed in opioid-dependent populations or were inconclusive or moderate. No instrument scored perfectly on both the content and properties. The limited suitability of instruments for opioid-dependent people hinders accurate and sensitive measurement of QOL in this population. Future research is in need of an opioid dependence-specific QOL instrument to measure the true impact of the disease on people's lives and to evaluate treatment-related services.

Understanding the Effects of Host Evolution and Skin Bacteria Composition on Disease Vector Choices

DTIC Science & Technology

2016-04-14

attractiveness of hosts to microbes suggests that if we are to develop a probiotic that deters mosquitoes that its value will depend greatly on the genome of the...influence of a single human gene on the attractiveness of hosts to microbes suggests that if we are to develop a probiotic that deters mosquitoes that

Disease progression model for Clinical Dementia Rating–Sum of Boxes in mild cognitive impairment and Alzheimer’s subjects from the Alzheimer’s Disease Neuroimaging Initiative

PubMed Central

Samtani, Mahesh N; Raghavan, Nandini; Novak, Gerald; Nandy, Partha; Narayan, Vaibhav A

2014-01-01

Background The objective of this analysis was to develop a nonlinear disease progression model, using an expanded set of covariates that captures the longitudinal Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB) scores. These were derived from the Alzheimer’s Disease Neuroimaging Initiative ADNI-1 study, of 301 Alzheimer’s disease and mild cognitive impairment patients who were followed for 2–3 years. Methods The model describes progression rate and baseline disease score as a function of covariates. The covariates that were tested fell into five groups: a) hippocampal volume; b) serum and cerebrospinal fluid (CSF) biomarkers; c) demographics and apolipoprotein Epsilon 4 (ApoE4) allele status; d) baseline cognitive tests; and e) disease state and comedications. Results Covariates associated with baseline disease severity were disease state, hippocampal volume, and comedication use. Disease progression rate was influenced by baseline CSF biomarkers, Trail-Making Test part A score, delayed logical memory test score, and current level of impairment as measured by CDR–SB. The rate of disease progression was dependent on disease severity, with intermediate scores around the inflection point score of 10 exhibiting high disease progression rate. The CDR–SB disease progression rate in a typical patient, with late mild cognitive impairment and mild Alzheimer’s disease, was estimated to be approximately 0.5 and 1.4 points/year, respectively. Conclusions In conclusion, this model describes disease progression in terms of CDR–SB changes in patients and its dependency on novel covariates. The CSF biomarkers included in the model discriminate mild cognitive impairment subjects as progressors and nonprogressors. Therefore, the model may be utilized for optimizing study designs, through patient population enrichment and clinical trial simulations. PMID:24926196

Considering sex and gender in Alzheimer disease and other dementias.

PubMed

Podcasy, Jessica L; Epperson, C Neill

2016-12-01

Suffering related to dementia is multifaceted because cognitive and physical functioning slowly deteriorates. Advanced age and sex, two of the most prominent risk factors for dementia, are not modifiable. Lifestyle factors such as smoking, excessive alcohol use, and poor diet modulate susceptibility to dementia in both males and females. The degree to which the resulting health conditions (eg, obesity, type 2 diabetes, and cardiovascular disease) impact dementia risk varies by sex. Depending on the subtype of dementia, the ratio of male to female prevalence differs. For example, females are at greater risk of developing Alzheimer disease dementia, whereas males are at greater risk of developing vascular dementia. This review examines sex and gender differences in the development of dementia with the goal of highlighting factors that require further investigation. Considering sex as a biological variable in dementia research promises to advance our understanding of the pathophysiology and treatment of these conditions.

Considering sex and gender in Alzheimer disease and other dementias

PubMed Central

Podcasy, Jessica L.; Epperson, C. Neill

2016-01-01

Suffering related to dementia is multifaceted because cognitive and physical functioning slowly deteriorates. Advanced age and sex, two of the most prominent risk factors for dementia, are not modifiable. Lifestyle factors such as smoking, excessive alcohol use, and poor diet modulate susceptibility to dementia in both males and females. The degree to which the resulting health conditions (eg, obesity, type 2 diabetes, and cardiovascular disease) impact dementia risk varies by sex. Depending on the subtype of dementia, the ratio of male to female prevalence differs. For example, females are at greater risk of developing Alzheimer disease dementia, whereas males are at greater risk of developing vascular dementia. This review examines sex and gender differences in the development of dementia with the goal of highlighting factors that require further investigation. Considering sex as a biological variable in dementia research promises to advance our understanding of the pathophysiology and treatment of these conditions. PMID:28179815

Risk Matrix for Prediction of Disease Progression in a Referral Cohort of Patients with Crohn's Disease.

PubMed

Lakatos, Peter L; Sipeki, Nora; Kovacs, Gyorgy; Palyu, Eszter; Norman, Gary L; Shums, Zakera; Golovics, Petra A; Lovasz, Barbara D; Antal-Szalmas, Peter; Papp, Maria

2015-10-01

Early identification of patients with Crohn's disease (CD) at risk of subsequent complications is essential for adapting the treatment strategy. We aimed to develop a prediction model including clinical and serological markers for assessing the probability of developing advanced disease in a prospective referral CD cohort. Two hundred and seventy-one consecutive CD patients (42.4% males, median follow-up 108 months) were included and followed up prospectively. Anti-Saccharomyces cerevisiae antibodies (ASCA IgA/IgG) were determined by enzyme-linked immunosorbent assay. The final analysis was limited to patients with inflammatory disease behaviour at diagnosis. The final definition of advanced disease outcome was having intestinal resection or disease behaviour progression. Antibody (ASCA IgA and/or IgG) status, disease location and need for early azathioprine were included in a 3-, 5- and 7-year prediction matrix. The probability of advanced disease after 5 years varied from 6.2 to 55% depending on the combination of predictors. Similar findings were obtained in Kaplan-Meier analysis; the combination of ASCA, location and early use of azathioprine was associated with the probability of developing advanced disease (p < 0.001, log rank test). Our prediction models identified substantial differences in the probability of developing advanced disease in the early disease course of CD. Markers identified in this referral cohort were different from those previously published in a population-based cohort, suggesting that different prediction models should be used in the referral setting. 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.

Alzheimer disease: diagnosis, costs, and dimensions of treatment.

PubMed

DeKosky, S T; Orgogozo, J M

2001-08-01

Alzheimer disease (AD) is the most frequent cause of dementia in developed Western countries. Over time, affected patients invariably develop cognitive and functional decline, and most develop early or later behavioral disturbances. Declining cognitive and functional abilities contribute to loss of independent living and feelings of denial, confusion, fear and guilt until, finally, the patient loses most abilities to think, move, speak, or perceive. As patients' dependency on assistance increases, the level of caregiver strain rises. The caregiver may develop feelings of anger, grief, loneliness and resentment, and the health and well-being of most caregivers are often affected. Approximately 3-4 million people currently have AD in the USA, at an annual cost of up to US$100 billion, and the disease is expected to reach epidemic proportions by 2020. To achieve a clinically relevant, long-term outcome, pharmacotherapy must have sustained favorable effects on cognitive, functional and behavioral symptoms of AD. Slowing the development of these features of the disease will mean a long-term improvement in quality of life for patients and caregivers. Postponing the emergence of behavioral symptoms would bring about direct beneficial effects on patients with AD and their families, help delay long-term care placement and lower costs.

[Early coronary heart disease together with tyoe II diabetes mellitus in persons of Hindustani origin].

PubMed

Bongers, I; Westendorp, R G; Stolk, B; Huysmans, H A; Vandenbroucke, J P

1995-01-07

To investigate the association between early coronary heart disease and non insulin dependent diabetes mellitus in South Asian patients in the Netherlands, a homogeneous population which descends from Indian immigrants to Surinam in the late nineteenth century. Case control study. University hospital Leiden. South Asian patients (n = 38) and control patients (n = 76) were identified in an automated data base comprising all patients who had aortocoronary surgery in the period January 1st 1990 to January 1st 1993. Control patients were from the general population and matched for calendar time. Patients' characteristics such as the onset of coronary heart disease and the presence of non insulin dependent diabetes mellitus were obtained from the medical records at the time of surgery. The onset of coronary heart disease in South Asian patients occurred about eight years earlier than in control patients (49.8 versus 58.2 years; 95% confidence interval of the difference: 4.3-12.5). Non insulin dependent diabetes mellitus was about four times more frequent in South Asian patients (50% versus 13%; 19-54). This difference was the same after correction for differences in sex, age, and body mass index. Diabetes mellitus caused by insulin resistance significantly contributes to early coronary heart disease in South Asian immigrant patients, in accordance with the literature on the present population of India. These findings strengthen the belief that genetic factor are important in the development of insulin resistance and atherosclerosis.

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis.

PubMed

Liu, Luyan; Okada, Satoshi; Kong, Xiao-Fei; Kreins, Alexandra Y; Cypowyj, Sophie; Abhyankar, Avinash; Toubiana, Julie; Itan, Yuval; Audry, Magali; Nitschke, Patrick; Masson, Cécile; Toth, Beata; Flatot, Jérome; Migaud, Mélanie; Chrabieh, Maya; Kochetkov, Tatiana; Bolze, Alexandre; Borghesi, Alessandro; Toulon, Antoine; Hiller, Julia; Eyerich, Stefanie; Eyerich, Kilian; Gulácsy, Vera; Chernyshova, Ludmyla; Chernyshov, Viktor; Bondarenko, Anastasia; Grimaldo, Rosa María Cortés; Blancas-Galicia, Lizbeth; Beas, Ileana Maria Madrigal; Roesler, Joachim; Magdorf, Klaus; Engelhard, Dan; Thumerelle, Caroline; Burgel, Pierre-Régis; Hoernes, Miriam; Drexel, Barbara; Seger, Reinhard; Kusuma, Theresia; Jansson, Annette F; Sawalle-Belohradsky, Julie; Belohradsky, Bernd; Jouanguy, Emmanuelle; Bustamante, Jacinta; Bué, Mélanie; Karin, Nathan; Wildbaum, Gizi; Bodemer, Christine; Lortholary, Olivier; Fischer, Alain; Blanche, Stéphane; Al-Muhsen, Saleh; Reichenbach, Janine; Kobayashi, Masao; Rosales, Francisco Espinosa; Lozano, Carlos Torres; Kilic, Sara Sebnem; Oleastro, Matias; Etzioni, Amos; Traidl-Hoffmann, Claudia; Renner, Ellen D; Abel, Laurent; Picard, Capucine; Maródi, László; Boisson-Dupuis, Stéphanie; Puel, Anne; Casanova, Jean-Laurent

2011-08-01

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

Development of Rasch-based item banks for the assessment of work performance in patients with musculoskeletal diseases.

PubMed

Mueller, Evelyn A; Bengel, Juergen; Wirtz, Markus A

2013-12-01

This study aimed to develop a self-description assessment instrument to measure work performance in patients with musculoskeletal diseases. In terms of the International Classification of Functioning, Disability and Health (ICF), work performance is defined as the degree of meeting the work demands (activities) at the actual workplace (environment). To account for the fact that work performance depends on the work demands of the job, we strived to develop item banks that allow a flexible use of item subgroups depending on the specific work demands of the patients' jobs. Item development included the collection of work tasks from literature and content validation through expert surveys and patient interviews. The resulting 122 items were answered by 621 patients with musculoskeletal diseases. Exploratory factor analysis to ascertain dimensionality and Rasch analysis (partial credit model) for each of the resulting dimensions were performed. Exploratory factor analysis resulted in four dimensions, and subsequent Rasch analysis led to the following item banks: 'impaired productivity' (15 items), 'impaired cognitive performance' (18), 'impaired coping with stress' (13) and 'impaired physical performance' (low physical workload 20 items, high physical workload 10 items). The item banks exhibited person separation indices (reliability) between 0.89 and 0.96. The assessment of work performance adds the activities component to the more commonly employed participation component of the ICF-model. The four item banks can be adapted to specific jobs where necessary without losing comparability of person measures, as the item banks are based on Rasch analysis.

Development of diet-induced insulin resistance in adult Drosophila melanogaster.

PubMed

Morris, Siti Nur Sarah; Coogan, Claire; Chamseddin, Khalil; Fernandez-Kim, Sun Ok; Kolli, Santharam; Keller, Jeffrey N; Bauer, Johannes H

2012-08-01

The fruit fly Drosophila melanogaster is increasingly utilized as an alternative to costly rodent models to study human diseases. Fly models exist for a wide variety of human conditions, such as Alzheimer's and Parkinson's Disease, or cardiac function. Advantages of the fly system are its rapid generation time and its low cost. However, the greatest strength of the fly system are the powerful genetic tools that allow for rapid dissection of molecular disease mechanisms. Here, we describe the diet-dependent development of metabolic phenotypes in adult fruit flies. Depending on the specific type of nutrient, as well as its relative quantity in the diet, flies show weight gain and changes in the levels of storage macromolecules. Furthermore, the activity of insulin-signaling in the major metabolic organ of the fly, the fat body, decreases upon overfeeding. This decrease in insulin-signaling activity in overfed flies is moreover observed when flies are challenged with an acute food stimulus, suggesting that overfeeding leads to insulin resistance. Similar changes were observed in aging flies, with the development of the insulin resistance-like phenotype beginning at early middle ages. Taken together, these data demonstrate that imbalanced diet disrupts metabolic homeostasis in adult D. melanogaster and promotes insulin-resistant phenotypes. Therefore, the fly system may be a useful alternative tool in the investigation of molecular mechanisms of insulin resistance and the development of pharmacologic treatment options. © 2012 Elsevier B.V. All rights reserved.

Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins

PubMed Central

Corbi, Graziamaria; Bianco, Andrea; Turchiarelli, Viviana; Cellurale, Michele; Fatica, Federica; Daniele, Aurora; Mazzarella, Gennaro; Ferrara, Nicola

2013-01-01

The development of atherosclerosis is a multi-step process, at least in part controlled by the vascular endothelium function. Observations in humans and experimental models of atherosclerosis have identified monocyte recruitment as an early event in atherogenesis. Chronic inflammation is associated with ageing and its related diseases (e.g., atherosclerosis and chronic obstructive pulmonary disease). Recently it has been discovered that Sirtuins (NAD+-dependent deacetylases) represent a pivotal regulator of longevity and health. They appear to have a prominent role in vascular biology and regulate aspects of age-dependent atherosclerosis. Many studies demonstrate that SIRT1 exhibits anti-inflammatory properties in vitro (e.g., fatty acid-induced inflammation), in vivo (e.g., atherosclerosis, sustainment of normal immune function in knock-out mice) and in clinical studies (e.g., patients with chronic obstructive pulmonary disease). Because of a significant reduction of SIRT1 in rodent lungs exposed to cigarette smoke and in lungs of patients with chronic obstructive pulmonary disease (COPD), activation of SIRT1 may be a potential target for chronic obstructive pulmonary disease therapy. We review the inflammatory mechanisms involved in COPD-CVD coexistence and the potential role of SIRT1 in the regulation of these systems. PMID:23774840

Role of Apoptosis in disease

PubMed Central

Favaloro, B.; Allocati, N.; Graziano, V.; Di Ilio, C.; De Laurenzi, V.

2012-01-01

Since the initial description of apoptosis, a number of different forms of cell death have been described. In this review we will focus on classic caspase-dependent apoptosis and its variations that contribute to diseases. Over fifty years of research have clarified molecular mechanisms involved in apoptotic signaling as well and shown that alterations of these pathways lead to human diseases. Indeed both reduced and increased apoptosis can result in pathology. More recently these findings have led to the development of therapeutic approaches based on regulation of apoptosis, some of which are in clinical trials or have entered medical practice. PMID:22683550

Value And Limitations Of Current Laser Immunology Instrumentation

NASA Astrophysics Data System (ADS)

Goldman, John A.

1982-12-01

Laser instrumentation for the study of immunologic disease and the immune response, as well as for therapy in immunologic associated diseases is still a very new field. The laser nephelometer is the most standard of the instruments now used, because of its ability to exactly measure and quantitate various materials. Fluorescent techniques to help identify various materials including various subsets of lymphocyte population in concert with monoclonal antibodies is a field for further study and development. The therapeutic use of laser, in immunologic and rheumatic diseases, will depend upon in vitro, and in vivo animal and human design studies.

A realistic host-vector transmission model for describing malaria prevalence pattern.

PubMed

Mandal, Sandip; Sinha, Somdatta; Sarkar, Ram Rup

2013-12-01

Malaria continues to be a major public health concern all over the world even after effective control policies have been employed, and considerable understanding of the disease biology have been attained, from both the experimental and modelling perspective. Interactions between different general and local processes, such as dependence on age and immunity of the human host, variations of temperature and rainfall in tropical and sub-tropical areas, and continued presence of asymptomatic infections, regulate the host-vector interactions, and are responsible for the continuing disease prevalence pattern.In this paper, a general mathematical model of malaria transmission is developed considering short and long-term age-dependent immunity of human host and its interaction with pathogen-infected mosquito vector. The model is studied analytically and numerically to understand the role of different parameters related to mosquitoes and humans. To validate the model with a disease prevalence pattern in a particular region, real epidemiological data from the north-eastern part of India was used, and the effect of seasonal variation in mosquito density was modelled based on local climactic data. The model developed based on general features of host-vector interactions, and modified simply incorporating local environmental factors with minimal changes, can successfully explain the disease transmission process in the region. This provides a general approach toward modelling malaria that can be adapted to control future outbreaks of malaria.

Pre-clinical MR elastography: Principles, techniques, and applications

NASA Astrophysics Data System (ADS)

Bayly, P. V.; Garbow, J. R.

2018-06-01

Magnetic resonance elastography (MRE) is a method for measuring the mechanical properties of soft tissue in vivo, non-invasively, by imaging propagating shear waves in the tissue. The speed and attenuation of waves depends on the elastic and dissipative properties of the underlying material. Tissue mechanical properties are essential for biomechanical models and simulations, and may serve as markers of disease, injury, development, or recovery. MRE is already established as a clinical technique for detecting and characterizing liver disease. The potential of MRE for diagnosing or characterizing disease in other organs, including brain, breast, and heart is an active research area. Studies involving MRE in the pre-clinical setting, in phantoms and artificial biomaterials, in the mouse, and in other mammals, are critical to the development of MRE as a robust, reliable, and useful modality.

Planning horizon affects prophylactic decision-making and epidemic dynamics

DOE PAGES

Nardin, Luis G.; Miller, Craig R.; Ridenhour, Benjamin J.; ...

2016-11-08

The spread of infectious diseases can be impacted by human behavior, and behavioral decisions often depend implicitly on a planning horizon?the time in the future over which options are weighed. We investigate the effects of planning horizons on epidemic dynamics. We developed an epidemiological agent-based model (along with an ODE analog) to explore the decision-making of self-interested individuals on adopting prophylactic behavior. The decision-making process incorporates prophylaxis efficacy and disease prevalence with the individuals? payoffs and planning horizon. Our results show that for short and long planning horizons individuals do not consider engaging in prophylactic behavior. In contrast, individuals adoptmore » prophylactic behavior when considering intermediate planning horizons. Such adoption, however, is not always monotonically associated with the prevalence of the disease, depending on the perceived protection efficacy and the disease parameters. Adoption of prophylactic behavior reduces the epidemic peak size while prolonging the epidemic and potentially generates secondary waves of infection. Lastly, these effects can be made stronger by increasing the behavioral decision frequency or distorting an individual's perceived risk of infection.« less

Planning horizon affects prophylactic decision-making and epidemic dynamics

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

Nardin, Luis G.; Miller, Craig R.; Ridenhour, Benjamin J.

The spread of infectious diseases can be impacted by human behavior, and behavioral decisions often depend implicitly on a planning horizon?the time in the future over which options are weighed. We investigate the effects of planning horizons on epidemic dynamics. We developed an epidemiological agent-based model (along with an ODE analog) to explore the decision-making of self-interested individuals on adopting prophylactic behavior. The decision-making process incorporates prophylaxis efficacy and disease prevalence with the individuals? payoffs and planning horizon. Our results show that for short and long planning horizons individuals do not consider engaging in prophylactic behavior. In contrast, individuals adoptmore » prophylactic behavior when considering intermediate planning horizons. Such adoption, however, is not always monotonically associated with the prevalence of the disease, depending on the perceived protection efficacy and the disease parameters. Adoption of prophylactic behavior reduces the epidemic peak size while prolonging the epidemic and potentially generates secondary waves of infection. Lastly, these effects can be made stronger by increasing the behavioral decision frequency or distorting an individual's perceived risk of infection.« less

Planning horizon affects prophylactic decision-making and epidemic dynamics.

PubMed

Nardin, Luis G; Miller, Craig R; Ridenhour, Benjamin J; Krone, Stephen M; Joyce, Paul; Baumgaertner, Bert O

2016-01-01

The spread of infectious diseases can be impacted by human behavior, and behavioral decisions often depend implicitly on a planning horizon-the time in the future over which options are weighed. We investigate the effects of planning horizons on epidemic dynamics. We developed an epidemiological agent-based model (along with an ODE analog) to explore the decision-making of self-interested individuals on adopting prophylactic behavior. The decision-making process incorporates prophylaxis efficacy and disease prevalence with the individuals' payoffs and planning horizon. Our results show that for short and long planning horizons individuals do not consider engaging in prophylactic behavior. In contrast, individuals adopt prophylactic behavior when considering intermediate planning horizons. Such adoption, however, is not always monotonically associated with the prevalence of the disease, depending on the perceived protection efficacy and the disease parameters. Adoption of prophylactic behavior reduces the epidemic peak size while prolonging the epidemic and potentially generates secondary waves of infection. These effects can be made stronger by increasing the behavioral decision frequency or distorting an individual's perceived risk of infection.

Planning horizon affects prophylactic decision-making and epidemic dynamics

PubMed Central

Ridenhour, Benjamin J.; Krone, Stephen M.

2016-01-01

The spread of infectious diseases can be impacted by human behavior, and behavioral decisions often depend implicitly on a planning horizon—the time in the future over which options are weighed. We investigate the effects of planning horizons on epidemic dynamics. We developed an epidemiological agent-based model (along with an ODE analog) to explore the decision-making of self-interested individuals on adopting prophylactic behavior. The decision-making process incorporates prophylaxis efficacy and disease prevalence with the individuals’ payoffs and planning horizon. Our results show that for short and long planning horizons individuals do not consider engaging in prophylactic behavior. In contrast, individuals adopt prophylactic behavior when considering intermediate planning horizons. Such adoption, however, is not always monotonically associated with the prevalence of the disease, depending on the perceived protection efficacy and the disease parameters. Adoption of prophylactic behavior reduces the epidemic peak size while prolonging the epidemic and potentially generates secondary waves of infection. These effects can be made stronger by increasing the behavioral decision frequency or distorting an individual’s perceived risk of infection. PMID:27843714

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

PubMed

Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

2017-06-01

Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43 Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43 Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

Excitation-transcription coupling in parvalbumin-positive interneurons employs a novel CaM Kinase-dependent pathway distinct from excitatory neurons

PubMed Central

Cohen, Samuel M.; Ma, Huan; Kuchibhotla, Kishore V.; Watson, Brendon O.; Buzsáki, György; Froemke, Robert C.; Tsien, Richard W.

2016-01-01

Properly functional CNS circuits depend on inhibitory interneurons that in turn rely upon activity-dependent gene expression for morphological development, connectivity and excitatory-inhibitory coordination. Despite its importance, excitation-transcription coupling in inhibitory interneurons is poorly understood. Here, we report that PV+ interneurons employ a novel CaMK-dependent pathway to trigger CREB phosphorylation and gene expression. As in excitatory neurons, voltage-gated Ca2+ influx through CaV1 channels triggers CaM nuclear translocation via local Ca2+ signaling. However, PV+ interneurons are distinct in that nuclear signaling is mediated by γCaMKI, not γCaMKII. CREB phosphorylation also proceeds with slow, sigmoid kinetics, rate-limited by paucity of CaMKIV, protecting against saturation of phospho-CREB in the face of higher firing rates and bigger Ca2+ transients. Our findings support the generality of CaM shuttling to drive nuclear CaMK activity, and are relevant to disease pathophysiology, insofar as dysfunction of PV+ interneurons and molecules underpinning their excitation-transcription coupling both relate to neuropsychiatric disease. PMID:27041500

Fetal cerebrovascular acclimatization responses to high-altitude, long-term hypoxia: a model for prenatal programming of adult disease?

PubMed

Longo, Lawrence D; Pearce, William J

2005-01-01

During the past several decades, many risk factors for cerebrovascular and cardiovascular disease have been identified. More recently, it has been appreciated that inadequate nutrition and/or other intrauterine factors during fetal development may play an important role in the genesis of these conditions. An additional stress factor that may "program" the fetus for disease later in life is chronic hypoxia. In studies originally designed to examine the function of developing cerebral arterial function in response to long-term hypoxia (LTH), it has become clear that many cellular and subcellular changes may have important implications for later life. Here we review some of the significant alterations in fetal cerebral artery structure and function induced by high-altitude (3,820 m, 12,470 ft) LTH ( approximately 110 days). LTH is associated with augmentation or upregulation of presynaptic functions, including responses to perivascular (i.e., sympathetic) nerve stimulation, and structural maturational changes. In contrast, many postsynaptic functions related to the Ca(2+)-dependent contractile pathway tend to be downregulated, whereas elements of the Ca(2+)-independent contraction pathway are upregulated. The results emphasize the role of high-altitude LTH in modulating many aspects of electromechanical and pharmacomechanical coupling in the developing cerebral vasculature. A complicating factor is that the regulation of cerebrovascular tone by Ca(2+)-dependent and Ca(2+)-independent pathways changes significantly as a function of maturational age. In addition to highlighting independent regulation of various elements of the signal transduction cascade, the studies demonstrate the potential for LTH to program the fetus for cerebrovascular and other disease as an adult.

Balance impairment in individuals with Wolfram syndrome

PubMed Central

Pickett, Kristen A.; Duncan, Ryan P.; Paciorkowski, Alex R.; Permutt, Alan; Marshall, Bess; Hershey, Tamara; Earhart, Gammon M.

2012-01-01

AIM Wolfram syndrome (WFS), a rare neurodegenerative disorder, is characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities. Although previously unreported, we hypothesized that neurological complications may be detectable in relatively early stages of the disease. As the cerebellum and brainstem seem particularly vulnerable in WFS, we focused on balance functions critically dependent on these regions. The primary goal of this investigation was to compare balance in young individuals with WFS, in relatively early stages of the disease, to an age-matched cohort using a clinically applicable test. METHOD Balance was assessed via the mini-BESTest in 13 children, adolescents and young adults with WFS and 30 typically developing age-matched individuals. RESULTS A significant difference was observed between groups in balance as well as in three of four subcomponents of the mini-BESTest and in two timed tasks related to balance. Mini-BESTest scores were correlated with age (p < 0.001, rs = 0.59) among typically developing individuals. In the WFS group, mini-BESTest scores were related to overall motor dysfunction, but not age. INTERPRETATION Impairments in balance in WFS may occur earlier in the disease process than previously recognized and appear to be related to overall neurological progression rather than chronological age. Recognizing balance impairments and understanding which balance systems contribute to balance deficits in those with WFS may allow for development of effective patient-centered treatment paradigms. PMID:22771154

[Medical safety in infectious disease--chairmen's introductory remarks].

PubMed

Shimetani, Naoto; Miida, Takashi

2012-10-01

"The National Joint Action of Risk Management" was started in May 2008. The Japanese Society of Laboratory Medicine took this opportunity to set up a Medical Safety Committee as a participant in this Action. The Society holds symposia concerning medical safety to educate the Society members. Nosocomial infections are medical accidents. Whereas community-acquired infections are likely to develop depending on a balance between pathogens and hosts, nosocomial infections are implicated with medical practices, so they develop depending on the interrelationship among pathogens, hosts, and medical practices. Medical practices are mostly indispensable for providing medical services; therefore, activities against nosocomial infections are critical for establishing medical safety, freedom from anxiety, and reliability. Hence, this symposium deals with five themes: Countermeasures against and the management of needle-stick and cut accidents, collaboration between the infection control team (ICT) and the bacteriology laboratory, information transmission from the clinical laboratory department to physicians engaged in infectious disease treatment, utilization of laboratory data for infection control, and medical safety against tuberculosis infection.

Chronic Colovesical Fistula Leading to Chronic Urinary Tract Infection Resulting in End-Stage Renal Disease in a Chronic Granulomatous Disease Patient.

PubMed

Siddiqui, M R; Sanford, T; Nair, A; Zerbe, C S; Hughes, M S; Folio, L; Agarwal, Piyush K; Brancato, S J

2017-02-01

A 46-year old man with X-linked chronic granulomatous disease (CGD) being followed at the National Institute of Health with uncontrolled CGD colitis who developed chronic colovesical fistula, and end-stage renal disease (ESRD). Despite aggressive medical management of symptoms with immunomodulators and antibiotic prophylaxis, the chronic colovesical fistula led to chronic pyelonephritis, recurrent urinary tract infections, persistent air in the collecting system and bladder, and post-renal obstruction resulting in renal failure. Patient is now hemodialysis dependent and required diverting loop ileostomy placement. This report highlights multiple potential etiologies of rising serum creatinine in patients with CGD.

Is susceptibility to tuberculosis acquired or inherited?

PubMed

Schurr, E

2007-02-01

Tuberculosis is an ongoing major public health problem on a global scale. One of the striking features of the disease is that only an estimated 10% of immunocompetent persons infected by the causative pathogen Mycobacterium tuberculosis will develop clinical signs of disease. This well-established epidemiological observation has prompted an intense search for the factors that trigger advancement of infection to disease in the small proportion of susceptible individuals. Central to this search is the questions if tuberculosis patients are inherently susceptible to the disease or if disease development is promoted by specific environmental factors. It is known that genetic and non-genetic factors of both the bacterium and the host have impact on the host response to M. tuberculosis. Yet, little is known about the interaction of these different factors and the resulting impact on disease development. Recent work suggests that in addition to common host susceptibility genes a second group of susceptibility loci exists the action of which strongly depends on the individual's clinical and exposure history. The latter genes may have a very strong effect on promoting advancement from infection to disease only in specific epidemiological settings. These findings suggest that a more detailed knowledge of gene-environment interactions in tuberculosis is necessary to understand why a small proportion of individuals are susceptible to the disease whilst the majority of humans are naturally resistant to tuberculosis.

G2019S LRRK2 mutant fibroblasts from Parkinson's disease patients show increased sensitivity to neurotoxin 1-methyl-4-phenylpyridinium dependent of autophagy.

PubMed

Yakhine-Diop, Sokhna M S; Bravo-San Pedro, José M; Gómez-Sánchez, Rubén; Pizarro-Estrella, Elisa; Rodríguez-Arribas, Mario; Climent, Vicente; Aiastui, Ana; López de Munain, Adolfo; Fuentes, José M; González-Polo, Rosa A

2014-10-03

Parkinson's disease (PD) is a neurodegenerative disorder of unknown etiology. It is considered as a multifactorial disease dependent on environmental and genetic factors. Deregulation in cell degradation has been related with a significant increase in cell damage, becoming a target for studies on the PD etiology. In the present study, we have characterized the parkinsonian toxin 1-methyl-4-phenylpyridinium ion (MPP(+))-induced damage in fibroblasts from Parkinson's patients with the mutation G2019S in leucine-rich repeat kinase 2 protein (LRRK2) and control individuals without this mutation. The results reveal that MPP(+) induces mTOR-dependent autophagy in fibroblasts. Moreover, the effects of caspase-dependent cell death to MPP(+) were higher in cells with the G2019S LRRK2 mutation, which showed basal levels of autophagy due to the G2019S LRRK2 mutation (mTOR-independent). The inhibition of autophagy by 3-methyladenine (3-MA) treatment reduces these sensitivity differences between both cell types, however, the inhibition of autophagosome-lysosome fusion by bafilomycin A1 (Baf A1) increases these differences. This data confirm the importance of the combination of genetic and environmental factors in the PD etiology. Thereby, the sensitivity to the same damage may be different in function of a genetic predisposition, reason why individuals with certain mutations can develop some early-onset diseases, such as individuals with G2019S LRRK2 mutation and PD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

[The effect of different types of sports and athletes' age on the pathological changes of the musculoskeletal system].

PubMed

Achkasov, E E; Puzin, S N; Litvinenko, A S; Kurshev, V V; Bezuglov, E N

2014-01-01

Our aim was to determine the most common musculoskeletal diseases, depending on the type of sports and athletes' age. The results of examination of 976 athletes aged from 16 to 42 years (average age - 28,9±2,3) with musculoskeletal diseases were analyzed. Medical diagnostic procedures included clinical, laboratory, instrumental (radiography, magnetic resonance imaging, ultrasound) investigations and functional testing (goniometry, manual muscle testing). Majority of patients were diagnosed to have diseases of the knee (17.9%) and ankle joints (11.3%), the heel bone (12.9%), Achilles tendon (10.2%), post-traumatic musculoskeletal diseases (16.2%), degenerative-dystrophic diseases of the spine (12.8%). In the young age group (16 to 20 years) post-traumatic disorders were most common. In the middle-age group (21 to 30 years) along with post-traumatic disorders diseases of the knee frequently occurred. For athletes over 30 years old, along with diseases of the knee spinal diseases were found to occur 2-3 times more frequently in comparison with other age groups. Injuries which are more common for different types of sports were identified: acute traumas - competitive sports, diseases of the calcaneus - sports with running and jumping (athletics, volleyball, soccer), disease of ankle joints - sport with sharp change in movement direction (hockey, figure skating), disease of the knee - sports with high load of the knee joint (figure skating, gymnastics, volleyball, diseases of bones and joints of the upper extremity - tennis, disease of spine - weightlifting. pathological changes in the musculoskeletal system depend on the type of sports and the age of athletes. The combination of age and risk factors associated with type of sport increases the possibility of development of these diseases of the musculoskeletal system.

Models of cooperative dynamics from biomolecules to magnets

NASA Astrophysics Data System (ADS)

Mobley, David Lowell

This work details application of computer models to several biological systems (prion diseases and Alzheimer's disease) and a magnetic system. These share some common themes, which are discussed. Here, simple lattice-based models are applied to aggregation of misfolded protein in prion diseases like Mad Cow disease. These can explain key features of the diseases. The modeling is based on aggregation being essential in establishing the time-course of infectivity. Growth of initial aggregates is assumed to dominate the experimentally observed lag phase. Subsequent fission, regrowth, and fission set apart the exponential doubling phase in disease progression. We explore several possible modes of growth for 2-D aggregates and suggest the model providing the best explanation for the experimental data. We develop testable predictions from this model. Like prion disease, Alzheimer's disease (AD) is an amyloid disease characterized by large aggregates in the brain. However, evidence increasingly points away from these as the toxic agent and towards oligomers of the Abeta peptide. We explore one possible toxicity mechanism---insertion of Abeta into cell membranes and formation of harmful ion channels. We find that mutations in this peptide which cause familial Alzheimer's disease (FAD) also affect the insertion of this peptide into membranes in a fairly consistent way, suggesting that this toxicity mechanism may be relevant biologically. We find a particular inserted configuration which may be especially harmful and develop testable predictions to verify whether or not this is the case. Nucleation is an essential feature of our models for prion disease, in that it protects normal, healthy individuals from getting prion disease. Nucleation is important in many other areas, and we modify our lattice-based nucleation model to apply to a hysteretic magnetic system where nucleation has been suggested to be important. From a simple model, we find qualitative agreement with experiment, and make testable experimental predictions concerning time-dependence and temperature-dependence of the major hysteresis loop and reversal curves which have been experimentally verified. We argue why this model may be suitable for systems like these and explain implications for Ising-like models. We suggest implications for future modeling work. Finally, we present suggestions for future work in all three areas.

Analysis of epidemiological studies: facts and artifacts.

PubMed

Wright, Anne L

2002-09-01

Cohort studies have provided the foundation for much of our knowledge of childhood asthma. Four important lessons have been learned from these longitudinal studies: that asthma is a complex disease, encompassing many phenotypes; that it is linked to the development of the immune system and respiratory tract in the first years of life; that early life events strongly affect the development of asthma risk and that relationships between certain exposures and asthma risk are age dependent. The Tucson Children's Respiratory Study is used to exemplify these lessons and to illustrate the advantages of cohort studies in investigating a complex disease. Copyright 2002 Elsevier Science Ltd.

A meta-analysis of education effects on chronic disease: the causal dynamics of the Population Education Transition Curve.

PubMed

Smith, William C; Anderson, Emily; Salinas, Daniel; Horvatek, Renata; Baker, David P

2015-02-01

As the Epidemiological Transition progresses worldwide, chronic diseases account for the majority of deaths in developed countries and a rising proportion in developing countries indicating a new global pattern of mortality and health challenges into the future. Attainment of formal education is widely reported to have a negative gradient with risk factors and onset of chronic disease, yet there has not been a formal assessment of this research. A random-effects meta-analysis finds that across 414 published effects more education significantly reduces the likelihood of chronic disease, except for neoplastic diseases with substantial genetic causes. Some studies, however, report null effects and other research on infectious disease report positive education gradients. Instead of assuming these contradictory results are spurious, it is suggested that they are part of a predictable systemic interaction between multiple mediating effects of education and the Epidemiological Transition stage of the population; and thus represent one case of the Population Education Transition Curve modeling changes in the association between education and health as dependent on population context. Copyright © 2014 Elsevier Ltd. All rights reserved.

The emergence of Aspergillus species in chronic respiratory disease.

PubMed

Yii, Anthony Ca; Koh, Mariko S; Lapperre, Therese S; Tan, Gan L; Chotirmall, Sanjay H

2017-01-01

Chronic lung disease is recognized as an important risk factor for developing pulmonary aspergillosis. The development of specific aspergillus-associated syndromes depends on host immunity and underlying lung disease. In the setting of asthma, hypersensitivity to Aspergillus can lead to allergic bronchopulmonary aspergillosis (ABPA) or severe asthma with fungal sensitization (SAFS). Chronic use of systemic or inhaled corticosteroids coupled with recurrent antibiotic use for exacerbations prevalent in chronic obstructive pulmonary disease (COPD) predisposes to chronic pulmonary aspergillosis (CPA). Prior pulmonary tuberculosis is a risk factor for CPA, a syndrome with a wide range of presentations including a simple aspergilloma, chronic cavities, necrosis or fibrosis. Accumulating evidence suggests that the presence of or colonization by Aspergillus in the setting of chronic lung disease can worsen clinical course and outcomes even in the absence of overt pulmonary aspergillosis. We propose that understanding the complex interplay between host and fungi may provide key insights into the pathogenesis of Aspergillus -associated pulmonary syndromes in the setting of chronic lung disease, and provide novel therapeutic approaches to improve its identification and management.

Small Animal Models for Evaluating Filovirus Countermeasures.

PubMed

Banadyga, Logan; Wong, Gary; Qiu, Xiangguo

2018-05-11

The development of novel therapeutics and vaccines to treat or prevent disease caused by filoviruses, such as Ebola and Marburg viruses, depends on the availability of animal models that faithfully recapitulate clinical hallmarks of disease as it is observed in humans. In particular, small animal models (such as mice and guinea pigs) are historically and frequently used for the primary evaluation of antiviral countermeasures, prior to testing in nonhuman primates, which represent the gold-standard filovirus animal model. In the past several years, however, the filovirus field has witnessed the continued refinement of the mouse and guinea pig models of disease, as well as the introduction of the hamster and ferret models. We now have small animal models for most human-pathogenic filoviruses, many of which are susceptible to wild type virus and demonstrate key features of disease, including robust virus replication, coagulopathy, and immune system dysfunction. Although none of these small animal model systems perfectly recapitulates Ebola virus disease or Marburg virus disease on its own, collectively they offer a nearly complete set of tools in which to carry out the preclinical development of novel antiviral drugs.

Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism.

PubMed

Jeon, Kye-Im; Xu, Xiangbin; Aizawa, Toru; Lim, Jae Hyang; Jono, Hirofumi; Kwon, Dong-Seok; Abe, Jun-Ichi; Berk, Bradford C; Li, Jian-Dong; Yan, Chen

2010-05-25

Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-alpha-induced NF-kappaB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-alpha- or LPS-induced up-regulation of proinflammatory mediators, including TNF-alpha, IL-1beta, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-alpha- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-kappaB-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca(2+) regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases.

Vinpocetine inhibits NF-κB–dependent inflammation via an IKK-dependent but PDE-independent mechanism

PubMed Central

Jeon, Kye-Im; Xu, Xiangbin; Aizawa, Toru; Lim, Jae Hyang; Jono, Hirofumi; Kwon, Dong-Seok; Berk, Bradford C.; Li, Jian-Dong; Yan, Chen

2010-01-01

Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-α–induced NF-κB activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-α- or LPS-induced up-regulation of proinflammatory mediators, including TNF-α, IL-1β, and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonuclear leukocytes in a mouse model of TNF-α- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-κB–dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and Ca2+ regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases. PMID:20448200

The global impact of noncommunicable diseases: estimates and projections.

PubMed

Manton, K G

1988-01-01

With the aging of populations in developing countries there is both a demographic and an epidemiological transition which affects the impact of chronic degenerative diseases on the health status of the populations. Demographic transition takes place in countries where there are effective programmes of disease control which allow for survival during the early years of childhood and adolescence. This results in an increase in life expectancy which places larger proportions of the population in the age range (60 years and older) in which chronic degenerative diseases become the major determinants of health status. Epidemiological transition in diseases may also be brought about by shifts in social and economic patterns which favour detrimental changes in risk factors for the chronic degenerative diseases. Such changes may include health-related behaviour which augments dietary consumption of fats and alcohol, increases obesity, increases smoking and decreases physical activity. Such changes in risk-factor levels increase the prevalence of chronic degenerative diseases which manifest themselves at later ages, and for which early preventive actions could be cost-effective. In order to illustrate the impact of both demographic and risk-factor effects, analyses are made of the impact of increases in life expectancy on cause-specific mortality in both developing and developed countries. It is shown that there is great similarity in the effect of major noncommunicable diseases on the life expectancy of adults in both developed and developing countries. The major differences are seen to be in the proportions of deaths expected from such diseases as cancer, diabetes, heart disease, stroke and cirrhosis; but not in the distribution of age at death which is the better measure of disease impact. Demographic analyses, computing indirect estimates of mortality, also demonstrate that there are currently more chronic disease deaths in developing than developed countries and that as expectation of life increases in developing countries the global chronic disease burden will be greatly concentrated in the developing countries. Analyses of risk-factor reduction by feasible intervention strategies, e.g. smoking cessation campaigns, treatment of high blood pressure, using relationships between risk factors and diseases established in longitudinal studies carried out in developed countries, point out that the effect of risk-factor control in long-living populations can be hidden by the dependency of risk factors and various related causes of death, e.g. smoking has an impact on lung cancer, ischaemic heart disease and emphysema, but at different ages.(ABSTRACT TRUNCATED AT 400 WORDS)

Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer's Disease.

PubMed

Winick-Ng, Warren; Rylett, R Jane

2018-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed.

Deer density and disease prevalence influence transmission of Chronic Wasting Disease in White-tailed Deer

USGS Publications Warehouse

Samuel, Michael D.; Richards, Bryan J.; Storm, Daniel J.; Rolley, Robert E.; Shelton, Paul; Nicholas S. Keuler,; Timothy R. Van Deelen,

2013-01-01

Host-parasite dynamics and strategies for managing infectious diseases of wildlife depend on the functional relationship between disease transmission rates and host density. However, the disease transmission function is rarely known for free-living wildlife, leading to uncertainty regarding the impacts of diseases on host populations and effective control actions. We evaluated the influence of deer density, landscape features, and soil clay content on transmission of chronic wasting disease (CWD) in young (<2-year-old) white-tailed deer (Odocoileus virginianus) in south-central Wisconsin, USA. We evaluated how frequency-dependent, density-dependent, and intermediate transmission models predicted CWD incidence rates in harvested yearling deer. An intermediate transmission model, incorporating both disease prevalence and density of infected deer, performed better than simple density- and frequency-dependent models. Our results indicate a combination of social structure, non-linear relationships between infectious contact and deer density, and distribution of disease among groups are important factors driving CWD infection in young deer. The landscape covariates % deciduous forest cover and forest edge density also were positively associated with infection rates, but soil clay content had no measurable influences on CWD transmission. Lack of strong density-dependent transmission rates indicates that controlling CWD by reducing deer density will be difficult. The consequences of non-linear disease transmission and aggregation of disease on cervid populations deserves further consideration.

Modeling seasonal behavior changes and disease transmission with application to chronic wasting disease.

PubMed

Oraby, Tamer; Vasilyeva, Olga; Krewski, Daniel; Lutscher, Frithjof

2014-01-07

Behavior and habitat of wildlife animals change seasonally according to environmental conditions. Mathematical models need to represent this seasonality to be able to make realistic predictions about the future of a population and the effectiveness of human interventions. Managing and modeling disease in wild animal populations requires particular care in that disease transmission dynamics is a critical consideration in the etiology of both human and animal diseases, with different transmission paradigms requiring different disease risk management strategies. Since transmission of infectious diseases among wildlife depends strongly on social behavior, mechanisms of disease transmission could also change seasonally. A specific consideration in this regard confronted by modellers is whether the contact rate between individuals is density-dependent or frequency-dependent. We argue that seasonal behavior changes could lead to a seasonal shift between density and frequency dependence. This hypothesis is explored in the case of chronic wasting disease (CWD), a fatal disease that affects deer, elk and moose in many areas of North America. Specifically, we introduce a strategic CWD risk model based on direct disease transmission that accounts for the seasonal change in the transmission dynamics and habitats occupied, guided by information derived from cervid ecology. The model is composed of summer and winter susceptible-infected (SI) equations, with frequency-dependent and density-dependent transmission dynamics, respectively. The model includes impulsive birth events with density-dependent birth rate. We determine the basic reproduction number as a weighted average of two seasonal reproduction numbers. We parameterize the model from data derived from the scientific literature on CWD and deer ecology, and conduct global and local sensitivity analyses of the basic reproduction number. We explore the effectiveness of different culling strategies for the management of CWD: although summer culling seems to be an effective disease eradication strategy, the total culling rate is limited by the requirement to preserve the herd. © 2013 Elsevier Ltd. All rights reserved.

Hepatitis E in transfusion-dependent thalassaemia patients, in Greece: a single centre experience.

PubMed

Klonizakis, P; Gioula, G; Exindari, M; Apostolou, C; Kotsiafti, A; Vlachaki, E

2017-10-01

Hepatitis E is considered an emerging disease that may be a threat in both developing and industrialized countries all over the world. The risk of chronic hepatitis E virus infection is higher among immunocompromised patients. This study aimed to assess the status of hepatitis E infection in patients with transfusion-dependent thalassaemia from a single centre, in Greece. Our results suggest that the prevalence of hepatitis E infection in this group of patients is low. © 2017 International Society of Blood Transfusion.

Cushing's syndrome: aftermath of the cure.

PubMed

Pivonello, Rosario; De Martino, Maria Cristina; De Leo, Monica; Tauchmanovà, Libuse; Faggiano, Antongiulio; Lombardi, Gaetano; Colao, Annamaria

2007-11-01

Cushing's syndrome (CS) is a chronic and systemic disease caused by endogenous or exogenous hypercortisolism, associated with an increase of mortality rate due to the clinical consequences of glucocorticoid excess, especially cardiovascular diseases. After cure, usually obtained by the surgical removal of the tumor responsible for the disease, the normalization of cortisol secretion is not constantly followed by the recovery of the clinical complications developed during the active disease, and it is often followed by the development of novel clinical manifestations induced by the fall of cortisol levels. These evidences were mostly documented in patients with pituitary-dependent CS, after surgical resection of the pituitary tumor. Indeed, despite an improvement of the mortality rate, metabolic syndrome and the consequent cardiovascular risk have been found to partially persist after disease remission, strictly correlated to the insulin resistance. Skeletal diseases, mainly osteoporosis, improve after normalization of cortisol levels but require a long period of time or the use of specific treatment, mainly bisphosphonates, to reach the normalization of bone mass. A relevant improvement or resolution of mental disturbances has been described in patients cured from CS, although in several cases, cognitive decline persisted and psychological or psychiatric improvement was erratic, delayed, or incomplete. On the other hand, development or exacerbation of autoimmune disorders, mainly thyroid autoimmune diseases, was documented in predisposed patients with CS after disease remission. The totality of these complications persisting or occurring after successful treatment contribute to the impairment of quality of life registered in patients with CS after disease cure.

Functions of autophagy in normal and diseased liver

PubMed Central

Czaja, Mark J.; Ding, Wen-Xing; Donohue, Terrence M.; Friedman, Scott L.; Kim, Jae-Sung; Komatsu, Masaaki; Lemasters, John J.; Lemoine, Antoinette; Lin, Jiandie D.; Ou, Jing-hsiung James; Perlmutter, David H.; Randall, Glenn; Ray, Ratna B.; Tsung, Allan; Yin, Xiao-Ming

2013-01-01

Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. Investigations specifically employing the liver or hepatocytes as experimental models have contributed significantly to our current knowledge of autophagic regulation and function. The diverse cellular functions of autophagy, along with unique features of the liver and its principal cell type the hepatocyte, suggest that the liver is highly dependent on autophagy for both normal function and to prevent the development of disease states. However, instances have also been identified in which autophagy promotes pathological changes such as the development of hepatic fibrosis. Considerable evidence has accumulated that alterations in autophagy are an underlying mechanism of a number of common hepatic diseases including toxin-, drug- and ischemia/reperfusion-induced liver injury, fatty liver, viral hepatitis and hepatocellular carcinoma. This review summarizes recent advances in understanding the roles that autophagy plays in normal hepatic physiology and pathophysiology with the intent of furthering the development of autophagy-based therapies for human liver diseases. PMID:23774882

Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

PubMed Central

Papamatheakis, Demosthenes G.; Blood, Arlin B.; Kim, Joon H.; Wilson, Sean M.

2015-01-01

This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression. PMID:24063380

[Various pathways leading to the progression of chronic liver diseases].

PubMed

Egresi, Anna; Lengyel, Gabriella; Somogyi, Anikó; Blázovics, Anna; Hagymási, Krisztina

2016-02-21

As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression.

Nursing contributions to chronic disease management in primary care.

PubMed

Lukewich, Julia; Edge, Dana S; VanDenKerkhof, Elizabeth; Tranmer, Joan

2014-02-01

As the prevalence of chronic diseases continues to increase, emphasis is being placed on the development of primary care strategies that enhance healthcare delivery. Innovations include interprofessional healthcare teams and chronic disease management strategies. To determine the roles of nurses working in primary care settings in Ontario and the extent to which chronic disease management strategies have been implemented. We conducted a cross-sectional survey of a random sample of primary care nurses, including registered practical nurses, registered nurses, and nurse practitioners, in Ontario between May and July 2011. Nurses in primary care reported engaging in chronic disease management activities but to different extents depending on their regulatory designation (licensure category). Chronic disease management strategy implementation was not uniform across primary care practices where the nurses worked. There is the potential to optimize and standardize the nursing role within primary care and improve the implementation of chronic disease management strategies.

Disease control operations

USGS Publications Warehouse

Friend, M.; Franson, J.C.

1999-01-01

Individual disease outbreaks have killed many thousands of animals on numerous occasions. Tens of thousands of migratory birds have died in single die-offs with as many as 1,000 birds succumbing in 1 day. The ability to successfully combat such explosive situations is highly dependent on the readiness of field personnel to deal with them. Because many disease agents can spread through wildlife populations very quickly, advance preparation is essential for preventing infected animals from spreading disease to additional species and locations. Carefully thought-out disease contingency plans should be developed as practical working documents for field personnel and updated as necessary. Well-designed plans can prove invaluable in minimizing wildlife losses and the costs associated with disease control activities.Although requirements for disease control operations vary and must be tailored to each situation, all disease contingency planning involves general concepts and basic biological information. This chapter, which is intended to be a practical guide, identifies the major activities and needs of disease control operations, and relates them to disease contingency planning.

Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction

PubMed Central

Manigrasso, Michaele B.; Pan, Jinhong; Rai, Vivek; Zhang, Jinghua; Reverdatto, Sergey; Quadri, Nosirudeen; DeVita, Robert J.; Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie

2016-01-01

The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer’s disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI). PMID:26936329

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

PubMed Central

Ishibashi, Hidetoshi; Minakawa, Eiko N.; Motohashi, Hideyuki H.; Takayama, Osamu; Popiel, H. Akiko; Puentes, Sandra; Owari, Kensuke; Nakatani, Terumi; Nogami, Naotake; Yamamoto, Kazuhiro; Yonekawa, Takahiro; Tanaka, Yoko; Fujita, Naoko; Suzuki, Hikaru; Aizawa, Shu; Nagano, Seiichi; Yamada, Daisuke; Wada, Keiji; Kohsaka, Shinichi

2017-01-01

Abstract Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases. PMID:28374014

Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus

PubMed Central

Moreno-Indias, Isabel; Cardona, Fernando; Tinahones, Francisco J.; Queipo-Ortuño, María Isabel

2014-01-01

Obesity and its associated disorders are a major public health concern. Although obesity has been mainly related with perturbations of the balance between food intake and energy expenditure, other factors must nevertheless be considered. Recent insight suggests that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. This review discusses research aimed at understanding the role of gut microbiota in the pathogenesis of obesity and type 2 diabetes mellitus (TDM2). The establishment of gut microbiota is dependent on the type of birth. With effect from this point, gut microbiota remain quite stable, although changes take place between birth and adulthood due to external influences, such as diet, disease and environment. Understand these changes is important to predict diseases and develop therapies. A new theory suggests that gut microbiota contribute to the regulation of energy homeostasis, provoking the development of an impairment in energy homeostasis and causing metabolic diseases, such as insulin resistance or TDM2. The metabolic endotoxemia, modifications in the secretion of incretins and butyrate production might explain the influence of the microbiota in these diseases. PMID:24808896

Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus.

PubMed

Moreno-Indias, Isabel; Cardona, Fernando; Tinahones, Francisco J; Queipo-Ortuño, María Isabel

2014-01-01

Obesity and its associated disorders are a major public health concern. Although obesity has been mainly related with perturbations of the balance between food intake and energy expenditure, other factors must nevertheless be considered. Recent insight suggests that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. This review discusses research aimed at understanding the role of gut microbiota in the pathogenesis of obesity and type 2 diabetes mellitus (TDM2). The establishment of gut microbiota is dependent on the type of birth. With effect from this point, gut microbiota remain quite stable, although changes take place between birth and adulthood due to external influences, such as diet, disease and environment. Understand these changes is important to predict diseases and develop therapies. A new theory suggests that gut microbiota contribute to the regulation of energy homeostasis, provoking the development of an impairment in energy homeostasis and causing metabolic diseases, such as insulin resistance or TDM2. The metabolic endotoxemia, modifications in the secretion of incretins and butyrate production might explain the influence of the microbiota in these diseases.

Matrix metalloproteinases in kidney homeostasis and diseases

PubMed Central

Tan, Roderick J.

2012-01-01

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have been increasingly linked to both normal physiology and abnormal pathology in the kidney. Collectively able to degrade all components of the extracellular matrix, MMPs were originally thought to antagonize the development of fibrotic diseases solely through digestion of excessive matrix. However, increasing evidence has shown that MMPs play a wide variety of roles in regulating inflammation, epithelial-mesenchymal transition, cell proliferation, angiogenesis, and apoptosis. We now have robust evidence for MMP dysregulation in a multitude of renal diseases including acute kidney injury, diabetic nephropathy, glomerulonephritis, inherited kidney disease, and chronic allograft nephropathy. The goal of this review is to summarize current findings regarding the role of MMPs in kidney diseases as well as the mechanisms of action of this family of proteases. PMID:22492945

[Living with Parkinson's disease from the perspective of parkinsonians and their relatives].

PubMed

Navarro-Peternella, Fabiana Magalhães; Marcon, Sonia Silva

2010-09-01

The objective of the study is to investigate what it is like for the patients and relatives to live with Parkinson's disease This was a qualitative descriptive study, developed with ten individuals with Parkinson's disease and their relatives, summing up twenty informers, through semistructured interviews. Through discourse analysis, we verified that in spite of the difficulties, many patients show acceptance or conformity regarding to the limitations imposed by the disease, while others still experience anger and hope for a cure. The greatest changes demonstrated by patients and family members regard to the question of dependence and loss of autonomy for work, daily life and leisure activities, which impact on the entire family dynamic. This way, small interventions could contribute to a better coexistence with the disease.

Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue.

PubMed

Choi, Catherine H; McBride, Sean M J; Schoenfeld, Brian P; Liebelt, David A; Ferreiro, David; Ferrick, Neal J; Hinchey, Paul; Kollaros, Maria; Rudominer, Rebecca L; Terlizzi, Allison M; Koenigsberg, Eric; Wang, Yan; Sumida, Ai; Nguyen, Hanh T; Bell, Aaron J; McDonald, Thomas V; Jongens, Thomas A

2010-06-01

Fragile X syndrome afflicts 1 in 2,500 individuals and is the leading heritable cause of mental retardation worldwide. The overriding clinical manifestation of this disease is mild to severe cognitive impairment. Age-dependent cognitive decline has been identified in Fragile X patients, although it has not been fully characterized nor examined in animal models. A Drosophila model of this disease has been shown to display phenotypes bearing similarity to Fragile X symptoms. Most notably, we previously identified naive courtship and memory deficits in young adults with this model that appear to be due to enhanced metabotropic glutamate receptor (mGluR) signaling. Herein we have examined age-related cognitive decline in the Drosophila Fragile X model and found an age-dependent loss of learning during training. We demonstrate that treatment with mGluR antagonists or lithium can prevent this age-dependent cognitive impairment. We also show that treatment with mGluR antagonists or lithium during development alone displays differential efficacy in its ability to rescue naive courtship, learning during training and memory in aged flies. Furthermore, we show that continuous treatment during aging effectively rescues all of these phenotypes. These results indicate that the Drosophila model recapitulates the age-dependent cognitive decline observed in humans. This places Fragile X in a category with several other diseases that result in age-dependent cognitive decline. This demonstrates a role for the Drosophila Fragile X Mental Retardation Protein (dFMR1) in neuronal physiology with regard to cognition during the aging process. Our results indicate that misregulation of mGluR activity may be causative of this age onset decline and strengthens the possibility that mGluR antagonists and lithium may be potential pharmacologic compounds for counteracting several Fragile X symptoms.

Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis

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

Ahrenhoerster, Lori S.; Leuthner, Tess C.; Tate, Everett R.

2015-03-01

Over half of T cell acute lymphoblastic leukemia (T-ALL) patients have activating mutations in the Notch gene. Moreover, the contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen that mediates its toxicity through the aryl hydrocarbon receptor (AHR), and crosstalk between activated AHR and Notch signaling pathways has previously been observed. Given the importance of Notch signaling in thymocyte development and T-ALL disease progression, we hypothesized that the activated AHR potentiates disease initiation and progression in an in vivo model of Notch1-induced thymoma. This hypothesis was tested utilizing adult and developmental exposure paradigms to TCDD in mice expressing a constitutively activemore » Notch1 transgene (Notch{sup ICN-TG}). Following exposure of adult Notch{sup ICN-TG} mice to a single high dose of TCDD, we observed a significant increase in the efficiency of CD8 thymocyte generation. We next exposed pregnant mice to 3 μg/kg of TCDD throughout gestation and lactation to elucidate effects of developmental AHR activation on later-life T cell development and T-ALL-like thymoma susceptibility induced by Notch1. We found that the vehicle-exposed Notch{sup ICN-TG} offspring have a peripheral T cell pool heavily biased toward the CD4 lineage, while TCDD-exposed Notch{sup ICN-TG} offspring were biased toward the CD8 lineage. Furthermore, while the vehicle-exposed NotchICN-TG mice showed increased splenomegaly and B to T cell ratios indicative of disease, mice developmentally exposed to TCDD were largely protected from disease. These studies support a model where developmental AHR activation attenuates later-life Notch1-dependent impacts on thymocyte development and disease progression. - Highlights: • Adult mice exposed to 30 μg/kg TCDD have higher efficiency of CD8 thymocyte generation. • Mice carrying a constitutively active Notch transgene were exposed to 3 μg/kg TCDD throughout development. • Progression of Notch-induced thymoma was different in offspring exposed to TCDD developmentally. • Developmental AHR activation attenuates later-life Notch1-dependent impacts on T cell differentiation.« less

Alcohol-related diseases and alcohol dependence syndrome is associated with increased gout risk: A nationwide population-based cohort study.

PubMed

Tu, Hung-Pin; Tung, Yi-Ching; Tsai, Wen-Chan; Lin, Gau-Tyan; Ko, Ying-Chin; Lee, Su-Shin

2017-03-01

Alcohol intake is strongly associated with hyperuricemia, which may cause gout. This study evaluated the risk of gout in patients with alcohol-related diseases and alcohol dependence syndrome. We used the Taiwan National Health Insurance Research Database (NHIRD) to conduct a nationwide population-based cohort study to assess the risk of gout and gout incidence in patients with alcohol-related diseases and alcohol dependence syndrome (as defined by the International Classification of Diseases, Ninth Revision). In the NHIRD records from 1998 to 2008, we identified 11,675 cases of alcohol-related diseases. The control group comprised 23,350 cases without alcohol-related diseases propensity score-matched (1 case: 2 controls) for age, age group, and sex. The results revealed that alcohol-related diseases were significantly associated with gout risk (adjusted hazard ratio 1.88; P<0.0001). Of the alcohol-related disease cases, 34.1% of the patients had alcohol dependence syndrome (males 34.8%; females 32.4%), and alcohol dependence was independently associated with gout occurrence (relative risk [RR] 2.01; P<0.0001). Severe alcohol-dependent patients (who were also the heavy benzodiazepines users), were associated with an increased risk of gout (RR 1.71 to 4.21, P≤0.0182). Physicians should be aware of the association between alcohol dependence syndrome and gout occurrence, and alcohol use assessment and measures to prevent alcohol dependence should be implemented in the integrative care for patients with gout. Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Scale dependence of disease impacts on quaking aspen (Populus tremuloides) mortality in the southwestern United States

USGS Publications Warehouse

Bell, David M.; Bradford, John B.; Lauenroth, William K.

2015-01-01

By examining variation in disease prevalence, mortality of healthy trees, and mortality of diseased trees, we showed that the role of disease in aspen tree mortality depended on the scale of inference. For variation among individuals in diameter, disease tended to expose intermediate-size trees experiencing moderate risk to greater risk. For spatial variation in summer temperature, disease exposed lower risk populations to greater mortality probabilities, but the magnitude of this exposure depended on summer precipitation. Furthermore, the importance of diameter and slenderness in mediating responses to climate supports the increasing emphasis on trait variation in studies of ecological responses to global change.

Malaria treatment using novel nano-based drug delivery systems.

PubMed

Baruah, Uday Krishna; Gowthamarajan, Kuppusamy; Vanka, Ravisankar; Karri, Veera Venkata Satyanarayana Reddy; Selvaraj, Kousalya; Jojo, Gifty M

2017-08-01

We reside in an era of technological innovation and advancement despite which infectious diseases like malaria remain to be one of the greatest threats to the humans. Mortality rate caused by malaria disease is a huge concern in the twenty-first century. Multiple drug resistance and nonspecific drug targeting of the most widely used drugs are the main reasons/drawbacks behind the failure in malarial therapy. Dose-related toxicity because of high doses is also a major concern. Therefore, to overcome these problems nano-based drug delivery systems are being developed to facilitate site-specific or target-based drug delivery and hence minimizing the development of resistance progress and dose-dependent toxicity issues. In this review, we discuss about the shortcomings in treating malaria and how nano-based drug delivery systems can help in curtailing the infectious disease malaria.

Innate Immune Responses in Leprosy

PubMed Central

Pinheiro, Roberta Olmo; Schmitz, Veronica; Silva, Bruno Jorge de Andrade; Dias, André Alves; de Souza, Beatriz Junqueira; de Mattos Barbosa, Mayara Garcia; de Almeida Esquenazi, Danuza; Pessolani, Maria Cristina Vidal; Sarno, Euzenir Nunes

2018-01-01

Leprosy is an infectious disease that may present different clinical forms depending on host immune response to Mycobacterium leprae. Several studies have clarified the role of various T cell populations in leprosy; however, recent evidences suggest that local innate immune mechanisms are key determinants in driving the disease to its different clinical manifestations. Leprosy is an ideal model to study the immunoregulatory role of innate immune molecules and its interaction with nervous system, which can affect homeostasis and contribute to the development of inflammatory episodes during the course of the disease. Macrophages, dendritic cells, neutrophils, and keratinocytes are the major cell populations studied and the comprehension of the complex networking created by cytokine release, lipid and iron metabolism, as well as antimicrobial effector pathways might provide data that will help in the development of new strategies for leprosy management. PMID:29643852

Successful technologies and approaches used to develop and manage resistance against crop diseases and pests

USDA-ARS?s Scientific Manuscript database

Food security is highly dependent on many factors including biological, climate related, and political. Soon after Mendel showed that phenotypic traits could be inherited through hybridization, scientists have been using classical genetics to increase crop production. Part of the increase in crop pr...

A Time Bomb for Leukemia.

PubMed

Maryanovich, Maria; Frenette, Paul S

2016-04-07

Alterations of the circadian clock have been linked to cancer development. Puram et al. (in this issue) now uncover differential requirements between healthy hematopoietic and diseased leukemic stem cells for core circadian transcription factors, wherein leukemic cells depend on the clock machinery for survival and growth. Copyright © 2016 Elsevier Inc. All rights reserved.

ACR Appropriateness Criteria Crohn Disease.

PubMed

Kim, David H; Carucci, Laura R; Baker, Mark E; Cash, Brooks D; Dillman, Jonathan R; Feig, Barry W; Fowler, Kathryn J; Gage, Kenneth L; Noto, Richard B; Smith, Martin P; Yaghmai, Vahid; Yee, Judy; Lalani, Tasneem

2015-10-01

Crohn disease is a chronic inflammatory disorder involving the gastrointestinal tract, characterized by episodic flares and times of remission. Underlying structural damage occurs progressively, with recurrent bouts of inflammation. The diagnosis and management of this disease process is dependent on several clinical, laboratory, imaging, endoscopic, and histologic factors. In recent years, with the maturation of CT enterography, and MR enterography, imaging has played an increasingly important role in relation to Crohn Disease. In addition to these specialized examination modalities, ultrasound and routine CT have potential uses. Fluoroscopy, radiography, and nuclear medicine may be less beneficial depending on the clinical scenario. The imaging modality best suited to evaluating this disease may change, depending on the target population, severity of presentation, and specific clinical situation. This document presents seven clinical scenarios (variants) in both the adult and pediatric populations and rates the appropriateness of the available imaging options. They are summarized in a consolidated table, and the underlying rationale and supporting literature are presented in the accompanying narrative. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Copyright © 2015 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

PubMed Central

Liu, Luyan; Okada, Satoshi; Kong, Xiao-Fei; Kreins, Alexandra Y.; Cypowyj, Sophie; Abhyankar, Avinash; Toubiana, Julie; Itan, Yuval; Audry, Magali; Nitschke, Patrick; Masson, Cécile; Toth, Beata; Flatot, Jérome; Migaud, Mélanie; Chrabieh, Maya; Kochetkov, Tatiana; Bolze, Alexandre; Borghesi, Alessandro; Toulon, Antoine; Hiller, Julia; Eyerich, Stefanie; Eyerich, Kilian; Gulácsy, Vera; Chernyshova, Ludmyla; Chernyshov, Viktor; Bondarenko, Anastasia; María Cortés Grimaldo, Rosa; Blancas-Galicia, Lizbeth; Madrigal Beas, Ileana Maria; Roesler, Joachim; Magdorf, Klaus; Engelhard, Dan; Thumerelle, Caroline; Burgel, Pierre-Régis; Hoernes, Miriam; Drexel, Barbara; Seger, Reinhard; Kusuma, Theresia; Jansson, Annette F.; Sawalle-Belohradsky, Julie; Belohradsky, Bernd; Jouanguy, Emmanuelle; Bustamante, Jacinta; Bué, Mélanie; Karin, Nathan; Wildbaum, Gizi; Bodemer, Christine; Lortholary, Olivier; Fischer, Alain; Blanche, Stéphane; Al-Muhsen, Saleh; Reichenbach, Janine; Kobayashi, Masao; Rosales, Francisco Espinosa; Lozano, Carlos Torres; Kilic, Sara Sebnem; Oleastro, Matias; Etzioni, Amos; Traidl-Hoffmann, Claudia; Renner, Ellen D.; Abel, Laurent; Picard, Capucine; Maródi, László; Boisson-Dupuis, Stéphanie

2011-01-01

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity. PMID:21727188

Current Progress in Therapeutic Gene Editing for Monogenic Diseases

PubMed Central

Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

2016-01-01

Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects. PMID:26765770

A Model for Sclerotinia sclerotiorum Infection and Disease Development in Lettuce, Based on the Effects of Temperature, Relative Humidity and Ascospore Density

PubMed Central

Clarkson, John P.; Fawcett, Laura; Anthony, Steven G.; Young, Caroline

2014-01-01

The plant pathogen Sclerotinia sclerotiorum can cause serious losses on lettuce crops worldwide and as for most other susceptible crops, control relies on the application of fungicides, which target airborne ascospores. However, the efficacy of this approach depends on accurate timing of these sprays, which could be improved by an understanding of the environmental conditions that are conducive to infection. A mathematical model for S. sclerotiorum infection and disease development on lettuce is presented here for the first time, based on quantifying the effects of temperature, relative humidity (RH) and ascospore density in multiple controlled environment experiments. It was observed that disease can develop on lettuce plants inoculated with dry ascospores in the absence of apparent leaf wetness (required for spore germination). To explain this, the model conceptualises an infection court area containing microsites (in leaf axils and close to the stem base) where conditions are conducive to infection, the size of which is modified by ambient RH. The model indicated that minimum, maximum and optimum temperatures for ascospore germination were 0.0, 29.9 and 21.7°C respectively and that maximum rates of disease development occurred at spore densities >87 spores cm−2. Disease development was much more rapid at 80–100% RH at 20°C, compared to 50–70% RH and resulted in a greater proportion of lettuce plants infected. Disease development was also more rapid at 15–27°C compared to 5–10°C (85% RH). The model was validated by a further series of independent controlled environment experiments where both RH and temperature were varied and generally simulated the pattern of disease development well. The implications of the results in terms of Sclerotinia disease forecasting are discussed. PMID:24736409

Simulation of MAD Cow Disease Propagation

NASA Astrophysics Data System (ADS)

Magdoń-Maksymowicz, M. S.; Maksymowicz, A. Z.; Gołdasz, J.

Computer simulation of dynamic of BSE disease is presented. Both vertical (to baby) and horizontal (to neighbor) mechanisms of the disease spread are considered. The game takes place on a two-dimensional square lattice Nx×Ny = 1000×1000 with initial population randomly distributed on the net. The disease may be introduced either with the initial population or by a spontaneous development of BSE in an item, at a small frequency. Main results show a critical probability of the BSE transmission above which the disease is present in the population. This value is vulnerable to possible spatial clustering of the population and it also depends on the mechanism responsible for the disease onset, evolution and propagation. A threshold birth rate below which the population is extinct is seen. Above this threshold the population is disease free at equilibrium until another birth rate value is reached when the disease is present in population. For typical model parameters used for the simulation, which may correspond to the mad cow disease, we are close to the BSE-free case.

Modeling treatment of ischemic heart disease with partially observable Markov decision processes.

PubMed

Hauskrecht, M; Fraser, H

1998-01-01

Diagnosis of a disease and its treatment are not separate, one-shot activities. Instead they are very often dependent and interleaved over time, mostly due to uncertainty about the underlying disease, uncertainty associated with the response of a patient to the treatment and varying cost of different diagnostic (investigative) and treatment procedures. The framework of Partially observable Markov decision processes (POMDPs) developed and used in operations research, control theory and artificial intelligence communities is particularly suitable for modeling such a complex decision process. In the paper, we show how the POMDP framework could be used to model and solve the problem of the management of patients with ischemic heart disease, and point out modeling advantages of the framework over standard decision formalisms.

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

Imaging Amyloidopathy in Parkinson Disease and Parkinsonian Dementia Syndromes.

PubMed

Frey, Kirk A; Petrou, Myria

2015-02-01

Dementia arising in patients with Parkinson disease or parkinsonian neurodegeneration comprises a heterogeneous neuropathology. Clinical labeling of patients with both dementia and Parkinson disease is dichotomous, depending on the temporal development of cognitive impairment and motor parkinsonism. Patients with dementia arising first (or within the first year of PD) are classified as dementia with Lewy bodies; patients with PD for more than one year before cognitive decline are classified as Parkinson disease with dementia. Despite this differential clinical classification, autopsy studies demonstrate variable admixtures of cortical synuicleinopathy, Aβ-amyloidopathy and tau neurofibrillary tangle deposition. There are no routine clinical diagnostic measures that accurately distinguish the underlying neuropathologies in individual patients. In the present paper, we review the published literature describing characteristics of fibrillary Aβ-amyloid deposition on the basis of PET radiotracer imaging in patients with Parkinson disease and in parkinsonian dementia syndromes. Although individual reports often include only small-to-modest subject numbers, there is overall suggestion that PD patients have a lower incidence of Aβ-amyloid deposition than seen amongst elderly normal subjects, and that Parkinson disease with dementia patients have a lower incidence of Aβ-amyloid deposition than do patients with dementia with Lewy bodies. These apparent features contrast the findings of Aβ-amyloid-PET imaging in normal aging and the development of Alzheimer disease, where Aβ-amyloid deposition arises asymptomatically and apparently many years before development of signs or symptoms of dementia. It is proposed that focused, prospective studies are needed to further address and understand the complex role(s) of Aβ-amyloid pathology in Parkinson disease, and that this understanding will be critical to the development of targeted disease-modifying therapy for dementia in PD.

[Insulin resistance--a physiopathological condition with numerous sequelae: non-insulin-dependent diabetes mellitus (NIDDM), android obesity, essential hypertension, dyslipidemia and atherosclerosis].

PubMed

Pedersen, O

1992-05-11

Recent research has demonstrated that reduced insulin-stimulated glucose metabolism in skeletal muscle (insulin resistance) and hyperinsulinism are common features in widespread diseases such as essential hypertension, android obesity, non-insulin dependent diabetes mellitus, dyslipidemia (in the form of raised serum triglyceride and reduced serum high-density lipoprotein (HDL) cholesterol) and arteriosclerosis. Simultaneously, investigations in a comprehensive group of healthy middle-aged men have revealed insulin resistance in one fourth. On the basis of these observations, a working hypothesis is suggested which postulates that genetic abnormalities in one or more of the candidate genes in the modes of action of insulin occur in a great proportion of the population. These may result in insulin resistance (primary genetic insulin resistance). Primary insulin resistance may be potentiated by a series of circumstances such as ageing, high-fat diet, lack of physical activity, hormonal and metabolic abnormalities or drugs (secondary insulin resistance). As a consequence of the reduced effect of insulin on muscle tissue, compensatory hyperinsulinism develops. Depending on the remaining vulnerability of the individual the hyperinsulinism is presumed to result in development of one or more phenotypes. For example if the beta-cells of the pancreas are unable to secrete sufficient insulin to compensate the insulin resistance on account of genetic defects, glucose intolerance will develop. In a similar manner, hyperinsulinism in insulin-resistant individuals who are predisposed to essential hypertension is presumed to reveal genetic defects in the blood pressure regulating mechanisms and thus contribute to development of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of ultraviolet-B radiation on fungal disease development in Cucumis sativus

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

Orth, A.B.; Teramura, A.H.; Sisler, H.D.

1990-09-01

Stratospheric ozone depletion due to increased atmospheric pollutants has received considerable attention because of the potential increase in ultraviolet-B (UV-B, 280-320 nm) radiation that will reach the earth's surface. Three cucumber (Cucumis sativus L.) cultivars were exposed to a daily dose of 11.6 kJ m{sup {minus}2} biologically effective ultraviolet-B (UV-B{sub BE}) radiation in an unshaded greenhouse before and/or after injection by Colletotrichum lagenarium (Pass.) Ell. and Halst. or Cladosporium cucumerinum Ell. and Arth. and analyzed for disease development. Two of these cultivars, Poinsette and Calypso Hybrid, were disease resistant, while the third cultivar, Straight-8, was disease susceptible. Preinfectional treatment ofmore » 1 to 7 days with UV-B{sub BE} in Straight-8 led to greater severity of both diseases. Postinfectional UV treatment did not lead to increased disease severity caused by C. lagenarium, while preinfectional UV treatment in both Straight-8 and Poinsette substantially increased disease severity. Although resistant cultivars Poinsette and Calypso Hybrid showed increased anthracnose disease severity when exposed to UV-B, this effect was apparent only on the cotyledons. Both higher spore concentration and exposure to UV-B radiation resulted in greater disease severity. Of the cucumber cultivars tested for UV-B sensitivity, growth in Poinsette was most sensitive and Calypso Hybrid was least sensitive. These preliminary results indicate that the effects of UV-B radiation on disease development in cucumber vary depending on cultivar, timing and duration of UV-B exposure, inoculation level, and plant age.« less

From SARS to strategic actions reframing systems.

PubMed

Macdonald, Marilyn T

2004-09-01

The developed world responds to new and re-emerging diseases through the discovery of medications. Disease can be transmitted around the world in a day, but the development of medications does not occur at this rate. The world has one environment and the focus in health care must be on identifying factors in this environment that coalesce to produce disease. The aim of this paper is to introduce the integrative model of environmental health and explore its potential to illuminate the Toronto SARS experience. SARS affected people on three continents in a matter of days. Response to this new disease varied from one area to another and was dependent upon the level of integration of health services and communication across services. The present focus of the health care system is on treating the results of disease rather than the causative factors. Reacting to a new disease had grave social and economic consequences. The time for a new global environmental approach to health is now. The Toronto SARS experience was examined using the integrative model of environmental health and the upstream perspective as exemplars to interrupt the traditional approach to disease. All health care providers share the responsibility to learn about and to understand how our environment creates disease. This knowledge comes through research on topics such as; chemicals, pesticides, soil erosion, killing of forests, contamination of water, destabilization of climate, and social disruption from wars. Health care systems in the developed world continue to focus on the treatment of disease. A global ecological initiative for an integrated disease prevention system must be negotiated among nations.

Eradication of melanoma in vitro and in vivo via targeting with a Killer-Red-containing telomerase-dependent adenovirus.

PubMed

Takehara, Kiyoto; Yano, Shuya; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Narii, Nobuhiro; Mizuguchi, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M

2017-08-18

Melanoma is a highly recalcitrant cancer and transformative therapy is necessary for the cure of this disease. We recently developed a telomerase-dependent adenovirus containing the fluorescent protein Killer-Red. In the present report, we first determined the efficacy of Killer-Red adenovirus combined with laser irradiation on human melanoma cell lines in vitro. Cell viability of human melanoma cells was reduced in a dose-dependent and irradiation-time-dependent manner. We used an intradermal xenografted melanoma model in nude mice to determine efficacy of the Killer-Red adenovirus. Intratumoral injection of Killer-Red adenovirus, combined with laser irradiation, eradicated the melanoma indicating the potential of a new paradigm of cancer therapy.

The Validity of Dependence as a Health Outcome Measure in Alzheimer’s Disease

PubMed Central

Spackman, D. Eldon; Kadiyala, Srikanth; Neumann, Peter J.; Veenstra, David L.; Sullivan, Sean D.

2013-01-01

Background Relating to Alzheimer’s disease (AD), dependence has been defined as the increased need for assistance due to deterioration in cognition, physical functioning, and behavior. Our objective was to evaluate the association between dependence and measures of functional impairment. Methods Data were compiled by the National Alzheimer’s Coordinating Center. We used multinomial logistic regression to estimate the association between dependence and cognition, physical functioning, and behavior. Results The independent association with dependence was positive. Dependence was most strongly associated with physical functioning. A secondary analysis suggested a strong association of dependence with multiple impairments, as measured by the interaction terms, in more severe patients. Conclusions We find that dependence is simultaneously associated with physical functioning, cognition, and behavior, which support the construct validity of dependence. Dependence might be a more simple measure to explain the multifaceted disease progression of AD and convey the increasing need for care. PMID:23512996

The validity of dependence as a health outcome measure in Alzheimer's disease.

PubMed

Spackman, D Eldon; Kadiyala, Srikanth; Neumann, Peter J; Veenstra, David L; Sullivan, Sean D

2013-05-01

Relating to Alzheimer's disease (AD), dependence has been defined as the increased need for assistance due to deterioration in cognition, physical functioning, and behavior. Our objective was to evaluate the association between dependence and measures of functional impairment. Data were compiled by the National Alzheimer's Coordinating Center. We used multinomial logistic regression to estimate the association between dependence and cognition, physical functioning, and behavior. The independent association with dependence was positive. Dependence was most strongly associated with physical functioning. A secondary analysis suggested a strong association of dependence with multiple impairments, as measured by the interaction terms, in more severe patients. We find that dependence is simultaneously associated with physical functioning, cognition, and behavior, which support the construct validity of dependence. Dependence might be a more simple measure to explain the multifaceted disease progression of AD and convey the increasing need for care.

A framework for responding to coral disease outbreaks that facilitates adaptive management.

PubMed

Beeden, Roger; Maynard, Jeffrey A; Marshall, Paul A; Heron, Scott F; Willis, Bette L

2012-01-01

Predicted increases in coral disease outbreaks associated with climate change have implications for coral reef ecosystems and the people and industries that depend on them. It is critical that coral reef managers understand these implications and have the ability to assess and reduce risk, detect and contain outbreaks, and monitor and minimise impacts. Here, we present a coral disease response framework that has four core components: (1) an early warning system, (2) a tiered impact assessment program, (3) scaled management actions and (4) a communication plan. The early warning system combines predictive tools that monitor the risk of outbreaks of temperature-dependent coral diseases with in situ observations provided by a network of observers who regularly report on coral health and reef state. Verified reports of an increase in disease prevalence trigger a tiered response of more detailed impact assessment, targeted research and/or management actions. The response is scaled to the risk posed by the outbreak, which is a function of the severity and spatial extent of the impacts. We review potential management actions to mitigate coral disease impacts and facilitate recovery, considering emerging strategies unique to coral disease and more established strategies to support reef resilience. We also describe approaches to communicating about coral disease outbreaks that will address common misperceptions and raise awareness of the coral disease threat. By adopting this framework, managers and researchers can establish a community of practice and can develop response plans for the management of coral disease outbreaks based on local needs. The collaborations between managers and researchers we suggest will enable adaptive management of disease impacts following evaluating the cost-effectiveness of emerging response actions and incrementally improving our understanding of outbreak causation.

A Framework for Responding to Coral Disease Outbreaks that Facilitates Adaptive Management

NASA Astrophysics Data System (ADS)

Beeden, Roger; Maynard, Jeffrey A.; Marshall, Paul A.; Heron, Scott F.; Willis, Bette L.

2012-01-01

Predicted increases in coral disease outbreaks associated with climate change have implications for coral reef ecosystems and the people and industries that depend on them. It is critical that coral reef managers understand these implications and have the ability to assess and reduce risk, detect and contain outbreaks, and monitor and minimise impacts. Here, we present a coral disease response framework that has four core components: (1) an early warning system, (2) a tiered impact assessment program, (3) scaled management actions and (4) a communication plan. The early warning system combines predictive tools that monitor the risk of outbreaks of temperature-dependent coral diseases with in situ observations provided by a network of observers who regularly report on coral health and reef state. Verified reports of an increase in disease prevalence trigger a tiered response of more detailed impact assessment, targeted research and/or management actions. The response is scaled to the risk posed by the outbreak, which is a function of the severity and spatial extent of the impacts. We review potential management actions to mitigate coral disease impacts and facilitate recovery, considering emerging strategies unique to coral disease and more established strategies to support reef resilience. We also describe approaches to communicating about coral disease outbreaks that will address common misperceptions and raise awareness of the coral disease threat. By adopting this framework, managers and researchers can establish a community of practice and can develop response plans for the management of coral disease outbreaks based on local needs. The collaborations between managers and researchers we suggest will enable adaptive management of disease impacts following evaluating the cost-effectiveness of emerging response actions and incrementally improving our understanding of outbreak causation.

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

PubMed Central

Hong, Sangjin; Pedersen, Peter L.

2008-01-01

Summary: ATP synthase, a double-motor enzyme, plays various roles in the cell, participating not only in ATP synthesis but in ATP hydrolysis-dependent processes and in the regulation of a proton gradient across some membrane-dependent systems. Recent studies of ATP synthase as a potential molecular target for the treatment of some human diseases have displayed promising results, and this enzyme is now emerging as an attractive molecular target for the development of new therapies for a variety of diseases. Significantly, ATP synthase, because of its complex structure, is inhibited by a number of different inhibitors and provides diverse possibilities in the development of new ATP synthase-directed agents. In this review, we classify over 250 natural and synthetic inhibitors of ATP synthase reported to date and present their inhibitory sites and their known or proposed modes of action. The rich source of ATP synthase inhibitors and their known or purported sites of action presented in this review should provide valuable insights into their applications as potential scaffolds for new therapeutics for human and animal diseases as well as for the discovery of new pesticides and herbicides to help protect the world's food supply. Finally, as ATP synthase is now known to consist of two unique nanomotors involved in making ATP from ADP and Pi, the information provided in this review may greatly assist those investigators entering the emerging field of nanotechnology. PMID:19052322

Viral delivery of C9orf72 hexanucleotide repeat expansions in mice leads to repeat-length-dependent neuropathology and behavioural deficits

PubMed Central

Herranz-Martin, Saul; Lewis, Katherine; Mulcahy, Padraig; Higginbottom, Adrian; Walker, Callum; Valenzuela, Isabel Martinez-Pena y; Coldicott, Ian; Shaw, Pamela J.

2017-01-01

ABSTRACT Intronic GGGGCC repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two major pathologies stemming from the hexanucleotide RNA expansions (HREs) have been identified in postmortem tissue: intracellular RNA foci and repeat-associated non-ATG dependent (RAN) dipeptides, although it is unclear how these and other hallmarks of disease contribute to the pathophysiology of neuronal injury. Here, we describe two novel lines of mice that overexpress either 10 pure or 102 interrupted GGGGCC repeats mediated by adeno-associated virus (AAV) and recapitulate the relevant human pathology and disease-related behavioural phenotypes. Similar levels of intracellular RNA foci developed in both lines of mice, but only mice expressing 102 repeats generated C9orf72 RAN pathology, neuromuscular junction (NMJ) abnormalities, dispersal of the hippocampal CA1, enhanced apoptosis, and deficits in gait and cognition. Neither line of mice, however, showed extensive TAR DNA-binding protein 43 (TDP-43) pathology or neurodegeneration. Our data suggest that RNA foci pathology is not a good predictor of C9orf72 RAN dipeptide formation, and that RAN dipeptides and NMJ dysfunction are drivers of C9orf72 disease pathogenesis. These AAV-mediated models of C9orf72-associated ALS/FTD will be useful tools for studying disease pathophysiology and developing new therapeutic approaches. PMID:28550099

Myeloid-derived suppressor cells regulate T cell and B cell responses during autoimmune disease.

PubMed

Crook, Kristen R; Jin, Mengyao; Weeks, Michael F; Rampersad, Rishi R; Baldi, Robert M; Glekas, Amy S; Shen, Yajuan; Esserman, Denise A; Little, Paul; Schwartz, Todd A; Liu, Peng

2015-03-01

MDSCs are a heterogeneous group of myeloid cells that suppress T cell activity in cancer and autoimmune disease. The effect of MDSCs on B cell function is not clear. Using the CIA model of autoimmune disease, we found an increase in M-MDSCs in the periphery of WT mice with CIA compared with naïve mice. These MDSCs were absent from the periphery of CCR2(-/-) mice that developed exacerbated disease. M-MDSCs, isolated from immunized mice, inhibited autologous CD4(+) T cell proliferation. The M-MDSC-mediated suppression of T cell proliferation was NO and IFN-γ dependent but IL-17 independent. Furthermore, we demonstrated for the first time that M-MDSCs from CIA mice also inhibited autologous B cell proliferation and antibody production. The suppression of B cells by M-MDSCs was dependent on the production of NO and PGE2 and required cell-cell contact. Administration of M-MDSCs rescued CCR2(-/-) mice from the exacerbated CIA phenotype and ameliorated disease in WT mice. Furthermore, adoptive transfer of M-MDSCs reduced autoantibody production by CCR2(-/-) and WT mice. In summary, M-MDSCs inhibit T cell and B cell function in CIA and may serve as a therapeutic approach in the treatment of autoimmune arthritis. © Society for Leukocyte Biology.

Disease-specific health-related quality of life in patients with esophageal achalasia before and after therapy.

PubMed

Garrigues, V; Ortiz, V; Casanova, C; Bujanda, L; Moreno-Osset, E; Rodríguez-Téllez, M; Montserrat, A; Brotons, A; Fort, E; Ponce, J

2010-07-01

To evaluate disease-specific health-related quality of life (HRQoL) in patients with symptomatic esophageal achalasia before and after therapy. Symptoms and disease-specific HRQoL were evaluated before and 3 months after therapy. Therapy selection, either dilatation or myotomy, depended exclusively on the opinion of the physician on charge of the patient. Symptom severity was graded from 0 to 3, using a scoring system. A disease-specific questionnaire for achalasia developed and validated in Spanish language with 18 items and four subscales (AE-18) was used to evaluate HRQoL. Changes after therapy in HRQoL and its association with clinical improvement were analyzed. Sixty-five patients were prospectively included in eight hospitals in Spain. Of them, 47 were treated with dilatation, and 18 with laparoscopic Heller myotomy. After therapy, AE-18 global and subscales scores improved significantly. Changes in HRQoL were associated with improvement in symptoms. An important improvement in symptoms (>or=50%) was needed to obtain a minimal clinically important improvement (>or=20%) in HRQoL. Disease-specific HRQoL improves in patients with symptomatic achalasia after therapy with dilatation or myotomy. The degree of improvement of HRQoL depends on the degree of improvement of esophageal symptoms.

Interleukin-6 Contributes to Inflammation and Remodeling in a Model of Adenosine Mediated Lung Injury

PubMed Central

Pedroza, Mesias; Schneider, Daniel J.; Karmouty-Quintana, Harry; Coote, Julie; Shaw, Stevan; Corrigan, Rebecca; Molina, Jose G.; Alcorn, Joseph L.; Galas, David; Gelinas, Richard; Blackburn, Michael R.

2011-01-01

Background Chronic lung diseases are the third leading cause of death in the United States due in part to an incomplete understanding of pathways that govern the progressive tissue remodeling that occurs in these disorders. Adenosine is elevated in the lungs of animal models and humans with chronic lung disease where it promotes air-space destruction and fibrosis. Adenosine signaling increases the production of the pro-fibrotic cytokine interleukin-6 (IL-6). Based on these observations, we hypothesized that IL-6 signaling contributes to tissue destruction and remodeling in a model of chronic lung disease where adenosine levels are elevated. Methodology/Principal Findings We tested this hypothesis by neutralizing or genetically removing IL-6 in adenosine deaminase (ADA)-deficient mice that develop adenosine dependent pulmonary inflammation and remodeling. Results demonstrated that both pharmacologic blockade and genetic removal of IL-6 attenuated pulmonary inflammation, remodeling and fibrosis in this model. The pursuit of mechanisms involved revealed adenosine and IL-6 dependent activation of STAT-3 in airway epithelial cells. Conclusions/Significance These findings demonstrate that adenosine enhances IL-6 signaling pathways to promote aspects of chronic lung disease. This suggests that blocking IL-6 signaling during chronic stages of disease may provide benefit in halting remodeling processes such as fibrosis and air-space destruction. PMID:21799929

What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells.

PubMed

Wildner, Gerhild; Kaufmann, Ulrike

2013-09-01

Most human autoimmune diseases have a relapsing-remitting or a chronic progressive course, while animal models are usually acute and monophasic. In our experimental animal model the disease can be either monophasic or remitting, depending on the autoantigen used for induction, and it appears to lie in the effector phenotype of the elicited T helper cell response. Since both, monophasic and relapsing courses of disease are induced by immunization as well as by adoptive transfer of peptide-specific, CD4(+) T cells, we were able to directly compare the transcriptomes of pathogenic T cell lines by gene array analysis and qPCR as well as protein expression. Upregulated genes were only determined in T cells inducing relapsing uveitis and belong to certain pathways of antigen presentation, activation, inflammation, migration and survival, comprising WNT, Hedgehog, MAP-kinase and JAK/STAT-pathways. These pathways are partially interacting with each other, and the central molecule upregulated in T cells causing relapsing disease was found to be IFN-γ. Here the course of the autoimmune diseases strictly depends on the characteristics of the autoreactive T cells, which are already determined at their early stage of antigen-specific activation. Our rat models of experimental autoimmune uveitis could help elucidating the immune mechanisms behind relapsing autoimmunity in order to develop better therapeutic strategies. Copyright © 2013 Elsevier B.V. All rights reserved.

Perfringolysin O: The Underrated Clostridium perfringens Toxin?

PubMed Central

Verherstraeten, Stefanie; Goossens, Evy; Valgaeren, Bonnie; Pardon, Bart; Timbermont, Leen; Haesebrouck, Freddy; Ducatelle, Richard; Deprez, Piet; Wade, Kristin R.; Tweten, Rodney; Van Immerseel, Filip

2015-01-01

The anaerobic bacterium Clostridium perfringens expresses multiple toxins that promote disease development in both humans and animals. One such toxin is perfringolysin O (PFO, classically referred to as θ toxin), a pore-forming cholesterol-dependent cytolysin (CDC). PFO is secreted as a water-soluble monomer that recognizes and binds membranes via cholesterol. Membrane-bound monomers undergo structural changes that culminate in the formation of an oligomerized prepore complex on the membrane surface. The prepore then undergoes conversion into the bilayer-spanning pore measuring approximately 250–300 Å in diameter. PFO is expressed in nearly all identified C. perfringens strains and harbors interesting traits that suggest a potential undefined role for PFO in disease development. Research has demonstrated a role for PFO in gas gangrene progression and bovine necrohemorrhagic enteritis, but there is limited data available to determine if PFO also functions in additional disease presentations caused by C. perfringens. This review summarizes the known structural and functional characteristics of PFO, while highlighting recent insights into the potential contributions of PFO to disease pathogenesis. PMID:26008232

Perfringolysin O: The Underrated Clostridium perfringens Toxin?

PubMed

Verherstraeten, Stefanie; Goossens, Evy; Valgaeren, Bonnie; Pardon, Bart; Timbermont, Leen; Haesebrouck, Freddy; Ducatelle, Richard; Deprez, Piet; Wade, Kristin R; Tweten, Rodney; Van Immerseel, Filip

2015-05-14

The anaerobic bacterium Clostridium perfringens expresses multiple toxins that promote disease development in both humans and animals. One such toxin is perfringolysin O (PFO, classically referred to as θ toxin), a pore-forming cholesterol-dependent cytolysin (CDC). PFO is secreted as a water-soluble monomer that recognizes and binds membranes via cholesterol. Membrane-bound monomers undergo structural changes that culminate in the formation of an oligomerized prepore complex on the membrane surface. The prepore then undergoes conversion into the bilayer-spanning pore measuring approximately 250-300 Å in diameter. PFO is expressed in nearly all identified C. perfringens strains and harbors interesting traits that suggest a potential undefined role for PFO in disease development. Research has demonstrated a role for PFO in gas gangrene progression and bovine necrohemorrhagic enteritis, but there is limited data available to determine if PFO also functions in additional disease presentations caused by C. perfringens. This review summarizes the known structural and functional characteristics of PFO, while highlighting recent insights into the potential contributions of PFO to disease pathogenesis.

Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases.

PubMed

Cabeza, Marisa; Sánchez-Márquez, Araceli; Garrido, Mariana; Silva, Aylín; Bratoeff, Eugene

2016-01-01

This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.

Immunopathologic effects of silicone breast implants.

PubMed Central

Teuber, S S; Yoshida, S H; Gershwin, M E

1995-01-01

Silicone-gel breast implants have been associated with a myriad of autoimmune and connective tissue disorders by anecdotal reports and small observational series. To date, no prospective epidemiologic studies have been done to substantiate these observations, but an increasing body of literature is being developed and older studies are being recognized that point to immunotoxic or inflammatory effects of these breast implant components. The development of disease due to implants would depend on the interaction of genetic host factors so that only a few patients would potentially be at risk. Based on the example of other chemically mediated disorders, such as scleroderma in association with silica exposure, latency periods of more than 30 years before disease develops may be possible. Herein we review studies on silicone and immunity. PMID:7785255

The rhizosphere microbial community in a multiple parallel mineralization system suppresses the pathogenic fungus Fusarium oxysporum

PubMed Central

Fujiwara, Kazuki; Iida, Yuichiro; Iwai, Takashi; Aoyama, Chihiro; Inukai, Ryuya; Ando, Akinori; Ogawa, Jun; Ohnishi, Jun; Terami, Fumihiro; Takano, Masao; Shinohara, Makoto

2013-01-01

The rhizosphere microbial community in a hydroponics system with multiple parallel mineralization (MPM) can potentially suppress root-borne diseases. This study focused on revealing the biological nature of the suppression against Fusarium wilt disease, which is caused by the fungus Fusarium oxysporum, and describing the factors that may influence the fungal pathogen in the MPM system. We demonstrated that the rhizosphere microbiota that developed in the MPM system could suppress Fusarium wilt disease under in vitro and greenhouse conditions. The microbiological characteristics of the MPM system were able to control the population dynamics of F. oxysporum, but did not eradicate the fungal pathogen. The roles of the microbiological agents underlying the disease suppression and the magnitude of the disease suppression in the MPM system appear to depend on the microbial density. F. oxysporum that survived in the MPM system formed chlamydospores when exposed to the rhizosphere microbiota. These results suggest that the microbiota suppresses proliferation of F. oxysporum by controlling the pathogen's morphogenesis and by developing an ecosystem that permits coexistence with F. oxysporum. PMID:24311557

Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat.

PubMed

Wang, Xiaofang; Gattone, Vincent; Harris, Peter C; Torres, Vicente E

2005-04-01

cAMP plays a major role in cystogenesis. Recent in vitro studies suggested that cAMP stimulates B-Raf/ERK activation and proliferation of cyst-derived cells in a Ca(2+) inhibitable, Ras-dependent manner. OPC-31260, a vasopressin V2 receptor (VPV2) antagonist, was shown to lower renal cAMP and inhibit renal disease development and progression in models orthologous to human cystic diseases. Here it is shown that OPC-41061, an antagonist chosen for its potency and selectivity for human VPV2, is effective in PCK rats. PCK kidneys have increased Ras-GTP and phosphorylated ERK levels and 95-kD/68-kD B-Raf ratios, changes that are corrected by the administration of OPC-31260 or OPC-41061. These results support the importance of cAMP in the pathogenesis of polycystic kidney disease, confirm the effectiveness of a VPV2 antagonist to be used in clinical trials for this disease, and suggest that OPC-31260 and OPC-41061 inhibit Ras/mitogen-activated protein kinase signaling in polycystic kidneys.

Why industry propaganda and political interference cannot disguise the inevitable role played by human exposure to aluminum in neurodegenerative diseases, including Alzheimer's disease.

PubMed

Exley, Christopher

2014-01-01

In the aluminum age, it is clearly unpalatable for aluminum, the globe's most successful metal, to be implicated in human disease. It is unpalatable because for approximately 100 years human beings have reaped the rewards of the most abundant metal of the Earth's crust without seriously considering the potential consequences for human health. The aluminum industry is a pillar of the developed and developing world and irrespective of the tyranny of human exposure to aluminum it cannot be challenged without significant consequences for businesses, economies, and governments. However, no matter how deep the dependency or unthinkable the withdrawal, science continues to document, if not too slowly, a burgeoning body burden of aluminum in human beings. Herein, I will make the case that it is inevitable both today and in the future that an individual's exposure to aluminum is impacting upon their health and is already contributing to, if not causing, chronic diseases such as Alzheimer's disease. This is the logical, if uncomfortable, consequence of living in the aluminum age.

Improving the clinical management of traumatic brain injury through the pharmacokinetic modeling of peripheral blood biomarkers.

PubMed

Dadas, Aaron; Washington, Jolewis; Marchi, Nicola; Janigro, Damir

2016-11-30

Blood biomarkers of neurovascular damage are used clinically to diagnose the presence severity or absence of neurological diseases, but data interpretation is confounded by a limited understanding of their dependence on variables other than the disease condition itself. These include half-life in blood, molecular weight, and marker-specific biophysical properties, as well as the effects of glomerular filtration, age, gender, and ethnicity. To study these factors, and to provide a method for markers' analyses, we developed a kinetic model that allows the integrated interpretation of these properties. The pharmacokinetic behaviors of S100B (monomer and homodimer), Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase L1 were modeled using relevant chemical and physical properties; modeling results were validated by comparison with data obtained from healthy subjects or individuals affected by neurological diseases. Brain imaging data were used to model passage of biomarkers across the blood-brain barrier. Our results show the following: (1) changes in biomarker serum levels due to age or disease progression are accounted for by differences in kidney filtration; (2) a significant change in the brain-to-blood volumetric ratio, which is characteristic of infant and adult development, contributes to variation in blood concentration of biomarkers; (3) the effects of extracranial contribution at steady-state are predicted in our model to be less important than suspected, while the contribution of blood-brain barrier disruption is confirmed as a significant factor in controlling markers' appearance in blood, where the biomarkers are typically detected; (4) the contribution of skin to the marker S100B blood levels depends on a direct correlation with pigmentation and not ethnicity; the contribution of extracranial sources for other markers requires further investigation. We developed a multi-compartment, pharmacokinetic model that integrates the biophysical properties of a given brain molecule and predicts its time-dependent concentration in blood, for populations of varying physical and anatomical characteristics. This model emphasizes the importance of the blood-brain barrier as a gatekeeper for markers' blood appearance and, ultimately, for rational clinical use of peripherally-detected brain protein.

TGF-ß Regulates Cathepsin Activation during Normal and Pathogenic Development.

PubMed

Flanagan-Steet, Heather; Christian, Courtney; Lu, Po-Nien; Aarnio-Peterson, Megan; Sanman, Laura; Archer-Hartmann, Stephanie; Azadi, Parastoo; Bogyo, Matthew; Steet, Richard A

2018-03-13

Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases. The data support a pathogenic mechanism where TGF-ß signals enhance the proteolytic processing of pro-Ctsk by modulating the expression of chondroitin 4-sulfate (C4-S). In MLII, elevated C4-S corresponds with TGF-ß-mediated increases in chst11 expression. Inhibiting chst11 impairs the proteolytic activation of Ctsk and alleviates the MLII phenotypes. These findings uncover a regulatory loop between TGF-ß signaling and Ctsk activation that is altered in the context of lysosomal disease. This work highlights the power of ABPs to identify mechanisms underlying pathogenic development in living animals. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Possible link between Toxoplasma gondii and the anosmia associated with neurodegenerative diseases.

PubMed

Prandota, Joseph

2014-05-01

Toxoplasma gondii is an intracellular protozoan infecting 30% to 50% of global human population. Recently, it was suggested that chronic latent neuroinflammation caused by the parasite may be responsible for the development of several neurodegenerative diseases manifesting with the loss of smell. Studies in animals inoculated with the parasite revealed cysts in various regions of the brain, including olfactory bulb. Development of behavioral changes was paralleled by the preferential persistence of cysts in defined anatomic structures of the brain, depending on the host, strain of the parasite, its virulence, and route of inoculation. Olfactory dysfunction reported in Alzheimer's disease, multiple sclerosis, and schizophrenia was frequently associated with the significantly increased serum anti-T gondii immunoglobulin G antibody levels. Damage of the olfactory system may be also at least in part responsible for the development of depression because T gondii infection worsened mood in such patients, and the olfactory bulbectomized rat serves as a model of depression.

Predictors of patient dependence in mild-to-moderate Alzheimer's disease.

PubMed

Benke, Thomas; Sanin, Günter; Lechner, Anita; Dal-Bianco, Peter; Ransmayr, Gerhard; Uranüs, Margarete; Marksteiner, Josef; Gaudig, Maren; Schmidt, Reinhold

2015-01-01

Patient dependence has rarely been studied in mild-to-moderate Alzheimer's disease (AD). To identify factors which predict patient dependence in mild-to-moderate AD. We studied 398 non-institutionalized AD patients (234 females) of the ongoing Prospective Registry on Dementia (PRODEM) in Austria. The Dependence Scale (DS) was used to assess patient dependence. Patient assessment comprised functional abilities, neuropsychiatric symptoms and cognitive functions. A multiple linear regression analysis was performed to identify predictors of patient dependence. AD patients were mildly-to-moderately impaired (mean scores and SDs were: CDR 0.84 ± 0.43; DAD 74.4 ± 23.3, MMSE = 22.5 ± 3.6). Psychopathology and caregiver burden were in the low range (mean NPI score 13.2, range 0 to 98; mean ZBI score 18, range 0-64). Seventy five percent of patients were classified as having a mild level of patient dependence (DS sum score 0 to 6). Patient dependence correlated significantly and positively with age, functional measures, psychopathology and depression, disease duration, and caregiver burden. Significant negative, but low correlations were found between patient dependence, cognitive variables, and global cognition. Activities of daily living, patient age, and disease severity accounted for 63% of variance in patient dependence, whereas cognitive variables accounted for only 11%. Dependence in this cohort was mainly related to age and functional impairment, and less so to cognitive and neuropsychiatric variables. This differs from studies investigating patients in more advanced disease stages which found abnormal behavior and impairments of cognition as main predictors of patient dependence.

Genetic Causes of Rickets

PubMed Central

Acar, Sezer; Demir, Korcan; Shi, Yufei

2017-01-01

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches. PMID:29280738

Plug-and-Play Multicellular Circuits with Time-Dependent Dynamic Responses.

PubMed

Urrios, Arturo; Gonzalez-Flo, Eva; Canadell, David; de Nadal, Eulàlia; Macia, Javier; Posas, Francesc

2018-04-20

Synthetic biology studies aim to develop cellular devices for biomedical applications. These devices, based on living instead of electronic or electromechanic technology, might provide alternative treatments for a wide range of diseases. However, the feasibility of these devices depends, in many cases, on complex genetic circuits that must fulfill physiological requirements. In this work, we explored the potential of multicellular architectures to act as an alternative to complex circuits for implementation of new devices. As a proof of concept, we developed specific circuits for insulin or glucagon production in response to different glucose levels. Here, we show that fundamental features, such as circuit's affinity or sensitivity, are dependent on the specific configuration of the multicellular consortia, providing a method for tuning these properties without genetic engineering. As an example, we have designed and built circuits with an incoherent feed-forward loop architecture (FFL) that can be easily adjusted to generate single pulse responses. Our results might serve as a blueprint for future development of cellular devices for glycemia regulation in diabetic patients.

NO-Rich Diet for Lifestyle-Related Diseases

PubMed Central

Kobayashi, Jun; Ohtake, Kazuo; Uchida, Hiroyuki

2015-01-01

Decreased nitric oxide (NO) availability due to obesity and endothelial dysfunction might be causally related to the development of lifestyle-related diseases such as insulin resistance, ischemic heart disease, and hypertension. In such situations, instead of impaired NO synthase (NOS)-dependent NO generation, the entero-salivary nitrate-nitrite-NO pathway might serve as a backup system for NO generation by transmitting NO activities in the various molecular forms including NO and protein S-nitrosothiols. Recently accumulated evidence has demonstrated that dietary intake of fruits and vegetables rich in nitrate/nitrite is an inexpensive and easily-practicable way to prevent insulin resistance and vascular endothelial dysfunction by increasing the NO availability; a NO-rich diet may also prevent other lifestyle-related diseases, including osteoporosis, chronic obstructive pulmonary disease (COPD), and cancer. This review provides an overview of our current knowledge of NO generation through the entero-salivary pathway and discusses its safety and preventive effects on lifestyle-related diseases. PMID:26091235

Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody

PubMed Central

Weiss, Lola; Slavin, Shimon; Reich, Shoshana; Cohen, Patrizia; Shuster, Svetlana; Stern, Robert; Kaganovsky, Ella; Okon, Elimelech; Rubinstein, Ariel M.; Naor, David

2000-01-01

Inflammatory destruction of insulin-producing β cells in the pancreatic islets is the hallmark of insulin-dependent diabetes mellitus, a spontaneous autoimmune disease of non-obese diabetic mice resembling human juvenile (type I) diabetes. Histochemical analysis of diabetic pancreata revealed that mononuclear cells infiltrating the islets and causing autoimmune insulitis, as well as local islet cells, express the CD44 receptor; hyaluronic acid, the principal ligand of CD44, is detected in the islet periphery and islet endothelium. Injection of anti-CD44 mAb 1 hr before cell transfer of diabetogenic splenocytes and subsequently on alternate days for 4 weeks induced considerable resistance to diabetes in recipient mice, reflected by reduced insulitis. Contact sensitivity to oxazolone was not influenced by this treatment. A similar antidiabetic effect was observed even when the anti-CD44 mAb administration was initiated at the time of disease onset: i.e., 4–7 weeks after cell transfer. Administration of the enzyme hyaluronidase also induced appreciable resistance to insulin-dependent diabetes mellitus, suggesting that the CD44–hyaluronic acid interaction is involved in the development of the disease. These findings demonstrate that CD44-positive inflammatory cells may be a potential therapeutic target in insulin-dependent diabetes. PMID:10618410

Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice.

PubMed

Otomo, Kotaro; Koga, Tomohiro; Mizui, Masayuki; Yoshida, Nobuya; Kriegel, Christina; Bickerton, Sean; Fahmy, Tarek M; Tsokos, George C

2015-12-15

Treatment of autoimmune diseases is still largely based on the use of systemically acting immunosuppressive drugs, which invariably cause severe side effects. Calcium/calmodulin-dependent protein kinase IV is involved in the suppression of IL-2 and the production of IL-17. Its pharmacologic or genetic inhibition limits autoimmune disease in mice. In this study, we demonstrate that KN93, a small-molecule inhibitor of calcium/calmodulin-dependent protein kinase IV, targeted to CD4(+) T cells via a nanolipogel delivery system, markedly reduced experimental autoimmune encephalomyelitis and was 10-fold more potent than the free systemically delivered drug in the lupus mouse models. The targeted delivery of KN93 did not deplete T cells but effectively blocked Th17 cell differentiation and expansion as measured in the spinal cords and kidneys of mice developing experimental autoimmune encephalomyelitis or lupus, respectively. These results highlight the promise of cell-targeted inhibition of molecules involved in the pathogenesis of autoimmunity as a means of advancing the treatment of autoimmune diseases. Copyright © 2015 by The American Association of Immunologists, Inc.

Dietary proanthocyanidins prevent ultraviolet radiation-induced non-melanoma skin cancer through enhanced repair of damaged DNA-dependent activation of immune sensitivity.

PubMed

Katiyar, Santosh K; Pal, Harish C; Prasad, Ram

2017-10-01

Numerous plant products have been used to prevent and manage a wide variety of diseases for centuries. These products are now considered as promising options for the development of more effective and less toxic alternatives to the systems of medicine developed primarily in developed countries in the modern era. Grape seed proanthocyanidins (GSPs) are of great interest due to their anti-carcinogenic effects that have been demonstrated using various tumor models including ultraviolet (UV) radiation-induced non-melanoma skin cancer. In a pre-clinical mouse model supplementation of a control diet (AIN76A) with GSPs at concentrations of 0.2% and 0.5% (w/w) significantly inhibits the growth and multiplicity of UVB radiation-induced skin tumors. In this review, we summarize the evidence that this inhibition of UVB-induced skin tumor development by dietary GSPs is mediated by a multiplicity of coordinated effects including: (i) Promotion of the repair of damaged DNA by nuclear excision repair mechanisms, and (ii) DNA repair-dependent stimulation of the immune system following the functional activation of dendritic cells and effector T cells. Dietary GSPs hold promise for the development of an effective alternative strategy for the prevention of excessive solar UVB radiation exposure-induced skin diseases including the risk of non-melanoma skin cancer in humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

Clarification of serotonin-induced effects in peripheral artery disease observed through the femoral artery response in models of diabetes and vascular occlusion: The role of calcium ions.

PubMed

Stojanović, Marko; Prostran, Milica; Janković, Radmila; Radenković, Miroslav

2017-07-01

Recent findings have demonstrated that serotonin is an important participant in the development and progression of peripheral artery diseases. Taking this into consideration, the goals of this study were to investigate the effects of serotonin on isolated Wistar rat femoral arteries in both healthy and diabetic animals, with and without artery occlusion, with a particular focus on determining the role of calcium in this process. Contraction experiments with serotonin on intact and denuded femoral artery rings, in the presence or absence of nifedipine and ouabain (both separately, or in combination), as well as Ca 2+ -free Krebs-Ringer bicarbonate solution were performed. The serotonin-induced results were concentration dependent, but only in healthy animals. The endothelium-dependent contraction of the femoral artery was assessed. In healthy animals, the endothelium-reliant part of contraction was dependent on the extracellular calcium, while the smooth muscle-related part was instead dependent on the intracellular calcium. In diabetic animals, both nifedipine and ouabain influenced serotonin-induced vascular effects by blocking intracellular calcium pathways. However, this was diminished after the simultaneous administration of both blockers. © 2017 John Wiley & Sons Australia, Ltd.

Examining Object Location and Object Recognition Memory in Mice

PubMed Central

Vogel-Ciernia, Annie; Wood, Marcelo A.

2014-01-01

Unit Introduction The ability to store and recall our life experiences defines a person's identity. Consequently, the loss of long-term memory is a particularly devastating part of a variety of cognitive disorders, diseases and injuries. There is a great need to develop therapeutics to treat memory disorders, and thus a variety of animal models and memory paradigms have been developed. Mouse models have been widely used both to study basic disease mechanisms and to evaluate potential drug targets for therapeutic development. The relative ease of genetic manipulation of Mus musculus has led to a wide variety of genetically altered mice that model cognitive disorders ranging from Alzheimer's disease to autism. Rodents, including mice, are particularly adept at encoding and remembering spatial relationships, and these long-term spatial memories are dependent on the medial temporal lobe of the brain. These brain regions are also some of the first and most heavily impacted in disorders of human memory including Alzheimer's disease. Consequently, some of the simplest and most commonly used tests of long-term memory in mice are those that examine memory for objects and spatial relationships. However, many of these tasks, such as Morris water maze and contextual fear conditioning, are dependent upon the encoding and retrieval of emotionally aversive and inherently stressful training events. While these types of memories are important, they do not reflect the typical day-to-day experiences or memories most commonly affected in human disease. In addition, stress hormone release alone can modulate memory and thus obscure or artificially enhance these types of tasks. To avoid these sorts of confounds, we and many others have utilized tasks testing animals’ memory for object location and novel object recognition. These tasks involve exploiting rodents’ innate preference for novelty, and are inherently not stressful. In this protocol we detail how memory for object location and object identity can be used to evaluate a wide variety of mouse models and treatments. PMID:25297693

A Neurocomputational model of tonic and phasic dopamine in action selection: A comparison with cognitive deficits in Parkinson’s disease

PubMed Central

Guthrie, M.; Myers, C.E.; Gluck, M.A.

2015-01-01

The striatal dopamine signal has multiple facets; tonic level, phasic rise and fall, and variation of the phasic rise/fall depending on the expectation of reward/punishment. We have developed a network model of the striatal direct pathway using an ionic current level model of the medium spiny neuron that incorporates currents sensitive to changes in the tonic level of dopamine. The model neurons in the network learn action selection based on a novel set of mathematical rules that incorporate the phasic change in the dopamine signal. This network model is capable of learning to perform a sequence learning task that in humans is thought to be dependent on the basal ganglia. When both tonic and phasic levels of dopamine are decreased, as would be expected in unmedicated Parkinson’s disease (PD), the model reproduces the deficits seen in a human PD group off medication. When the tonic level is increased to normal, but with reduced phasic increases and decreases in response to reward and punishment respectively, as would be expected in PD medicated with L-Dopa, the model again reproduces the human data. These findings support the view that the cognitive dysfunctions seen in Parkinson’s disease are not solely due to either the decreased tonic level of dopamine or to the decreased responsiveness of the phasic dopamine signal to reward and punishment, but to a combination of the two factors that varies dependent on disease stage and medication status. PMID:19162084

Identification of Small Molecule Activators of Cryptochrome

PubMed Central

Hirota, Tsuyoshi; Lee, Jae Wook; St. John, Peter C.; Sawa, Mariko; Iwaisako, Keiko; Noguchi, Takako; Pongsawakul, Pagkapol Y.; Sonntag, Tim; Welsh, David K.; Brenner, David A.; Doyle, Francis J.; Schultz, Peter G.; Kay, Steve A.

2013-01-01

Impairment of the circadian clock has been associated with numerous disorders, including metabolic disease. Although small molecules that modulate clock function might offer therapeutic approaches to such diseases, only a few compound have been identified that selectively target core clock proteins. From an unbiased cell-based circadian screen, we identified KL001, a small molecule that specifically interacts with cryptochrome (CRY). KL001 prevented ubiquitin-dependent degradation of CRY, resulting in lengthening of the circadian period. In combination with mathematical modeling, KL001 revealed that CRY1 and CRY2 share a similar functional role in the period regulation. Furthermore, KL001- mediated CRY stabilization inhibited glucagon-induced gluconeogenesis in primary hepatocytes. KL001 thus provides a tool to study the regulation of CRY-dependent physiology and aid development of clock-based therapeutics of diabetes. PMID:22798407

[Core principles of treatment of corneal damage in patients with thyroid eye disease].

PubMed

Grusha, Y O; Ismailova, D S; Sherstneva, L V

To develop a therapeutic approach and to estimate the efficiency of complex treatment of corneal damage in patients with thyroid eye disease (TED). The study enrolled 44 patients (52 eyes) divided into 2 groups depending on the severity of corneal damage. Treatment of those with severe involvement included pathogenetic measures (pulse steroid therapy and/or radiation therapy) and surgery (orbital decompression, eyelid and corneal surgery). As the result of the treatment, orbital inflammation decreased and the state of the cornea improved in all patients. The treatment of corneal damage in patients with TED may differ depending on numerous factors, such as the severity of corneal damage and activity of orbital inflammation. Taking into account the potential danger of corneal involvement, one should make efforts to early detection and management of the risk factors.

Systematic drug repositioning for a wide range of diseases with integrative analyses of phenotypic and molecular data.

PubMed

Iwata, Hiroaki; Sawada, Ryusuke; Mizutani, Sayaka; Yamanishi, Yoshihiro

2015-02-23

Drug repositioning, or the application of known drugs to new indications, is a challenging issue in pharmaceutical science. In this study, we developed a new computational method to predict unknown drug indications for systematic drug repositioning in a framework of supervised network inference. We defined a descriptor for each drug-disease pair based on the phenotypic features of drugs (e.g., medicinal effects and side effects) and various molecular features of diseases (e.g., disease-causing genes, diagnostic markers, disease-related pathways, and environmental factors) and constructed a statistical model to predict new drug-disease associations for a wide range of diseases in the International Classification of Diseases. Our results show that the proposed method outperforms previous methods in terms of accuracy and applicability, and its performance does not depend on drug chemical structure similarity. Finally, we performed a comprehensive prediction of a drug-disease association network consisting of 2349 drugs and 858 diseases and described biologically meaningful examples of newly predicted drug indications for several types of cancers and nonhereditary diseases.

Symptoms of depression and anxiety in Serbian patients with systemic sclerosis: impact of disease severity and socioeconomic factors.

PubMed

Ostojic, Predrag; Zivojinovic, Sladjana; Reza, Tamara; Damjanov, Nemanja

2010-08-01

This study aimed to assess symptoms of depression and anxiety in Serbian patients with systemic sclerosis (SSc) and to estimate the impact of disease severity and socioeconomic factors on development of depression and anxiety in SSc. Thirty-five patients with SSc and 30 age- and gender-matched healthy individuals participated. Symptoms of depression and anxiety were evaluated using the Beck's depression inventory and Zung's anxiety self-assessment scale. We estimated the impact of gender, age, economic status, marital status, disease duration, disease subset (limited or diffuse), and some clinical features on development of depressive symptoms and anxiety in patients with SSc. Symptoms of depression were found in 68.6% of patients (compared with 23.3% in the control group), were more frequent in patients with longer disease duration and in female and older patients, and were more common in unemployed and retired patients than in employed individuals. No differences in anxiety and depressive symptoms was noticed between patients with limited and diffuse SSc or those with or without restrictive lung disease, pulmonary hypertension, finger-tip ulcers, and heart involvement. Symptoms of depression were associated with severe pain. Symptoms of anxiety were found in 80% of patients compared with 13.3% of healthy individuals and were equally as frequent in patients of different gender, age, socioeconomic status, and disease duration and severity. Symptoms of depression and anxiety are common in Serbian patients with SSc. Depressive symptoms depended mostly on socioeconomic factors, disease duration, and pain intensity, whereas disease severity had no significant impact on development of depressive symptoms and anxiety.

Modelling uveal melanoma

PubMed Central

Foss, A.; Cree, I.; Dolin, P.; Hungerford, J.

1999-01-01

BACKGROUND/AIM—There has been no consistent pattern reported on how mortality for uveal melanoma varies with age. This information can be useful to model the complexity of the disease. The authors have examined ocular cancer trends, as an indirect measure for uveal melanoma mortality, to see how rates vary with age and to compare the results with their other studies on predicting metastatic disease.
METHODS—Age specific mortality was examined for England and Wales, the USA, and Canada. A log-log model was fitted to the data. The slopes of the log-log plots were used as measure of disease complexity and compared with the results of previous work on predicting metastatic disease.
RESULTS—The log-log model provided a good fit for the US and Canadian data, but the observed rates deviated for England and Wales among people over the age of 65 years. The log-log model for mortality data suggests that the underlying process depends upon four rate limiting steps, while a similar model for the incidence data suggests between three and four rate limiting steps. Further analysis of previous data on predicting metastatic disease on the basis of tumour size and blood vessel density would indicate a single rate limiting step between developing the primary tumour and developing metastatic disease.
CONCLUSIONS—There is significant underreporting or underdiagnosis of ocular melanoma for England and Wales in those over the age of 65 years. In those under the age of 65, a model is presented for ocular melanoma oncogenesis requiring three rate limiting steps to develop the primary tumour and a fourth rate limiting step to develop metastatic disease. The three steps in the generation of the primary tumour involve two key processes—namely, growth and angiogenesis within the primary tumour. The step from development of the primary to development of metastatic disease is likely to involve a single rate limiting process.

 PMID:10216060

Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer

PubMed Central

Sheh, A; Muthupalani, S; Bryant, EM; Puglisi, DA; Holcombe, H; Conaway, EA; Parry, NAP; Bakthavatchalu, V; Short, SP; Williams, CS; Wogan, GN; Tannenbaum, SR; Fox, JG; Horwitz, BH

2017-01-01

The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh-infection induces DNA damage in this model and whether this depends on NO has not been determined. Here, we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22 dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process. PMID:28198364

Variation in pestivirus growth in testicle primary cell culture is more dependent on the individual cell donor than cattle breed

USDA-ARS?s Scientific Manuscript database

Bovine respiratory disease complex (BRDC) affects cattle from all breeds living in all regions. However, different breeds of cattle appear to have different susceptibilities to developing BRDC. The causes of BRDC are multifactorial and include infection with both viral and bacterial pathogens. Infec...

Analysis of Mycobacterium avium subspecies paratuberculosis mutant libraries reveals loci-dependent transposition biases and strategies to novel mutant discovery

USDA-ARS?s Scientific Manuscript database

Mycobacterium avium subsp. paratuberculosis (MAP), the etiologic agent of Johne’s disease, is one of the most important bacterial pathogens in ruminants. The lack of efficacious control measures demands a thorough understanding of MAP pathogenesis to develop new vaccines and diagnostic tests. The ge...

Altered transport and metabolism of phenolic compounds in obesity and diabetes: implications for functional food development and assessment

USDA-ARS?s Scientific Manuscript database

Interest in application of phenolic compounds from diet or supplements for prevention of chronic diseases has grown significantly, but efficacy of such approaches in humans is largely dependent on the bioavailability and metabolism of these compounds. While food and dietary factors have been the foc...

Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of nonalcoholic fatty liver disease

USDA-ARS?s Scientific Manuscript database

Obesity is often associated with a cluster of increased health risks collectively known as "Metabolic Syndrome" (MS). MS is often accompanied by development of fatty liver. Sometimes fatty liver results in damage leading to reduced liver function, and need for a transplant. This condition is known...

The future of southern forests

Treesearch

David N. Wear

2016-01-01

The southeastern United States contains expansive and diverse forests that provide many values and services. The future of these forests will depend on many factors, including wood products markets, urban growth and development, insects and diseases, and climate changes.

IgM nephropathy; can we still ignore it.

PubMed

Vanikar, Aruna

2013-04-01

IgM nephropathy (IgMN) is a relatively less recognized clinico-immunopathological entity in the domain of glomerulonephritis , often thought to be a bridge between minimal change disease and focal segmental glomerulosclerosis. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science has been searched. IgM nephropathy can present as nephritic syndrome or less commonly with subnephrotic proteinuria or rarely hematuria. About 30% patients respond to steroids whereas others are steroid dependent / resistant. They should be given a trial of Rituximab or stem cell therapy. IgM nephropathy (IgMN) is an important and rather neglected pathology responsible for renal morbidity in children and adults in developing countries as compared to developed nations with incidence of 2-18.5% of native biopsies. Abnormal T-cell function with hyperfunctioning suppressor T-cells are believed to be responsible for this disease entity. Approximately one third of the patients are steroid responders where as the remaining two thirds are steroid resistant or dependent. Therapeutic trials including cell therapies targeting suppressor T-cells are required.

IgM nephropathy; can we still ignore it

PubMed Central

Vanikar, Aruna

2013-01-01

Context:IgM nephropathy (IgMN) is a relatively less recognized clinico-immunopathological entity in the domain of glomerulonephritis , often thought to be a bridge between minimal change disease and focal segmental glomerulosclerosis. Evidence Acquisitions: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science has been searched. Results: IgM nephropathy can present as nephritic syndrome or less commonly with subnephrotic proteinuria or rarely hematuria. About 30% patients respond to steroids whereas others are steroid dependent / resistant. They should be given a trial of Rituximab or stem cell therapy. Conclusions:IgM nephropathy (IgMN) is an important and rather neglected pathology responsible for renal morbidity in children and adults in developing countries as compared to developed nations with incidence of 2-18.5% of native biopsies. Abnormal T-cell function with hyperfunctioning suppressor T-cells are believed to be responsible for this disease entity. Approximately one third of the patients are steroid responders where as the remaining two thirds are steroid resistant or dependent. Therapeutic trials including cell therapies targeting suppressor T-cells are required. PMID:24475434

MACVIA clinical decision algorithm in adolescents and adults with allergic rhinitis.

PubMed

Bousquet, Jean; Schünemann, Holger J; Hellings, Peter W; Arnavielhe, Sylvie; Bachert, Claus; Bedbrook, Anna; Bergmann, Karl-Christian; Bosnic-Anticevich, Sinthia; Brozek, Jan; Calderon, Moises; Canonica, G Walter; Casale, Thomas B; Chavannes, Niels H; Cox, Linda; Chrystyn, Henry; Cruz, Alvaro A; Dahl, Ronald; De Carlo, Giuseppe; Demoly, Pascal; Devillier, Phillipe; Dray, Gérard; Fletcher, Monica; Fokkens, Wytske J; Fonseca, Joao; Gonzalez-Diaz, Sandra N; Grouse, Lawrence; Keil, Thomas; Kuna, Piotr; Larenas-Linnemann, Désirée; Lodrup Carlsen, Karin C; Meltzer, Eli O; Mullol, Jaoquim; Muraro, Antonella; Naclerio, Robert N; Palkonen, Susanna; Papadopoulos, Nikolaos G; Passalacqua, Giovanni; Price, David; Ryan, Dermot; Samolinski, Boleslaw; Scadding, Glenis K; Sheikh, Aziz; Spertini, François; Valiulis, Arunas; Valovirta, Erkka; Walker, Samantha; Wickman, Magnus; Yorgancioglu, Arzu; Haahtela, Tari; Zuberbier, Torsten

2016-08-01

The selection of pharmacotherapy for patients with allergic rhinitis (AR) depends on several factors, including age, prominent symptoms, symptom severity, control of AR, patient preferences, and cost. Allergen exposure and the resulting symptoms vary, and treatment adjustment is required. Clinical decision support systems (CDSSs) might be beneficial for the assessment of disease control. CDSSs should be based on the best evidence and algorithms to aid patients and health care professionals to jointly determine treatment and its step-up or step-down strategy depending on AR control. Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR [fighting chronic diseases for active and healthy ageing]), one of the reference sites of the European Innovation Partnership on Active and Healthy Ageing, has initiated an allergy sentinel network (the MACVIA-ARIA Sentinel Network). A CDSS is currently being developed to optimize AR control. An algorithm developed by consensus is presented in this article. This algorithm should be confirmed by appropriate trials. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibition of dengue virus replication by novel inhibitors of RNA-dependent RNA polymerase and protease activities.

PubMed

Pelliccia, Sveva; Wu, Yu-Hsuan; Coluccia, Antonio; La Regina, Giuseppe; Tseng, Chin-Kai; Famiglini, Valeria; Masci, Domiziana; Hiscott, John; Lee, Jin-Ching; Silvestri, Romano

2017-12-01

Dengue virus (DENV) is the leading mosquito-transmitted viral infection in the world. With more than 390 million new infections annually, and up to 1 million clinical cases with severe disease manifestations, there continues to be a need to develop new antiviral agents against dengue infection. In addition, there is no approved anti-DENV agents for treating DENV-infected patients. In the present study, we identified new compounds with anti-DENV replication activity by targeting viral replication enzymes - NS5, RNA-dependent RNA polymerase (RdRp) and NS3 protease, using cell-based reporter assay. Subsequently, we performed an enzyme-based assay to clarify the action of these compounds against DENV RdRp or NS3 protease activity. Moreover, these compounds exhibited anti-DENV activity in vivo in the ICR-suckling DENV-infected mouse model. Combination drug treatment exhibited a synergistic inhibition of DENV replication. These results describe novel prototypical small anti-DENV molecules for further development through compound modification and provide potential antivirals for treating DENV infection and DENV-related diseases.

Left-right asymmetry and cardiac looping: implications for cardiac development and congenital heart disease.

PubMed

Kathiriya, I S; Srivastava, D

2000-01-01

Proper morphogenesis and positioning of internal organs requires delivery and interpretation of precise signals along the anterior-posterior, dorsal-ventral, and left-right axes. An elegant signaling cascade determines left- versus right-sided identity in visceral organs in a concordant fashion, resulting in a predictable left-right (LR) organ asymmetry in all vertebrates. The complex morphogenesis of the heart and its connections to the vasculature are particularly dependent upon coordinated LR signaling pathways. Disorganization of LR signals can result in myriad congenital heart defects that are a consequence of abnormal looping and remodeling of the primitive heart tube into a multi-chambered organ. A framework for understanding how LR asymmetric signals contribute to normal organogenesis has emerged and begins to explain the basis of many human diseases of LR asymmetry. Here we review the impact of LR signaling pathways on cardiac development and congenital heart disease.

Plasmacytoid predendritic cells initiate psoriasis through interferon-α production

PubMed Central

Nestle, Frank O.; Conrad, Curdin; Tun-Kyi, Adrian; Homey, Bernhard; Gombert, Michael; Boyman, Onur; Burg, Günter; Liu, Yong-Jun; Gilliet, Michel

2005-01-01

Psoriasis is one of the most common T cell–mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)-α–producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN-α early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN-α signaling or inhibiting the ability of PDCs to produce IFN-α prevented the T cell–dependent development of psoriasis. Furthermore, IFN-α reconstitution experiments demonstrated that PDC-derived IFN-α is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN-α represent potential early targets for the treatment of psoriasis. PMID:15998792

A systems model for immune cell interactions unravels the mechanism of inflammation in human skin.

PubMed

Valeyev, Najl V; Hundhausen, Christian; Umezawa, Yoshinori; Kotov, Nikolay V; Williams, Gareth; Clop, Alex; Ainali, Crysanthi; Ouzounis, Christos; Tsoka, Sophia; Nestle, Frank O

2010-12-02

Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes.

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.

Implications of the global financial crisis for the response to diseases of poverty within overall health sector development: the case of tuberculosis.

PubMed

Maher, Dermot

2010-01-01

The global financial crisis poses a threat to global health, and may exacerbate diseases of poverty, e.g. HIV, malaria and tuberculosis. Exploring the implications of the global financial crisis for the health sector response to tuberculosis is useful to illustrate the practical problems and propose possible solutions. The response to tuberculosis is considered in the context of health sector development. Problems and solutions are considered in five key areas: financing, prioritization, government regulation, integration and decentralization. Securing health gains in global tuberculosis control depends on protecting expenditure by governments of countries badly affected by tuberculosis and by donors, taking measures to increase efficiencies, prioritizing health expenditures and strengthening government regulation. Lessons learned will be valuable for stakeholders involved in the health sector response to tuberculosis and other diseases of poverty.

Diagnosis of abnormal biliary copper excretion by positron emission tomography with targeting of 64Copper-asialofetuin complex in LEC rat model of Wilson’s disease

PubMed Central

Bahde, Ralf; Kapoor, Sorabh; Bhargava, Kuldeep K; Palestro, Christopher J; Gupta, Sanjeev

2014-01-01

Identification by molecular imaging of key processes in handling of transition state metals, such as copper (Cu), will be of considerable clinical value. For instance, the ability to diagnose Wilson’s disease with molecular imaging by identifying copper excretion in an ATP7B-dependent manner will be very significant. To develop highly effective diagnostic approaches, we hypothesized that targeting of radiocopper via the asialoglycoprotein receptor will be appropriate for positron emission tomography, and examined this approach in a rat model of Wilson’s disease. After complexing 64Cu to asialofetuin we studied handling of this complex compared with 64Cu in healthy LEA rats and diseased homozygous LEC rats lacking ATP7B and exhibiting hepatic copper toxicosis. We analyzed radiotracer clearance from blood, organ uptake, and biliary excretion, including sixty minute dynamic positron emission tomography recordings. In LEA rats, 64Cu-asialofetuin was better cleared from blood followed by liver uptake and greater biliary excretion than 64Cu. In LEC rats, 64Cu-asialofetuin activity cleared even more rapidly from blood followed by greater uptake in liver, but neither 64Cu-asialofetuin nor 64Cu appeared in bile. Image analysis demonstrated rapid visualization of liver after 64Cu-asialofetuin administration followed by decreased liver activity in LEA rats while liver activity progressively increased in LEC rats. Image analysis resolved this difference in hepatic activity within one hour. We concluded that 64Cu-asialofetuin complex was successfully targeted to the liver and radiocopper was then excreted into bile in an ATP7B-dependent manner. Therefore, hepatic targeting of radiocopper will be appropriate for improving molecular diagnosis and for developing drug/cell/gene therapies in Wilson’s disease. PMID:25250203

Update on Meningococcal Disease with Emphasis on Pathogenesis and Clinical Management

PubMed Central

van Deuren, Marcel; Brandtzaeg, Petter; van der Meer, Jos W. M.

2000-01-01

The only natural reservoir of Neisseria meningitidis is the human nasopharyngeal mucosa. Depending on age, climate, country, socioeconomic status, and other factors, approximately 10% of the human population harbors meningococci in the nose. However, invasive disease is relatively rare, as it occurs only when the following conditions are fulfilled: (i) contact with a virulent strain, (ii) colonization by that strain, (iii) penetration of the bacterium through the mucosa, and (iv) survival and eventually outgrowth of the meningococcus in the bloodstream. When the meningococcus has reached the bloodstream and specific antibodies are absent, as is the case for young children or after introduction of a new strain in a population, the ultimate outgrowth depends on the efficacy of the innate immune response. Massive outgrowth leads within 12 h to fulminant meningococcal sepsis (FMS), characterized by high intravascular concentrations of endotoxin that set free high concentrations of proinflammatory mediators. These mediators belonging to the complement system, the contact system, the fibrinolytic system, and the cytokine system induce shock and diffuse intravascular coagulation. FMS can be fatal within 24 h, often before signs of meningitis have developed. In spite of the increasing possibilities for treatment in intensive care units, the mortality rate of FMS is still 30%. When the outgrowth of meningococci in the bloodstream is impeded, seeding of bacteria in the subarachnoidal compartment may lead to overt meningitis within 24 to 36 h. With appropriate antibiotics and good clinical surveillance, the mortality rate of this form of invasive disease is 1 to 2%. The overall mortality rate of meningococcal disease can only be reduced when patients without meningitis, i.e., those who may develop FMS, are recognized early. This means that the fundamental nature of the disease as a meningococcus septicemia deserves more attention. PMID:10627495

Large Mammalian Animal Models of Heart Disease

PubMed Central

Camacho, Paula; Fan, Huimin; Liu, Zhongmin; He, Jia-Qiang

2016-01-01

Due to the biological complexity of the cardiovascular system, the animal model is an urgent pre-clinical need to advance our knowledge of cardiovascular disease and to explore new drugs to repair the damaged heart. Ideally, a model system should be inexpensive, easily manipulated, reproducible, a biological representative of human disease, and ethically sound. Although a larger animal model is more expensive and difficult to manipulate, its genetic, structural, functional, and even disease similarities to humans make it an ideal model to first consider. This review presents the commonly-used large animals—dog, sheep, pig, and non-human primates—while the less-used other large animals—cows, horses—are excluded. The review attempts to introduce unique points for each species regarding its biological property, degrees of susceptibility to develop certain types of heart diseases, and methodology of induced conditions. For example, dogs barely develop myocardial infarction, while dilated cardiomyopathy is developed quite often. Based on the similarities of each species to the human, the model selection may first consider non-human primates—pig, sheep, then dog—but it also depends on other factors, for example, purposes, funding, ethics, and policy. We hope this review can serve as a basic outline of large animal models for cardiovascular researchers and clinicians. PMID:29367573

Risk of complications in coeliac patients depends on age at diagnosis and type of clinical presentation.

PubMed

Biagi, Federico; Schiepatti, Annalisa; Maiorano, Gregorio; Fraternale, Giacomo; Agazzi, Simona; Zingone, Fabiana; Ciacci, Carolina; Volta, Umberto; Caio, Giacomo; Tortora, Raffaella; Klersy, Catherine; Corazza, Gino R

2018-06-01

Coeliac disease is characterised by an increased mortality mostly due to its complications. To study the risk of developing complications according to clinical presentation and age at diagnosis, a combined retrospective-prospective longitudinal study was performed in three Italian centres. Incidence of complications and mortality rates were calculated using type and age at diagnosis of coeliac disease, sex, and centre of diagnosis as predictors. Patients referred after being found to suffer from coeliac disease elsewhere were excluded. Between 01/1999 and 06/2015, 2225 adult coeliac patients were directly diagnosed in our centres. 17 of them developed a complication and 29 died. In patients older than 60 years at diagnosis of coeliac disease, the risk of complication is 18 times higher than in patients diagnosed at 18-40 years and 9 times higher than in patients diagnosed at 40-60 years. Classical presentation increases the risk of complications by 7 times compared to non-classical presentation; in asymptomatic patients the risk of complication is virtually absent. The risk of developing complications in coeliac patients is linked to age at diagnosis of coeliac disease and type of clinical presentation. Follow-up methods of coeliac patients should be tailored according to these parameters. Copyright © 2017. Published by Elsevier Ltd.

Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer’s Disease

PubMed Central

Winick-Ng, Warren; Rylett, R. Jane

2018-01-01

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed. PMID:29541020

Cellular automata and epidemiological models with spatial dependence

NASA Astrophysics Data System (ADS)

Fuentes, M. A.; Kuperman, M. N.

We present a cellular automata model developed to study the evolution of an infectivity nucleus in several conditions and for two kinds of epidemiologically different diseases. We analyse the role of the model parameters, concerning the epidemiological and demographic aspects of the problem, and of the evolution rules in relation to the spread of such infectious diseases, the arising of periodic temporal modulations related to the infectivity and recovery fronts, and the evolution of travelling waves. Among the obtained results we find analogies to endemic situations and pandemics.

The contribution of chronic diseases to the prevalence of dependence among older people in Latin America, China and India: a 10/66 Dementia Research Group population-based survey.

PubMed

Sousa, Renata M; Ferri, Cleusa P; Acosta, Daisy; Guerra, Mariella; Huang, Yueqin; Jacob, Ks; Jotheeswaran, At; Hernandez, Milagros A Guerra; Liu, Zhaorui; Pichardo, Guillermina Rodriguez; Rodriguez, Juan J Llibre; Salas, Aquiles; Sosa, Ana Luisa; Williams, Joseph; Zuniga, Tirso; Prince, Martin

2010-08-06

The number of older people is set to increase dramatically worldwide. Demographic changes are likely to result in the rise of age-related chronic diseases which largely contribute to years lived with a disability and future dependence. However dependence is much less studied although intrinsically linked to disability. We investigated the prevalence and correlates of dependence among older people from middle income countries. A one-phase cross-sectional survey was carried out at 11 sites in seven countries (urban sites in Cuba, Venezuela, and Dominican Republic, urban and rural sites in Peru, Mexico, China and India). All those aged 65 years and over living in geographically defined catchment areas were eligible. In all, 15,022 interviews were completed with an informant interview for each participant. The full 10/66 Dementia Research Group survey protocol was applied, including ascertainment of depression, dementia, physical impairments and self-reported diagnoses. Dependence was interviewer-rated based on a key informant's responses to a set of open-ended questions on the participant's needs for care. We estimated the prevalence of dependence and the independent contribution of underlying health conditions. Site-specific prevalence ratios were meta-analysed, and population attributable prevalence fractions (PAPF) calculated. The prevalence of dependence increased with age at all sites, with a tendency for the prevalence to be lower in men than in women. Age-standardised prevalence was lower in all sites than in the USA. Other than in rural China, dementia made the largest independent contribution to dependence, with a median PAPF of 34% (range 23%-59%). Other substantial contributors were limb impairment (9%, 1%-46%), stroke (8%, 2%-17%), and depression (8%, 1%-27%). The demographic and health transitions will lead to large and rapid increases in the numbers of dependent older people particularly in middle income countries (MIC). The prevention and control of chronic neurological and neuropsychiatric diseases and the development of long-term care policies and plans should be urgent priorities.

"The contribution of chronic diseases to the prevalence of dependence among older people in Latin America, China and India: a 10/66 Dementia Research Group population-based survey"

PubMed Central

2010-01-01

Background The number of older people is set to increase dramatically worldwide. Demographic changes are likely to result in the rise of age-related chronic diseases which largely contribute to years lived with a disability and future dependence. However dependence is much less studied although intrinsically linked to disability. We investigated the prevalence and correlates of dependence among older people from middle income countries. Methods A one-phase cross-sectional survey was carried out at 11 sites in seven countries (urban sites in Cuba, Venezuela, and Dominican Republic, urban and rural sites in Peru, Mexico, China and India). All those aged 65 years and over living in geographically defined catchment areas were eligible. In all, 15,022 interviews were completed with an informant interview for each participant. The full 10/66 Dementia Research Group survey protocol was applied, including ascertainment of depression, dementia, physical impairments and self-reported diagnoses. Dependence was interviewer-rated based on a key informant's responses to a set of open-ended questions on the participant's needs for care. We estimated the prevalence of dependence and the independent contribution of underlying health conditions. Site-specific prevalence ratios were meta-analysed, and population attributable prevalence fractions (PAPF) calculated. Results The prevalence of dependence increased with age at all sites, with a tendency for the prevalence to be lower in men than in women. Age-standardised prevalence was lower in all sites than in the USA. Other than in rural China, dementia made the largest independent contribution to dependence, with a median PAPF of 34% (range 23%-59%). Other substantial contributors were limb impairment (9%, 1%-46%), stroke (8%, 2%-17%), and depression (8%, 1%-27%). Conclusion The demographic and health transitions will lead to large and rapid increases in the numbers of dependent older people particularly in middle income countries (MIC). The prevention and control of chronic neurological and neuropsychiatric diseases and the development of long-term care policies and plans should be urgent priorities. PMID:20691064

Laser treatment for retinopathy of prematurity through the incubator wall.

PubMed

Dogra, Mangat R; Vinekar, Anand; Viswanathan, Kavitha; Sangtam, Tiakumzuk; Das, Pranab; Gupta, Amod; Dutta, Sourab

2008-01-01

In this era of early treatment for retinopathy of prematurity, sick infants who develop aggressive diseases or remain oxygen and temperature dependent may be treated while they are inside the incubator itself, thus avoiding unnecessary delays. This article describes the treatment of eight infants with retinopathy of prematurity who were dependent on an incubator by using a laser indirect ophthalmoscope delivery system through the slanting transparent wall of the incubator. In this series, which is the largest to date, the relative advantages and disadvantages of the procedure are discussed.

Towards Chagas disease elimination: Neonatal screening for congenital transmission in rural communities.

PubMed

Pennington, Pamela Marie; Juárez, José Guillermo; Arrivillaga, Margarita Rivera; De Urioste-Stone, Sandra María; Doktor, Katherine; Bryan, Joe P; Escobar, Clara Yaseli; Cordón-Rosales, Celia

2017-09-01

Chagas disease is a neglected tropical disease that continues to affect populations living in extreme poverty in Latin America. After successful vector control programs, congenital transmission remains as a challenge to disease elimination. We used the PRECEDE-PROCEED planning model to develop strategies for neonatal screening of congenital Chagas disease in rural communities of Guatemala. These communities have persistent high triatomine infestations and low access to healthcare. We used mixed methods with multiple stakeholders to identify and address maternal-infant health behaviors through semi-structured interviews, participatory group meetings, archival reviews and a cross-sectional survey in high risk communities. From December 2015 to April 2016, we jointly developed a strategy to illustratively advertise newborn screening at the Health Center. The strategy included socioculturally appropriate promotional and educational material, in collaboration with midwives, nurses and nongovernmental organizations. By March 2016, eight of 228 (3.9%) pregnant women had been diagnosed with T. cruzi at the Health Center. Up to this date, no neonatal screening had been performed. By August 2016, seven of eight newborns born to Chagas seropositive women had been parasitologically screened at the Health Center, according to international standards. Thus, we implemented a successful community-based neonatal screening strategy to promote congenital Chagas disease healthcare in a rural setting. The success of the health promotion strategies developed will depend on local access to maternal-infant services, integration with detection of other congenital diseases and reliance on community participation in problem and solution definition.

Towards Chagas disease elimination: Neonatal screening for congenital transmission in rural communities

PubMed Central

Juárez, José Guillermo; Arrivillaga, Margarita Rivera; De Urioste-Stone, Sandra María; Doktor, Katherine; Bryan, Joe P.; Escobar, Clara Yaseli; Cordón-Rosales, Celia

2017-01-01

Chagas disease is a neglected tropical disease that continues to affect populations living in extreme poverty in Latin America. After successful vector control programs, congenital transmission remains as a challenge to disease elimination. We used the PRECEDE-PROCEED planning model to develop strategies for neonatal screening of congenital Chagas disease in rural communities of Guatemala. These communities have persistent high triatomine infestations and low access to healthcare. We used mixed methods with multiple stakeholders to identify and address maternal-infant health behaviors through semi-structured interviews, participatory group meetings, archival reviews and a cross-sectional survey in high risk communities. From December 2015 to April 2016, we jointly developed a strategy to illustratively advertise newborn screening at the Health Center. The strategy included socioculturally appropriate promotional and educational material, in collaboration with midwives, nurses and nongovernmental organizations. By March 2016, eight of 228 (3.9%) pregnant women had been diagnosed with T. cruzi at the Health Center. Up to this date, no neonatal screening had been performed. By August 2016, seven of eight newborns born to Chagas seropositive women had been parasitologically screened at the Health Center, according to international standards. Thus, we implemented a successful community-based neonatal screening strategy to promote congenital Chagas disease healthcare in a rural setting. The success of the health promotion strategies developed will depend on local access to maternal-infant services, integration with detection of other congenital diseases and reliance on community participation in problem and solution definition. PMID:28892479

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.

Routine Discovery of Complex Genetic Models using Genetic Algorithms

PubMed Central

Moore, Jason H.; Hahn, Lance W.; Ritchie, Marylyn D.; Thornton, Tricia A.; White, Bill C.

2010-01-01

Simulation studies are useful in various disciplines for a number of reasons including the development and evaluation of new computational and statistical methods. This is particularly true in human genetics and genetic epidemiology where new analytical methods are needed for the detection and characterization of disease susceptibility genes whose effects are complex, nonlinear, and partially or solely dependent on the effects of other genes (i.e. epistasis or gene-gene interaction). Despite this need, the development of complex genetic models that can be used to simulate data is not always intuitive. In fact, only a few such models have been published. We have previously developed a genetic algorithm approach to discovering complex genetic models in which two single nucleotide polymorphisms (SNPs) influence disease risk solely through nonlinear interactions. In this paper, we extend this approach for the discovery of high-order epistasis models involving three to five SNPs. We demonstrate that the genetic algorithm is capable of routinely discovering interesting high-order epistasis models in which each SNP influences risk of disease only through interactions with the other SNPs in the model. This study opens the door for routine simulation of complex gene-gene interactions among SNPs for the development and evaluation of new statistical and computational approaches for identifying common, complex multifactorial disease susceptibility genes. PMID:20948983

Gender differences in chronic obstructive pulmonary diseases: a narrative review.

PubMed

Nicolini, Antonello; Barbagelata, Elena; Tagliabue, Elena; Colombo, Daniela; Monacelli, Fiammetta; Braido, Fulvio

2018-06-01

Chronic obstructive pulmonary disease (COPD) is generally considered to be prevalent in males. However, smoking is rising in women in developing and developed countries, while exposure to biomass fuel for domestic purposes is a recognized risk factor among females. Females developing more severe COPD patterns due to tobacco exposure than men maybe due to a genetic predisposition, a greater dose-dependent effect of smoke related to smaller airways caliber and an increased oxidative stress with augmented TGF-beta1 signaling. Gender hormones also seem to be involved in tobacco-smoke metabolism and in lung and pulmonary development. while menopause is associated with accelerated alveolar loss and decline of lung function pulmonary function. The time to diagnosis differs between the sexes since a lower rate of spirometry is performed in women. Also comorbidities differ between genders: osteoporosis, inflammatory bowel diseases, reflux, hypertension, rheumatoid arthritis, and mental diseases are more common in women. Women pay more attention to breathlessness, maybe due to higher emotional response and anxiety. These elements could lead to higher hospitalization rates in women. The aim of this review is to provide the available evidence with the aim of inviting healthcare professionals to evaluate gender differences in patients with COPD, key point for optimizing the care plan.

Planning treatment of ischemic heart disease with partially observable Markov decision processes.

PubMed

Hauskrecht, M; Fraser, H

2000-03-01

Diagnosis of a disease and its treatment are not separate, one-shot activities. Instead, they are very often dependent and interleaved over time. This is mostly due to uncertainty about the underlying disease, uncertainty associated with the response of a patient to the treatment and varying cost of different diagnostic (investigative) and treatment procedures. The framework of partially observable Markov decision processes (POMDPs) developed and used in the operations research, control theory and artificial intelligence communities is particularly suitable for modeling such a complex decision process. In this paper, we show how the POMDP framework can be used to model and solve the problem of the management of patients with ischemic heart disease (IHD), and demonstrate the modeling advantages of the framework over standard decision formalisms.

Principles of treatment for mammary gland tumors.

PubMed

Novosad, C Andrew

2003-05-01

The mammary glands are frequent locations for the development of tumors. In the dog and cat, early detection and rapid therapy are necessary to prevent both local and distant metastasis. In the dog, this disease can have a range of biologic behaviors, whereas in the cat it is almost always an extremely aggressive disease. Treatment options depend on tumor staging and can include surgery, radiation therapy, chemotherapy, or a combination. As we become better at early diagnosis and are able to implement aggressive therapy, we are becoming more and more successful in the treatment of this disease. In the following article, we will discuss current thoughts surrounding the diagnosis and treatment options for both canine and feline mammary gland tumors.

How should Malaysia respond to its ageing society?

PubMed

Forsyth, D R; Chia, Y C

2009-03-01

As Malaysia ages its health and social care systems will have to adapt to a changing pattern of disease and dependency. Improved public health measures extend life expectancy at the relative expense of increased prevalence of currently incurable conditions such as dementia and Parkinson's disease. In this article we discuss how these demographic changes will impact and suggest possible means of coping with the altered epidemiology of disease and disability. Malaysia will need to swiftly develop sufficient expertise in acute Geriatric Medicine, rehabilitation of older people; the management of long-term conditions in older people with multiple complex problems within Primary Care; as well as an infrastructure for home and institutional care.

[The quantitative testing of V617F mutation in gen JAK2 using pyrosequencing technique].

PubMed

Dunaeva, E A; Mironov, K O; Dribnokhodova, T E; Subbotina, E E; Bashmakova; Ol'hovskiĭ, I A; Shipulin, G A

2014-11-01

The somatic mutation V617F in gen JAK2 is a frequent cause of chronic myeloprolific diseases not conditioned by BCR/ABL mutation. The quantitative testing of relative percentage of mutant allele can be used in establishing severity of disease and its prognosis and in prescription of remedy inhibiting activity of JAK2. To quantitatively test mutation the pyrosequencing technique was applied. The developed technique permits detecting and quantitatively, testing percentage of mutation fraction since 7%. The "gray zone" is presented by samples with percentage of mutant allele from 4% to 7%. The dependence of expected percentage of mutant fraction in analyzed sample from observed value of signal is described by equation of line with regression coefficients y = - 0.97, x = -1.32 and at that measurement uncertainty consists ± 0.7. The developed technique is approved officially on clinical material from 192 patients with main forms of myeloprolific diseases not conditioned by BCR/ABL mutation. It was detected 64 samples with mautant fraction percentage from 13% to 91%. The developed technique permits implementing monitoring of therapy of myeloprolific diseases and facilitates to optimize tactics of treatment.

Biomedical and social contributions to sustainability.

PubMed

Wilmut, Ian; Wongtawan, Tuempong; Quigley, Mindy; Sullivan, Gareth

2011-05-13

Over the past two or three centuries, biomedical advances have provided methods to prevent and treat infectious diseases. These changes have greatly reduced human suffering and enhanced sustainability by allowing people to live longer and healthier lives. The challenge for the coming centuries will be to ensure that these longer, healthier lives are also more productive lives. We must build on the gains of the past by translating new discoveries in regenerative medicine into therapies for degenerative and genetic diseases. Stem cells may be used to identify drugs that prevent the development of symptoms or to replace cells that have either died or lost their physiological function. In the case of genetic diseases, it may be possible to correct the genetic error. While most conditions that might be treated in these ways are common to all communities, some are more prevalent in specific races. Provision of these and other benefits depends not only on attainment of the research objectives, but also upon our ability to make treatment opportunities available throughout both developed and developing communities. The long history of researching and treating infectious diseases shows that it may take many decades to reap the full benefit of the new biological understanding. © 2011 Royal Society

Imaging techniques in the management of chronic kidney disease: current developments and future perspectives.

PubMed

Herget-Rosenthal, Stefan

2011-05-01

The measurement of both renal function and structure is critical in clinical nephrology to detect, stage, and monitor chronic kidney disease (CKD). Current imaging modalities especially ultrasound (US), computed tomography, and magnetic resonance imaging (MRI) provide adequate information on structural changes but little on functional impairment in CKD. Although not yet considered first-line procedures for evaluating patients with renal disease, new US and MR imaging techniques may permit the assessment of renal function in the near future. Combined with established imaging techniques, contrast-enhanced US, dynamic contrast-enhanced MRI, blood oxygen level dependency MRI, or diffusion-weighted imaging may provide rapid, accurate, simultaneous, and noninvasive imaging of the structure of kidneys, macrovascular and microvascular renal perfusion, oxygenation, and glomerular filtration rate. Recent developments in molecular imaging indicate that pathophysiological pathways of renal diseases such as apoptosis, coagulation, fibrosis, and ischemia will be visualized at the tissue level. These major advances in imaging and developments in hardware and software could enable comprehensive imaging of renal structure and function in four dimensions (three dimensions plus time), and imaging is expected to play an increasing role in the management of CKD. Copyright © 2011 Elsevier Inc. All rights reserved.

Protein Kinase Cα Modulates Estrogen-Receptor-Dependent Transcription and Proliferation in Endometrial Cancer Cells

PubMed Central

Thorne, Alicia M.; Jackson, Twila A.; Willis, Van C.; Bradford, Andrew P.

2013-01-01

Endometrial cancer is the most common invasive gynecologic malignancy in developed countries. The most prevalent endometrioid tumors are linked to excessive estrogen exposure and hyperplasia. However, molecular mechanisms and signaling pathways underlying their etiology and pathophysiology remain poorly understood. We have shown that protein kinase Cα (PKCα) is aberrantly expressed in endometrioid tumors and is an important mediator of endometrial cancer cell survival, proliferation, and invasion. In this study, we demonstrate that expression of active, myristoylated PKCα conferred ligand-independent activation of estrogen-receptor- (ER-) dependent promoters and enhanced responses to estrogen. Conversely, knockdown of PKCα reduced ER-dependent gene expression and inhibited estrogen-induced proliferation of endometrial cancer cells. The ability of PKCα to potentiate estrogen activation of ER-dependent transcription was attenuated by inhibitors of phosphoinositide 3-kinase (PI3K) and Akt. Evidence suggests that PKCα and estrogen signal transduction pathways functionally interact, to modulate ER-dependent growth and transcription. Thus, PKCα signaling, via PI3K/Akt, may be a critical element of the hyperestrogenic environment and activation of ER that is thought to underlie the development of estrogen-dependent endometrial hyperplasia and malignancy. PKCα-dependent pathways may provide much needed prognostic markers of aggressive disease and novel therapeutic targets in ER positive tumors. PMID:23843797

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

Activation Of Wild-Type Hras Suppresses The Earliest Stages Of Pancreatic Cancer.

PubMed

Weyandt, Jamie

2015-08-01

The RAS family of small GTPases is comprised of HRAS, NRAS, and KRAS. KRAS is invariably oncogenically mutated in pancreatic cancers, which is known to induce this disease. Beyond oncogenic KRAS, redox-dependent reactions have been implicated in the activation of the remaining wild-type RAS proteins in pancreatic cancer cell lines. These results suggest a possible involvement of wild-type RAS proteins in pancreatic cancer. To evaluate the impact of genetically suppressing wild-type RAS expression on pancreatic cancer. Hras homozygous null mice (Hras -/- ) were crossed into a Pdx-Cre; LSL-Kras G12D/+ (KC) murine background in which oncogenic Kras is activated in the pancreas to promote preinvasive pancreatic cancer. Tumor burden was then measured at different stages of disease. HRas -/- ;KC mice exhibited more precancerous lesions in the pancreas and more off-target skin papillomas compared to their wild-type counterparts, suggesting that Hras suppresses early oncogenic Kras-driven tumorigenesis, possibly at the time of initiation. Loss of Hras also reduced the survival of mice engineered to develop aggressive pancreatic cancer by the additional disruption of one allele of the tumor suppressor p53 (Trp53 R172H/+ ). However, this survival advantage was lost when both alleles of Trp53 were mutated, suggesting that wild-type Hras inhibits tumorigenesis in a p53-dependent fashion. Loss of wild-type Hras promotes the earliest stages of pancreatic tumorigenesis, and moreover results in more rapid progression of the disease. As such, mechanisms leading to activation of wild-type Ras proteins, including but not limited to redox-dependent reactions, may influence the development of pancreatic cancer. Copyright © 2015. Published by Elsevier B.V.

RAS and sex differences in diabetic nephropathy.

PubMed

Clotet, Sergi; Riera, Marta; Pascual, Julio; Soler, Maria José

2016-03-09

The incidence and progression of kidney diseases are influenced by sex. The renin-angiotensin system (RAS) is an important regulator of cardiovascular and renal function. Sex differences in the renal response to RAS blockade have been demonstrated. Circulating and renal RAS has been shown to be altered in type 1 and type 2 diabetes; this enzymatic cascade plays a critical role in the development of diabetic nephropathy (DN). Angiotensin converting enzyme (ACE) and ACE2 are differentially regulated depending on its localization within the diabetic kidney. Furthermore, clinical and experimental studies have shown that circulating levels of sex hormones are clearly modulated in the context of diabetes, suggesting that sex-dependent RAS regulation may be also be affected in these individuals. The effect of sex hormones on circulating and renal RAS may be involved in the sex differences observed in DN progression. In this paper we will review the influence of sex hormones on RAS expression and its relation to diabetic kidney disease. A better understanding of the sex dimorphism on RAS might provide a new approach for diabetic kidney disease treatment. Copyright © 2015, American Journal of Physiology - Renal Physiology.

Progression of pathogenic events in cynomolgus macaques infected with variola virus.

PubMed

Wahl-Jensen, Victoria; Cann, Jennifer A; Rubins, Kathleen H; Huggins, John W; Fisher, Robert W; Johnson, Anthony J; de Kok-Mercado, Fabian; Larsen, Thomas; Raymond, Jo Lynne; Hensley, Lisa E; Jahrling, Peter B

2011-01-01

Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of antivirals and improved vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary smallpox model, lymphoid and myeloid hyperplasias were consistently found whereas lymphocytolysis and hematopoietic necrosis developed in hemorrhagic smallpox. Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary smallpox model. In contrast, in the hemorrhagic model antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic smallpox developed only in the presence of secondary bacterial infections - an observation also commonly noted in historical reports of human smallpox. Together, our results support the macaque model as an excellent surrogate for human smallpox in terms of disease onset, acute disease course, and gross and histopathological lesions.

Calcitriol accelerates vascular calcification irrespective of vitamin K status in a rat model of CKD with hyperphosphatemia and secondary hyperparathyroidism.

PubMed

McCabe, Kristin M; Zelt, Jason G; Kaufmann, Martin; Laverty, Kimberly; Ward, Emilie; Barron, Henry; Jones, Glenville; Adams, Michael A; Holden, Rachel M

2018-06-14

Patients with chronic kidney disease have a markedly increased risk for developing cardiovascular disease. Non-traditional risk factors, such as increased phosphate retention, and deficiencies in vitamins D and K metabolism, likely play key roles in the development of vascular calcification during CKD progression. Calcitriol (1,25-(OH)2-D3) is a key transcriptional regulator of Matrix Gla protein (MGP), a vitamin K dependent protein that inhibits vascular calcification. The objective of this study was to determine if calcitriol treatment could inhibit the development of vascular calcification and if this inhibition was dependent on vitamin K status in a rat model of CKD. Rats were treated with dietary adenine (0.25%) to induce CKD, with either 0, 20 or 80 ng/kg of calcitriol with low or high dietary vitamin K1 (0.2 or 100 mg/kg) for 7 weeks. Calcitriol at both low (20 ng/kg) and moderate (80 ng/kg) doses increased the severity of vascular calcification and, contrary to our hypothesis, this was unaffected by high dietary vitamin K1. Calcitriol had a dose-dependent effect on: (i) lowering serum PTH, (ii) increasing serum calcium and (iii) increasing serum FGF-23. Calcitriol treatment significantly increased aortic expression of the calcification genes Runx2 and Pit-1. This data also implicates impaired vitamin D catabolism in CKD, which may contribute to the development of calcitriol toxicity and increased vascular calcification. The present findings demonstrate that in an adenine-induced rat model of CKD, calcitriol treatment at doses as low as 20 ng/kg can increase the severity of vascular calcification regardless of vitamin K status. The American Society for Pharmacology and Experimental Therapeutics.

Disease control operations

USGS Publications Warehouse

Friend, Milton; Franson, J. Christian

1987-01-01

Individual disease outbreaks have killed many thousands of animals on numerous occasions. Tens of thousands of migratory birds have died in single die-offs with as many as 1,000 birds succumbing in 1 day. In mammals, individual disease outbreaks have killed hundreds to thousands of animals with, for example, hemorrhagic disease in white-tailed deer, distemper in raccoon, Errington's disease in muskrat, and sylvatic plague in wild rodents. The ability to successfully combat such explosive situations is highly dependent n the readiness of field personnel to deal with them. Because many disease agents can spread though wildlife populations very fast, advance preparation is essential in preventing infected animals from spreading disease to additional species and locations. Carefully though-out disease contingency plans should be developed as practical working documents for field personnel and updated as necessary. Such well-designed plans can prove invaluable in minimizing wildlife losses and costs associated with disease control activities. Although requirements for disease control operations vary and must be tailored to each situation, all disease contingency planning involved general concepts and basic biological information. This chapter, intended as a practical guide, identifies the major activities and needs of disease control operations, and relates them to disease contingency planning.

Matrix Metalloproteinases and Neurotrauma: Evolving Roles in Injury and Reparative Processes

PubMed Central

Zhang, Haoqian; Adwanikar, Hita; Werb, Zena; Noble-Haeusslein, Linda J.

2010-01-01

Matrix metalloproteinases (MMPs) are involved in a wide range of proteolytic events in fetal development and normal tissue remodeling as well as wound healing and inflammation. In the CNS, they have been implicated in a variety of neurodegenerative diseases ranging from multiple sclerosis to Alzheimer disease and are integral to stroke-related cell damage. Although studies implicate increased activity of MMPs in pathogenesis in the CNS, there is also a growing literature to support their participation in events that support recovery processes. Here the authors provide a brief overview of MMPs and their regulation, address their complex roles following traumatic injuries to the adult and developing CNS, and consider their time- and context-dependent signatures that influence both injury and reparative processes. PMID:20400713

Recent Advances in Drug Design and Drug Discovery for Androgen-Dependent Diseases

PubMed Central

Cabeza, Marisa; Sánchez-Márquez, Araceli; Garrido, Mariana; Silva, Aylín; Bratoeff, Eugene

2016-01-01

This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase. PMID:26861003

The influence of phospho-τ on dendritic spines of cortical pyramidal neurons in patients with Alzheimer's disease.

PubMed

Merino-Serrais, Paula; Benavides-Piccione, Ruth; Blazquez-Llorca, Lidia; Kastanauskaite, Asta; Rábano, Alberto; Avila, Jesús; DeFelipe, Javier

2013-06-01

The dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses and they are fundamental structures in memory, learning and cognition. In the present study, we used intracellular injections of Lucifer yellow in fixed tissue to analyse over 19 500 dendritic spines that were completely reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons in the parahippocampal cortex and CA1 of patients with Alzheimer's disease. Following intracellular injection, sections were immunostained for anti-Lucifer yellow and with tau monoclonal antibodies AT8 and PHF-1, which recognize tau phosphorylated at Ser202/Thr205 and at Ser396/404, respectively. We observed that the diffuse accumulation of phospho-tau in a putative pre-tangle state did not induce changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines (loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the degree of tangle development. Thus, the presence of phospho-tau in neurons does not necessarily mean that they suffer severe and irreversible effects as thought previously but rather, the characteristic cognitive impairment in Alzheimer's disease is likely to depend on the relative number of neurons that have well developed tangles.

Merging economics and epidemiology to improve the prediction and management of infectious disease.

PubMed

Perrings, Charles; Castillo-Chavez, Carlos; Chowell, Gerardo; Daszak, Peter; Fenichel, Eli P; Finnoff, David; Horan, Richard D; Kilpatrick, A Marm; Kinzig, Ann P; Kuminoff, Nicolai V; Levin, Simon; Morin, Benjamin; Smith, Katherine F; Springborn, Michael

2014-12-01

Mathematical epidemiology, one of the oldest and richest areas in mathematical biology, has significantly enhanced our understanding of how pathogens emerge, evolve, and spread. Classical epidemiological models, the standard for predicting and managing the spread of infectious disease, assume that contacts between susceptible and infectious individuals depend on their relative frequency in the population. The behavioral factors that underpin contact rates are not generally addressed. There is, however, an emerging a class of models that addresses the feedbacks between infectious disease dynamics and the behavioral decisions driving host contact. Referred to as "economic epidemiology" or "epidemiological economics," the approach explores the determinants of decisions about the number and type of contacts made by individuals, using insights and methods from economics. We show how the approach has the potential both to improve predictions of the course of infectious disease, and to support development of novel approaches to infectious disease management.

Mechanisms of Autoantibody-Induced Pathology

PubMed Central

Ludwig, Ralf J.; Vanhoorelbeke, Karen; Leypoldt, Frank; Kaya, Ziya; Bieber, Katja; McLachlan, Sandra M.; Komorowski, Lars; Luo, Jie; Cabral-Marques, Otavio; Hammers, Christoph M.; Lindstrom, Jon M.; Lamprecht, Peter; Fischer, Andrea; Riemekasten, Gabriela; Tersteeg, Claudia; Sondermann, Peter; Rapoport, Basil; Wandinger, Klaus-Peter; Probst, Christian; El Beidaq, Asmaa; Schmidt, Enno; Verkman, Alan; Manz, Rudolf A.; Nimmerjahn, Falk

2017-01-01

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves’ disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein. PMID:28620373

The Ubiquitin–Proteasome System and the Autophagic–Lysosomal System in Alzheimer Disease

PubMed Central

Ihara, Yasuo; Morishima-Kawashima, Maho; Nixon, Ralph

2012-01-01

As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles—a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin–proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal–lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target. PMID:22908190

Dental caries and periodontal diseases in the ageing population: call to action to protect and enhance oral health and well-being as an essential component of healthy ageing - Consensus report of group 4 of the joint EFP/ORCA workshop on the boundaries between caries and periodontal diseases.

PubMed

Tonetti, Maurizio S; Bottenberg, Peter; Conrads, Georg; Eickholz, Peter; Heasman, Peter; Huysmans, Marie-Charlotte; López, Rodrigo; Madianos, Phoebus; Müller, Frauke; Needleman, Ian; Nyvad, Bente; Preshaw, Philip M; Pretty, Iain; Renvert, Stefan; Schwendicke, Falk; Trombelli, Leonardo; van der Putten, Gert-Jan; Vanobbergen, Jacques; West, Nicola; Young, Alix; Paris, Sebastian

2017-03-01

Over the last two decades, progress in prevention and treatment of caries and periodontal diseases has been translated to better oral health and improved tooth retention in the adult population. The ageing population and the increasing expectations of good oral health-related quality of life in older age pose formidable challenges to clinical care and healthcare systems. The objective of this workshop was to critically review scientific evidence and develop specific recommendations to: (i) prevent tooth loss and retain oral function through prevention and treatment of caries and periodontal diseases later in life and (ii) increase awareness of the health benefits of oral health as an essential component of healthy ageing. Discussions were initiated by three systematic reviews covering aspects of epidemiology of caries and periodontal diseases in elders, the impact of senescence on caries and periodontal diseases and the effectiveness of interventions. Recommendations were developed based on evidence from the systematic reviews and expert opinion. Key messages included: (i) the ageing population, trends in risk factors and improved tooth retention point towards an expected increase in the total burden of disease posed by caries and periodontal diseases in the older population; (ii) specific surveillance is required to monitor changes in oral health in the older population; (iii) senescence impacts oral health including periodontitis and possibly caries susceptibility; (iv) evidence indicates that caries and periodontal diseases can be prevented and treated also in older adults; (v) oral health and functional tooth retention later in life provides benefits both in terms of oral and general quality of life and in terms of preventing physical decline and dependency by fostering a healthy diet; (vi) oral healthcare professionals and individuals should not base decisions impacting tooth retention on chronological age but on level of dependency, life expectancy, frailty, comfort and quality of life; and (vii) health policy should remove barriers to oral health care for vulnerable elders. Consensus was reached on specific actionable priorities for public health officials, oral healthcare professionals, educators and workforce planners, caregivers and relatives as well as for the public and ageing patients. Some priorities have major implications for policymakers as health systems need to adapt to the challenge by systemwide changes to enable (promote) tooth retention later in life and management of deteriorating oral health in increasingly dependent elders. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Knowledge, Attitude, and Experience of Cervical Cancer and Screening among Sub-saharan African Female Students in a UK University

PubMed Central

Ogbonna, Faith Sopuruchukwu

2017-01-01

Background: Cervical cancer is one of the major diseases that affect women of child bearing age. Its main cause is the human papilloma virus; although, other associated factors have been evidenced to increase its risk. Pap-smear screening and vaccination which has been shown to be successful in reducing the incidence and prevalence of the disease in developed countries, has been neglected in developing countries due to lack of knowledge, misconceptions, and cultural beliefs. Materials and Methods: A cross-sectional study involving only female Sub-Saharan Africa (SSA) students in a UK university setting. Results: One hundred and eighty-six (42%) African female students were recruited from the 442 SSA students attending one of the major Universities in the UK. Seventy-one (38.2%) of the students were aware of cervical screening, but only 20 (10.8%) reported having knowledge of cervical cancer. A small percentage of about 26.9% (50 Students) were already part of this screening program; although, 81 (43.5%) showed willingness to participate in future screening programs. More so, it was evident that student's perception was dependent on their experience of the disease (P = 000) just as their participation in screening program was dependent on their awareness level (P ≤ 0.01). Conclusion: Female African students from the SSA region have poor knowledge of the disease which influenced their attitude toward screening. More needs to be carried out to increase awareness and uptake of screening within the school environment as university setting provides a viable platform to promote healthy behavior. PMID:28300047

Mast cells and basophils are essential for allergies: mechanisms of allergic inflammation and a proposed procedure for diagnosis

PubMed Central

He, Shao-heng; Zhang, Hui-yun; Zeng, Xiao-ning; Chen, Dong; Yang, Ping-chang

2013-01-01

The current definition of allergy is a group of IgE-mediated diseases. However, a large portion of patients with clinical manifestations of allergies do not exhibit elevated serum levels of IgE (sIgEs). In this article, three key factors, ie soluble allergens, sIgEs and mast cells or basophils, representing the causative factors, messengers and primary effector cells in allergic inflammation, respectively, were discussed. Based on current knowledge on allergic diseases, we propose that allergic diseases are a group of diseases mediated through activated mast cells and/or basophils in sensitive individuals, and allergic diseases include four subgroups: (1) IgE dependent; (2) other immunoglobulin dependent; (3) non-immunoglobulin mediated; (4) mixture of the first three subgroups. According to our proposed definition, pseudo-allergic-reactions, in which mast cell or basophil activation is not mediated via IgE, or to a lesser extent via IgG or IgM, should be non-IgE-mediated allergic diseases. Specific allergen challenge tests (SACTs) are gold standard tests for diagnosing allergies in vivo, but risky. The identification of surface membrane activation markers of mast cells and basophils (CD203c, CCR3, CD63, etc) has led to development of the basophil activation test (BAT), an in vitro specific allergen challenge test (SACT). Based on currently available laboratory allergy tests, we here propose a laboratory examination procedure for allergy. PMID:23974516

The therapeutic potential of metabolic hormones in the treatment of age-related cognitive decline and Alzheimer’s disease

PubMed Central

Grizzanti, John; Lee, Hyoung-Gon; Camins, Antoni; Pallas, Merce; Casadesus, Gemma

2017-01-01

Aging leads to a number of physiological alterations, specifically changes in circulating hormone levels, increases in fat deposition, decreases in metabolism, changes in inflammatory responses, and reductions in growth factors. These progressive changes in physiology and metabolism are exacerbated by modern culture and Western diet and give rise to diseases such as obesity, metabolic syndrome, and type 2 (non–insulin-dependent) diabetes (T2D). These age and lifestyle-related metabolic diseases are often accompanied by insulin and leptin resistance, as well as aberrant amylin production and signaling. Many of these alterations in hormone production and signaling are directly influenced by an increase in both oxidative stress and inflammation. Importantly, changes in hormone production and signaling have direct effects on brain function and the development of age-related neurologic disorders. Therefore, this review aims to present evidence on the effects that diet and metabolic disease have on age-related cognitive decline and the development of cognitive diseases, particularly Alzheimer disease. This review will focus on the metabolic hormones insulin, leptin, and amylin and their role in cognitive decline, as well as the therapeutic potential of these hormones in treating cognitive disease. Future investigations targeting the long-term effects of insulin and leptin treatment may reveal evidence to reduce risk of cognitive decline and Alzheimer disease. PMID:27923524

[Hyperthyroidism and diabetes mellitus: analysis of 10 African cases].

PubMed

Sidibé, E H; Dia, M; Toure-Sow, H; Sow, A M; Seck-Gassama, S M; Ndoye, R

1999-03-01

This retrospective study of 10 patients with hyperthyroidisma and diabetes mellitus concerned 8 women and 2 men, aged from 15 to 77 years. The two disease developed at the same time in 8 cases. Diabetes mellitus occurred first in 2 cases. Common signs were loss of weight. Hyperthyroidism led to tachycardia at more than 100 bpm. Diarrhea was observed simultaneously in 2 cases and muscular weakness in 5. Goiter was found in 10 cases with a diffuse aspect. Graves' disease was diagnosed with exophthalmia in 9 cases and affected both eyes in 8. Elevated levels of thyroid hormones confirmed diagnosis in 8 cases. Diabetes was insulin-dependent in 3 cases and non-insulin dependent in the 7 others. IDDM patients (2 female and 1 male) were aged 15, 17 and 38. Keto acidosis was the first symptom in all cases. NIDDM patients (6 female and 1 male) were aged between 37 and 77.

Image enhancement based on in vivo hyperspectral gastroscopic images: a case study

NASA Astrophysics Data System (ADS)

Gu, Xiaozhou; Han, Zhimin; Yao, Liqing; Zhong, Yunshi; Shi, Qiang; Fu, Ye; Liu, Changsheng; Wang, Xiguang; Xie, Tianyu

2016-10-01

Hyperspectral imaging (HSI) has been recognized as a powerful tool for noninvasive disease detection in the gastrointestinal field. However, most of the studies on HSI in this field have involved ex vivo biopsies or resected tissues. We proposed an image enhancement method based on in vivo hyperspectral gastroscopic images. First, we developed a flexible gastroscopy system capable of obtaining in vivo hyperspectral images of different types of stomach disease mucosa. Then, depending on a specific object, an appropriate band selection algorithm based on dependence of information was employed to determine a subset of spectral bands that would yield useful spatial information. Finally, these bands were assigned to be the color components of an enhanced image of the object. A gastric ulcer case study demonstrated that our method yields higher color tone contrast, which enhanced the displays of the gastric ulcer regions, and that it will be valuable in clinical applications.

HIV and HLA Class I: an evolving relationship

PubMed Central

Goulder, Philip J.R.; Walker, Bruce D

2014-01-01

Successful vaccine development for infectious diseases has largely been achieved in settings where natural immunity to the pathogen results in clearance in at least some individuals. HIV presents an additional challenge in that natural clearance of infection does not occur, and the correlates of immune protection are still uncertain. However, partial control of viremia and markedly different outcomes of disease are observed in HIV infected persons. Here we examine the antiviral mechanisms implicated by one variable that has been consistently associated with extremes of outcome, namely HLA class I alleles, and in particular HLA-B, and examine the mechanisms by which this modulation is likely to occur, and the impact of these interactions on evolution of the virus and the host. Studies to date provide evidence for both HLA-dependent and epitope-dependent influences on viral control and viral evolution, and have important implications for the continued quest for an effective HIV vaccine. PMID:22999948

Characterizing Fibrosis in Mouse Kidney using Label Free Fluorescence Lifetime and Second Harmonic Generation Imaging Microscopy in Unilateral Ureteral Obstruction Model

PubMed Central

Ranjit, Suman; Dobrinskikh, Evgenia; Montford, John; Dvornikov, Alexander; Lehman, Allison; Orlicky, David J.; Nemenoff, Raphael; Gratton, Enrico; Levi, Moshe; Furgeson, Seth

2017-01-01

All forms of progressive renal diseases develop a final pathway of tubulointerstitial fibrosis and glomerulosclerosis. Renal fibrosis is usually quantified using histological staining, a process that is time-consuming and pathologist dependent. The work described here shows the development of a fast and operator-independent method to measure fibrosis. To study renal fibrosis, the unilateral ureteral obstruction (UUO) model was chosen. Mice develop a time-dependent increase in obstructed kidneys; contralateral kidneys are used as controls. After UUO, kidneys were analyzed at three time points: 7 days, 14 days, and 21 days. Fibrosis was investigated using FLIM (Fluorescence Lifetime Imaging) and SHG (Second Harmonic Generation) in the deep tissue imaging microscope called DIVER (Deep Imaging via Enhanced photon Recovery). This microscope was developed for deep tissue and SHG and THG (Third Harmonic Generation) imaging and has extraordinary sensitivity towards harmonic generation. SHG data suggests the presence of more fibrillar collagen in the diseased kidneys. The combinations of short wavelength FLIM and SHG analysis results in a robust analysis procedure independent of observer interpretation and let us create a criterion to quantify the extent of fibrosis directly from the image. The progression of fibrosis in UUO model has been studied using this new FLIM-SHG technique and it shows remarkable improvement in quantification of fibrosis compared to standard histological techniques. PMID:27555119

[Investigation of glucocorticoid-induced side effects in patients with autoimmune diseases].

PubMed

Nakajima, Aya; Doki, Kosuke; Homma, Masato; Sagae, Terumi; Saito, Reiko; Ito, Satoshi; Sumida, Takayuki; Kohda, Yukinao

2009-04-01

High dose glucocorticoids (GC) are commonly used for the treatment of autoimmune diseases. The frequencies, occurrence day and dose-dependency for side effects may be different among the events such as diabetes mellitus, hyperlipidemia, infectious disease, osteoporosis, and peptic ulcer. We investigated GC-induced side effects in 68 patients treated with GC for autoimmune diseases. Initial dose of GC (prednisolone equivalent) was 0.67+/-0.35 mg/kg/d. Hypercholesterolemia (66%), hypertension (62%), insomnia (50%), hypertriglyceridemia (44%), excessive appetite (38%), hyperglycemia (18%), digestive symptom (16%), moon-shaped face (13%) and oral candidiasis (12%) were observed in 63 patients treated with GC. Hypercholesterolemia, excessive appetite, digestive symptom, moon-shaped face, and oral candidiasis were associated with the initial dose of prednisolone greater than 0.80 mg/kg/d. Insomnia [median 6 days (range 1-88)], excessive appetite [7 days (2-57)], hypertension [8 days (1-37)], digestive symptom [15 days (1-87)] and hypercholesterolemia [19 days (3-77)] were observed early after 6-19 days starting GC. On the other hand, hypertriglyceridemia [33 days (2-131)], oral candidiasis [35 days (7-52)] and hyperglycemia [60 days (4-134)] were developed after 33-60 days starting GC. Since the frequencies, dose-dependency and occurrence day were different among the side effects of GC, medical staffs including physicians and pharmacists should pay attention such features of the events in the treatment of autoimmune diseases.

Analyzing transmission dynamics of cholera with public health interventions.

PubMed

Posny, Drew; Wang, Jin; Mukandavire, Zindoga; Modnak, Chairat

2015-06-01

Cholera continues to be a serious public health concern in developing countries and the global increase in the number of reported outbreaks suggests that activities to control the diseases and surveillance programs to identify or predict the occurrence of the next outbreaks are not adequate. These outbreaks have increased in frequency, severity, duration and endemicity in recent years. Mathematical models for infectious diseases play a critical role in predicting and understanding disease mechanisms, and have long provided basic insights in the possible ways to control infectious diseases. In this paper, we present a new deterministic cholera epidemiological model with three types of control measures incorporated into a cholera epidemic setting: treatment, vaccination and sanitation. Essential dynamical properties of the model with constant intervention controls which include local and global stabilities for the equilibria are carefully analyzed. Further, using optimal control techniques, we perform a study to investigate cost-effective solutions for time-dependent public health interventions in order to curb disease transmission in epidemic settings. Our results show that the basic reproductive number (R0) remains the model's epidemic threshold despite the inclusion of a package of cholera interventions. For time-dependent controls, the results suggest that these interventions closely interplay with each other, and the costs of controls directly affect the length and strength of each control in an optimal strategy. Copyright © 2015 Elsevier Inc. All rights reserved.

Risk of developing major depression and bipolar disorder among adolescents with atopic diseases: A nationwide longitudinal study in Taiwan.

PubMed

Wei, Han-Ting; Lan, Wen-Hsuan; Hsu, Ju-Wei; Huang, Kai-Lin; Su, Tung-Ping; Li, Cheng-Ta; Lin, Wei-Chen; Chen, Tzeng-Ji; Bai, Ya-Mei; Chen, Mu-Hong

2016-10-01

Previous studies have found an increased prevalence of atopic diseases among patients with major depression and bipolar disorder. But the temporal association between atopic diseases in adolescence and the subsequent risk of developing mood disorders has been rarely investigated. Using the Taiwan National Health Insurance Research Databases, 5075 adolescents with atopic diseases (atopic cohort) and 44,729 without (non-atopic cohort) aged between 10 and 17 in 2000 were enrolled into our study and followed to the end of 2010. Subjects who developed major depression or bipolar disorder during the follow-up were identified. The atopic cohort had an increased risk of developing major depression (HR: 2.45, 95% CI: 1.93~3.11) and bipolar disorder (HR: 2.51, 95% CI: 1.71~3.67) compared to the non-atopic cohort, with a dose-dependent relationship between having a greater number of atopic comorbidities and a greater likelihood of major depression (1 atopic disease: HR: 1.80, 95% CI: 1.29~2.50; 2 atopic comorbidities: HR: 2.42, 95% CI: 1.93~3.04;≥3 atopic comorbidities: HR: 3.79, 95% CI: 3.05~4.72) and bipolar disorder (HR: 1.40, 95% CI: 0.57~3.44; HR: 2.81, 95% CI: 1.68~4.68; HR: 3.02, 95% CI: 1.69~5.38). Having atopic diseases in adolescence increased the risk of developing major depression and bipolar disorder in later life. Further studies may be required to clarify the underlying mechanism between atopy and mood disorders, and to investigate whether prompt intervention may decrease the risk of subsequent mood disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Mapping multiple forest threats in the northwestern United States

Treesearch

Jeffrey D. Kline; Becky K. Kerns; Michelle A. Day; Roger B. Hammer

2013-01-01

US forestlands are increasingly subject to disturbances including wildfire, insects and disease, and urban and exurban development. Devising strategies for addressing these “forest threats” depends on anticipating where individual disturbances are most likely and where they might occur in combination. However, many spatial data sets describing forest threats are...

Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3-dependent lymphangiogenesis.

PubMed

Chen, Xiaodong; Zhou, Huanjiao Jenny; Huang, Qunhua; Lu, Lin; Min, Wang

2014-01-01

Auranofin is a gold compound initially developed for the treatment of rheumatoid arthritis. Recent data suggest that auranofin has promise in the treatment of other inflammatory and proliferative diseases. However, the mechanisms of action of auranofin have not been well defined. In the present study, we identify vascular endothelial growth factor receptor-3 (VEGFR3), an endothelial cell (EC) surface receptor essential for angiogiogenesis and lymphangiogenesis, as a novel target of auranofin. In both primary EC and EC cell lines, auranofin induces downregulation of VEGFR3 in a dose-dependent manner. Auranofin at high doses (≥1 µM) decreases cellular survival protein thioredoxin reductase (TrxR2), TrxR2-dependent Trx2 and transcription factor NF-κB whereas increases stress signaling p38MAPK, leading to EC apoptosis. However, auranofin at low doses (≤0.5 µM) specifically induces downregulation of VEGFR3 and VEGFR3-mediated EC proliferation and migration, two critical steps required for in vivo lymphangiogenesis. Mechanistically, we show that auranofin-induced VEGFR3 downregulation is blocked by antioxidant N-acetyl-L-cysteine (NAC) and lysosome inhibitor chloroquine, but is promoted by proteasomal inhibitor MG132. These results suggest that auranofin induces VEGFR3 degradation through a lysosome-dependent pathway. Auranofin may be a potent therapeutic agent for the treatment of lymphangiogenesis-dependent diseases such as lymphedema and cancer metastasis.

Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis

PubMed Central

Manieri, Nicholas A.; Mack, Madison R.; Himmelrich, Molly D.; Worthley, Daniel L.; Hanson, Elaine M.; Eckmann, Lars; Wang, Timothy C.; Stappenbeck, Thaddeus S.

2015-01-01

Mesenchymal stem cell (MSC) therapy is an emerging field of regenerative medicine; however, it is often unclear how these cells mediate repair. Here, we investigated the use of MSCs in the treatment of intestinal disease and modeled abnormal repair by creating focal wounds in the colonic mucosa of prostaglandin-deficient mice. These wounds developed into ulcers that infiltrated the outer intestinal wall. We determined that penetrating ulcer formation in this model resulted from increased hypoxia and smooth muscle wall necrosis. Prostaglandin I2 (PGI2) stimulated VEGF-dependent angiogenesis to prevent penetrating ulcers. Treatment of mucosally injured WT mice with a VEGFR inhibitor resulted in the development of penetrating ulcers, further demonstrating that VEGF is critical for mucosal repair. We next used this model to address the role of transplanted colonic MSCs (cMSCs) in intestinal repair. Compared with intravenously injected cMSCs, mucosally injected cMSCs more effectively prevented the development of penetrating ulcers, as they were more efficiently recruited to colonic wounds. Importantly, mucosally injected cMSCs stimulated angiogenesis in a VEGF-dependent manner. Together, our results reveal that penetrating ulcer formation results from a reduction of local angiogenesis and targeted injection of MSCs can optimize transplantation therapy. Moreover, local MSC injection has potential for treating diseases with features of abnormal angiogenesis and repair. PMID:26280574

Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis.

PubMed

Manieri, Nicholas A; Mack, Madison R; Himmelrich, Molly D; Worthley, Daniel L; Hanson, Elaine M; Eckmann, Lars; Wang, Timothy C; Stappenbeck, Thaddeus S

2015-09-01

Mesenchymal stem cell (MSC) therapy is an emerging field of regenerative medicine; however, it is often unclear how these cells mediate repair. Here, we investigated the use of MSCs in the treatment of intestinal disease and modeled abnormal repair by creating focal wounds in the colonic mucosa of prostaglandin-deficient mice. These wounds developed into ulcers that infiltrated the outer intestinal wall. We determined that penetrating ulcer formation in this model resulted from increased hypoxia and smooth muscle wall necrosis. Prostaglandin I₂ (PGI₂) stimulated VEGF-dependent angiogenesis to prevent penetrating ulcers. Treatment of mucosally injured WT mice with a VEGFR inhibitor resulted in the development of penetrating ulcers, further demonstrating that VEGF is critical for mucosal repair. We next used this model to address the role of transplanted colonic MSCs (cMSCs) in intestinal repair. Compared with intravenously injected cMSCs, mucosally injected cMSCs more effectively prevented the development of penetrating ulcers, as they were more efficiently recruited to colonic wounds. Importantly, mucosally injected cMSCs stimulated angiogenesis in a VEGF-dependent manner. Together, our results reveal that penetrating ulcer formation results from a reduction of local angiogenesis and targeted injection of MSCs can optimize transplantation therapy. Moreover, local MSC injection has potential for treating diseases with features of abnormal angiogenesis and repair.

Age-Related Alterations in Signaling Pathways in Articular Chondrocytes: Implications for the Pathogenesis and Progression of Osteoarthritis - A Mini-Review.

PubMed

van der Kraan, Peter; Matta, Csaba; Mobasheri, Ali

2017-01-01

Musculoskeletal conditions are a major burden on individuals, healthcare systems, and social care systems throughout the world, with indirect costs having a predominant economic impact. Aging is a major contributing factor to the development and progression of arthritic and musculoskeletal diseases. Indeed, aging and inflammation (often referred to as 'inflammaging') are critical risk factors for the development of osteoarthritis (OA), which is one of the most common forms of joint disease. The term 'chondrosenescence' has recently been introduced to define the age-dependent deterioration of chondrocyte function and how it undermines cartilage function in OA. An important component of chondrosenescence is the age-related deregulation of subcellular signaling pathways in chondrocytes. This mini-review discusses the role of age-related alterations in chondrocyte signaling pathways. We focus our attention on two major areas: age-dependent alterations in transforming growth factor-β signaling and changes in protein kinase and phosphoprotein phosphatase activities in aging chondrocytes. A better understanding of the basic signaling mechanisms underlying aging in chondrocytes is likely to facilitate the development of new therapeutic and preventive strategies for OA and a range of other age-related osteoarticular disorders. © 2016 The Author(s) Published by S. Karger AG, Basel.

Perturbed Mucosal Immunity and Dysbiosis Accompany Clinical Disease in a Rat Model of Spondyloarthritis

PubMed Central

Asquith, Mark; Stauffer, Patrick; Davin, Sean; Mitchell, Claire; Lin, Phoebe; Rosenbaum, James T.

2017-01-01

Objective The HLA-B27/β2 microglobulin (β2m) transgenic rat is a leading model of B27-associated spondyloarthopathy and disease is dependent on the presence of intestinal bacteria. We have shown previously that adult HLA-B27/β2m rats have an altered intestinal microbiota. In this study we sought to better define age-dependent changes to both mucosal immune function and dysbiosis in this model. Methods Intestinal contents were collected from wild type and HLA-B27/β2m+ rats post-weaning (3 and 6 weeks), at disease onset (10 wks) and after the establishment of disease (16 wks). Microbial community structure was determined by 16s sequencing and qRT-PCR. Mucosal and systemic Th1, Th17 and Treg responses were analyzed by flow cytometry, as was the frequency of IgA-coated intestinal bacteria. Intestinal expression of inflammatory cytokines and antimicrobial peptides (AMPs) was determined by qRT-PCR. Results An inflammatory cytokine signature and elevated AMP expression during the post-weaning period preceded the development of clinical bowel inflammation and dysbiosis in HLA-B27/β2m+ rats. An early and sustained expansion of the Th17 pool was specifically observed in cecal and colonic mucosa of HLA-B27/β2m rats. Strongly elevated Akkermansia mucinphilia colonization and IgA coating of intestinal bacteria was significantly associated with HLA-B27 expression and arthritis development. Conclusions and Perspectives HLA-B27/β2m expression in this rat model renders the host hyper-responsive to microbial antigens from infancy. Early activation of innate immunity and expansion of a mucosal Th17 signature are soon followed by dysbiosis in HLA-B27/β2m+ve animals. Perturbed mucosal immunity and dysbiosis strongly merit further study in both pre-diseased and diseased SpA patient populations. PMID:26992013

The effect of regulatory T-cell depletion on the spectrum of organ-specific autoimmune diseases in nonobese diabetic mice at different ages.

PubMed

Nakahara, Mami; Nagayama, Yuji; Ichikawa, Tatsuki; Yu, Liping; Eisenbarth, George S; Abiru, Norio

2011-09-01

The nonobese diabetic (NOD) mouse spontaneously develops several autoimmune diseases, including type 1 diabetes and to a lesser extent thyroiditis and sialitis. Imbalance between effector T cells (Teffs) and regulatory T cells (Tregs) has recently been proposed as a mechanism for the disease pathogenesis in NOD mice, but previous studies have shown the various outcomes by different timing and methods of Treg-depletion. This study was, therefore, designed to compare the consequences of Treg-depletion by the same method (anti-CD25 antibody) on the spectrum of organ-specific autoimmune diseases in NOD mice of different ages. Treg-depletion by anti-CD25 antibody at 10 days of age accelerated development of all three diseases we examined (insulitis/diabetes, thyroiditis, and sialitis); Treg-depletion at 4 weeks of age accelerated only diabetes but not thyroiditis or sialitis; and Treg-depletion at 12 weeks of age hastened only development of thyroiditis and exhibited little influence on diabetes or sialitis. Increased levels of insulin autoantibodies (IAA) were, however, observed in mice depleted of Tregs at 10 days of age, not in those at 4 weeks. Thus, the consequences of Treg-depletion on the spectrum of organ-specific autoimmune diseases depend on the timing of anti-CD25 antibody injection in NOD mice. Aging gradually tips balance between Teffs and Tregs toward Teff-dominance for diabetes, but this balance for thyroiditis and sialitis likely alters more intricately. Our data also suggest that the levels of IAA are not necessarily correlated with diabetes development.

A Critical Role of STAYGREEN/Mendel’s I Locus in Controlling Disease Symptom Development during Pseudomonas syringae pv tomato Infection of Arabidopsis1[W][OA

PubMed Central

Mecey, Christy; Hauck, Paula; Trapp, Marisa; Pumplin, Nathan; Plovanich, Anne; Yao, Jian; He, Sheng Yang

2011-01-01

Production of disease symptoms represents the final phase of infectious diseases and is a main cause of crop loss and/or marketability. However, little is known about the molecular basis of disease symptom development. In this study, a genetic screening was conducted to identify Arabidopsis (Arabidopsis thaliana) mutants that are impaired specifically in the development of disease symptoms (leaf chlorosis and/or necrosis) after infection with the bacterial pathogen Pseudomonas syringae pv tomato (Pst) DC3000. An ethyl methanesulfonate-induced Arabidopsis mutant (no chlorosis1 [noc1]) was identified. In wild-type plants, the abundance of chlorophylls decreased markedly after Pst DC3000 infection, whereas the total amount of chlorophylls remained relatively unchanged in the noc1 mutant. Interestingly, noc1 mutant plants also exhibited reduced disease symptoms in response to the fungal pathogen Alternaria brassicicola. Genetic and molecular analyses showed that the nuclear gene STAYGREEN (SGR; or Mendel’s I locus) is mutated (resulting in the aspartic acid to tyrosine substitution at amino acid position 88) in noc1 plants. Transforming wild-type SGR cDNA into the noc1 mutant rescued the chlorosis phenotype in response to Pst DC3000 infection. The SGR transcript was highly induced by Pst DC3000, A. brassicicola, or coronatine (COR), a bacterial phytotoxin that promotes chlorosis. The induction of SGR expression by COR is dependent on COI1, a principal component of the jasmonate receptor complex. These results suggest that pathogen/COR-induced expression of SGR is a critical step underlying the development of plant disease chlorosis. PMID:21994350

Collection and Characterization of Samples for Establishment of a Serum Repository for Lyme Disease Diagnostic Test Development and Evaluation

PubMed Central

Molins, Claudia R.; Sexton, Christopher; Young, John W.; Ashton, Laura V.; Pappert, Ryan; Beard, Charles B.

2014-01-01

Serological assays and a two-tiered test algorithm are recommended for laboratory confirmation of Lyme disease. In the United States, the sensitivity of two-tiered testing using commercially available serology-based assays is dependent on the stage of infection and ranges from 30% in the early localized disease stage to near 100% in late-stage disease. Other variables, including subjectivity in reading Western blots, compliance with two-tiered recommendations, use of different first- and second-tier test combinations, and use of different test samples, all contribute to variation in two-tiered test performance. The availability and use of sample sets from well-characterized Lyme disease patients and controls are needed to better assess the performance of existing tests and for development of improved assays. To address this need, the Centers for Disease Control and Prevention and the National Institutes of Health prospectively collected sera from patients at all stages of Lyme disease, as well as healthy donors and patients with look-alike diseases. Patients and healthy controls were recruited using strict inclusion and exclusion criteria. Samples from all included patients were retrospectively characterized by two-tiered testing. The results from two-tiered testing corroborated the need for novel and improved diagnostics, particularly for laboratory diagnosis of earlier stages of infection. Furthermore, the two-tiered results provide a baseline with samples from well-characterized patients that can be used in comparing the sensitivity and specificity of novel diagnostics. Panels of sera and accompanying clinical and laboratory testing results are now available to Lyme disease serological test users and researchers developing novel tests. PMID:25122862

Reproductive Toxicity of T Cells in Early Life: Abnormal Immune Development and Postnatal Diseases.

PubMed

Liu, Han-Xiao; Jiang, Aifang; Chen, Ting; Qu, Wen; Yan, Hui-Yi; Ping, Jie

2017-01-01

Immunity is a balanced status with adequate biological defenses to recognize and fight "non-self", as well as adequate tolerance to recognize "self". To maintain this immune homeostasis, a well-organized T cell immune network is required, which in part depends on the well-controlled development of alternative effector T cells, with different cytokine repertoires. Recent researches have pointed that developing fetal T cells network is a remarkably sensitive toxicological target for adverse factors in early life. Epidemiological and experimental studies showed an inseparable relationship between T cell developmental toxicity and immune diseases in adults. Considering that the inflammatory and immune disorders have become a growing health problem worldwide, increasing attention is now being paid to the T cell developmental toxicity. We propose that adverse factors may have programming effects on the crucial functions of immune system during early life which is critical for fetal T cell development and the establishment of the distinct T cell repertoires balance. The permanently disturbed intrathymic or peripheral T cell development may in turn lead to the immune disorders in later life. In this manuscript, we reviewed how adverse factors affected T cell development in early-life with the consequence of the immune dysfunction and immune diseases, and further elucidate the mechanisms. These mechanisms will be helpful in prevention and treatment of the increased prevalence of immune diseases by interfering those pathways. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Fears and Health Needs of Patients with Diabetes: A Qualitative Research in Rural Population.

PubMed

Papaspurou, Maria; Laschou, Vasiliki C; Partsiopoulou, Paraskevi; Fradelos, Evangelos C; Kleisiaris, Christos F; Kalota, Malamati A; Neroliatsiou, Anna; Papathanasiou, Ioanna V

2015-06-01

Insulin-dependent patients are individuals with chronic disease who are well adapted to living and dealing with any health needs and fears arising. An important aspect in the process of adaptation to chronic illness is the provision of nursing care in the early stages of the disease, because this contributes to its acceptance and the early identification and management of potential complications. To investigate the health needs and self-management problems faced by patients with diabetes daily, especially those who use insulin. Furthermore purpose of this study was to investigate the fears experienced by patients in the early stage of the disease, but also in its subsequent development and to study possible differences between sexes. This is a qualitative study, using interpretative phenomenological approach. Fifteen (nine women and six men) insulin-dependent patients, recounted their personal fears and their needs, through semi-structured interviews, which took place in Central Greece. The method used for processing the results is the Mayering one. The analysis of the narratives showed that patients have a variety of fears and needs associated with the diagnosis, treatment, expected consequences, prognosis and everyday life in the management of the disease. Most patients express the concept of need as desire. Care needs, psychological support and education to recognize and prevent hypoglycemia. Insulin-dependent patients express fears and needs in their daily lives. Nurses providing care aimed at enhancing the level of health, while putting self-care information and training them. Patients want the nurse next to them, so that information is continuous and permanent.

Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases.

PubMed

Van Rompaey, Luc; Galien, René; van der Aar, Ellen M; Clement-Lacroix, Philippe; Nelles, Luc; Smets, Bart; Lepescheux, Liên; Christophe, Thierry; Conrath, Katja; Vandeghinste, Nick; Vayssiere, Béatrice; De Vos, Steve; Fletcher, Stephen; Brys, Reginald; van 't Klooster, Gerben; Feyen, Jean H M; Menet, Christel

2013-10-01

The JAKs receive continued interest as therapeutic targets for autoimmune, inflammatory, and oncological diseases. JAKs play critical roles in the development and biology of the hematopoietic system, as evidenced by mouse and human genetics. JAK1 is critical for the signal transduction of many type I and type II inflammatory cytokine receptors. In a search for JAK small molecule inhibitors, GLPG0634 was identified as a lead compound belonging to a novel class of JAK inhibitors. It displayed a JAK1/JAK2 inhibitor profile in biochemical assays, but subsequent studies in cellular and whole blood assays revealed a selectivity of ∼30-fold for JAK1- over JAK2-dependent signaling. GLPG0634 dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. Oral dosing of GLPG0634 in a therapeutic set-up in a collagen-induced arthritis model in rodents resulted in a significant dose-dependent reduction of the disease progression. Paw swelling, bone and cartilage degradation, and levels of inflammatory cytokines were reduced by GLPG0634 treatment. Efficacy of GLPG0634 in the collagen-induced arthritis models was comparable to the results obtained with etanercept. In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases.

Fears and Health Needs of Patients with Diabetes: A Qualitative Research in Rural Population

PubMed Central

Papaspurou, Maria; Laschou, Vasiliki C.; Partsiopoulou, Paraskevi; Fradelos, Evangelos C.; Kleisiaris, Christos F.; Kalota, Malamati A.; Neroliatsiou, Anna; Papathanasiou, Ioanna V.

2015-01-01

Introduction: Insulin-dependent patients are individuals with chronic disease who are well adapted to living and dealing with any health needs and fears arising. An important aspect in the process of adaptation to chronic illness is the provision of nursing care in the early stages of the disease, because this contributes to its acceptance and the early identification and management of potential complications. Purpose: To investigate the health needs and self-management problems faced by patients with diabetes daily, especially those who use insulin. Furthermore purpose of this study was to investigate the fears experienced by patients in the early stage of the disease, but also in its subsequent development and to study possible differences between sexes. Methodology: This is a qualitative study, using interpretative phenomenological approach. Fifteen (nine women and six men) insulin-dependent patients, recounted their personal fears and their needs, through semi-structured interviews, which took place in Central Greece. The method used for processing the results is the Mayering one. Results: The analysis of the narratives showed that patients have a variety of fears and needs associated with the diagnosis, treatment, expected consequences, prognosis and everyday life in the management of the disease. Most patients express the concept of need as desire. Care needs, psychological support and education to recognize and prevent hypoglycemia. Conclusions: Insulin-dependent patients express fears and needs in their daily lives. Nurses providing care aimed at enhancing the level of health, while putting self-care information and training them. Patients want the nurse next to them, so that information is continuous and permanent. PMID:26261390

Urbanization and health in developing countries: a systematic review.

PubMed

Eckert, Sophie; Kohler, Stefan

2014-01-01

Future population growth will take place predominantly in cities of the developing world. The impact of urbanization on health is discussed controversially. We review recent research on urban-rural and intra-urban health differences in developing countries and investigate whether a health advantage was found for urban areas. We systematically searched the databases JSTOR, PubMed, ScienceDirect and SSRN for studies that compare health status in urban and rural areas. The studies had to examine selected World Health Organization health indicators. Eleven studies of the association between urbanization and the selected health indicators in developing countries met our selection criteria. Urbanization was associated with a lower risk of undernutrition but a higher risk of overweight in children. A lower total fertility rate and lower odds of giving birth were found for urban areas. The association between urbanization and life expectancy was positive but insignificant. Common risk factors for chronic diseases were more prevalent in urban areas. Urban-rural differences in mortality from communicable diseases depended on the disease studied. Several health outcomes were correlated with urbanization in developing countries. Urbanization may improve some health problems developing countries face and worsen others. Therefore, urbanization itself should not be embraced as a solution to health problems but should be accompanied by an informed and reactive health policy. Copyright © 2013 Longwoods Publishing.

An update on dry eye disease molecular treatment: advances in drug pipelines.

PubMed

Colligris, Basilio; Crooke, Almudena; Huete-Toral, Fernando; Pintor, Jesus

2014-07-01

Dry eye disease is a common disorder provoking changes in tear film and ocular surface. Untreated dry eye could cause ocular infections, corneal ulcer and blindness. Only a few drugs are authorized so far for the treatment of dry eye disease and the possibilities of evolution in this sector are immense. Consequently, a significant number of new potential solutions are under development or placed in the pharmaceutical pipeline, promising better results and lesser side effects. In this article, the corresponding literature and recent Phase III clinical trial data and the corresponding literature, for dry eye disease treatment are reviewed, revealing the new strategic movements in drug pipelines. From the clinical trial results, the advancement in tear substitutes and secretagogues in addressing specific deficiencies of tear components even though not resolving the underlying conditions of the disease is evident. The vast majority of new compounds under development are anti-inflammatories, steroids, non-steroids and antibiotics; however, there are also some novel lubricating drops and mucin-tear secretagogues. A future aggressive therapy for dry eye, depending on the severity of the symptoms, would include combinations of soft steroids, anti-inflammatories, such as cyclosporine A, with the addition of the new polyvalent mucin and tear secretagogues.

The rhizosphere microbial community in a multiple parallel mineralization system suppresses the pathogenic fungus Fusarium oxysporum.

PubMed

Fujiwara, Kazuki; Iida, Yuichiro; Iwai, Takashi; Aoyama, Chihiro; Inukai, Ryuya; Ando, Akinori; Ogawa, Jun; Ohnishi, Jun; Terami, Fumihiro; Takano, Masao; Shinohara, Makoto

2013-12-01

The rhizosphere microbial community in a hydroponics system with multiple parallel mineralization (MPM) can potentially suppress root-borne diseases. This study focused on revealing the biological nature of the suppression against Fusarium wilt disease, which is caused by the fungus Fusarium oxysporum, and describing the factors that may influence the fungal pathogen in the MPM system. We demonstrated that the rhizosphere microbiota that developed in the MPM system could suppress Fusarium wilt disease under in vitro and greenhouse conditions. The microbiological characteristics of the MPM system were able to control the population dynamics of F. oxysporum, but did not eradicate the fungal pathogen. The roles of the microbiological agents underlying the disease suppression and the magnitude of the disease suppression in the MPM system appear to depend on the microbial density. F. oxysporum that survived in the MPM system formed chlamydospores when exposed to the rhizosphere microbiota. These results suggest that the microbiota suppresses proliferation of F. oxysporum by controlling the pathogen's morphogenesis and by developing an ecosystem that permits coexistence with F. oxysporum. © 2013 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

Cross-talk between virus and host innate immunity in pediatric HIV-1 infection and disease progression.

PubMed

Freguja, Riccardo; Gianesin, Ketty; Zanchetta, Marisa; De Rossi, Anita

2012-07-01

Variability in the susceptibility to HIV-1 infection and disease progression depends on both virus and host determinants. Some exposed individuals remain HIV-1-uninfected and HIV-1-infected subjects develop disease at varying intervals with a small percentage remaining long-term non-progressors. As innate immunity is the earliest response to microbial entry and injury, host factors that impact innate immunity may play a role in viral infectivity and pathogenesis. In the pediatric population the interactions between the virus and the host may be of particular relevance due to the still developing adaptive immune system. Data indicate that genetic variants of defensins and Toll-Like Receptors (TLRs), key elements of innate immunity, play a role in mother-to-child transmission (MTCT) of HIV-1, and in the outcome of pediatric HIV-1 disease. Although the mechanisms by which these genetic variants influence HIV-1 interactions with the host are still largely unknown, defensins and TLRs, along with their link with regulatory T cells (Tregs), may play a critical role in the onset and persistence of immune activation, a hallmark of HIV-1 disease.

Impact of diet on the immunological microenvironment of the pregnant uterus and its relationship to allergic disease in the offspring--a review of the recent literature.

PubMed

Moore, Daniella Campelo Batalha Cox; Elsas, Pedro Xavier; Maximiano, Elisabeth Santos; Elsas, Maria Ignez Capella Gaspar

2006-09-07

Medical progress has reduced the mortality from infectious diseases in most countries, but allergic diseases have become more prevalent worldwide over the same period, especially in industrialized countries. This has prompted speculation that modern lifestyles have altered the relationship between heredity and environment so as to promote development of an atopic phenotype when exposure to infection decreases. A healthy uterine microenvironment is known to favor Th2 lymphocyte development. However, some evidence suggests that persistence of the Th2 pattern of immunity directs the developing organism's immune response towards a long-lasting atopic phenotype. Even though the outcome also depends on other factors (such as infection, functional state of the intestinal microflora, and exposure to environmental allergens at times critical to development), it seems that the immune system during the perinatal period is responsive to interventions that are no longer effective in adulthood. We have reviewed the literature accessible through Medline to identify recent advances in the prevention of allergic disease through interventions in the fetal-maternal relationship. Diet seems to have a significant impact on the immunological profile of the pregnant uterus, as well as on the postnatal development of allergic disease in the offspring, as suggested by the effects of probiotic bacteria and by manipulations of the dietary content of polyunsaturated fatty acids and antioxidants. This highlights the need for further studies, in order to define the best intervention methods, the most appropriate time interval and the individuals who will most likely benefit from them.

Hypoxia as a target for tissue specific gene therapy.

PubMed

Rhim, Taiyoun; Lee, Dong Yun; Lee, Minhyung

2013-12-10

Hypoxia is a hallmark of various ischemic diseases such as ischemic heart disease, ischemic limb, ischemic stroke, and solid tumors. Gene therapies for these diseases have been developed with various therapeutic genes including growth factors, anti-apoptotic genes, and toxins. However, non-specific expression of these therapeutic genes may induce dangerous side effects in the normal tissues. To avoid the side effects, gene expression should be tightly regulated in an oxygen concentration dependent manner. The hypoxia inducible promoters and enhancers have been evaluated as a transcriptional regulation tool for hypoxia inducible gene therapy. The hypoxia inducible UTRs were also used in gene therapy for spinal cord injury as a translational regulation strategy. In addition to transcriptional and translational regulations, post-translational regulation strategies have been developed using the HIF-1α ODD domain. Hypoxia inducible transcriptional, translational, and post-translational regulations are useful for tissue specific gene therapy of ischemic diseases. In this review, hypoxia inducible gene expression systems are discussed and their applications are introduced. Copyright © 2013 Elsevier B.V. All rights reserved.

Persistent effects of chlorine inhalation on respiratory health

PubMed Central

Hoyle, Gary W.; Svendsen, Erik R.

2016-01-01

Chlorine gas is a toxic respiratory irritant that is considered a chemical threat agent because of the potential for release in industrial accidents or terrorist attacks. Chlorine inhalation damages the respiratory tract, including the airways and distal lung, and can result in acute lung injury. Some individuals exposed to chlorine experience a full recovery from acute injury, whereas others develop persistent adverse effects, such as respiratory symptoms, inflammation, and lung-function decrements. In animal models, chlorine can produce persistent inflammation, remodeling, and obstruction in large or small airways, depending on species. Airways with pseudostratified epithelium are repaired efficiently, with surviving basal epithelial cells serving as progenitor cells that repopulate the complement of differentiated cell types. Distal airways lacking basal cells are repaired less efficiently, leading to chronic inflammation and fibrosis at these sites. Persistent chlorine-induced airway disease in humans is treated with asthma medication to relieve symptoms. However, such treatment does not ameliorate the underlying disease pathogenesis, so treatments that are more effective at preventing initial development of airway disease after irritant gas exposure and at reversing established disease are needed. PMID:27385061

Rare disease landscape in Brazil: report of a successful experience in inborn errors of metabolism.

PubMed

Giugliani, Roberto; Vairo, Filippo P; Riegel, Mariluce; de Souza, Carolina F M; Schwartz, Ida V D; Pena, Sérgio D J

2016-06-10

Brazil is a country of continental dimensions, with many social inequalities. The latter are reflected on its health system, which comprises a large public component called SUS, a small paid health insurance component and a third very small private component, in which patients pay personally for medical services. Seventy five percent of the population depends on SUS, which thus far does not provide adequate coverage for genetic medical procedures. In 2014, SUS introduced the "Policy for the Integral Attention to Subjects with Rare Diseases", establishing guidelines for offering diagnosis and treatment. The policy defines the two main axes, genetic and non-genetic rare diseases. In this fashion, public genetic services in SUS will be installed and funded not by themselves, but as part of the more general policy of rare diseases. Unfortunately, up to now this policy is still depending on financial allowances to be effectively launched. In this article, our intention was to describe activities developed in the area of inborn errors of metabolism by a Brazilian reference center. In spite of the lack of support of SUS, thousands of Brazilian families affected by rare genetic metabolic disorders, and many health professionals from all regions of Brazil, already have benefited from the services, training programs and research projects provided by this comprehensive center.

Treatment planning and delivery of involved field radiotherapy in advanced Hodgkin's disease: results from a questionnaire-based audit for the UK Stanford V regimen vs ABVD clinical trial quality assurance programme (ISRCTN 64141244).

PubMed

Diez, P; Hoskin, P J; Aird, E G A

2007-10-01

This questionnaire forms the basis of the quality assurance (QA) programme for the UK randomized Phase III study of the Stanford V regimen versus ABVD for treatment of advanced Hodgkin's disease to assess differences between participating centres in treatment planning and delivery of involved-field radiotherapy for Hodgkin's lymphoma The questionnaire, which was circulated amongst 42 participating centres, consisted of seven sections: target volume definition and dose prescription; critical structures; patient positioning and irradiation techniques; planning; dose calculation; verification; and future developments The results are based on 25 responses. One-third plan using CT alone, one-third use solely the simulator and the rest individualize, depending on disease site. Eleven centres determine a dose distribution for each patient. Technique depends on disease site and whether CT or simulator planning is employed. Most departments apply isocentric techniques and use immobilization and customized shielding. In vivo dosimetry is performed in 7 centres and treatment verification occurs in 24 hospitals. In conclusion, the planning and delivery of treatment for lymphoma patients varies across the country. Conventional planning is still widespread but most centres are moving to CT-based planning and virtual simulation with extended use of immobilization, customized shielding and compensation.

Environment-dependent striatal gene expression in the BACHD rat model for Huntington disease.

PubMed

Novati, Arianna; Hentrich, Thomas; Wassouf, Zinah; Weber, Jonasz J; Yu-Taeger, Libo; Déglon, Nicole; Nguyen, Huu Phuc; Schulze-Hentrich, Julia M

2018-04-11

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene which results in progressive neurodegeneration in the striatum, cortex, and eventually most brain areas. Despite being a monogenic disorder, environmental factors influence HD characteristics. Both human and mouse studies suggest that mutant HTT (mHTT) leads to gene expression changes that harbor potential to be modulated by the environment. Yet, the underlying mechanisms integrating environmental cues into the gene regulatory program have remained largely unclear. To better understand gene-environment interactions in the context of mHTT, we employed RNA-seq to examine effects of maternal separation (MS) and environmental enrichment (EE) on striatal gene expression during development of BACHD rats. We integrated our results with striatal consensus modules defined on HTT-CAG length and age-dependent co-expression gene networks to relate the environmental factors with disease progression. While mHTT was the main determinant of expression changes, both MS and EE were capable of modulating these disturbances, resulting in distinctive and in several cases opposing effects of MS and EE on consensus modules. This bivalent response to maternal separation and environmental enrichment may aid in explaining their distinct effects observed on disease phenotypes in animal models of HD and related neurodegenerative disorders.

Congenital Chagas disease as an ecological model of interactions between Trypanosoma cruzi parasites, pregnant women, placenta and fetuses.

PubMed

Carlier, Yves; Truyens, Carine

2015-11-01

The aim of this paper is to discuss the main ecological interactions between the parasite Trypanosoma cruzi and its hosts, the mother and the fetus, leading to the transmission and development of congenital Chagas disease. One or several infecting strains of T. cruzi (with specific features) interact with: (i) the immune system of a pregnant woman whom responses depend on genetic and environmental factors, (ii) the placenta harboring its own defenses, and, finally, (iii) the fetal immune system displaying responses also susceptible to be modulated by maternal and environmental factors, as well as his own genetic background which is different from her mother. The severity of congenital Chagas disease depends on the magnitude of such final responses. The paper is mainly based on human data, but integrates also complementary observations obtained in experimental infections. It also focuses on important gaps in our knowledge of this congenital infection, such as the role of parasite diversity vs host genetic factors, as well as that of the maternal and placental microbiomes and the microbiome acquisition by infant in the control of infection. Investigations on these topics are needed in order to improve the programs aiming to diagnose, manage and control congenital Chagas disease. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

AUTEN-67, an autophagy-enhancing drug candidate with potent antiaging and neuroprotective effects.

PubMed

Papp, Diána; Kovács, Tibor; Billes, Viktor; Varga, Máté; Tarnóci, Anna; Hackler, László; Puskás, László G; Liliom, Hanna; Tárnok, Krisztián; Schlett, Katalin; Borsy, Adrienn; Pádár, Zsolt; Kovács, Attila L; Hegedűs, Krisztina; Juhász, Gábor; Komlós, Marcell; Erdős, Attila; Gulyás, Balázs; Vellai, Tibor

2016-01-01

Autophagy is a major molecular mechanism that eliminates cellular damage in eukaryotic organisms. Basal levels of autophagy are required for maintaining cellular homeostasis and functioning. Defects in the autophagic process are implicated in the development of various age-dependent pathologies including cancer and neurodegenerative diseases, as well as in accelerated aging. Genetic activation of autophagy has been shown to retard the accumulation of damaged cytoplasmic constituents, delay the incidence of age-dependent diseases, and extend life span in genetic models. This implies that autophagy serves as a therapeutic target in treating such pathologies. Although several autophagy-inducing chemical agents have been identified, the majority of them operate upstream of the core autophagic process, thereby exerting undesired side effects. Here, we screened a small-molecule library for specific inhibitors of MTMR14, a myotubularin-related phosphatase antagonizing the formation of autophagic membrane structures, and isolated AUTEN-67 (autophagy enhancer-67) that significantly increases autophagic flux in cell lines and in vivo models. AUTEN-67 promotes longevity and protects neurons from undergoing stress-induced cell death. It also restores nesting behavior in a murine model of Alzheimer disease, without apparent side effects. Thus, AUTEN-67 is a potent drug candidate for treating autophagy-related diseases.

Mitochondria and NMDA Receptor-Dependent Toxicity of Berberine Sensitizes Neurons to Glutamate and Rotenone Injury

PubMed Central

Kysenius, Kai; Brunello, Cecilia A.; Huttunen, Henri J.

2014-01-01

The global incidence of metabolic and age-related diseases, including type 2 diabetes and Alzheimer's disease, is on the rise. In addition to traditional pharmacotherapy, drug candidates from complementary and alternative medicine are actively being pursued for further drug development. Berberine, a nutraceutical traditionally used as an antibiotic, has recently been proposed to act as a multi-target protective agent against type 2 diabetes, dyslipidemias, ischemic brain injury and neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. However, the safety profile of berberine remains controversial, as isolated reports suggest risks with acute toxicity, bradycardia and exacerbation of neurodegeneration. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content. Berberine does not induce caspase-3 activation and the resulting neurotoxicity remains unaffected by pan-caspase inhibitor treatment. Interestingly, inhibition of NMDA receptors by memantine and MK-801 completely blocked berberine-induced neurotoxicity. Additionally, subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine. PMID:25192195

Oxidative Stress Parameters in Saliva and Its Association with Periodontal Disease and Types of Bacteria.

PubMed

Almerich-Silla, Jose Manuel; Montiel-Company, Jose María; Pastor, Sara; Serrano, Felipe; Puig-Silla, Miriam; Dasí, Francisco

2015-01-01

To determine the association between oxidative stress parameters with periodontal disease, bleeding, and the presence of different periodontal bacteria. A cross-sectional study in a sample of eighty-six patients, divided into three groups depending on their periodontal status. Thirty-three with chronic periodontitis, sixteen with gingivitis, and thirty-seven with periodontal healthy as control. Oxidative stress biomarkers (8-OHdG and MDA), total antioxidant capacity (TAOC), and the activity of two antioxidant enzymes (GPx and SOD) were determined in saliva. Subgingival plaque samples were obtained from the deepest periodontal pocket and PCR was used to determine the presence of the 6 fimA genotypes of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia, and Treponema denticola. Periodontal disease was found to be associated with increased oxidative stress parameter levels. These levels rose according to the number and type of different periodontal bacteria found in the periodontal pockets. The presence of different types of periodontal bacteria is predictive independent variables in linear regresion models of oxidative stress parameters as dependent variable, above all 8-OHdG. Oxidative stress parameter levels are correlated with the presence of different types of bacteria. Determination of these levels and periodontal bacteria could be a potent tool for controlling periodontal disease development.

Ionizing radiation and autoimmunity: Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells

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

Sakaguchi, N.; Sakaguchi, S.; Miyai, K.

1992-11-01

Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and themore » peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4[sup +] T cells mediated the autoimmune prevention but CD8[sup +] T cells did not. CD4[sup +] T cells also appeared to mediate the TLI-induced autoimmune disease because CD4[sup +] T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells. 62 refs., 9 figs., 2 tabs.« less

Comparative Proteomic Analysis of Liver Steatosis and Fibrosis after Oral Hepatotoxicant Administration in Sprague-Dawley Rats.

PubMed

McDyre, B Claire; AbdulHameed, Mohamed Diwan M; Permenter, Matthew G; Dennis, William E; Baer, Christine E; Koontz, Jason M; Boyle, Molly H; Wallqvist, Anders; Lewis, John A; Ippolito, Danielle L

2018-02-01

The past decade has seen an increase in the development and clinical use of biomarkers associated with histological features of liver disease. Here, we conduct a comparative histological and global proteomics analysis to identify coregulated modules of proteins in the progression of hepatic steatosis or fibrosis. We orally administered the reference chemicals bromobenzene (BB) or 4,4'-methylenedianiline (4,4'-MDA) to male Sprague-Dawley rats for either 1 single administration or 5 consecutive daily doses. Livers were preserved for histopathology and global proteomics assessment. Analysis of liver sections confirmed a dose- and time-dependent increase in frequency and severity of histopathological features indicative of lipid accumulation after BB or fibrosis after 4,4'-MDA. BB administration resulted in a dose-dependent increase in the frequency and severity of inflammation and vacuolation. 4,4'-MDA administration resulted in a dose-dependent increase in the frequency and severity of periportal collagen accumulation and inflammation. Pathway analysis identified a time-dependent enrichment of biological processes associated with steatogenic or fibrogenic initiating events, cellular functions, and toxicological states. Differentially expressed protein modules were consistent with the observed histology, placing physiologically linked protein networks into context of the disease process. This study demonstrates the potential for protein modules to provide mechanistic links between initiating events and histopathological outcomes.

APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer’s disease

PubMed Central

Donix, Markus; Burggren, Alison C.; Scharf, Maria; Marschner, Kira; Suthana, Nanthia A.; Siddarth, Prabha; Krupa, Allison K.; Jones, Michael; Martin-Harris, Laurel; Ercoli, Linda M.; Miller, Karen J.; Werner, Annett; von Kummer, Rüdiger; Sauer, Cathrin; Small, Gary W.; Holthoff, Vjera A.; Bookheimer, Susan Y.

2013-01-01

Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer’s disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer’s disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer’s disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer’s disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology. PMID:24080518

Humanized Mouse Model of Ebola Virus Disease Mimics the Immune Responses in Human Disease.

PubMed

Bird, Brian H; Spengler, Jessica R; Chakrabarti, Ayan K; Khristova, Marina L; Sealy, Tara K; Coleman-McCray, JoAnn D; Martin, Brock E; Dodd, Kimberly A; Goldsmith, Cynthia S; Sanders, Jeanine; Zaki, Sherif R; Nichol, Stuart T; Spiropoulou, Christina F

2016-03-01

Animal models recapitulating human Ebola virus disease (EVD) are critical for insights into virus pathogenesis. Ebola virus (EBOV) isolates derived directly from human specimens do not, without adaptation, cause disease in immunocompetent adult rodents. Here, we describe EVD in mice engrafted with human immune cells (hu-BLT). hu-BLT mice developed EVD following wild-type EBOV infection. Infection with high-dose EBOV resulted in rapid, lethal EVD with high viral loads, alterations in key human antiviral immune cytokines and chemokines, and severe histopathologic findings similar to those shown in the limited human postmortem data available. A dose- and donor-dependent clinical course was observed in hu-BLT mice infected with lower doses of either Mayinga (1976) or Makona (2014) isolates derived from human EBOV cases. Engraftment of the human cellular immune system appeared to be essential for the observed virulence, as nonengrafted mice did not support productive EBOV replication or develop lethal disease. hu-BLT mice offer a unique model for investigating the human immune response in EVD and an alternative animal model for EVD pathogenesis studies and therapeutic screening. Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner.

PubMed

Zhang, Yiwei; Zeng, Shelya X; Hao, Qian; Lu, Hua

2017-03-01

Although p53 is not essential for normal embryonic development, it plays a pivotal role in many biological and pathological processes, including cell fate determination-dependent and independent events and diseases. The expression and activity of p53 largely depend on its two biological inhibitors, MDM2 and MDMX, which have been shown to form a complex in order to tightly control p53 to an undetectable level during early stages of embryonic development. However, more delicate studies using conditional gene-modification mouse models show that MDM2 and MDMX may function separately or synergistically on p53 regulation during later stages of embryonic development and adulthood in a cell and tissue-specific manner. Here, we report the role of the MDM2/MDMX-p53 pathway in pancreatic islet morphogenesis and functional maintenance, using mouse lines with specific deletion of MDM2 or MDMX in pancreatic endocrine progenitor cells. Interestingly, deletion of MDM2 results in defects of embryonic endocrine pancreas development, followed by neonatal hyperglycemia and lethality, by inducing pancreatic progenitor cell apoptosis and inhibiting cell proliferation. However, unlike MDM2-knockout animals, mice lacking MDMX in endocrine progenitor cells develop normally. But, surprisingly, the survival rate of adult MDMX-knockout mice drastically declines compared to control mice, as blockage of neonatal development of endocrine pancreas by inhibition of cell proliferation and subsequent islet dysfunction and hyperglycemia eventually lead to type 1 diabetes-like disease with advanced diabetic nephropathy. As expected, both MDM2 and MDMX deletion-caused pancreatic defects are completely rescued by loss of p53, verifying the crucial role of the MDM2 and/or MDMX in regulating p53 in a spatio-temporal manner during the development, functional maintenance, and related disease progress of endocrine pancreas. Also, our study suggests a possible mouse model of advanced diabetic nephropathy, which is complementary to other established diabetic models and perhaps useful for the development of anti-diabetes therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Lawrence, T.S.; Robertson, J.M.; Anscher, M.S.

Radiation-induced liver disease (RILD), often called radiation hepatitis, is a syndrome characterized by the development of anicteric ascites approximately 2 weeks to 4 months after hepatic irradiation. There has been a renewed interest in hepatic irradiation because of two significant advances in cancer treatment; three dimensional radiation therapy treatment planning and bone marrow transplantation using total body irradiation. RILD resulting from liver radiation can usually be distinguished clinically from the resulting from the preparative regime associated with bone marrow transplantation. However, both syndromes demonstrate the same pathological lesion; veno-occlusive disease. Recent evidence suggests that elevated transforming growth factor {beta} levelsmore » may play a role in the development of veno-occlusive disease. Three dimensional treatment planning offers the potential to determine the radiation dose and volume dependence of RILD, permitting the safe delivery of high doses of radiation to parts of the liver. The chief therapy for RILD is diuretics, although some advocate steroids of severe cases. The characteristics of RILD permit the development of a grading system modeled after the NCI Acute Common Toxicity Criteria, which incorporates standard criteria of hepatic dysfunction. 64 refs., 5 figs., 1 tab.« less

Follicular helper T cells in immunity and systemic autoimmunity.

PubMed

Craft, Joseph E

2012-05-01

Follicular helper T (T(FH)) cells are essential for B-cell maturation and immunoglobulin production after immunization with thymus-dependent antigens. Nevertheless, the development and function of T(FH) cells have been less clearly defined than classic CD4(+) effector T-cell subsets, including T-helper-1 (T(H)1), T(H)2 and T(H)17 cells. As such, our understanding of the genesis of T(FH) cells in humans and their role in the development of autoimmunity remains incomplete. However, evidence from animal models of systemic lupus erythematosus (SLE) and patients with systemic autoimmune diseases suggests that these cells are necessary for pathogenic autoantibody production, in a manner analogous to their role in promotion of B-cell maturation during normal immune responses. In this Review, I discuss the findings that have increased our knowledge of T(FH)-cell development and function in normal and aberrant immune responses. Such information might improve our understanding of autoimmune diseases, such as SLE, and highlights the potential of T(FH) cells as therapeutic targets in these diseases.

Promoting health in schools through a board game.

PubMed

Bartfay, W J; Bartfay, E

1994-08-01

Primary prevention and health promotion have become salient topics in Canadian society and in nursing during the past two decades. The noncommunicable chronic diseases, such as heart disease and cancer, have been linked to specific lifestyle behaviors or habits, which often develop early in life. The success of public health efforts to improve the health status of all Canadians depends substantially on the success of educational programs directed toward children. Effective teaching strategies that seek to promote health and wellness in children need to be developed and empirically evaluated. Educational games may provide an efficient vehicle for carrying out developmentally specific nursing interventions in school settings. This article begins with a brief overview of the historical origins of games, along with their advantages and disadvantages as educational strategies. The results of a pretest-posttest control group design study that evaluated the effectiveness of a board game as a primary prevention teaching strategy with 23 sixth grade children in Winnipeg, Manitoba are presented. The experimental group had significant gains in knowledge related to anatomy and physiology, diet, and lifestyle risk factors associated with the development of heart disease and cancer.

Emerging topical onychomycosis therapies - quo vadis?

PubMed

Elkeeb, Rania; Hui, Xiaoying; Murthy, Narasimha; Maibach, Howard I

2014-12-01

Onychomycosis, a common chronic fungal infection affecting fingernails and toenails, globally may affect 10 - 30% of the population. This chronic disease is difficult to eradicate. The goal of developing a highly effective and safe topical treatment has not yet been reached as it depends on the type of onychomycosis and the variety of invaders. Topical drug delivery to the nail is highly desirable in treating nail disorders. However, efficacy of topical therapies is low due to their limited permeability across the nail plate. Advances have especially been made by the development of new therapeutic options including new drug entities, new formulations and reformulations. This overview updates emerging topical treatments for onychomycosis, research progress and future perspectives. Development of novel effective noninvasive topical therapy for treating onychomycosis and other nail diseases such as psoriasis is long overdue. Previously there was a lack of basic knowledge about nail and its barrier properties, but with the recent increased interest in this field both from industry and academia, we hope extensive research will continue in this field to bring about successful and safe treatments for such chronic diseases.

Utilization of RNA polymerase I promoter and terminator sequences to develop a DNA transfection system for the study of hepatitis C virus internal ribosomal entry site-dependent translation.

PubMed

Oem, Jae-Ku; Xiang, Zhonghua; Zhou, Yan; Babiuk, Lorne A; Liu, Qiang

2007-09-01

Hepatitis C virus (HCV) causes severe liver diseases in a large population worldwide. HCV protein translation is controlled by an internal ribosomal entry site (IRES) within the 5'-untranslated region (UTR). HCV IRES-dependent translation is critical for HCV-associated pathogenesis. To develop a plasmid DNA transfection system by using RNA polymerase I promoter and terminator sequences for studying HCV IRES-dependent translation. A gene cassette containing HCV 5'-UTR, Renilla luciferase reporter gene, and HCV 3'-UTR was inserted between RNA polymerase I promoter and terminator sequences. HCV IRES-directed translation was determined by luciferase assay after transfection. Transfection of the RNA polymerase I-HCV IRES plasmid into human hepatoma Huh-7 and HepG2 cells resulted in luciferase gene expression. Deletion of the IIIf domain in HCV IRES dramatically reduced luciferase activity. Our results indicated that the plasmid vector system-based on RNA polymerase I promoter and terminator sequences represents an effective approach for the study of HCV IRES-dependent translation.

Substance abuse and pharmacy practice: what the community pharmacist needs to know about drug abuse and dependence

PubMed Central

Tommasello, Anthony C

2004-01-01

Pharmacists, the most accessible of health care professionals, are well positioned to help prevent and treat substance use disorders and should prepare themselves to perform these functions. New research improves our knowledge about the pharmacological and behavioral risks of drug abuse, supports the clinical impression that drug dependence is associated with long-lasting neurochemical changes, and demonstrates effective pharmacological treatments for certain kinds of drug dependencies. The profession is evolving. Pharmacists are engaging in new practice behaviors such as helping patients manage their disease states. Collaborative practice agreements and new federal policies set the stage for pharmacists to assist in the clinical management of opioid and other drug dependencies. Pharmacists need to be well informed about issues related to addiction and prepared not only to screen, assess, and refer individual cases and to collaborate with physicians caring for chemically dependent patients, but also to be agents of change in their communities in the fight against drug abuse. At the end of this article the pharmacist will be better able to: 1. Explain the disease concept of chemical dependence 2. Gather the information necessary to conduct a screen for chemical dependence 3. Inform patients about the treatment options for chemical dependence 4. Locate resources needed to answer questions about the effects of common drugs of abuse (alcohol, marijuana, narcotics, "ecstasy", and cocaine) 5. Develop a list of local resources for drug abuse treatment 6. Counsel parents who are concerned about drug use by their children 7. Counsel individuals who are concerned about drug use by a loved one. 8. Counsel individuals who are concerned about their own drug use PMID:15169544

Scale-dependence of desease impacts on quaking aspen (Populus tremuloides) mortality risk in the southwestern U.S.

Treesearch

David M. Bell; John B. Bradford; William K. Lauenroth

2015-01-01

Depending on how disease impacts tree exposure to risk, both the prevalence of disease and disease effects on survival may contribute to patterns of mortality risk across a species’ range. Disease may accelerate tree species’ declines in response to global change factors, such as drought, biotic interactions, such as competition, or functional traits, such as allometry...

Quantifying penetrance in a dominant disease gene using large population control cohorts

PubMed Central

Minikel, Eric Vallabh; Vallabh, Sonia M.; Lek, Monkol; Estrada, Karol; Samocha, Kaitlin E.; Sathirapongsasuti, J. Fah; McLean, Cory Y.; Tung, Joyce Y.; Yu, Linda P.C.; Gambetti, Pierluigi; Blevins, Janis; Zhang, Shulin; Cohen, Yvonne; Chen, Wei; Yamada, Masahito; Hamaguchi, Tsuyoshi; Sanjo, Nobuo; Mizusawa, Hidehiro; Nakamura, Yosikazu; Kitamoto, Tetsuyuki; Collins, Steven J.; Boyd, Alison; Will, Robert G.; Knight, Richard; Ponto, Claudia; Zerr, Inga; Kraus, Theo F.J.; Eigenbrod, Sabina; Giese, Armin; Calero, Miguel; de Pedro-Cuesta, Jesús; Haïk, Stéphane; Laplanche, Jean-Louis; Bouaziz-Amar, Elodie; Brandel, Jean-Philippe; Capellari, Sabina; Parchi, Piero; Poleggi, Anna; Ladogana, Anna; O'Donnell-Luria, Anne H.; Karczewski, Konrad J.; Marshall, Jamie L.; Boehnke, Michael; Laakso, Markku; Mohlke, Karen L.; Kähler, Anna; Chambert, Kimberly; McCarroll, Steven; Sullivan, Patrick F.; Hultman, Christina M.; Purcell, Shaun M.; Sklar, Pamela; van der Lee, Sven J.; Rozemuller, Annemieke; Jansen, Casper; Hofman, Albert; Kraaij, Robert; van Rooij, Jeroen G.J.; Ikram, M. Arfan; Uitterlinden, André G.; van Duijn, Cornelia M.; Daly, Mark J.; MacArthur, Daniel G.

2016-01-01

More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance - the probability that a carrier of the purported disease-causing genotype will indeed develop the disease - is generally unknown. Here we assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe, Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30× more common in the population than expected based on genetic prion disease prevalence. While some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1% to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, supporting the safety of therapeutic suppression of prion protein expression. PMID:26791950

Role of Antioxidants and Natural Products in Inflammation

PubMed Central

Fard, Masoumeh Tangestani; Tan, Woan Sean; Gothai, Sivapragasam; Kumar, S. Suresh

2016-01-01

Inflammation is a comprehensive array of physiological response to a foreign organism, including human pathogens, dust particles, and viruses. Inflammations are mainly divided into acute and chronic inflammation depending on various inflammatory processes and cellular mechanisms. Recent investigations have clarified that inflammation is a major factor for the progression of various chronic diseases/disorders, including diabetes, cancer, cardiovascular diseases, eye disorders, arthritis, obesity, autoimmune diseases, and inflammatory bowel disease. Free radical productions from different biological and environmental sources are due to an imbalance of natural antioxidants which further leads to various inflammatory associated diseases. In this review article, we have outlined the inflammatory process and its cellular mechanisms involved in the progression of various chronic modern human diseases. In addition, we have discussed the role of free radicals-induced tissue damage, antioxidant defence, and molecular mechanisms in chronic inflammatory diseases/disorders. The systematic knowledge regarding the role of inflammation and its associated adverse effects can provide a clear understanding in the development of innovative therapeutic targets from natural sources that are intended for suppression of various chronic inflammations associated diseases. PMID:27803762

Rheumatoid Arthritis-Associated Interstitial Lung Disease: Current Concepts.

PubMed

Brito, Yoel; Glassberg, Marilyn K; Ascherman, Dana P

2017-11-09

Among the many extra-articular complications of rheumatoid arthritis (RA), interstitial lung disease (ILD) contributes significantly to morbidity and mortality. Prevalence estimates for RA-ILD vary widely depending on the specific clinical, radiographic, and functional criteria used to establish the diagnosis. A key unresolved issue is whether early, subclinical forms of RA-ILD represent a precursor to end stage, fibrotic lung disease. Based on uncertainties surrounding the natural history of RA-ILD, incomplete understanding of underlying disease pathogenesis, and lack of controlled clinical trials, evidence-based therapeutic strategies remain largely undefined. Correlative clinico-epidemiological studies have identified key risk factors for disease progression. Complementing these findings, the identification of specific molecular and serological markers of RA-ILD has improved our understanding of disease pathogenesis and established the foundation for predictive biomarker profiling. Experience from case series and cohort studies suggests that newer biological agents such as rituximab may be viable treatment options. RA-ILD continues to have a major impact on "disease intrinsic" morbidity and mortality. Increased understanding of disease pathogenesis and the natural history of subclinical RA-ILD will promote the development of more refined therapeutic strategies.

Adaptive modeling of viral diseases in bats with a focus on rabies.

PubMed

Dimitrov, Dobromir T; Hallam, Thomas G; Rupprecht, Charles E; McCracken, Gary F

2008-11-07

Many emerging and reemerging viruses, such as rabies, SARS, Marburg, and Ebola have bat populations as disease reservoirs. Understanding the spillover from bats to humans and other animals, and the associated health risks requires an analysis of the disease dynamics in bat populations. Traditional compartmental epizootic models, which are relatively easy to implement and analyze, usually impose unrealistic aggregation assumptions about disease-related structure and depend on parameters that frequently are not measurable in field conditions. We propose a novel combination of computational and adaptive modeling approaches that address the maintenance of emerging diseases in bat colonies through individual (intra-host) models of the response of the host to a viral challenge. The dynamics of the individual models are used to define survival, susceptibility and transmission conditions relevant to epizootics as well as to develop and parametrize models of the disease evolution into uniform and diverse populations. Applications of the proposed approach to modeling the effects of immunological heterogeneity on the dynamics of bat rabies are presented.

In Search of 'Birth Month Genes': Using Existing Data Repositories to Locate Genes Underlying Birth Month-Disease Relationships.

PubMed

Boland, Mary Regina; Tatonetti, Nicholas P

2016-01-01

Prenatal and perinatal exposures vary seasonally (e.g., sunlight, allergens) and many diseases are linked with variance in exposure. Epidemiologists often measure these changes using birth month as a proxy for seasonal variance. Likewise, Genome-Wide Association Studies have associated or implicated these same diseases with many genes. Both disparate data types (epidemiological and genetic) can provide key insights into the underlying disease biology. We developed an algorithm that links 1) epidemiological data from birth month studies with 2) genetic data from published gene-disease association studies. Our framework uses existing data repositories - PubMed, DisGeNET and Gene Ontology - to produce a bipartite network that connects enriched seasonally varying biofactorss with birth month dependent diseases (BMDDs) through their overlapping developmental gene sets. As a proof-of-concept, we investigate 7 known BMDDs and highlight three important biological networks revealed by our algorithm and explore some interesting genetic mechanisms potentially responsible for the seasonal contribution to BMDDs.

Experimental psychiatric illness and drug abuse models: from human to animal, an overview.

PubMed

Edwards, Scott; Koob, George F

2012-01-01

Preclinical animal models have supported much of the recent rapid expansion of neuroscience research and have facilitated critical discoveries that undoubtedly benefit patients suffering from psychiatric disorders. This overview serves as an introduction for the following chapters describing both in vivo and in vitro preclinical models of psychiatric disease components and briefly describes models related to drug dependence and affective disorders. Although there are no perfect animal models of any psychiatric disorder, models do exist for many elements of each disease state or stage. In many cases, the development of certain models is essentially restricted to the human clinical laboratory domain for the purpose of maximizing validity, whereas the use of in vitro models may best represent an adjunctive, well-controlled means to model specific signaling mechanisms associated with psychiatric disease states. The data generated by preclinical models are only as valid as the model itself, and the development and refinement of animal models for human psychiatric disorders continues to be an important challenge. Collaborative relationships between basic neuroscience and clinical modeling could greatly benefit the development of new and better models, in addition to facilitating medications development.

Diagnosis and classification of Addison's disease (autoimmune adrenalitis).

PubMed

Brandão Neto, Rodrigo Antonio; de Carvalho, Jozélio Freire

2014-01-01

Autoimmune adrenalitis, or autoimmune Addison disease (AAD), is the most prevalent cause of primary adrenal insufficiency in the developed world. AAD is rare and can easily be misdiagnosed as other conditions. The diagnosis depends on demonstrating inappropriately low cortisol production and the presence of high titers of adrenal cortex autoantibodies (ACAs), along with excluding other causes of adrenal failure using other tests as necessary. The treatment corticosteroid replacement, and the prognosis following the treatment is the same as the normal population. Spontaneous recovery of adrenal function has been described but is rare. Copyright © 2014 Elsevier B.V. All rights reserved.

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

PubMed

Sandham, David A; Arnold, Nicola; Aschauer, Heinrich; Bala, Kamlesh; Barker, Lucy; Brown, Lyndon; Brown, Zarin; Budd, David; Cox, Brian; Docx, Cerys; Dubois, Gerald; Duggan, Nicholas; England, Karen; Everatt, Brian; Furegati, Marcus; Hall, Edward; Kalthoff, Frank; King, Anna; Leblanc, Catherine J; Manini, Jodie; Meingassner, Josef; Profit, Rachael; Schmidt, Alfred; Simmons, Jennifer; Sohal, Bindi; Stringer, Rowan; Thomas, Matthew; Turner, Katharine L; Walker, Christoph; Watson, Simon J; Westwick, John; Willis, Jennifer; Williams, Gareth; Wilson, Caroline

2013-11-01

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development. Copyright © 2013 Elsevier Ltd. All rights reserved.

Advances in assessment, diagnosis, and treatment of hyperthyroidism in children.

PubMed

Amer, Kim Siarkowski

2005-04-01

The thyroid gland is responsible for regulating multiple complex metabolic processes that affect most organs. Physical growth and cognitive development are dependent on proper levels of thyroid hormone. This article will review common challenges in the diagnosis of hyperthyroidism in children, the approaches to treatment, and the nursing interventions guided toward child and family responses to thyroid disease. A comparison of signs and symptoms of hypothyroidism and hyperthyroidism is also included. The nursing interventions addressed in the article integrate the biological, psychological, social, and environmental stresses and adaptations necessary to cope with hyperthyroid disease.

Nobiletin and its related flavonoids with CRE-dependent transcription-stimulating and neuritegenic activities.

PubMed

Nagase, Hiroyuki; Omae, Naoki; Omori, Akiko; Nakagawasai, Osamu; Tadano, Takeshi; Yokosuka, Akihito; Sashida, Yutaka; Mimaki, Yoshihiro; Yamakuni, Tohru; Ohizumi, Yasushi

2005-12-02

cAMP response element (CRE) transcription is dysregulated in neurodegenerative disorders in the central nervous system (CNS), including polyglutamine diseases. As the first step to find natural compounds with protective action against neurodegeneration in the CNS, we here examined whether six citrus flavonoids, namely nobiletin, 5-demethylnobiletin, tangeretin, sinensetin, 6-demethoxytangeretin, and 6-demethoxynobiletin, stimulated CRE-dependent transcription and induced neurite outgrowth in PC12D cells. Among the compounds, nobiletin most potently enhanced CRE-dependent transcription and neurite outgrowth by activating ERK/MAP kinase-dependent signalling to increase CREB phosphorylation. The transcription and neurite outgrowth were stimulated by nobiletin in a concentration-dependent manner, with a strong correlation between them. Furthermore, a 11-day oral administration of nobiletin rescued impaired memory in olfactory-bulbectomized mice documented to be accompanied by a cholinergic neurodegeneration. These results suggest that nobiletin with the activity to improve impaired memory may become a potential leading compound for drug development for neurodegenerative disorders exhibiting the dysregulated CRE-dependent transcription.

[Subclinical and manifested hypothyroidism as a consequence of thyroid autoimmune disease].

PubMed

Milosević, Dragoslav P; Djurica, Snezana; Davidović, Mladen; Stević, Radmila; Rajić, Miodrag; Marković, Natasa

2005-10-01

Chronic thyroiditis (Hashimoto's disease) is a slowly developing persistent inflamation of the thyroid gland, which frequently leads to hypothyroidism. Some of the up-to-date knowledge about hypothyroidism, both subclinical and manifested, caused by autoimmune disease, was presented. Autoimmune thyroid gland disease can occur at any age, but predominantly affects women after periods of high emotional and physical stress or accidents, as well as during periods of hormonal changes. It can also develop in families, and having an autoimmune disease slightly increases the risk of developing another. This paper showed an increasing incidence of subclinical hypothyroidism (4.17%) in elderly, and, at the same time, the incidence of primary hypothyroidism accounting for 1%. It is very usefull to estimate the stimulated thyrotropin (TSH) response, as well as the value of fast, short time thyroid gland reserves, analyzed by T3 and T4 serum level at 60th minute after TRH stimulation. Treatment of choice for HT (hypothyroidism of any cause) is thyroid hormone replacement. Drug of choice is orally administered levothyroxine sodium, usually for life-time. The standard dose is 1.6-1.8 mcg/kg body weight per day, but is in most cases patient dependent. Elderly patients usually require smaller replacement dose of levothyroxine, sometimes less than 1 mcg/kg body weight per day with coronary dilatator at the same time.

How to treat Parkinson's disease in 2013.

PubMed

Worth, Paul F

2013-02-01

Parkinson's disease is a common, progressive, debilitating disease with substantial physical, psychological and social implications. Pharmacological management is complex and should be individualised according to the needs of the patient. In early disease, treatment is generally highly effective, but medication becomes increasingly inadequate in controlling motor fluctuations and dyskinesias as the disease progresses. Non-motor symptoms, especially depression and dementia, require a holistic, multidisciplinary approach to maximise quality of life for patients and their carers. For the future, the ideal solution remains neuroprotection and restoration. Progress has been hampered by the lack of animal models that reflect the widespread brain pathology presumed to cause both motor and non-motor symptoms of PD in humans. Currently, agents are undergoing clinical trials in early, mildly affected patients, such as the plant-derived substance PYM50028 (Cogane), which promotes expression of endogenous neural growth factors and has shown promise in vitro and in animal models. Gene-therapy trials in progress rely on the viral vectors used to deliver the enzymatic machinery required for dopamine synthesis to the striatum. As PD progresses, adequate control of motor symptoms depends increasingly on continuous drug delivery, and greater physiological stimulation of dopamine receptors may help to prevent the development of LIDs and motor fluctuations. Efforts thus are afoot to develop better delivery systems for levodopa, and a new sustained-release formulation is in development.

The Visual System of Zebrafish and its Use to Model Human Ocular Diseases

PubMed Central

Gestri, Gaia; Link, Brian A; Neuhauss, Stephan CF

2011-01-01

Free swimming zebrafish larvae depend mainly on their sense of vision to evade predation and to catch prey. Hence there is strong selective pressure on the fast maturation of visual function and indeed the visual system already supports a number of visually-driven behaviors in the newly hatched larvae. The ability to exploit the genetic and embryonic accessibility of the zebrafish in combination with a behavioral assessment of visual system function has made the zebrafish a popular model to study vision and its diseases. Here, we review the anatomy, physiology and development of the zebrafish eye as the basis to relate the contributions of the zebrafish to our understanding of human ocular diseases. PMID:21595048

Eye Disease Resulting From Increased Use of Fluorescent Lighting as a Climate Change Mitigation Strategy

PubMed Central

Walls, Kelvin L.; Benke, Geza

2011-01-01

Increased use of fluorescent lighting as a climate change mitigation strategy may increase eye disease. The safe range of light to avoid exposing the eye to potentially damaging ultraviolet (UV) radiation is 2000 to 3500K and greater than 500 nanometers. Some fluorescent lights fall outside this safe range. Fluorescent lighting may increase UV-related eye diseases by up to 12% and, according to our calculations, may cause an additional 3000 cases of cataracts and 7500 cases of pterygia annually in Australia. Greater control of UV exposure from fluorescent lights is required. This may be of particular concern for aging populations in developed countries and countries in northern latitudes where there is a greater dependence on artificial lighting. PMID:22021286

Tobacco-Smoking, Alcohol-Drinking, and Betel-Quid-Chewing Behaviors: Development and Use of a Web-Based Survey System.

PubMed

Hsu, Kuo-Yao; Tsai, Yun-Fang; Huang, Chu-Ching; Yeh, Wen-Ling; Chang, Kai-Ping; Lin, Chen-Chun; Chen, Ching-Yen; Lee, Hsiu-Lan

2018-06-11

Smoking tobacco, drinking alcohol, and chewing betel quid are health-risk behaviors for several diseases, such as cancer, cardiovascular disease, and diabetes, with severe impacts on health. However, health care providers often have limited time to assess clients' behaviors regarding smoking tobacco, drinking alcohol, and chewing betel quid and intervene, if needed. The objective of this study was to develop a Web-based survey system; determine the rates of tobacco-smoking, alcohol-drinking, and betel-quid-chewing behaviors; and estimate the efficiency of the system (time to complete the survey). Patients and their family members or friends were recruited from gastrointestinal medical-surgical, otolaryngology, orthopedics, and rehabilitation clinics or wards at a medical center in northern Taiwan. Data for this descriptive, cross-sectional study were extracted from a large series of research studies. A Web-based survey system was developed using a Linux, Apache, MySQL, PHP stack solution. The Web survey was set up to include four questionnaires: the Chinese-version Fagerstrom Tolerance Questionnaire, the Chinese-version Alcohol Use Disorders Identification Test, the Betel Nut Dependency Scale, and a sociodemographic form with several chronic diseases. After the participants completed the survey, the system automatically calculated their score, categorized their risk level for each behavior, and immediately presented and explained their results. The system also recorded the time each participant took to complete the survey. Of 782 patient participants, 29.6% were addicted to nicotine, 13.3% were hazardous, harmful, or dependent alcohol drinkers, and 1.5% were dependent on chewing betel quid. Of 425 family or friend participants, 19.8% were addicted to nicotine, 5.6% were hazardous, harmful, or dependent alcohol drinkers, and 0.9% were dependent on chewing betel quid. Regarding the mean time to complete the survey, patients took 7.9 minutes (SD 3.0; range 3-20) and family members or friends took 7.7 minutes (SD 2.8; range 3-18). Most of the participants completed the survey within 5-10 minutes. The Web-based survey was easy to self-administer. Health care providers can use this Web-based survey system to save time in assessing these risk behaviors in clinical settings. All smokers had mild-to-severe nicotine addiction, and 5.6%-12.3% of patients and their family members or friends were at risk of alcohol dependence. Considering that these three behaviors, particularly in combination, dramatically increase the risk of esophageal cancer, appropriate and convenient interventions are necessary for preserving public health in Taiwan. ©Kuo-Yao Hsu, Yun-Fang Tsai, Chu-Ching Huang, Wen-Ling Yeh, Kai-Ping Chang, Chen-Chun Lin, Ching-Yen Chen, Hsiu-Lan Lee. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 11.06.2018.

A lethal model of disseminated dengue virus type 1 infection in AG129 mice.

PubMed

Milligan, Gregg N; Sarathy, Vanessa V; White, Mellodee M; Greenberg, M Banks; Campbell, Gerald A; Pyles, Richard B; Barrett, Alan D T; Bourne, Nigel

2017-10-01

The mosquito-borne disease dengue is caused by four serologically and genetically related flaviviruses termed DENV-1 to DENV-4. Dengue is a global public health concern, with both the geographical range and burden of disease increasing rapidly. Clinically, dengue ranges from a relatively mild self-limiting illness to a severe life-threatening and sometimes fatal disease. Infection with one DENV serotype produces life-long homotypic immunity, but incomplete and short-term heterotypic protection. The development of small-animal models that recapitulate the characteristics of the disseminated disease seen clinically has been difficult, slowing the development of vaccines and therapeutics. The AG129 mouse (deficient in interferon alpha/beta and gamma receptor signalling) has proven to be valuable for this purpose, with the development of models of disseminated DENV-2,-3 and -4 disease. Recently, a DENV-1 AG129 model was described, but it requires antibody-dependent enhancement (ADE) to produce lethality. Here we describe a new AG129 model utilizing a non-mouse-adapted DENV-1 strain, West Pacific 74, that does not require ADE to induce lethal disease. Following high-titre intraperitoneal challenge, animals experience a virus infection with dissemination to multiple visceral tissues, including the liver, spleen and intestine. The animals also become thrombocytopenic, but vascular leakage is less prominent than in AG129 models with other DENV serotypes. Taken together, our studies demonstrate that this model is an important addition to dengue research, particularly for understanding the pathological basis of the disease between DENV serotypes and allowing the full spectrum of activity to test comparisons for putative vaccines and antivirals.

Diet and nutritional factors in inflammatory bowel diseases.

PubMed

Owczarek, Danuta; Rodacki, Tomasz; Domagała-Rodacka, Renata; Cibor, Dorota; Mach, Tomasz

2016-01-21

Inflammatory bowel disease (IBD) development is affected by complex interactions between environmental factors, changes in intestinal flora, various predisposing genetic properties and changes in the immune system. Dietary factors seem to play an underestimated role in the etiopathogenesis and course of the disease. However, research about food and IBD is conflicting. An excessive consumption of sugar, animal fat and linoleic acid is considered a risk factor for IBD development, whereas a high fiber diet and citrus fruit consumption may play a protective role. Also, appropriate nutrition in particular periods of the disease may facilitate achieving or prolonging remissions and most of all, improve the quality of life for patients. During disease exacerbation, a low fiber diet is recommended for most patients. In the remission time, an excessive consumption of alcohol and sulfur products may have a negative effect on the disease course. Attempts are also made at employing diets composed in detail in order to supplement IBD therapy. A diet with a modified carbohydrate composition, a semi-vegetarian diet and a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols are under investigation. Due to chronic inflammation as well as side effects of chronically used medications, patients with IBD are also at increased risk of nutritional factor deficiencies, including iron, calcium, vitamin D, vitamin B12, folic acid, zinc, magnesium and vitamin A. It should also be remembered that there is no single common diet suitable for all IBD patients; each of them is unique and dietary recommendations must be individually developed for each patient, depending on the course of the disease, past surgical procedures and type of pharmacotherapy.

Informatic support for processing the data regarding the environment factors possibly involved in the etiopathogenesis of insulin-dependent diabetes mellitus ETIODIAB.

PubMed

Alecu, S; Dadarlat, V; Stanciu, E; Ionescu-Tirgoviste, C; Konerth, A M

1997-01-01

Diabetes represents a heterogeneous group of disturbances, which can have a different aetiology, but have in common glucidic, lipidic and proteinic metabolic disturbances. Insulin-dependent diabetes appears in genetically susceptible persons, as an autoimmune disease activated by environment factors. Epidemiological studies performed in different countries, notice the increasing of diabetes cases in the last decades. Therefore the informatic system EtioDiab (from Etiopathological diabetes) has been developed. The purpose of this system is to assist the medical research regarding the environment factors involved in the etiopathogenesis of insulin-dependent diabetes. The system offers the possibility of calculation of many statistic indicators, of graphic representation of the recorded data, of verification of the statistical hypotheses.

Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis

PubMed Central

van der Heijden, Roel A.; Bijzet, Johan; Meijers, Wouter C.; Yakala, Gopala K.; Kleemann, Robert; Nguyen, Tri Q.; de Boer, Rudolf A.; Schalkwijk, Casper G.; Hazenberg, Bouke P. C.; Tietge, Uwe J. F.; Heeringa, Peter

2015-01-01

Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process. PMID:26563579

Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis.

PubMed

van der Heijden, Roel A; Bijzet, Johan; Meijers, Wouter C; Yakala, Gopala K; Kleemann, Robert; Nguyen, Tri Q; de Boer, Rudolf A; Schalkwijk, Casper G; Hazenberg, Bouke P C; Tietge, Uwe J F; Heeringa, Peter

2015-11-13

Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process.

Thyroid-disrupting chemicals and brain development: an update

PubMed Central

Mughal, Bilal B; Fini, Jean-Baptiste; Demeneix, Barbara A

2018-01-01

This review covers recent findings on the main categories of thyroid hormone–disrupting chemicals and their effects on brain development. We draw mostly on epidemiological and experimental data published in the last decade. For each chemical class considered, we deal with not only the thyroid hormone–disrupting effects but also briefly mention the main mechanisms by which the same chemicals could modify estrogen and/or androgen signalling, thereby exacerbating adverse effects on endocrine-dependent developmental programmes. Further, we emphasize recent data showing how maternal thyroid hormone signalling during early pregnancy affects not only offspring IQ, but also neurodevelopmental disease risk. These recent findings add to established knowledge on the crucial importance of iodine and thyroid hormone for optimal brain development. We propose that prenatal exposure to mixtures of thyroid hormone–disrupting chemicals provides a plausible biological mechanism contributing to current increases in the incidence of neurodevelopmental disease and IQ loss. PMID:29572405

Vaccines: A review of immune-based interventions to prevent and treat disease.

PubMed

Alemayehu, Demissie; Utt, Eric; Knirsch, Charles

2015-03-01

The enormous gains made in public health during the 20th century, through the prevention and treatment of infectious disease, have contributed to dramatic improvements in the quality and length of the human lifespan. Continued advances in medicine are dependent on addressing several challenges including the increase in existing and new resistance to antibiotics, the decrease in productivity of the research and development (R&D) ecosystem, uncertain regulatory pathways, and an economic environment that rewards innovation for developing therapeutics that involve long cycle times from idea to a product. In this article, we consider important issues pertaining to the development of vaccines with particular emphasis on preclinical requirements, optimal dose selection, design, execution, and reporting of clinical trials for regulatory submission, planning and implementation of post-approval life-cycle programs, and emerging themes in therapeutic vaccines. © 2015, The American College of Clinical Pharmacology.

Seroincidence of Coccidioidomycosis during Military Desert Training Exercises

PubMed Central

Crum, Nancy F.; Potter, Mark; Pappagianis, Demosthenes

2004-01-01

Coccidioidomycosis is a common fungal infection acquired in the southwestern United States. This is the first study in over 2 decades to determine the seroincidence of Coccidioides immitis infections among U.S. military members performing training exercises in an area of endemicity. Only 8% of participants were aware of coccidioidomycosis, despite the majority having visited or lived previously in an area of endemicity. One (0.6%) of the 178 participants developed “definite” serologic evidence of infection over a 5-week training period; four (2.3%) additional patients developed “possible” coccidioidomycosis infections. None had complicated disease. The calculated annual incidence ranged from 6 to 32%. This study suggests that the risk of serious coccidioidomycosis is low among military personnel during desert training exercises; however, disease incidence may vary depending on specific activities and geographic factors. Due to the potential morbidity and mortality of this infection, preventative strategies, including vaccine development, are advocated. PMID:15472308

The development of a disease oriented eFolder for multiple sclerosis decision support

NASA Astrophysics Data System (ADS)

Ma, Kevin; Jacobs, Colin; Fernandez, James; Amezcua, Lilyana; Liu, Brent

2010-03-01

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. The chronic nature of MS necessitates multiple MRI studies to track disease progression. Currently, MRI assessment of multiple sclerosis requires manual lesion measurement and yields an estimate of lesion volume and change that is highly variable and user-dependent. In the setting of a longitudinal study, disease trends and changes become difficult to extrapolate from the lesions. In addition, it is difficult to establish a correlation between these imaged lesions and clinical factors such as treatment course. To address these clinical needs, an MS specific e-Folder for decision support in the evaluation and assessment of MS has been developed. An e-Folder is a disease-centric electronic medical record in contrast to a patient-centric electronic health record. Along with an MS lesion computer aided detection (CAD) package for lesion load, location, and volume, clinical parameters such as patient demographics, disease history, clinical course, and treatment history are incorporated to make the e-Folder comprehensive. With the integration of MRI studies together with related clinical data and informatics tools designed for monitoring multiple sclerosis, it provides a platform to improve the detection of treatment response in patients with MS. The design and deployment of MS e-Folder aims to standardize MS lesion data and disease progression to aid in decision making and MS-related research.

Intestinal fungi contribute to development of alcoholic liver disease.

PubMed

Yang, An-Ming; Inamine, Tatsuo; Hochrath, Katrin; Chen, Peng; Wang, Lirui; Llorente, Cristina; Bluemel, Sena; Hartmann, Phillipp; Xu, Jun; Koyama, Yukinori; Kisseleva, Tatiana; Torralba, Manolito G; Moncera, Kelvin; Beeri, Karen; Chen, Chien-Sheng; Freese, Kim; Hellerbrand, Claus; Lee, Serene Ml; Hoffman, Hal M; Mehal, Wajahat Z; Garcia-Tsao, Guadalupe; Mutlu, Ece A; Keshavarzian, Ali; Brown, Gordon D; Ho, Samuel B; Bataller, Ramon; Stärkel, Peter; Fouts, Derrick E; Schnabl, Bernd

2017-06-30

Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin-like receptor CLEC7A on Kupffer cells and possibly other bone marrow-derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non-alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.

Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies.

PubMed

López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

2016-02-04

Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer's disease (AD) and sporadic Parkinson's disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick's disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression.

Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

PubMed Central

López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

2016-01-01

Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer’s disease (AD) and sporadic Parkinson’s disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick’s disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression. PMID:26861289

Recent progress in the research field of neuropharmacology in China.

PubMed

Li, Jin

2008-02-01

In recent years, Chinese neuropharmacologists have done a lot of basic and practical work in neuropharmacology, especially in the fields of pain, drug dependence, depression, Alzheimer's disease, schizophrenia, having obtained some exciting results that are of great significance for the development of neuropharmacology. Here I would like to review recent progress in the research fields of neuropharmacology in China.

Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6. | Office of Cancer Genomics

Cancer.gov

In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions.

Animal Models to Study Gluten Sensitivity1

PubMed Central

Marietta, Eric V.; Murray, Joseph A.

2012-01-01

The initial development and maintenance of tolerance to dietary antigens is a complex process that, when prevented or interrupted, can lead to human disease. Understanding the mechanisms by which tolerance to specific dietary antigens is attained and maintained is crucial to our understanding of the pathogenesis of diseases related to intolerance of specific dietary antigens. Two diseases that are the result of intolerance to a dietary antigen are celiac disease (CD) and dermatitis herpetiformis (DH). Both of these diseases are dependent upon the ingestion of gluten (the protein fraction of wheat, rye, and barley) and manifest in the gastrointestinal tract and skin, respectively. These gluten-sensitive diseases are two examples of how devastating abnormal immune responses to a ubiquitous food can be. The well-recognized risk genotype for both is conferred by either of the HLA class II molecules DQ2 or DQ8. However, only a minority of individuals who carry these molecules will develop either disease. Also of interest is that the age at diagnosis can range from infancy to 70–80 years of age. This would indicate that intolerance to gluten may potentially be the result of two different phenomena. The first would be that, for various reasons, tolerance to gluten never developed in certain individuals, but that for other individuals, prior tolerance to gluten was lost at some point after childhood. Of recent interest is the concept of non-celiac gluten sensitivity, which manifests as chronic digestive or neurologic symptoms due to gluten, but through mechanisms that remain to be elucidated. This review will address how animal models of gluten-sensitive disorders have substantially contributed to a better understanding of how gluten intolerance can arise and cause disease. PMID:22572887

ATR-101, a selective ACAT1 inhibitor, decreases ACTH-stimulated cortisol concentrations in dogs with naturally occurring Cushing's syndrome.

PubMed

Langlois, Daniel K; Fritz, Michele C; Schall, William D; Bari Olivier, N; Smedley, Rebecca C; Pearson, Paul G; Bailie, Marc B; Hunt, Stephen W

2018-05-02

Cushing's syndrome in humans shares many similarities with its counterpart in dogs in terms of etiology (pituitary versus adrenal causes), clinical signs, and pathophysiologic sequelae. In both species, treatment of pituitary- and adrenal-dependent disease is met with limitations. ATR-101, a selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1), is a novel small molecule therapeutic currently in clinical development for the treatment of adrenocortical carcinoma, congenital adrenal hyperplasia, and Cushing's syndrome in humans. Previous studies in healthy dogs have shown that ATR-101 treatment led to rapid, dose-dependent decreases in adrenocorticotropic hormone (ACTH) stimulated cortisol levels. The purpose of this clinical study was to investigate the effects of ATR-101 in dogs with Cushing's syndrome. ATR-101 pharmacokinetics and activity were assessed in 10 dogs with naturally-occurring Cushing's syndrome, including 7 dogs with pituitary-dependent disease and 3 dogs with adrenal-dependent disease. ATR-101 was administered at 3 mg/kg PO once daily for one week, followed by 30 mg/kg PO once daily for one (n = 4) or three (n = 6) weeks. Clinical, biochemical, adrenal hormonal, and pharmacokinetic data were obtained weekly for study duration. ATR-101 exposure increased with increasing dose. ACTH-stimulated cortisol concentrations, the primary endpoint for the study, were significantly decreased with responders (9 of 10 dogs) experiencing a mean ± standard deviation reduction in cortisol levels of 50 ± 17% at study completion. Decreases in pre-ACTH-stimulated cortisol concentrations were observed in some dogs although overall changes in pre-ACTH cortisol concentrations were not significant. The compound was well-tolerated and no serious drug-related adverse effects were reported. This study highlights the potential utility of naturally occurring canine Cushing's syndrome as a model for human disease and provides proof of concept for ATR-101 as a novel agent for the treatment of endocrine disorders like Cushing's syndrome in humans.

Innovation and the burden of disease: retrospective observational study of new and emerging health technologies reported by the EuroScan Network from 2000 to 2009.

PubMed

Martino, Orsolina I; Ward, Derek J; Packer, Claire; Simpson, Sue; Stevens, Andrew

2012-01-01

Medical innovation in developed countries has been linked to burden of disease, with more innovation in areas representing greater investment return. This study used horizon scanning or early awareness and alert activity as a novel measure of innovation to determine whether new and emerging health technologies reported by international horizon scanning agencies reflected diseases constituting the greatest burden. This was a retrospective observational study of the 20 member agencies of EuroScan (the International Information Network on New and Emerging Health Technologies), representing 17 developed countries. Burden of disease was defined as disability-adjusted life-years, taken from the 2004 World Health Organization Global Burden of Disease estimates. This analysis focused on 102 specific diseases within 21 broader groups. Horizon scanning output was measured as the number of technologies reported by EuroScan member agencies between 2000 and 2009. At best there was a weak association between innovation and burden of disease. An apparent high-level association was dependent on just three high-prevalence disease groups: malignant neoplasms, neuropsychiatric conditions, and cardiovascular disease. Disaggregating broader groups into specific diseases further weakened the association. Innovation is disproportionately strong in cancer and nonischemic heart disease and disproportionately weak in mental health. Innovations reported by early awareness and alert systems do not always reflect conditions accounting for the highest morbidity and mortality. The results do not support previous reports of a positive relationship between burden of disease and innovation, but accord with evidence of notable discrepancies among key groups. Factors other than disease burden drive innovation. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB dependent manner

PubMed Central

Wang, Lin; Zhang, Huajia; Rodriguez, Sonia; Cao, Liyun; Parish, Jonathan; Mumaw, Christen; Zollman, Amy; Kamocka, Gosia; Mu, Jian; Chen, Danny Z.; Srour, Edward F.; Chitteti, Brahmananda R.; HogenEsch, Harm; Tu, Xiaolin; Bellido, Teresita M.; Boswell, Scott; Manshouri, Taghi; Verstovsek, Srdan; Yoder, Mervin C.; Kapur, Reuben; Cardoso, Angelo A.; Carlesso, Nadia

2014-01-01

Summary MicroRNA (miR)-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative-like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ-signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the NF-κB inhibitor κB-Ras1, NF-κB activation and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ-/- mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR155/kB-Ras1/NF-kB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders. PMID:24996169

sirt1-null mice develop an autoimmune-like condition

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

Sequeira, Jedon; Boily, Gino; Bazinet, Stephanie

2008-10-01

The sirt1 gene encodes a protein deacetylase with a broad spectrum of reported substrates. Mice carrying null alleles for sirt1 are viable on outbred genetic backgrounds so we have examined them in detail to identify the biological processes that are dependent on SIRT1. Sera from adult sirt1-null mice contain antibodies that react with nuclear antigens and immune complexes become deposited in the livers and kidneys of these animals. Some of the sirt1-null animals develop a disease resembling diabetes insipidus when they approach 2 years of age although the relationship to the autoimmunity remains unclear. We interpret these observations as consistentmore » with a role for SIRT1 in sustaining normal immune function and in this way delaying the onset of autoimmune disease.« less

Mucinous cystadenocarcinoma of the pancreas developing during hormone replacement therapy.

PubMed

Tanaka, Shinji; Kawamura, Toru; Nakamura, Noriaki; Teramoto, Kenichi; Arii, Shigeki

2007-05-01

Hormone replacement therapy (HRT) containing estrogens is generally used to relieve climacteric symptoms and to prevent osteoporosis and coronary heart disease [1], however, there has been increasing evidence of the HRT as the risk of hormone-dependent neoplasms including breast cancer [2], uterine endometrial cancer [3], ovarian cancer [4], and even lung cancer [5]. Noteworthy is mucinous cyst neoplasms (MCNs) of the pancreas, characterized by mucin-producing columnar epithelium supported by "ovarian-like" mesenchymal stroma, occur mostly in females expressing estrogen receptors [6, 7]. Although several reports regarding the closed relationship between MCNs and pregnancy [8, 9] might imply potential sex hormone-dependency of the MCNs [10], no correlation has been reported. This is the first case report of malignant MCN developing during continuous HRT after hysterectomy.

Variables and Strategies in Development of Therapeutic Post-Transcriptional Gene Silencing Agents

PubMed Central

Sullivan, Jack M.; Yau, Edwin H.; Kolniak, Tiffany A.; Sheflin, Lowell G.; Taggart, R. Thomas; Abdelmaksoud, Heba E.

2011-01-01

Post-transcriptional gene silencing (PTGS) agents such as ribozymes, RNAi and antisense have substantial potential for gene therapy of human retinal degenerations. These technologies are used to knockdown a specific target RNA and its cognate protein. The disease target mRNA may be a mutant mRNA causing an autosomal dominant retinal degeneration or a normal mRNA that is overexpressed in certain diseases. All PTGS technologies depend upon the initial critical annealing event of the PTGS ligand to the target RNA. This event requires that the PTGS agent is in a conformational state able to support hybridization and that the target have a large and accessible single-stranded platform to allow rapid annealing, although such platforms are rare. We address the biocomplexity that currently limits PTGS therapeutic development with particular emphasis on biophysical variables that influence cellular performance. We address the different strategies that can be used for development of PTGS agents intended for therapeutic translation. These issues apply generally to the development of PTGS agents for retinal, ocular, or systemic diseases. This review should assist the interested reader to rapidly appreciate critical variables in PTGS development and facilitate initial design and testing of such agents against new targets of clinical interest. PMID:21785698

Rheumatology in Africa-challenges and opportunities.

PubMed

Mody, Girish M

2017-03-07

Africa faces many health challenges despite sustained growth and development over the past decade. Contributory factors are the lack of financial resources, an inadequate health professional workforce, a high burden of communicable diseases, and an increasing burden of non-communicable diseases. Rheumatology services are limited or non-existent in many parts of sub-Saharan Africa. Over the past decade, partnerships with international academic institutions have resulted in some progress in the training of rheumatologists and health professionals and development of rheumatology services in countries such as Kenya, Nigeria, and Zambia. Basic diagnostic tests, biological agents, and arthroplasty are either unavailable or not affordable by the majority of the population. Urbanization has resulted in a change in the epidemiology of rheumatic diseases with an increase in the prevalence of gout, rheumatoid arthritis, systemic lupus erythematosus, and scleroderma over the past four decades. Future growth of rheumatology services will depend on identifying committed individuals in underserved countries for training and supporting them to educate medical students, physicians, and health professionals in their home countries. There is a need to develop models of care using all categories of health workers and identify prevention strategies and cost-effective management programs for low resource settings. Africa affords an opportunity for collaborative research, including genetic and epigenetic studies, to improve our understanding of many of the rheumatic diseases.

An intervention to stop smoking among patients suspected of TB--evaluation of an integrated approach.

PubMed

Siddiqi, Kamran; Khan, Amir; Ahmad, Maqsood; Shafiq-ur-Rehman

2010-03-25

In many low- and middle-income countries, where tobacco use is common, tuberculosis is also a major problem. Tobacco use increases the risk of developing tuberculosis, secondary mortality, poor treatment compliance and relapses. In countries with TB epidemic, even a modest relative risk leads to a significant attributable risk. Treating tobacco dependence, therefore, is likely to have benefits for controlling tuberculosis in addition to reducing the non-communicable disease burden associated with smoking. In poorly resourced health systems which face a dual burden of disease secondary to tuberculosis and tobacco, an integrated approach to tackle tobacco dependence in TB control could be economically desirable. During TB screening, health professionals come across large numbers of patients with respiratory symptoms, a significant proportion of which are likely to be tobacco users. These clinical encounters, considered to be "teachable moments", provide a window of opportunity to offer treatment for tobacco dependence. We aim to develop and trial a complex intervention to reduce tobacco dependence among TB suspects based on the WHO 'five steps to quit' model. This model relies on assessing personal motivation to quit tobacco use and uses it as the basis for assessing suitability for the different therapeutic options for tobacco dependence.We will use the Medical Research Council framework approach for evaluating complex interventions to: (a) design an evidence-based treatment package (likely to consist of training materials for health professionals and education tools for patients); (b) pilot the package to determine the delivery modalities in TB programme (c) assess the incremental cost-effectiveness of the package compared to usual care using a cluster RCT design; (d) to determine barriers and drivers to the provision of treatment of tobacco dependence within TB programmes; and (e) support long term implementation. The main outcomes to assess the effectiveness would be point abstinence at 4 weeks and continuous abstinence up to 6 months. This work will be carried out in Pakistan and is expected to have relevance for other low and middle income countries with high tobacco use and TB incidence. This will enhance our knowledge of the cost-effectiveness of treating tobacco dependence in patients suspected of TB. ISRCTN08829879.

Progression of Pathogenic Events in Cynomolgus Macaques Infected with Variola Virus

PubMed Central

Rubins, Kathleen H.; Huggins, John W.; Fisher, Robert W.; Johnson, Anthony J.; de Kok-Mercado, Fabian; Larsen, Thomas; Raymond, Jo Lynne; Hensley, Lisa E.; Jahrling, Peter B.

2011-01-01

Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of antivirals and improved vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary smallpox model, lymphoid and myeloid hyperplasias were consistently found whereas lymphocytolysis and hematopoietic necrosis developed in hemorrhagic smallpox. Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary smallpox model. In contrast, in the hemorrhagic model antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic smallpox developed only in the presence of secondary bacterial infections – an observation also commonly noted in historical reports of human smallpox. Together, our results support the macaque model as an excellent surrogate for human smallpox in terms of disease onset, acute disease course, and gross and histopathological lesions. PMID:21998632

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

Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.

PubMed

Xu, Qiang; Wang, Yanshu; Dabdoub, Alain; Smallwood, Philip M; Williams, John; Woods, Chad; Kelley, Matthew W; Jiang, Li; Tasman, William; Zhang, Kang; Nathans, Jeremy

2004-03-19

Incomplete retinal vascularization occurs in both Norrie disease and familial exudative vitreoretinopathy (FEVR). Norrin, the protein product of the Norrie disease gene, is a secreted protein of unknown biochemical function. One form of FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Wnt receptor. We show here that Norrin and Fz4 function as a ligand-receptor pair based on (1) the similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the high efficiency with which Norrin induces Fz4- and Lrp-dependent activation of the classical Wnt pathway, and (4) the signaling defects displayed by disease-associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling system that plays a central role in vascular development in the eye and ear, and they indicate that ligands unrelated to Wnts can act through Fz receptors.

T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation.

PubMed

Jawa, Vibha; Cousens, Leslie P; Awwad, Michel; Wakshull, Eric; Kropshofer, Harald; De Groot, Anne S

2013-12-01

Protein therapeutics hold a prominent and rapidly expanding place among medicinal products. Purified blood products, recombinant cytokines, growth factors, enzyme replacement factors, monoclonal antibodies, fusion proteins, and chimeric fusion proteins are all examples of therapeutic proteins that have been developed in the past few decades and approved for use in the treatment of human disease. Despite early belief that the fully human nature of these proteins would represent a significant advantage, adverse effects associated with immune responses to some biologic therapies have become a topic of some concern. As a result, drug developers are devising strategies to assess immune responses to protein therapeutics during both the preclinical and the clinical phases of development. While there are many factors that contribute to protein immunogenicity, T cell- (thymus-) dependent (Td) responses appear to play a critical role in the development of antibody responses to biologic therapeutics. A range of methodologies to predict and measure Td immune responses to protein drugs has been developed. This review will focus on the Td contribution to immunogenicity, summarizing current approaches for the prediction and measurement of T cell-dependent immune responses to protein biologics, discussing the advantages and limitations of these technologies, and suggesting a practical approach for assessing and mitigating Td immunogenicity. © 2013. Published by Elsevier Inc. All rights reserved.

Management and Risk Reduction of Rheumatoid Arthritis in Individuals with Obstructive Sleep Apnea: A Nationwide Population-Based Study in Taiwan.

PubMed

Chen, Wei-Sheng; Chang, Yu-Sheng; Chang, Chi-Ching; Chang, Deh-Ming; Chen, Yi-Hsuan; Tsai, Chang-Youh; Chen, Jin-Hua

2016-10-01

To explore associations between obstructive sleep apnea (OSA) and autoimmune diseases and evaluate whether OSA management reduces the incidence of autoimmune diseases. This was a retrospective cohort study using nationwide database research. The data was from 105,846 adult patients in whom OSA was diagnosed and recorded in the Taiwan National Health Insurance Research Database between 2002 and 2011 were the patients were analyzed retrospectively. Patients with antecedent autoimmune diseases were excluded. A comparison cohort of 423,384 participants without OSA served as age- and sex-matched controls. Multivariable Cox regression analysis was performed on both cohorts to compute risk of autoimmune diseases during follow-up. Time-dependent OSA treatment effect was analyzed among patients with OSA. There were no interventions. Among patients with OSA, overall risk for incident autoimmune diseases was significantly higher than that in controls (adjusted hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.66-2.27). Risk for individual autoimmune diseases, including rheumatoid arthritis (RA), Sjögren syndrome (SS), and Behçet disease, was significantly higher in patients with OSA than in controls (HRs [95% CI]: RA 1.33 [1.03-1.72, SS 3.45 [2.67-4.45] and Behçet disease 5.33 [2.45-12.66]). Increased risk for systemic lupus erythematosus (HR 1.00 [0.54-1.84]) and systemic sclerosis (HR 1.43 [0.51-3.96]) did not reach statistical significance. Patients with OSA receiving treatment had an overall reduced risk of RA and other autoimmune diseases (time-dependent HRs [95% CI]: 0.22 [0.05-0.94] and 0.51 [0.28-0.92], respectively). Patients with OSA are associated with higher risk for developing RA, SS, and Behçet disease. OSA management is associated with reduced risk of RA. © 2016 Associated Professional Sleep Societies, LLC.

Targeting oxidant-dependent mechanisms for the treatment of COPD and its comorbidities.

PubMed

Bernardo, Ivan; Bozinovski, Steven; Vlahos, Ross

2015-11-01

Chronic obstructive pulmonary disease (COPD) is an incurable global health burden and is characterised by progressive airflow limitation and loss of lung function. In addition to the pulmonary impact of the disease, COPD patients often develop comorbid diseases such as cardiovascular disease, skeletal muscle wasting, lung cancer and osteoporosis. One key feature of COPD, yet often underappreciated, is the contribution of oxidative stress in the onset and development of the disease. Patients experience an increased burden of oxidative stress due to the combined effects of excess reactive oxygen species (ROS) and nitrogen species (RNS) generation, antioxidant depletion and reduced antioxidant enzyme activity. Currently, there is a lack of effective treatments for COPD, and an even greater lack of research regarding interventions that treat both COPD and its comorbidities. Due to the involvement of oxidative stress in the pathogenesis of COPD and many of its comorbidities, a unique therapeutic opportunity arises where the treatment of a multitude of diseases may be possible with only one therapeutic target. In this review, oxidative stress and the roles of ROS/RNS in the context of COPD and comorbid cardiovascular disease, skeletal muscle wasting, lung cancer, and osteoporosis are discussed and the potential for therapeutic benefit of anti-oxidative treatment in these conditions is outlined. Because of the unique interplay between oxidative stress and these diseases, oxidative stress represents a novel target for the treatment of COPD and its comorbidities. Copyright © 2015. Published by Elsevier Inc.

Predictive Models for Tomato Spotted Wilt Virus Spread Dynamics, Considering Frankliniella occidentalis Specific Life Processes as Influenced by the Virus

PubMed Central

Ogada, Pamella Akoth; Moualeu, Dany Pascal; Poehling, Hans-Michael

2016-01-01

Several models have been studied on predictive epidemics of arthropod vectored plant viruses in an attempt to bring understanding to the complex but specific relationship between the three cornered pathosystem (virus, vector and host plant), as well as their interactions with the environment. A large body of studies mainly focuses on weather based models as management tool for monitoring pests and diseases, with very few incorporating the contribution of vector’s life processes in the disease dynamics, which is an essential aspect when mitigating virus incidences in a crop stand. In this study, we hypothesized that the multiplication and spread of tomato spotted wilt virus (TSWV) in a crop stand is strongly related to its influences on Frankliniella occidentalis preferential behavior and life expectancy. Model dynamics of important aspects in disease development within TSWV-F. occidentalis-host plant interactions were developed, focusing on F. occidentalis’ life processes as influenced by TSWV. The results show that the influence of TSWV on F. occidentalis preferential behaviour leads to an estimated increase in relative acquisition rate of the virus, and up to 33% increase in transmission rate to healthy plants. Also, increased life expectancy; which relates to improved fitness, is dependent on the virus induced preferential behaviour, consequently promoting multiplication and spread of the virus in a crop stand. The development of vector–based models could further help in elucidating the role of tri-trophic interactions in agricultural disease systems. Use of the model to examine the components of the disease process could also boost our understanding on how specific epidemiological characteristics interact to cause diseases in crops. With this level of understanding we can efficiently develop more precise control strategies for the virus and the vector. PMID:27159134

Predictive Models for Tomato Spotted Wilt Virus Spread Dynamics, Considering Frankliniella occidentalis Specific Life Processes as Influenced by the Virus.

PubMed

Ogada, Pamella Akoth; Moualeu, Dany Pascal; Poehling, Hans-Michael

2016-01-01

Several models have been studied on predictive epidemics of arthropod vectored plant viruses in an attempt to bring understanding to the complex but specific relationship between the three cornered pathosystem (virus, vector and host plant), as well as their interactions with the environment. A large body of studies mainly focuses on weather based models as management tool for monitoring pests and diseases, with very few incorporating the contribution of vector's life processes in the disease dynamics, which is an essential aspect when mitigating virus incidences in a crop stand. In this study, we hypothesized that the multiplication and spread of tomato spotted wilt virus (TSWV) in a crop stand is strongly related to its influences on Frankliniella occidentalis preferential behavior and life expectancy. Model dynamics of important aspects in disease development within TSWV-F. occidentalis-host plant interactions were developed, focusing on F. occidentalis' life processes as influenced by TSWV. The results show that the influence of TSWV on F. occidentalis preferential behaviour leads to an estimated increase in relative acquisition rate of the virus, and up to 33% increase in transmission rate to healthy plants. Also, increased life expectancy; which relates to improved fitness, is dependent on the virus induced preferential behaviour, consequently promoting multiplication and spread of the virus in a crop stand. The development of vector-based models could further help in elucidating the role of tri-trophic interactions in agricultural disease systems. Use of the model to examine the components of the disease process could also boost our understanding on how specific epidemiological characteristics interact to cause diseases in crops. With this level of understanding we can efficiently develop more precise control strategies for the virus and the vector.

Neuroimaging of Cerebrovascular Disease in the Aging Brain

PubMed Central

Gupta, Ajay; Nair, Sreejit; Schweitzer, Andrew D.; Kishore, Sirish; Johnson, Carl E.; Comunale, Joseph P.; Tsiouris, Apostolos J.; Sanelli, Pina C.

2012-01-01

Cerebrovascular disease remains a significant public health burden with its greatest impact on the elderly population. Advances in neuroimaging techniques allow detailed and sophisticated evaluation of many manifestations of cerebrovascular disease in the brain parenchyma as well as in the intracranial and extracranial vasculature. These tools continue to contribute to our understanding of the multifactorial processes that occur in the age-dependent development of cerebrovascular disease. Structural abnormalities related to vascular disease in the brain and vessels have been well characterized with CT and MRI based techniques. We review some of the pathophysiologic mechanisms in the aging brain and cerebral vasculature and the related structural abnormalities detectable on neuroimaging, including evaluation of age-related white matter changes, atherosclerosis of the cerebral vasculature, and cerebral infarction. In addition, newer neuroimaging techniques, such as diffusion tensor imaging, perfusion techniques, and assessment of cerebrovascular reserve, are also reviewed, as these techniques can detect physiologic alterations which complement the morphologic changes that cause cerebrovascular disease in the aging brain.Further investigation of these advanced imaging techniques has potential application to the understanding and diagnosis of cerebrovascular disease in the elderly. PMID:23185721

Proton pump inhibitors are associated with accelerated development of cirrhosis, hepatic decompensation and hepatocellular carcinoma in noncirrhotic patients with chronic hepatitis C infection: results from ERCHIVES.

PubMed

Li, D K; Yan, P; Abou-Samra, A-B; Chung, R T; Butt, A A

2018-01-01

Proton pump inhibitors are among the most commonly prescribed medications in the United States. Their safety in cirrhosis has recently been questioned, but their overall effect on disease progression in noncirrhotic patients with chronic liver disease remains unclear. To determine the impact of proton pump inhibitors on the progression of liver disease in noncirrhotic patients with hepatitis C virus (HCV) infection. Using the electronically retrieved cohort of HCV-infected veterans (ERCHIVES) database, we identified all subjects who received HCV treatment and all incident cases of cirrhosis, hepatic decompensation and hepatocellular carcinoma. Proton pump inhibitor use was measured using cumulative defined daily dose. Multivariate Cox regression analysis was performed after adjusting univariate predictors of cirrhosis and various indications for proton pump inhibitor use. Among 11 526 eligible individuals, we found that exposure to proton pump inhibitors was independently associated with an increased risk of developing cirrhosis (hazard ratio [HR]: 1.32; 95% confidence interval: [1.17, 1.49]). This association remained robust to sensitivity analysis in which only patients who achieved sustained virologic response were analysed as well as analysis excluding those with alcohol abuse/dependence. Proton pump inhibitor exposure was also independently associated with an increased risk of hepatic decompensation (HR: 3.79 [2.58, 5.57]) and hepatocellular carcinoma (HR: 2.01 [1.50, 2.70]). In patients with chronic HCV infection, increasing proton pump inhibitor use is associated with a dose-dependent risk of progression of chronic liver disease to cirrhosis, as well as an increased risk of hepatic decompensation and hepatocellular carcinoma. © 2017 John Wiley & Sons Ltd.

The Adaptor Molecule Signaling Lymphocytic Activation Molecule (SLAM)-associated Protein (SAP) Is Essential in Mechanisms Involving the Fyn Tyrosine Kinase for Induction and Progression of Collagen-induced Arthritis

PubMed Central

Zhong, Ming-Chao; Veillette, André

2013-01-01

Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types. PMID:24045941

The adaptor molecule signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is essential in mechanisms involving the Fyn tyrosine kinase for induction and progression of collagen-induced arthritis.

PubMed

Zhong, Ming-Chao; Veillette, André

2013-11-01

Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types.

Critical disease windows shaped by stress exposure alter allocation trade-offs between development and immunity.

PubMed

Kirschman, Lucas J; Crespi, Erica J; Warne, Robin W

2018-01-01

Ubiquitous environmental stressors are often thought to alter animal susceptibility to pathogens and contribute to disease emergence. However, duration of exposure to a stressor is likely critical, because while chronic stress is often immunosuppressive, acute stress can temporarily enhance immune function. Furthermore, host susceptibility to stress and disease often varies with ontogeny; increasing during critical developmental windows. How the duration and timing of exposure to stressors interact to shape critical windows and influence disease processes is not well tested. We used ranavirus and larval amphibians as a model system to investigate how physiological stress and pathogenic infection shape development and disease dynamics in vertebrates. Based on a resource allocation model, we designed experiments to test how exposure to stressors may induce resource trade-offs that shape critical windows and disease processes because the neuroendocrine stress axis coordinates developmental remodelling, immune function and energy allocation in larval amphibians. We used wood frog larvae (Lithobates sylvaticus) to investigate how chronic and acute exposure to corticosterone, the dominant amphibian glucocorticoid hormone, mediates development and immune function via splenocyte immunohistochemistry analysis in association with ranavirus infection. Corticosterone treatments affected immune function, as both chronic and acute exposure suppressed splenocyte proliferation, although viral replication rate increased only in the chronic corticosterone treatment. Time to metamorphosis and survival depended on both corticosterone treatment and infection status. In the control and chronic corticosterone treatments, ranavirus infection decreased survival and delayed metamorphosis, although chronic corticosterone exposure accelerated rate of metamorphosis in uninfected larvae. Acute corticosterone exposure accelerated metamorphosis increased survival in infected larvae. Interactions between stress exposure (via glucocorticoid actions) and infection impose resource trade-offs that shape optimal allocation between development and somatic function. As a result, critical disease windows are likely shaped by stress exposure because any conditions that induce changes in differentiation rates will alter the duration and susceptibility of organisms to stressors or disease. © 2017 The Authors. Journal of Animal Ecology © 2017 British Ecological Society.

Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.

PubMed

Overman, Jeroen; Fontaine, Frank; Moustaqil, Mehdi; Mittal, Deepak; Sierecki, Emma; Sacilotto, Natalia; Zuegg, Johannes; Robertson, Avril Ab; Holmes, Kelly; Salim, Angela A; Mamidyala, Sreeman; Butler, Mark S; Robinson, Ashley S; Lesieur, Emmanuelle; Johnston, Wayne; Alexandrov, Kirill; Black, Brian L; Hogan, Benjamin M; De Val, Sarah; Capon, Robert J; Carroll, Jason S; Bailey, Timothy L; Koopman, Peter; Jauch, Ralf; Smyth, Mark J; Cooper, Matthew A; Gambin, Yann; Francois, Mathias

2017-01-31

Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.

[Age diseases depending on geomagnetic field activity inside the womb period].

PubMed

Iamshanov, V A

2010-01-01

Between age diseases two are standing out: oncological and cardiovascular ones. They give a main contribution to mortality of the population. Those who avoid these diseases have a chance to live longer. The author suggests a hypothesis of one common factor, which deviation leads to oncology or cardiovascular illness. Such factor is a production of nitric oxide in the organism, which depends on the geomagnetic activity (GMA). At excess production of nitric oxide the risk of oncopathology (breast cancer, bladder and lung cancer and others) is increased. At low NO level in blood the risk of cardiovascular disease is increased. The ability of the organism to utilize the excess level of NO depends on GMA inside the womb period. The production of nitric oxide in the organism goes by different ways, including NO-synthase activity and destruction of neutrophiles, which depends on the GMA and sun activity.

Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins

PubMed Central

Sanicola, M.; Hession, C.; Worley, D.; Carmillo, P.; Ehrenfels, C.; Walus, L.; Robinson, S.; Jaworski, G.; Wei, H.; Tizard, R.; Whitty, A.; Pepinsky, R. B.; Cate, R. L.

1997-01-01

Glial cell line-derived neurotrophic factor (GDNF)-dependent activation of the tyrosine kinase receptor RET is necessary for kidney and enteric neuron development, and mutations in RET are associated with human diseases. Activation of RET by GDNF has been shown to require an accessory component, GDNFR-α (RETL1). We report the isolation and characterization of rat and human cDNAs for a novel cell-surface associated accessory protein, RETL2, that shares 49% identity with RETL1. Both RETL1 and RETL2 can mediate GDNF dependent phosphorylation of RET, but they exhibit different patterns of expression in fetal and adult tissues. The most striking differences in expression observed were in the adult central and peripheral nervous systems. In addition, the mechanisms by which the two accessory proteins facilitate the activation of RET by GDNF are quite distinct. In vitro binding experiments with soluble forms of RET, RETL1 and RETL2 demonstrate that while RETL1 binds GDNF tightly to form a membrane-associated complex which can then interact with RET, RETL2 only forms a high affinity complex with GDNF in the presence of RET. This strong RET dependence of the binding of RETL2 to GDNF was confirmed by FACS analysis on RETL1 and RETL2 expressing cells. Together with the recent discovery of a GDNF related protein, neurturin, these data raise the possibility that RETL1 and RETL2 have distinctive roles during development and in the nervous system of the adult. RETL1 and RETL2 represent new candidate susceptibility genes and/or modifier loci for RET-associated diseases. PMID:9177201

Recognizing the importance of chronic disease in driving healthcare expenditure in Tanzania: analysis of panel data from 1991 to 2010.

PubMed

Counts, Christopher J; Skordis-Worrall, Jolene

2016-05-01

 Despite the growing chronic disease burden in low- and middle-income countries, there are significant gaps in our understanding of the financial impact of these illnesses on households. As countries make progress towards universal health coverage, specific information is needed about how chronic disease care drives health expenditure over time, and how this spending differs from spending on acute disease care.  A 19-year panel dataset was constructed using data from the Kagera Health and Development Surveys. Health expenditure was modelled using multilevel regression for three different sub-populations of households: (1) all households that spent on healthcare, (2) households affected by chronic disease and (3) households affected by acute disease. Explanatory variables were identified from a review of the health expenditure literature, and all variables were analysed descriptively.  Households affected by chronic disease spent 22% more on healthcare than unaffected households. Catastrophic expenditure and zero expenditure are both common in chronic disease-affected households. Expenditure predictors were different between households affected by chronic disease and those unaffected. Expenditure over time is highly heterogeneous and household-dependent.  The financial burden of healthcare is greater for households affected by chronic disease than those unaffected. Households appear unable to sustain high levels of expenditure over time, likely resulting in both irregular chronic disease treatment and impoverishment. The Tanzanian government's current efforts to develop a National Health Financing Strategy present an important opportunity to prioritize policies that promote the long-term financial protection of households by preventing the catastrophic consequences of chronic disease care payments. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Development of an index to define overall disease severity in IBD.

PubMed

Siegel, Corey A; Whitman, Cynthia B; Spiegel, Brennan M R; Feagan, Brian; Sands, Bruce; Loftus, Edward V; Panaccione, Remo; D'Haens, Geert; Bernstein, Charles N; Gearry, Richard; Ng, Siew C; Mantzaris, Gerassimos J; Sartor, Balfour; Silverberg, Mark S; Riddell, Robert; Koutroubakis, Ioannis E; O'Morain, Colm; Lakatos, Peter L; McGovern, Dermot P B; Halfvarson, Jonas; Reinisch, Walter; Rogler, Gerhard; Kruis, Wolfgang; Tysk, Curt; Schreiber, Stefan; Danese, Silvio; Sandborn, William; Griffiths, Anne; Moum, Bjorn; Gasche, Christoph; Pallone, Francesco; Travis, Simon; Panes, Julian; Colombel, Jean-Frederic; Hanauer, Stephen; Peyrin-Biroulet, Laurent

2018-02-01

Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC. Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute. For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities. Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Drug-Abuse Nanotechnology: Opportunities and Challenges.

PubMed

Mahmoudi, Morteza; Pakpour, Sepideh; Perry, George

2018-05-31

Opioid drug abuse and dependence/addiction are complex disorders regulated by a wide range of interacting networks of genes and pathways that control a variety of phenotypes. Although the field has been extensively progressed since the birth of the National Institute on Drug Abuse in 1974, the fundamental knowledge and involved mechanisms that lead to drug dependence/addiction are poorly understood, and thus, there has been limited success in the prevention of drug addiction and development of therapeutics for definitive treatment and cure of addiction disease. The lack of success in both identification of addiction in at-risk populations and the development of efficient drugs has resulted in a serious social and economic burden from opioid drug abuse with global increasing rate of mortality from drug overdoses. This perspective aims to draw the attention of scientists to the potential role of nanotechnologies, which might pave the way for the development of more practical platforms for either drug development or identification and screening of patients who may be vulnerable to addiction after using opioid drugs.

Overlap between age-at-onset and disease-progression determinants in Huntington disease.

PubMed

Aziz, N Ahmad; van der Burg, Jorien M M; Tabrizi, Sarah J; Landwehrmeyer, G Bernhard

2018-05-09

A fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD. Using observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD. A total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat-dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation. Our findings imply that targeting of CAG repeat-dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Thoracic Diseases Associated with HIV Infection in the Era of Antiretroviral Therapy: Clinical and Imaging Findings

PubMed Central

Prabhu, Somnath J.; Crothers, Kristina; Stern, Eric J.; Godwin, J. David; Pipavath, Sudhakar N.

2014-01-01

The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) pandemic has entered its 4th decade. Since the introduction of combination antiretroviral therapy (ART) in 1996, the number of AIDS-related deaths has plateaued worldwide. Today, owing to the effectiveness of ART, the HIV-infected population is aging and HIV infection has become a chronic illness. Non-AIDS comorbidities are increasing, and the spectrum of HIV-related thoracic diseases is evolving. In developed countries, bacterial pneumonia has become more common than Pneumocystis pneumonia. Its imaging appearance depends on the responsible organism, most commonly Streptococcus pneumoniae. Mycobacterium tuberculosis continues to be a major threat. Its imaging patterns vary depending on CD4 count. Primary lung cancer and Hodgkin lymphoma are two important non–AIDS-defining malignancies that are increasingly encountered at chest imaging. Human herpesvirus 8, also known as Kaposi sarcoma–associated herpesvirus (KSHV), is strongly linked to HIV-related diseases, including Kaposi sarcoma, multicentric Castleman disease, KSHV inflammatory cytokine syndrome, and primary effusion lymphoma. Immune reconstitution inflammatory syndrome is a direct complication of ART whose manifestations vary with the underlying disease. Given the high rate of smoking among HIV-infected patients, chronic obstructive pulmonary disease is another important cause of morbidity and mortality. A high degree of suspicion is required for the early diagnosis of pulmonary arterial hypertension and lymphocytic interstitial pneumonia, given their nonspecific manifestations. Finally, multilocular thymic cyst manifests as a cystic anterior mediastinal mass. Recognition of the clinical and radiologic manifestations of these less traditional HIV-related diseases can expedite diagnosis and treatment in the ART era. © RSNA, 2014 PMID:25019430

A rare case of an ACTH/CRH co-secreting midgut neuroendocrine tumor mimicking Cushing's disease.

PubMed

Streuli, Regina; Krull, Ina; Brändle, Michael; Kolb, Walter; Stalla, Günter; Theodoropoulou, Marily; Enzler-Tschudy, Annette; Bilz, Stefan

2017-01-01

Ectopic ACTH/CRH co-secreting tumors are a very rare cause of Cushing's syndrome and only a few cases have been reported in the literature. Differentiating between Cushing's disease and ectopic Cushing's syndrome may be particularly difficult if predominant ectopic CRH secretion leads to pituitary corticotroph hyperplasia that may mimic Cushing's disease during dynamic testing with both dexamethasone and CRH as well as bilateral inferior petrosal sinus sampling (BIPSS). We present the case of a 24-year-old man diagnosed with ACTH-dependent Cushing's syndrome caused by an ACTH/CRH co-secreting midgut NET. Both high-dose dexamethasone testing and BIPSS suggested Cushing's disease. However, the clinical presentation with a rather rapid onset of cushingoid features, hyperpigmentation and hypokalemia led to the consideration of ectopic ACTH/CRH-secretion and prompted a further workup. Computed tomography (CT) of the abdomen revealed a cecal mass which was identified as a predominantly CRH-secreting neuroendocrine tumor. To the best of our knowledge, this is the first reported case of an ACTH/CRH co-secreting tumor of the cecum presenting with biochemical features suggestive of Cushing's disease. The discrimination between a Cushing's disease and ectopic Cushing's syndrome is challenging and has many caveats.Ectopic ACTH/CRH co-secreting tumors are very rare.Dynamic tests as well as BIPSS may be compatible with Cushing's disease in ectopic CRH-secretion.High levels of CRH may induce hyperplasia of the corticotroph cells in the pituitary. This could be the cause of a preserved pituitary response to dexamethasone and CRH.Clinical features of ACTH-dependent hypercortisolism with rapid development of Cushing's syndrome, hyperpigmentation, high circulating levels of cortisol with associated hypokalemia, peripheral edema and proximal myopathy should be a warning flag of ectopic Cushing's syndrome and lead to further investigations.

Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity.

PubMed

Randriamboavonjy, Voahanginirina; Mann, W Alexander; Elgheznawy, Amro; Popp, Rüdiger; Rogowski, Paul; Dornauf, Imke; Dröse, Stefan; Fleming, Ingrid

2015-08-31

Polycystic ovary syndrome (PCOS) is associated with decreased fertility, insulin resistance and an increased risk of developing cardiovascular disease. Treating PCOS patients with metformin improves fertility and decreases cardiovascular complications. Given that platelet activation contributes to both infertility and cardiovascular disease development, we assessed platelet reactivity in PCOS patients and the consequences of metformin treatment. Compared to washed platelets from healthy donors, platelets from PCOS patients demonstrated enhanced reactivity and impaired activation of the AMP-activated kinase (AMPK). PCOS platelets also demonstrated enhanced expression of mitochondrial proteins such as the cytochrome c reductase, ATP synthase and the voltage-dependent anion channel-1. However, mitochondrial function was impaired as demonstrated by a decreased respiration rate. In parallel, the phosphorylation of dynamin-related protein-1 (Drp-1) on Ser616 was increased while that on Ser637 decreased. The latter changes were accompanied by decreased mitochondrial size. In insulin-resistant PCOS patients (HOMA-IR> 2) metformin treatment (1.7 g per day for 4 weeks to 6 months) improved insulin sensitivity, restored mitochondrial integrity and function and normalised platelet aggregation. Treatment was without effect in PCOS patients with HOMA-IR< 2. Moreover, treatment of megakaryocytes with metformin enhanced mitochondrial content and in the same cells metformin enhanced the phosphorylation of the Drp-1 on Ser637 via an AMPKα1-dependent mechanism. In conclusion, the improvement of mitochondrial integrity and platelet reactivity may contribute to the beneficial effects of metformin on cardiovascular disease.

Studying dyadic structure-function relationships: a review of current modeling approaches and new insights into Ca2+ (mis)handling.

PubMed

Maleckar, Mary M; Edwards, Andrew G; Louch, William E; Lines, Glenn T

2017-01-01

Excitation-contraction coupling in cardiac myocytes requires calcium influx through L-type calcium channels in the sarcolemma, which gates calcium release through sarcoplasmic reticulum ryanodine receptors in a process known as calcium-induced calcium release, producing a myoplasmic calcium transient and enabling cardiomyocyte contraction. The spatio-temporal dynamics of calcium release, buffering, and reuptake into the sarcoplasmic reticulum play a central role in excitation-contraction coupling in both normal and diseased cardiac myocytes. However, further quantitative understanding of these cells' calcium machinery and the study of mechanisms that underlie both normal cardiac function and calcium-dependent etiologies in heart disease requires accurate knowledge of cardiac ultrastructure, protein distribution and subcellular function. As current imaging techniques are limited in spatial resolution, limiting insight into changes in calcium handling, computational models of excitation-contraction coupling have been increasingly employed to probe these structure-function relationships. This review will focus on the development of structural models of cardiac calcium dynamics at the subcellular level, orienting the reader broadly towards the development of models of subcellular calcium handling in cardiomyocytes. Specific focus will be given to progress in recent years in terms of multi-scale modeling employing resolved spatial models of subcellular calcium machinery. A review of the state-of-the-art will be followed by a review of emergent insights into calcium-dependent etiologies in heart disease and, finally, we will offer a perspective on future directions for related computational modeling and simulation efforts.

Genetic factors may play a prominent role in the development of coronary heart disease dependent on important environmental factors

PubMed Central

Song, C; Chang, Z; Magnusson, P K E; Ingelsson, E; Pedersen, N L

2014-01-01

Astract Song C, Chang Z, Magnusson PKE, Ingelsson E, Pedersen NL (Karolinska Institutet, Stockholm; Uppsala University, Uppsala; Sweden). Genetic factors may play a prominent role in the developmentofcoronary heart diseasedependenton important environmental factors. J InternMed2014; 275: 631–639. Objective The aim of the study was to examine whether various lifestyle factors modify genetic influences on coronary heart disease (CHD). Design The effect of lifestyle factors [including smoking, sedentary lifestyle, alcohol intake and body mass index (BMI)] on risk of CHD was evaluated via Cox regression models in a twin study of gene–environment interaction. Using structure equation modelling, we estimated genetic variance of CHD dependent on lifestyle factors. Subjects In total, 51 065 same-sex twins from 25 715 twin pairs born before 1958 and registered in the Swedish Twin Registry were eligible for this study. During the 40-year follow-up, 7264 incident CHD events were recorded. Results Smoking, sedentary lifestyle and above average BMI were significantly associated with increased CHD incidence. The heritability of CHD decreased with increasing age, as well as with increasing levels of BMI, in both men and women. Conclusions The difference in the genetic component of CHD as a function of BMI suggests that genetic factors may play a more prominent role for disease development in the absence of important environmental factors. Increased knowledge of gene–environment interactions will be important for a full understanding of the aetiology of CHD. PMID:24330166

High costs of infection: Alphavirus infection reduces digestive function and bone and feather growth in nestling house sparrows (Passer domesticus).

PubMed

Fassbinder-Orth, Carol A; Killpack, Tess L; Goto, Dylan S; Rainwater, Ellecia L; Shearn-Bochsler, Valerie I

2018-01-01

Increasingly, ecoimmunology studies aim to use relevant pathogen exposure to examine the impacts of infection on physiological processes in wild animals. Alphaviruses are arthropod-borne, single-stranded RNA (ssRNA) viruses ("arboviruses") responsible for millions of cases of human illnesses each year. Buggy Creek virus (BCRV) is a unique alphavirus that is transmitted by a cimicid insect, the swallow bug, and is amplified in two avian species: the house sparrow (Passer domesticus) and the cliff swallow (Petrochelidon pyrrhonota). BCRV, like many alphaviruses, exhibits age-dependent susceptibility where the young are most susceptible to developing disease and exhibit a high mortality rate. However, alphavirus disease etiology in nestling birds is unknown. In this study, we infected nestling house sparrows with Buggy Creek virus and measured virological, pathological, growth, and digestive parameters following infection. Buggy Creek virus caused severe encephalitis in all infected nestlings, and the peak viral concentration in brain tissue was over 34 times greater than any other tissue. Growth, tissue development, and digestive function were all significantly impaired during BCRV infection. However, based on histopathological analysis performed, this impairment does not appear to be the result of direct tissue damage by the virus, but likely caused by encephalitis and neuronal invasion and impairment of the central nervous system. This is the first study to examine the course of alphavirus diseases in nestling birds and these results will improve our understanding of age-dependent infections of alphaviruses in vertebrate hosts.

Redox proteomics and the dynamic molecular landscape of the aging brain.

PubMed

Perluigi, Marzia; Swomley, Aaron M; Butterfield, D Allan

2014-01-01

It is well established that the risk to develop neurodegenerative disorders increases with chronological aging. Accumulating studies contributed to characterize the age-dependent changes either at gene and protein expression level which, taken together, show that aging of the human brain results from the combination of the normal decline of multiple biological functions with environmental factors that contribute to defining disease risk of late-life brain disorders. Finding the "way out" of the labyrinth of such complex molecular interactions may help to fill the gap between "normal" brain aging and development of age-dependent diseases. To this purpose, proteomics studies are a powerful tool to better understand where to set the boundary line of healthy aging and age-related disease by analyzing the variation of protein expression levels and the major post translational modifications that determine "protein" physio/pathological fate. Increasing attention has been focused on oxidative modifications due to the crucial role of oxidative stress in aging, in addition to the fact that this type of modification is irreversible and may alter protein function. Redox proteomics studies contributed to decipher the complexity of brain aging by identifying the proteins that were increasingly oxidized and eventually dysfunctional as a function of age. The purpose of this review is to summarize the most important findings obtained by applying proteomics approaches to murine models of aging with also a brief overview of some human studies, in particular those related to dementia. Copyright © 2014. Published by Elsevier B.V.

Cell cycle-coupled expansion of AR activity promotes cancer progression.

PubMed

McNair, C; Urbanucci, A; Comstock, C E S; Augello, M A; Goodwin, J F; Launchbury, R; Zhao, S G; Schiewer, M J; Ertel, A; Karnes, J; Davicioni, E; Wang, L; Wang, Q; Mills, I G; Feng, F Y; Li, W; Carroll, J S; Knudsen, K E

2017-03-23

The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

High costs of infection: Alphavirus infection reduces digestive function and bone and feather growth in nestling house sparrows (Passer domesticus)

USGS Publications Warehouse

Fassbinder-Orth, Carol A.; Killpack, Tess L.; Goto, Dylan S.; Rainwater, Ellecia L.; Shearn-Bochsler, Valerie I.

2018-01-01

Increasingly, ecoimmunology studies aim to use relevant pathogen exposure to examine the impacts of infection on physiological processes in wild animals. Alphaviruses are arthropod-borne, single-stranded RNA (ssRNA) viruses (“arboviruses”) responsible for millions of cases of human illnesses each year. Buggy Creek virus (BCRV) is a unique alphavirus that is transmitted by a cimicid insect, the swallow bug, and is amplified in two avian species: the house sparrow (Passer domesticus) and the cliff swallow (Petrochelidon pyrrhonota). BCRV, like many alphaviruses, exhibits age-dependent susceptibility where the young are most susceptible to developing disease and exhibit a high mortality rate. However, alphavirus disease etiology in nestling birds is unknown. In this study, we infected nestling house sparrows with Buggy Creek virus and measured virological, pathological, growth, and digestive parameters following infection. Buggy Creek virus caused severe encephalitis in all infected nestlings, and the peak viral concentration in brain tissue was over 34 times greater than any other tissue. Growth, tissue development, and digestive function were all significantly impaired during BCRV infection. However, based on histopathological analysis performed, this impairment does not appear to be the result of direct tissue damage by the virus, but likely caused by encephalitis and neuronal invasion and impairment of the central nervous system. This is the first study to examine the course of alphavirus diseases in nestling birds and these results will improve our understanding of age-dependent infections of alphaviruses in vertebrate hosts.

Development of an anaesthetized-rat model of exercise hyperpnoea: an integrative model of respiratory control using an equilibrium diagram.

PubMed

Miyamoto, Tadayoshi; Manabe, Kou; Ueda, Shinya; Nakahara, Hidehiro

2018-05-01

What is the central question of this study? The lack of useful small-animal models for studying exercise hyperpnoea makes it difficult to investigate the underlying mechanisms of exercise-induced ventilatory abnormalities in various disease states. What is the main finding and its importance? We developed an anaesthetized-rat model for studying exercise hyperpnoea, using a respiratory equilibrium diagram for quantitative characterization of the respiratory chemoreflex feedback system. This experimental model will provide an opportunity to clarify the major determinant mechanisms of exercise hyperpnoea, and will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models. Exercise-induced ventilatory abnormalities in various disease states seem to arise from pathological changes of respiratory regulation. Although experimental studies in small animals are essential to investigate the pathophysiological basis of various disease models, the lack of an integrated framework for quantitatively characterizing respiratory regulation during exercise prevents us from resolving these problems. The purpose of this study was to develop an anaesthetized-rat model for studying exercise hyperpnoea for quantitative characterization of the respiratory chemoreflex feedback system. In 24 anaesthetized rats, we induced muscle contraction by stimulating bilateral distal sciatic nerves at low and high voltage to mimic exercise. We recorded breath-by-breath respiratory gas analysis data and cardiorespiratory responses while running two protocols to characterize the controller and plant of the respiratory chemoreflex. The controller was characterized by determining the linear relationship between end-tidal CO 2 pressure (P ETC O2) and minute ventilation (V̇E), and the plant by the hyperbolic relationship between V̇E and P ETC O2. During exercise, the controller curve shifted upward without change in controller gain, accompanying increased oxygen uptake. The hyperbolic plant curve shifted rightward and downward depending on exercise intensity as predicted by increased metabolism. Exercise intensity-dependent changes in operating points (V̇E and P ETC O2) were estimated by integrating the controller and plant curves in a respiratory equilibrium diagram. In conclusion, we developed an anaesthetized-rat model for studying exercise hyperpnoea, using systems analysis for quantitative characterization of the respiratory system. This novel experimental model will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models. © 2018 Morinomiya University of Medical Sciences. Experimental Physiology © 2018 The Physiological Society.

Plant-produced anti-dengue virus monoclonal antibodies exhibit reduced antibody-dependent enhancement of infection activity.

PubMed

Dent, Matthew; Hurtado, Jonathan; Paul, Amber M; Sun, Haiyan; Lai, Huafang; Yang, Ming; Esqueda, Adrian; Bai, Fengwei; Steinkellner, Herta; Chen, Qiang

2016-12-01

The mAb E60 has the potential to be a desirable therapeutic molecule since it efficiently neutralizes all four serotypes of dengue virus (DENV). However, mammalian-cell-produced E60 exhibits antibody-dependent enhancement of infection (ADE) activity, rendering it inefficacious in vivo, and treated animals more susceptible to developing more severe diseases during secondary infection. In this study, we evaluated a plant-based expression system for the production of therapeutically suitable E60. The mAb was transiently expressed in Nicotiana benthamianaWT and a ∆XFT line, a glycosylation mutant lacking plant-specific N-glycan residues. The mAb was efficiently expressed and assembled in leaves and exhibited highly homogenous N-glycosylation profiles, i.e. GnGnXF3 or GnGn structures, depending on the expression host. Both E60 glycovariants demonstrated equivalent antigen-binding specificity and in vitro neutralization potency against DENV serotypes 2 and 4 compared with their mammalian-cell-produced counterpart. By contrast, plant-produced E60 exhibited reduced ADE activity in Fc gamma receptor expressing human cells. Our results suggest the ability of plant-produced antibodies to minimize ADE, which may lead to the development of safe and highly efficacious antibody-based therapeutics against DENV and other ADE-prone viral diseases. Our study provides so far unknown insight into the relationship between mAb N-glycosylation and ADE, which contributes to our understanding of how sugar moieties of antibodies modulate Fc-mediated functions and viral pathogenesis.

Early growth and chronic disease: a public health overview.

PubMed

Law, Catherine

2005-07-01

Infant and childhood growth result from and reflect a range of influences in pre- and postnatal life. These include nutrition, burden of infection and the psycho-social environment. Nutrition in young children is dependent on individual level factors such as fetal experience, infant feeding and weaning practices, and on societal factors such as education of women and economic conditions. The relationship of early postnatal growth to adult disease may be indicative or causal, and may reveal both biological and sociological processes. Although non-insulin-dependent diabetes mellitus (NIDDM) and obesity are risk factors for ischaemic heart disease, the relationships of these three conditions to infant growth differ. Poor infant growth has been associated with higher levels of NIDDM and ischaemic heart disease, but lower levels of adult obesity. Most research has been of populations living in developed countries at different stages of nutritional transition. However, differences in context are not simply limited to the stage of the nutritional transition. They also need to consider the nature of that transition and its social correlates, which may result in the clustering of aetiological influences such as increased body mass and poverty. The size of effect of the relationship of infant growth to adult disease is important not only to determine its relative aetiological importance but also for its potential for public health policy. Such policy also needs to consider the relationships of infant growth to a range of outcomes, both health and human capital, which are not the subject of this workshop.

Manipulation of Neutrophils by Porphyromonas gingivalis in the Development of Periodontitis

PubMed Central

Sochalska, Maja; Potempa, Jan

2017-01-01

The pathogenesis of the chronic periodontal disease is associated with a skewed host inflammatory response to periodontal pathogens, such as Porphyromonas gingivalis, that accounts for the majority of periodontal tissue damage. Neutrophils are the most abundant leukocytes in periodontal pockets and depending on the stage of the disease, also plentiful PMNs are present in the inflamed gingival tissue and the gingival crevice. They are the most efficient phagocytes and eliminate pathogens by a variety of means, which are either oxygen-dependent or -independent. However, these secretory lethal weapons do not strictly discriminate between pathogens and host tissue. Current studies describe conflicting findings about neutrophil involvement in periodontal disease. On one hand literature indicate that hyper-reactive neutrophils are the main immune cell type responsible for this observed tissue damage and disease progression. Deregulation of neutrophil survival and functions, such as chemotaxis, migration, secretion of antimicrobial peptides or enzymes, and production of reactive oxygen species, contribute to observed tissue injury and the clinical signs of periodontal disease. On the other hand neutrophils deficiencies in patients and mice also result in periodontal phenotype. Therefore, P. gingivalis represents a periodontal pathogen that manipulates the immune responses of PMNs, employing several virulence factors, such as gingipains, serine proteases, lipid phosphatases, or fimbriae. This review will sum up studies devoted to understanding different strategies utilized by P. gingivalis to manipulate PMNs survival and functions in order to inhibit killing by a granular content, prolong inflammation, and gain access to nutrient resources. PMID:28589098

Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

PubMed Central

Frautschy, Sally

2014-01-01

The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer's disease, tauopathies, and Huntington's diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell. PMID:25386560

Nutrition and prevention of chronic diseases: a unifying eco-nutritional strategy.

PubMed

Wahlqvist, M L

2004-02-01

Increasing efforts are being made to address, in public health policy (PHP), both the persistence of nutritional deprivation in economically disadvantaged communities, and the increase in so-called "chronic disease" (abdominal obesity, diabetes, cardiovascular disease, certain cancers, osteoporosis, arthritides, and inflammatory disease) in communities at all stages of economic development. The problems in the "chronic disease" descriptor are that its origins may be as early as conception, rather than during the postnatal lifespan, or even in previous generations; it may appear abruptly or slowly; and it may be amenable to environmental and behavioural intervention well into its course and in older age groups. It is also not necessarily "non-communicable", a qualifier often used for "chronic disease" (chronic non-communicable disease or CNCD) and often has inflammatory features, for example the inflammatory marker C-reactive protein is a predictor of macrovascular disease and ischaemic events can, in part, be prevented in the affected by influenzal vaccination. The nexus between immunodeficiency, inflammatory processes and nutritional status which is characteristic of "infective" and food-borne illness, is also more and more evident in "chronic disease". It may be more helpful to consider "chronic disease" as "eco-disease" with its environmental and behavioural contributors, and to regard that which is clearly nutritionally dependent as "eco-nutritional disease".

[Treatment of Crohn's disease].

PubMed

Vavricka, St R; Rogler, G

2009-01-21

The therapy of Crohn's disease depends on its disease activity. For those different disease activities (such as flare, chronic active disease, remission) varying treatment concepts are followed. This overview presents important concepts in the treatment of Crohn's disease.

FUT2-dependent breast milk oligosaccharides and allergy at 2 and 5 years of age in infants with high hereditary allergy risk.

PubMed

Sprenger, Norbert; Odenwald, Hannah; Kukkonen, Anna Kaarina; Kuitunen, Mikael; Savilahti, Erkki; Kunz, Clemens

2017-04-01

Manifestation of allergic disease depends on genetic predisposition, diet and commensal microbiota. Genetic polymorphism of mothers determines their breast milk glycan composition. One major determinant is the fucosyltransferase 2 (FUT2, secretor gene) that was shown to be linked to commensal microbiota establishment. We studied whether FUT2-dependent breast milk oligosaccharides are associated with allergic disease in breast-fed infants later in life. We analyzed FUT2-dependent oligosaccharides in breast milk samples of mothers (n = 266) from the placebo group of a randomized placebo-controlled trial of prebiotics and probiotics as preventive against allergic disease in infants with high allergy risk (trial registry number: NCT00298337). Using logistic regression models, we studied associations between FUT2-dependent breast milk oligosaccharides and incidence of allergic disease at 2 and 5 years of age. At 2 years, but not at 5 years of age, we observed a presumed lower incidence (p < 0.1) for IgE-associated eczema manifestation in C-section-born infants who were fed breast milk containing FUT2-dependent oligosaccharides. By logistic regression, we observed a similar relation (p < 0.1) between presence of FUT2-dependent breast milk oligosaccharides and IgE-associated disease and IgE-associated eczema in C-section-born infants only. When testing with the levels of breast milk oligosaccharide 2'-fucosyllactose as proxy for FUT2 activity, we observed significant (p < 0.05) associations in the C-section-born infants with 'any allergic disease,' IgE-associated disease, eczema and IgE-associated eczema. The data indicate that infants born by C-section and having a high hereditary risk for allergies might have a lower risk to manifest IgE-associated eczema at 2 years, but not 5 years of age, when fed breast milk with FUT2-dependent milk oligosaccharides. Further studies with larger cohorts and especially randomized controlled intervention trials are required to build on these preliminary observations.

Selenium and its supplementation in cardiovascular disease--what do we know?

PubMed

Benstoem, Carina; Goetzenich, Andreas; Kraemer, Sandra; Borosch, Sebastian; Manzanares, William; Hardy, Gil; Stoppe, Christian

2015-04-27

The trace element selenium is of high importance for many of the body's regulatory and metabolic functions. Balanced selenium levels are essential, whereas dysregulation can cause harm. A rapidly increasing number of studies characterizes the wide range of selenium dependent functions in the human body and elucidates the complex and multiple physiological and pathophysiological interactions of selenium and selenoproteins. For the majority of selenium dependent enzymes, several biological functions have already been identified, like regulation of the inflammatory response, antioxidant properties and the proliferation/differentiation of immune cells. Although the potential role of selenium in the development and progression of cardiovascular disease has been investigated for decades, both observational and interventional studies of selenium supplementation remain inconclusive and are considered in this review. This review covers current knowledge of the role of selenium and selenoproteins in the human body and its functional role in the cardiovascular system. The relationships between selenium intake/status and various health outcomes, in particular cardiomyopathy, myocardial ischemia/infarction and reperfusion injury are reviewed. We describe, in depth, selenium as a biomarker in coronary heart disease and highlight the significance of selenium supplementation for patients undergoing cardiac surgery.

Uric acid inhibition of dipeptidyl peptidase IV in vitro is dependent on the intracellular formation of triuret.

PubMed

Mohandas, Rajesh; Sautina, Laura; Beem, Elaine; Schuler, Anna; Chan, Wai-Yan; Domsic, John; McKenna, Robert; Johnson, Richard J; Segal, Mark S

2014-08-01

Uric acid affects endothelial and adipose cell function and has been linked to diseases such as hypertension, metabolic syndrome, and cardiovascular disease. Interestingly uric acid has been shown to increase endothelial progenitor cell (EPC) mobilization, a potential mechanism to repair endothelial injury. Since EPC mobilization is dependent on activity of the enzyme CD26/dipeptidyl peptidase (DPP)IV, we examined the effect uric acid will have on CD26/DPPIV activity. Uric acid inhibited the CD26/DPPIV associated with human umbilical vein endothelial cells but not human recombinant (hr) CD26/DPPIV. However, triuret, a product of uric acid and peroxynitrite, could inhibit cell associated and hrCD26/DPPIV. Increasing or decreasing intracellular peroxynitrite levels enhanced or decreased the ability of uric acid to inhibit cell associated CD26/DPPIV, respectively. Finally, protein modeling demonstrates how triuret can act as a small molecule inhibitor of CD26/DPPIV activity. This is the first time that uric acid or a uric acid reaction product has been shown to affect enzymatic activity and suggests a novel avenue of research in the role of uric acid in the development of clinically important diseases. Published by Elsevier Inc.

Blood flow characteristics in the aortic arch

NASA Astrophysics Data System (ADS)

Prahl Wittberg, Lisa; van Wyk, Stevin; Mihaiescu, Mihai; Fuchs, Laszlo; Gutmark, Ephraim; Backeljauw, Philippe; Gutmark-Little, Iris

2012-11-01

The purpose with this study is to investigate the flow characteristics of blood in the aortic arch. Cardiovascular diseases are associated with specific locations in the arterial tree. Considering atherogenesis, it is claimed that the Wall Shear Stress (WSS) along with its temporal and spatial gradients play an important role in the development of the disease. The WSS is determined by the local flow characteristics, that in turn depends on the geometry as well as the rheological properties of blood. In this numerical work, the time dependent fluid flow during the entire cardiac cycle is fully resolved. The Quemada model is applied to account for the non-Newtonian properties of blood, an empirical model valid for different Red Blood Cell loading. Data obtained through Cardiac Magnetic Resonance Imaging have been used in order to reconstruct geometries of the the aortic arch. Here, three different geometries are studied out of which two display malformations that can be found in patients having the genetic disorder Turner's syndrome. The simulations show a highly complex flow with regions of secondary flow that is enhanced for the diseased aortas. The financial support from the Swedish Research Council (VR) and the Sweden-America Foundation is gratefully acknowledged.

Imaging and quantification of amyloid fibrillation in the cell nucleus.

PubMed

Arnhold, Florian; Scharf, Andrea; von Mikecz, Anna

2015-01-01

Xenobiotics, as well as intrinsic processes such as cellular aging, contribute to an environment that constantly challenges nuclear organization and function. While it becomes increasingly clear that proteasome-dependent proteolysis is a major player, the topology and molecular mechanisms of nuclear protein homeostasis remain largely unknown. We have shown previously that (1) proteasome-dependent protein degradation is organized in focal microenvironments throughout the nucleoplasm and (2) heavy metals as well as nanoparticles induce nuclear protein fibrillation with amyloid characteristics. Here, we describe methods to characterize the landscape of intranuclear amyloid on the global and local level in different systems such as cultures of mammalian cells and the soil nematode Caenorhabditis elegans. Application of discrete mathematics to imaging data is introduced as a tool to develop pattern recognition of intracellular protein fibrillation. Since stepwise fibrillation of otherwise soluble proteins to insoluble amyloid-like protein aggregates is a hallmark of neurodegenerative protein-misfolding disorders including Alzheimer's disease, CAG repeat diseases, and the prion encephalopathies, investigation of intracellular amyloid may likewise aid to a better understanding of the pathomechanisms involved. We consider aggregate profiling as an important experimental approach to determine if nuclear amyloid has toxic or protective roles in various disease processes.

Potential of Food and Natural Products to Promote Endothelial and Vascular Health.

PubMed

Auger, Cyril; Said, Amissi; Nguyen, Phuong Nga; Chabert, Philippe; Idris-Khodja, Noureddine; Schini-Kerth, Valérie B

2016-07-01

Endothelial dysfunction is now well established as a pivotal early event in the development of major cardiovascular diseases including hypertension, atherosclerosis, and diabetes. The alteration of the endothelial function is often triggered by an imbalance between the endothelial formation of vasoprotective factors including nitric oxide (NO) and endothelium-dependent hyperpolarization, and an increased level of oxidative stress involving several prooxidant enzymes such as NADPH oxidase and, often also, the appearance of cyclooxygenase-derived vasoconstrictors. Preclinical studies have indicated that polyphenol-rich food and food-derived products such as grape-derived products, black and red berries, green and black teas and cocoa, and omega-3 fatty acids can trigger activating pathways in endothelial cells promoting an increased formation of nitric oxide and endothelium-dependent hyperpolarization. Moreover, intake of such food-derived products has been associated with the prevention and/or the improvement of an established endothelial dysfunction in several experimental models of cardiovascular diseases and in humans with cardiovascular diseases. This review will discuss both experimental and clinical evidences indicating that different types of food and natural products are able to promote endothelial and vascular health, as well as the underlying mechanisms.

On the Estimation of Disease Prevalence by Latent Class Models for Screening Studies Using Two Screening Tests with Categorical Disease Status Verified in Test Positives Only

PubMed Central

Chu, Haitao; Zhou, Yijie; Cole, Stephen R.; Ibrahim, Joseph G.

2010-01-01

Summary To evaluate the probabilities of a disease state, ideally all subjects in a study should be diagnosed by a definitive diagnostic or gold standard test. However, since definitive diagnostic tests are often invasive and expensive, it is generally unethical to apply them to subjects whose screening tests are negative. In this article, we consider latent class models for screening studies with two imperfect binary diagnostic tests and a definitive categorical disease status measured only for those with at least one positive screening test. Specifically, we discuss a conditional independent and three homogeneous conditional dependent latent class models and assess the impact of misspecification of the dependence structure on the estimation of disease category probabilities using frequentist and Bayesian approaches. Interestingly, the three homogeneous dependent models can provide identical goodness-of-fit but substantively different estimates for a given study. However, the parametric form of the assumed dependence structure itself is not “testable” from the data, and thus the dependence structure modeling considered here can only be viewed as a sensitivity analysis concerning a more complicated non-identifiable model potentially involving heterogeneous dependence structure. Furthermore, we discuss Bayesian model averaging together with its limitations as an alternative way to partially address this particularly challenging problem. The methods are applied to two cancer screening studies, and simulations are conducted to evaluate the performance of these methods. In summary, further research is needed to reduce the impact of model misspecification on the estimation of disease prevalence in such settings. PMID:20191614

A Role for the Transcription Factor Nk2 Homeobox 1 in Schizophrenia: Convergent Evidence from Animal and Human Studies

PubMed Central

Malt, Eva A.; Juhasz, Katalin; Malt, Ulrik F.; Naumann, Thomas

2016-01-01

Schizophrenia is a highly heritable disorder with diverse mental and somatic symptoms. The molecular mechanisms leading from genes to disease pathology in schizophrenia remain largely unknown. Genome-wide association studies (GWASs) have shown that common single-nucleotide polymorphisms associated with specific diseases are enriched in the recognition sequences of transcription factors that regulate physiological processes relevant to the disease. We have used a “bottom-up” approach and tracked a developmental trajectory from embryology to physiological processes and behavior and recognized that the transcription factor NK2 homeobox 1 (NKX2-1) possesses properties of particular interest for schizophrenia. NKX2-1 is selectively expressed from prenatal development to adulthood in the brain, thyroid gland, parathyroid gland, lungs, skin, and enteric ganglia, and has key functions at the interface of the brain, the endocrine-, and the immune system. In the developing brain, NKX2-1-expressing progenitor cells differentiate into distinct subclasses of forebrain GABAergic and cholinergic neurons, astrocytes, and oligodendrocytes. The transcription factor is highly expressed in mature limbic circuits related to context-dependent goal-directed patterns of behavior, social interaction and reproduction, fear responses, responses to light, and other homeostatic processes. It is essential for development and mature function of the thyroid gland and the respiratory system, and is involved in calcium metabolism and immune responses. NKX2-1 interacts with a number of genes identified as susceptibility genes for schizophrenia. We suggest that NKX2-1 may lie at the core of several dose dependent pathways that are dysregulated in schizophrenia. We correlate the symptoms seen in schizophrenia with the temporal and spatial activities of NKX2-1 in order to highlight promising future research areas. PMID:27064909

Direct covalent modification as a strategy to inhibit nuclear factor-kappa B.

PubMed

Pande, Vineet; Sousa, Sérgio F; Ramos, Maria João

2009-01-01

Nuclear Factor-KkappaB (NF-kappaB) is a transcription factor whose inappropriate activation may result in the development of a number of diseases including cancer, inflammation, neurodegeneration and AIDS. Recent studies on NF-kappaB mediated pathologies, made therapeutic interventions leading to its inhibition an emerging theme in pharmaceutical research. NF-kappaB resides in the cytoplasm and is activated by several time-dependent factors, leading to proteasome-dependent degradation of its inhibitory protein (IkappaB), resulting in free NF-kappaB (p50 and p65 subunits, involved in disease states), which binds to target DNA sites, further resulting in enhanced transcription of several disease associated proteins. The complex pathway of NF-kappaB, finally leading to its DNA binding, has attracted several approaches interfering with this pathway. One such approach is that of a direct covalent modification of NF-kappaB. In this article, we present a critical review on the pharmacological agents that have been studied as inhibitors of NF-kappaB by covalently modifying redox-regulated cysteine residues in its subunits, ultimately resulting in the inhibition of kappaB DNA recognition and binding. Beginning with a general overview of NF-kappaB pathway and several possibilities of chemical interventions, the significance of redox-regulation in NF-kappaB activation and DNA binding is presented. Further, protein S-thiolation, S-nitrosylation and irreversible covalent modification are described as regular biochemical events in the cell, having provided a guideline for the development of NF-kappaB inhibitors discussed further. Although just a handful of inhibitors, with most of them being alkylating agents have been studied in the present context, this approach presents potential for the development of a new class of NF-kappaB-inhibitors.

Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis.

PubMed

Rankin, Andrew L; Seth, Nilufer; Keegan, Sean; Andreyeva, Tatyana; Cook, Tim A; Edmonds, Jason; Mathialagan, Nagappan; Benson, Micah J; Syed, Jameel; Zhan, Yutian; Benoit, Stephen E; Miyashiro, Joy S; Wood, Nancy; Mohan, Shashi; Peeva, Elena; Ramaiah, Shashi K; Messing, Dean; Homer, Bruce L; Dunussi-Joannopoulos, Kyri; Nickerson-Nutter, Cheryl L; Schnute, Mark E; Douhan, John

2013-11-01

Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton's tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxy]phenyl)-1H-pyrazole-4-carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF-06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti-dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF-06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector molecule-mediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients.

A research agenda for helminth diseases of humans: basic research and enabling technologies to support control and elimination of helminthiases.

PubMed

Lustigman, Sara; Geldhof, Peter; Grant, Warwick N; Osei-Atweneboana, Mike Y; Sripa, Banchob; Basáñez, María-Gloria

2012-01-01

Successful and sustainable intervention against human helminthiases depends on optimal utilisation of available control measures and development of new tools and strategies, as well as an understanding of the evolutionary implications of prolonged intervention on parasite populations and those of their hosts and vectors. This will depend largely on updated knowledge of relevant and fundamental parasite biology. There is a need, therefore, to exploit and apply new knowledge and techniques in order to make significant and novel gains in combating helminthiases and supporting the sustainability of current and successful mass drug administration (MDA) programmes. Among the fields of basic research that are likely to yield improved control tools, the Disease Reference Group on Helminth Infections (DRG4) has identified four broad areas that stand out as central to the development of the next generation of helminth control measures: 1) parasite genetics, genomics, and functional genomics; 2) parasite immunology; 3) (vertebrate) host-parasite interactions and immunopathology; and 4) (invertebrate) host-parasite interactions and transmission biology. The DRG4 was established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR). The Group was given the mandate to undertake a comprehensive review of recent advances in helminthiases research in order to identify notable gaps and highlight priority areas. This paper summarises recent advances and discusses challenges in the investigation of the fundamental biology of those helminth parasites under the DRG4 Group's remit according to the identified priorities, and presents a research and development agenda for basic parasite research and enabling technologies that will help support control and elimination efforts against human helminthiases.

Atopic Dermatitis in Children: Clinical Features, Pathophysiology and Treatment

PubMed Central

Lyons, Jonathan J.; Milner, Joshua D.; Stone, Kelly D.

2014-01-01

Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic skin condition resulting from disruption of the epithelial barrier and associated immune dysregulation in the skin of genetically predisposed hosts. AD generally develops in early childhood, has a characteristic age-dependent distribution and is commonly associated with elevated IgE, peripheral eosinophilia and other allergic diseases. Staphylococcus aureus colonization is common and may contribute to disease progression and severity. Targeted therapies to restore both impaired skin barrier and control inflammation are required for optimal outcomes for patients with moderate to severe disease. Pruritus is universal among patients with AD and has a dominant impact on diminishing quality of life. Medications such as anti-histamines have demonstrated poor efficacy in controlling AD-associated itch. Education of patients regarding the primary underlying defects and provision of a comprehensive skin care plan is essential for disease maintenance and management of flares. PMID:25459583

Streptococcus mitis Strains Causing Severe Clinical Disease in Cancer Patients

PubMed Central

Sahasrabhojane, Pranoti; Saldana, Miguel; Yao, Hui; Su, Xiaoping; Horstmann, Nicola; Thompson, Erika; Flores, Anthony R.

2014-01-01

The genetically diverse viridans group streptococci (VGS) are increasingly recognized as the cause of a variety of human diseases. We used a recently developed multilocus sequence analysis scheme to define the species of 118 unique VGS strains causing bacteremia in patients with cancer; Streptococcus mitis (68 patients) and S. oralis (22 patients) were the most frequently identified strains. Compared with patients infected with non–S. mitis strains, patients infected with S. mitis strains were more likely to have moderate or severe clinical disease (e.g., VGS shock syndrome). Combined with the sequence data, whole-genome analyses showed that S. mitis strains may more precisely be considered as >2 species. Furthermore, we found that multiple S. mitis strains induced disease in neutropenic mice in a dose-dependent fashion. Our data define the prominent clinical effect of the group of organisms currently classified as S. mitis and lay the groundwork for increased understanding of this understudied pathogen. PMID:24750901

Interrelationship between Periapical Lesion and Systemic Metabolic Disorders

PubMed Central

Sasaki, Hajime; Hirai, Kimito; Martins, Christine Men; Furusho, Hisako; Battaglino, Ricardo; Hashimoto, Koshi

2016-01-01

Periapical periodontitis, also known as periapical lesion, is a common dental disease, along with periodontitis (gum disease). Periapical periodontitis is a chronic inflammatory disease, caused by endodontic infection, and its development is regulated by the host immune/inflammatory response. Metabolic disorders, which are largely dependent on life style such as eating habits, have been interpreted as a “metabolically-triggered” low-grade systemic inflammation and may interact with periapical periodontitis by triggering immune modulation. The host immune system is therefore considered the common fundamental mechanism of both disease conditions. An elevated inflammatory state caused by metabolic disorders can impact the clinical outcome of periapical lesions and interfere with wound healing after endodontic treatment. Although additional well-designed clinical studies are needed, periapical lesions appear to affect insulin sensitivity and exacerbate non-alcoholic steatohepatitis. Immune regulatory cytokines produced by various cell types, including immune cells and adipose tissue, play an important role in this interrelationship. PMID:26881444

Nutrition in early life, and risk of cancer and metabolic disease: alternative endings in an epigenetic tale?

PubMed Central

Burdge, Graham C; Lillycrop, Karen A; Jackson, Alan A

2008-01-01

There is substantial evidence which shows that constraints in the early life environment is an important determinant of risk of metabolic and cardiovascular disease. There is emerging evidence that higher birth weight, which reflects a more abundant prenatal environment, is associated with increased risk of cancer, in particular breast cancer and childhood leukaemia. Using specific examples from epidemiology and experimental studies, this review discusses the hypothesis that increased susceptibility to cardiovascular, metabolic disease and cancer have a common origin in developmental changes induced in the developing fetus by aspects of the intra uterine environment including nutrition which involve stable changes to the epigenetic regulation of specific genes. However, the induction of specific disease risk is dependent upon the nature of the environmental challenge and interactions between the susceptibility set by the altered epigenome and the environment throughout the life course. PMID:19079817

Development of Partial Ontogenic Resistance to Powdery Mildew in Hop Cones and Its Management Implications

PubMed Central

Twomey, Megan C.; Wolfenbarger, Sierra N.; Woods, Joanna L.; Gent, David H.

2015-01-01

Knowledge of processes leading to crop damage is central to devising rational approaches to disease management. Multiple experiments established that infection of hop cones by Podosphaera macularis was most severe if inoculation occurred within 15 to 21 days after bloom. This period of infection was associated with the most pronounced reductions in alpha acids, cone color, and accelerated maturation of cones. Susceptibility of cones to powdery mildew decreased progressively after the transition from bloom to cone development, although complete immunity to the disease failed to develop. Maturation of cone tissues was associated with multiple significant affects on the pathogen manifested as reduced germination of conidia, diminished frequency of penetration of bracts, lengthening of the latent period, and decreased sporulation. Cones challenged with P. macularis in juvenile developmental stages also led to greater frequency of colonization by a complex of saprophytic, secondary fungi. Since no developmental stage of cones was immune to powdery mildew, the incidence of powdery mildew continued to increase over time and exceeded 86% by late summer. In field experiments with a moderately susceptible cultivar, the incidence of cones with powdery mildew was statistically similar when fungicide applications were made season-long or targeted only to the juvenile stages of cone development. These studies establish that partial ontogenic resistance develops in hop cones and may influence multiple phases of the infection process and pathogen reproduction. The results further reinforce the concept that the efficacy of a fungicide program may depend largely on timing of a small number of sprays during a relatively brief period of cone development. However in practice, targeting fungicide and other management tactics to periods of enhanced juvenile susceptibility may be complicated by a high degree of asynchrony in cone development and other factors that are situation-dependent. PMID:25811173

Interferon-alpha/beta deficiency greatly exacerbates arthritogenic disease in mice infected with wild-type chikungunya virus but not with the cell culture-adapted live-attenuated 181/25 vaccine candidate

PubMed Central

Gardner, Christina L.; Burke, Crystal W.; Higgs, Stephen T.; Klimstra, William B.; Ryman, Kate D.

2012-01-01

In humans, chikungunya virus (CHIKV) infection causes fever, rash, and acute and persisting polyarthalgia/arthritis associated with joint swelling. We report a new CHIKV disease model in adult mice that distinguishes the wild-type CHIKV-LR strain from the live-attenuated vaccine strain (CHIKV-181/25). Although eight-week old normal mice inoculated in the hind footpad developed no hind limb swelling with either virus, CHIKV-LR replicated in musculoskeletal tissues and caused detectable inflammation. In mice deficient in STAT1-dependent interferon (IFN) responses, CHIKV-LR caused significant swelling of the inoculated and contralateral limbs and dramatic inflammatory lesions, while CHIKV-181/25 vaccine and another arthritogenic alphavirus, Sindbis, failed to induce swelling. IFN responses suppressed CHIKV-LR and CHIKV-181/25 replication equally in dendritic cells in vitro whereas macrophages were refractory to infection independently of STAT1-mediated IFN responses. Glycosaminoglycan (GAG) binding may be a CHIKV vaccine attenuation mechanism as CHIKV-LR infectivity was not dependent upon GAG, while CHIKV-181/25 was highly dependent. PMID:22305131

Transcription control by the ENL YEATS domain in acute leukaemia.

PubMed

Erb, Michael A; Scott, Thomas G; Li, Bin E; Xie, Huafeng; Paulk, Joshiawa; Seo, Hyuk-Soo; Souza, Amanda; Roberts, Justin M; Dastjerdi, Shiva; Buckley, Dennis L; Sanjana, Neville E; Shalem, Ophir; Nabet, Behnam; Zeid, Rhamy; Offei-Addo, Nana K; Dhe-Paganon, Sirano; Zhang, Feng; Orkin, Stuart H; Winter, Georg E; Bradner, James E

2017-03-09

Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.

Radiopharmaceuticals for Assessment of Altered Metabolism and Biometal Fluxes in Brain Aging and Alzheimer's Disease with Positron Emission Tomography.

PubMed

Xie, Fang; Peng, Fangyu

2017-01-01

Aging is a risk factor for Alzheimer's disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis, and treatment of AD.

Impact of correlation of predictors on discrimination of risk models in development and external populations.

PubMed

Kundu, Suman; Mazumdar, Madhu; Ferket, Bart

2017-04-19

The area under the ROC curve (AUC) of risk models is known to be influenced by differences in case-mix and effect size of predictors. The impact of heterogeneity in correlation among predictors has however been under investigated. We sought to evaluate how correlation among predictors affects the AUC in development and external populations. We simulated hypothetical populations using two different methods based on means, standard deviations, and correlation of two continuous predictors. In the first approach, the distribution and correlation of predictors were assumed for the total population. In the second approach, these parameters were modeled conditional on disease status. In both approaches, multivariable logistic regression models were fitted to predict disease risk in individuals. Each risk model developed in a population was validated in the remaining populations to investigate external validity. For both approaches, we observed that the magnitude of the AUC in the development and external populations depends on the correlation among predictors. Lower AUCs were estimated in scenarios of both strong positive and negative correlation, depending on the direction of predictor effects and the simulation method. However, when adjusted effect sizes of predictors were specified in the opposite directions, increasingly negative correlation consistently improved the AUC. AUCs in external validation populations were higher or lower than in the derivation cohort, even in the presence of similar predictor effects. Discrimination of risk prediction models should be assessed in various external populations with different correlation structures to make better inferences about model generalizability.

Vectorization of Nucleic Acids for Therapeutic Approach: Tutorial Review.

PubMed

Geinguenaud, Frederic; Guenin, Erwann; Lalatonne, Yoann; Motte, Laurence

2016-05-20

Oligonucleotides present a high therapeutic potential for a wide variety of diseases. However, their clinical development is limited by their degradation by nucleases and their poor blood circulation time. Depending on the administration mode and the cellular target, these macromolecules will have to cross the vascular endothelium, to diffuse through the extracellular matrix, to be transported through the cell membrane, and finally to reach the cytoplasm. To overcome these physiological barriers, many strategies have been developed. Here, we review different methods of DNA vectorization, discuss limitations and advantages of the various vectors, and provide new perspectives for future development.

A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

PubMed Central

Naftalin, Richard J.

2016-01-01

A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP-1 agonist or glucagon antagonist usage. PMID:27347379

The Xanthomonas euvesicatoria type III effector XopAU is an active protein kinase that manipulates plant MAP kinase signaling.

PubMed

Teper, Doron; Girija, Anil Madhusoodana; Bosis, Eran; Popov, Georgy; Savidor, Alon; Sessa, Guido

2018-01-01

The Gram-negative bacterium Xanthomonas euvesicatoria (Xe) is the causal agent of bacterial spot disease of pepper and tomato. Xe delivers effector proteins into host cells through the type III secretion system to promote disease. Here, we show that the Xe effector XopAU, which is conserved in numerous Xanthomonas species, is a catalytically active protein kinase and contributes to the development of disease symptoms in pepper plants. Agrobacterium-mediated expression of XopAU in host and non-host plants activated typical defense responses, including MAP kinase phosphorylation, accumulation of pathogenesis-related (PR) proteins and elicitation of cell death, that were dependent on the kinase activity of the effector. XopAU-mediated cell death was not dependent on early signaling components of effector-triggered immunity and was also observed when the effector was delivered into pepper leaves by Xanthomonas campestris pv. campestris, but not by Xe. Protein-protein interaction studies in yeast and in planta revealed that XopAU physically interacts with components of plant immunity-associated MAP kinase cascades. Remarkably, XopAU directly phosphorylated MKK2 in vitro and enhanced its phosphorylation at multiple sites in planta. Consistent with the notion that MKK2 is a target of XopAU, silencing of the MKK2 homolog or overexpression of the catalytically inactive mutant MKK2K99R in N. benthamiana plants reduced XopAU-mediated cell death and MAPK phosphorylation. Furthermore, yeast co-expressing XopAU and MKK2 displayed reduced growth and this phenotype was dependent on the kinase activity of both proteins. Together, our results support the conclusion that XopAU contributes to Xe disease symptoms in pepper plants and manipulates host MAPK signaling through phosphorylation and activation of MKK2.

Sex-dependent and body weight-dependent associations between environmental PAHs exposure and insulin resistance: Korean urban elderly panel

PubMed Central

Choi, Yoon-Hyeong; Kim, Jin Hee; Hong, Yun-Chul

2015-01-01

Background The prevalence of metabolic diseases rises rapidly with an ageing population. Recent studies suggest the potential involvement of environmental chemicals in insulin resistance (IR) that plays a core role in the development of metabolic diseases. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous components of outdoor and indoor air pollution. The influence of PAHs on IR may differ depending on sex and weight. Objectives We examined the association between exposure to environmental PAHs and IR in Korean urban elderly adults controlling for major risk factors that contribute to an increase in IR. Methods Between 2008 and 2010, PAH metabolite levels (urinary 1-hydroxypyrene (1-OHP)) and the homoeostatic model assessment index (HOMA-IR) were repeatedly measured in 502 adults aged ≥60 years. Linear mixed effect models were fit to evaluate the associations of 1-OHP concentration with HOMA-IR. Subgroups were modelled by sex and weight. Results After adjusting for sociodemographics, air pollution and metabolic disease status, the highest (vs lowest) quartile of 1-OHP was associated with an 0.57 (95% CI 0.10 to 1.04) increase in the HOMA-IR score (p trend=0.037). When stratified by sex, women presented a significantly dose-dependent trend of 1-OHP with HOMA-IR (p trend=0.013), whereas no association was observed in men (p trend=0.904). When further stratified by weight (body mass index ≥25 vs <25 kg/m2), a significant association was found only in overweight women (p trend=0.023). Conclusions Our results suggest that environmental exposure to PAHs is associated with increased IR in elderly adults and that the association may be limited to overweight women. PMID:25669219

Non-communicable diseases and global health governance: enhancing global processes to improve health development

PubMed Central

Magnusson, Roger S

2007-01-01

This paper assesses progress in the development of a global framework for responding to non-communicable diseases, as reflected in the policies and initiatives of the World Health Organization (WHO), World Bank and the UN: the institutions most capable of shaping a coherent global policy. Responding to the global burden of chronic disease requires a strategic assessment of the global processes that are likely to be most effective in generating commitment to policy change at country level, and in influencing industry behaviour. WHO has adopted a legal process with tobacco (the WHO Framework Convention on Tobacco Control), but a non-legal, advocacy-based approach with diet and physical activity (the Global Strategy on Diet, Physical Activity and Health). The paper assesses the merits of the Millennium Development Goals (MDGs) and the FCTC as distinct global processes for advancing health development, before considering what lessons might be learned for enhancing the implementation of the Global Strategy on Diet. While global partnerships, economic incentives, and international legal instruments could each contribute to a more effective global response to chronic diseases, the paper makes a special case for the development of international legal standards in select areas of diet and nutrition, as a strategy for ensuring that the health of future generations does not become dependent on corporate charity and voluntary commitments. A broader frame of reference for lifestyle-related chronic diseases is needed: one that draws together WHO's work in tobacco, nutrition and physical activity, and that envisages selective use of international legal obligations, non-binding recommendations, advocacy and policy advice as tools of choice for promoting different elements of the strategy. PMID:17519005

Non-communicable diseases and global health governance: enhancing global processes to improve health development.

PubMed

Magnusson, Roger S

2007-05-22

This paper assesses progress in the development of a global framework for responding to non-communicable diseases, as reflected in the policies and initiatives of the World Health Organization (WHO), World Bank and the UN: the institutions most capable of shaping a coherent global policy. Responding to the global burden of chronic disease requires a strategic assessment of the global processes that are likely to be most effective in generating commitment to policy change at country level, and in influencing industry behaviour. WHO has adopted a legal process with tobacco (the WHO Framework Convention on Tobacco Control), but a non-legal, advocacy-based approach with diet and physical activity (the Global Strategy on Diet, Physical Activity and Health). The paper assesses the merits of the Millennium Development Goals (MDGs) and the FCTC as distinct global processes for advancing health development, before considering what lessons might be learned for enhancing the implementation of the Global Strategy on Diet. While global partnerships, economic incentives, and international legal instruments could each contribute to a more effective global response to chronic diseases, the paper makes a special case for the development of international legal standards in select areas of diet and nutrition, as a strategy for ensuring that the health of future generations does not become dependent on corporate charity and voluntary commitments. A broader frame of reference for lifestyle-related chronic diseases is needed: one that draws together WHO's work in tobacco, nutrition and physical activity, and that envisages selective use of international legal obligations, non-binding recommendations, advocacy and policy advice as tools of choice for promoting different elements of the strategy.

AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies

PubMed Central

Chesi, Marta; Robbiani, Davide F.; Sebag, Michael; Chng, Wee Joo; Affer, Maurizio; Tiedemann, Rodger; Valdez, Riccardo; Palmer, Stephen E.; Haas, Stephanie S.; Stewart, A. Keith; Fonseca, Rafael; Kremer, Richard; Cattoretti, Giorgio; Bergsagel, P. Leif

2008-01-01

Summary By misdirecting the activity of Activation-Induced Deaminase (AID) to a conditional MYC transgene, we have achieved sporadic, AID-dependent MYC activation in germinal center B-cells of Vk*MYC mice. Whereas control C57BL/6 mice develop benign monoclonal gammopathy with age, all Vk*MYC mice progress to an indolent multiple myeloma associated with the biological and clinical features highly characteristic of the human disease. Furthermore, antigen-dependent myeloma could be induced by immunization with a T-dependent antigen. Consistent with these findings in mice, more frequent MYC rearrangements, elevated levels of MYC mRNA and MYC target genes distinguish human patients with multiple myeloma from individuals with monoclonal gammopathy, implicating a causal role for MYC in the progression of monoclonal gammopathy to multiple myeloma in man. PMID:18242516

T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation.

PubMed

Kwong, Brandon; Rua, Rejane; Gao, Yuanyuan; Flickinger, John; Wang, Yan; Kruhlak, Michael J; Zhu, Jinfang; Vivier, Eric; McGavern, Dorian B; Lazarevic, Vanja

2017-10-01

The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46 + innate lymphoid cells (ILCs) in the initiation of CD4 + T H 17-mediated neuroinflammation. Loss of T-bet specifically in NKp46 + ILCs profoundly impaired the ability of myelin-reactive T H 17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46 + ILCs localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of proinflammatory cytokines, chemokines and matrix metalloproteinases, which together facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46 + ILCs in the development of CNS autoimmune disease.

Cardiac Expression of ms1/STARS, a Novel Gene Involved in Cardiac Development and Disease, Is Regulated by GATA4

PubMed Central

Kobayashi, Satoru; Peterson, Richard E.; He, Aibin; Motterle, Anna; Samani, Nilesh J.; Menick, Donald R.; Pu, William T.; Liang, Qiangrong

2012-01-01

Ms1/STARS is a novel muscle-specific actin-binding protein that specifically modulates the myocardin-related transcription factor (MRTF)-serum response factor (SRF) regulatory axis within striated muscle. This ms1/STARS-dependent regulatory axis is of central importance within the cardiac gene regulatory network and has been implicated in cardiac development and postnatal cardiac function/homeostasis. The dysregulation of ms1/STARS is associated with and causative of pathological cardiac phenotypes, including cardiac hypertrophy and cardiomyopathy. In order to gain an understanding of the mechanisms governing ms1/STARS expression in the heart, we have coupled a comparative genomic in silico analysis with reporter, gain-of-function, and loss-of-function approaches. Through this integrated analysis, we have identified three evolutionarily conserved regions (ECRs), α, SINA, and DINA, that act as cis-regulatory modules and confer differential cardiac cell-specific activity. Two of these ECRs, α and DINA, displayed distinct regulatory sensitivity to the core cardiac transcription factor GATA4. Overall, our results demonstrate that within embryonic, neonatal, and adult hearts, GATA4 represses ms1/STARS expression with the pathologically associated depletion of GATA4 (type 1/type 2 diabetic models), resulting in ms1/STARS upregulation. This GATA4-dependent repression of ms1/STARS expression has major implications for MRTF-SRF signaling in the context of cardiac development and disease. PMID:22431517

Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype

PubMed Central

Gupta, Saumya; Radhakrishnan, Aparna; Raharja-Liu, Pandu; Lin, Gen; Steinmetz, Lars M.; Gagneur, Julien; Sinha, Himanshu

2015-01-01

Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants’ effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression. PMID:26039065

The Impact of Big Data on Chronic Disease Management.

PubMed

Bhardwaj, Niharika; Wodajo, Bezawit; Spano, Anthony; Neal, Symaron; Coustasse, Alberto

Population health management and specifically chronic disease management depend on the ability of providers to prevent development of high-cost and high-risk conditions such as diabetes, heart failure, and chronic respiratory diseases and to control them. The advent of big data analytics has potential to empower health care providers to make timely and truly evidence-based informed decisions to provide more effective and personalized treatment while reducing the costs of this care to patients. The goal of this study was to identify real-world health care applications of big data analytics to determine its effectiveness in both patient outcomes and the relief of financial burdens. The methodology for this study was a literature review utilizing 49 articles. Evidence of big data analytics being largely beneficial in the areas of risk prediction, diagnostic accuracy and patient outcome improvement, hospital readmission reduction, treatment guidance, and cost reduction was noted. Initial applications of big data analytics have proved useful in various phases of chronic disease management and could help reduce the chronic disease burden.

Immunotherapy targeting α-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders.

PubMed

Lindström, Veronica; Ihse, Elisabet; Fagerqvist, Therese; Bergström, Joakim; Nordström, Eva; Möller, Christer; Lannfelt, Lars; Ingelsson, Martin

2014-01-01

Immunotherapy targeting α-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. α-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of α-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against α-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting α-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other α-synucleinopathies.

Osteoarthritis in the XXIst Century: Risk Factors and Behaviours that Influence Disease Onset and Progression

PubMed Central

Musumeci, Giuseppe; Aiello, Flavia Concetta; Szychlinska, Marta Anna; Di Rosa, Michelino; Castrogiovanni, Paola; Mobasheri, Ali

2015-01-01

Osteoarthritis (OA) is a growing public health problem across the globe, affecting more than half of the over 65 population. In the past, OA was considered a wear and tear disease, leading to the loss of articular cartilage and joint disability. Nowadays, thanks to advancements in molecular biology, OA is believed to be a very complex multifactorial disease. OA is a degenerative disease characterized by “low-grade inflammation” in cartilage and synovium, resulting in the loss of joint structure and progressive deterioration of cartilage. Although the disease can be dependent on genetic and epigenetic factors, sex, ethnicity, and age (cellular senescence, apoptosis and lubricin), it is also associated with obesity and overweight, dietary factors, sedentary lifestyle and sport injuries. The aim of this review is to highlight how certain behaviors, habits and lifestyles may be involved in the onset and progression of OA and to summarize the principal risk factors involved in the development of this complicated joint disorder. PMID:25785564

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

Modelling the propagation of social response during a disease outbreak.

PubMed

Fast, Shannon M; González, Marta C; Wilson, James M; Markuzon, Natasha

2015-03-06

Epidemic trajectories and associated social responses vary widely between populations, with severe reactions sometimes observed. When confronted with fatal or novel pathogens, people exhibit a variety of behaviours from anxiety to hoarding of medical supplies, overwhelming medical infrastructure and rioting. We developed a coupled network approach to understanding and predicting social response. We couple the disease spread and panic spread processes and model them through local interactions between agents. The social contagion process depends on the prevalence of the disease, its perceived risk and a global media signal. We verify the model by analysing the spread of disease and social response during the 2009 H1N1 outbreak in Mexico City and 2003 severe acute respiratory syndrome and 2009 H1N1 outbreaks in Hong Kong, accurately predicting population-level behaviour. This kind of empirically validated model is critical to exploring strategies for public health intervention, increasing our ability to anticipate the response to infectious disease outbreaks. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

The Impact of "Possible Patients" on Phenotyping Algorithms: Electronic Phenotype Algorithms Can Only Be Reproduced by Sharing Detailed Annotation Criteria.

PubMed

Kagawa, Rina; Kawazoe, Yoshimasa; Shinohara, Emiko; Imai, Takeshi; Ohe, Kazuhiko

2017-01-01

Phenotyping is an automated technique for identifying patients diagnosed with a particular disease based on electronic health records (EHRs). To evaluate phenotyping algorithms, which should be reproducible, the annotation of EHRs as a gold standard is critical. However, we have found that the different types of EHRs cannot be definitively annotated into CASEs or CONTROLs. The influence of such "possible patients" on phenotyping algorithms is unknown. To assess these issues, for four chronic diseases, we annotated EHRs by using information not directly referring to the diseases and developed two types of phenotyping algorithms for each disease. We confirmed that each disease included different types of possible patients. The performance of phenotyping algorithms differed depending on whether possible patients were considered as CASEs, and this was independent of the type of algorithms. Our results indicate that researchers must share annotation criteria for classifying the possible patients to reproduce phenotyping algorithms.

TSLP-elicited basophil responses can mediate the pathogenesis of eosinophilic esophagitis

PubMed Central

Noti, Mario; Tait Wojno, Elia D.; Kim, Brian S.; Siracusa, Mark C.; Giacomin, Paul R.; Nair, Meera G.; Benitez, Alain J.; Ruymann, Kathryn R.; Muir, Amanda B.; Hill, David A.; Chikwava, Kudakwashe R.; Moghaddam, Amin E.; Sattentau, Quentin J.; Alex, Aneesh; Zhou, Chao; Yearley, Jennifer H.; Menard-Katcher, Paul; Kubo, Masato; Obata-Ninomiya, Kazushige; Karasuyama, Hajime; Comeau, Michael R.; Brown-Whitehorn, Terri; de Waal Malefyt, Rene; Sleiman, Patrick M.; Hakonarson, Hakon; Cianferoni, Antonella; Falk, Gary W.; Wang, Mei-Lun; Spergel, Jonathan M.; Artis, David

2014-01-01

Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. EoE has become increasingly common, but current management strategies are nonspecific. Thus, there is an urgent need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis remains unknown. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE but was dependent on TSLP-elicited basophils. Therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. Critically, in human subjects with EoE, we observed elevated TSLP levels and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses. Together, these data suggest that the TSLP-basophil axis could be therapeutically targeted to treat EoE. PMID:23872715

Non-Alzheimer’s dementia 2

PubMed Central

Walker, Zuzana; Possin, Katherine L; Boeve, Bradley F; Aarsland, Dag

2018-01-01

The broad importance of dementia is undisputed, with Alzheimer’s disease justifiably getting the most attention. However, dementia with Lewy bodies and Parkinson’s disease dementia, now called Lewy body dementias, are the second most common type of degenerative dementia in patients older than 65 years. Despite this, Lewy body dementias receive little attention and patients are often misdiagnosed, leading to less than ideal management. Over the past 10 years, considerable effort has gone into improving diagnostic accuracy by refining diagnostic criteria and using imaging and other biomarkers. Dementia with Lewy bodies and Parkinson’s disease dementia share the same pathophysiology, and effective treatments will depend not only on successful treatment of symptoms but also on targeting the pathological mechanisms of disease, ideally before symptoms and clinical signs develop. We summarise the most pertinent progress from the past 10 years, outlining some of the challenges for the future, which will require refinement of diagnosis and clarification of the pathogenesis, leading to disease-modifying treatments. PMID:26595642

Modelling the propagation of social response during a disease outbreak

PubMed Central

Fast, Shannon M.; González, Marta C.; Wilson, James M.; Markuzon, Natasha

2015-01-01

Epidemic trajectories and associated social responses vary widely between populations, with severe reactions sometimes observed. When confronted with fatal or novel pathogens, people exhibit a variety of behaviours from anxiety to hoarding of medical supplies, overwhelming medical infrastructure and rioting. We developed a coupled network approach to understanding and predicting social response. We couple the disease spread and panic spread processes and model them through local interactions between agents. The social contagion process depends on the prevalence of the disease, its perceived risk and a global media signal. We verify the model by analysing the spread of disease and social response during the 2009 H1N1 outbreak in Mexico City and 2003 severe acute respiratory syndrome and 2009 H1N1 outbreaks in Hong Kong, accurately predicting population-level behaviour. This kind of empirically validated model is critical to exploring strategies for public health intervention, increasing our ability to anticipate the response to infectious disease outbreaks. PMID:25589575

Colitis and Colon Cancer in WASP-Deficient Mice Require Helicobacter Spp.

PubMed Central

Nguyen, Deanna D.; Muthupalani, Suresh; Goettel, Jeremy A.; Eston, Michelle A.; Mobley, Melissa; Taylor, Nancy S.; McCabe, Amanda; Marin, Romela; Snapper, Scott B.; Fox, James G.

2014-01-01

Background Wiskott-Aldrich Syndrome protein (WASP)-deficient patients and mice are immunodeficient and can develop inflammatory bowel disease. The intestinal microbiome is critical to the development of colitis in most animal models, in which, Helicobacter spp. have been implicated in disease pathogenesis. We sought to determine the role of Helicobacter spp. in colitis development in WASP-deficient (WKO) mice. Methods Feces from WKO mice raised under specific pathogen free conditions were evaluated for the presence of Helicobacter spp., after which, a subset of mice were rederived in Helicobacter spp.-free conditions. Helicobacter spp.-free WKO animals were subsequently infected with Helicobacter bilis. Results Helicobacter spp. were detected in feces from WKO mice. After re-derivation in Helicobacter spp.-free conditions, WKO mice did not develop spontaneous colitis but were susceptible to radiation-induced colitis. Moreover, a T-cell transfer model of colitis dependent on WASP-deficient innate immune cells also required Helicobacter spp. colonization. Helicobacter bilis infection of rederived WKO mice led to typhlitis and colitis. Most notably, several H. bilis-infected animals developed dysplasia with 10% demonstrating colon carcinoma, which was not observed in uninfected controls. Conclusions Spontaneous and T-cell transfer, but not radiation-induced, colitis in WKO mice is dependent on the presence of Helicobacter spp. Furthermore, H. bilis infection is sufficient to induce typhlocolitis and colon cancer in Helicobacter spp.-free WKO mice. This animal model of a human immunodeficiency with chronic colitis and increased risk of colon cancer parallels what is seen in human colitis and implicates specific microbial constituents in promoting immune dysregulation in the intestinal mucosa. PMID:23820270

Cryptosporidiosis: Environmental, therapeutic, and preventive challenges

PubMed Central

Collinet-Adler, Stefan; Ward, Honorine D.

2014-01-01

Cryptosporidium spp. are responsible for endemic and epidemic disease worldwide. Clinical manifestations may include acute, persistent, or chronic diarrhea, biliary, and pulmonary disease. Disease severity ranges from asymptomatic or mild to severe, intractable diarrhea with wasting depending on immune status, nutrition, and age. Transmission is fecal-oral with both human and animal reservoirs. Disease is often self limited in healthy individuals, but therapy remains a challenge in the immune-compromised. Prevention currently depends on appropriate hygiene and proper water management and treatment. PMID:20521158

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.

PubMed

Novarino, Gaia; Fenstermaker, Ali G; Zaki, Maha S; Hofree, Matan; Silhavy, Jennifer L; Heiberg, Andrew D; Abdellateef, Mostafa; Rosti, Basak; Scott, Eric; Mansour, Lobna; Masri, Amira; Kayserili, Hulya; Al-Aama, Jumana Y; Abdel-Salam, Ghada M H; Karminejad, Ariana; Kara, Majdi; Kara, Bulent; Bozorgmehri, Bita; Ben-Omran, Tawfeg; Mojahedi, Faezeh; El Din Mahmoud, Iman Gamal; Bouslam, Naima; Bouhouche, Ahmed; Benomar, Ali; Hanein, Sylvain; Raymond, Laure; Forlani, Sylvie; Mascaro, Massimo; Selim, Laila; Shehata, Nabil; Al-Allawi, Nasir; Bindu, P S; Azam, Matloob; Gunel, Murat; Caglayan, Ahmet; Bilguvar, Kaya; Tolun, Aslihan; Issa, Mahmoud Y; Schroth, Jana; Spencer, Emily G; Rosti, Rasim O; Akizu, Naiara; Vaux, Keith K; Johansen, Anide; Koh, Alice A; Megahed, Hisham; Durr, Alexandra; Brice, Alexis; Stevanin, Giovanni; Gabriel, Stacy B; Ideker, Trey; Gleeson, Joseph G

2014-01-31

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

Dendritic Cells: A Double-Edged Sword in Immune Responses during Chagas Disease

PubMed Central

Gil-Jaramillo, Natalia; Motta, Flávia N.; Favali, Cecília B. F.; Bastos, Izabela M. D.; Santana, Jaime M.

2016-01-01

Dendritic cells (DCs) are the most important member of the antigen presenting cells group due to their ability to recognize antigen at the infection site and their high specialized antigen internalization capacity. These cells have central role in connecting the innate and adaptive immune responses against Trypanosoma cruzi, the causative agent of Chagas disease. These first line defense cells modulate host immune response depending on type, maturation level, cytokine milieu and DC receptor involved in the interactions with T. cruzi, influencing the development of the disease clinic forms. Here, we present a review of DCs–T. cruzi interactions both in human and murine models, pointing out the parasite ability to manipulate DCs activity for the purpose of evading innate immune response and assuring its own survival and persistence. PMID:27471496

Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies

PubMed Central

Lee, Wei-Hua; Higuchi, Hitoshi; Ikeda, Sakae; Macke, Erica L; Takimoto, Tetsuya; Pattnaik, Bikash R; Liu, Che; Chu, Li-Fang; Siepka, Sandra M; Krentz, Kathleen J; Rubinstein, C Dustin; Kalejta, Robert F; Thomson, James A; Mullins, Robert F; Takahashi, Joseph S; Pinto, Lawrence H; Ikeda, Akihiro

2016-01-01

While the aging process is central to the pathogenesis of age-dependent diseases, it is poorly understood at the molecular level. We identified a mouse mutant with accelerated aging in the retina as well as pathologies observed in age-dependent retinal diseases, suggesting that the responsible gene regulates retinal aging, and its impairment results in age-dependent disease. We determined that a mutation in the transmembrane 135 (Tmem135) is responsible for these phenotypes. We observed localization of TMEM135 on mitochondria, and imbalance of mitochondrial fission and fusion in mutant Tmem135 as well as Tmem135 overexpressing cells, indicating that TMEM135 is involved in the regulation of mitochondrial dynamics. Additionally, mutant retina showed higher sensitivity to oxidative stress. These results suggest that the regulation of mitochondrial dynamics through TMEM135 is critical for protection from environmental stress and controlling the progression of retinal aging. Our study identified TMEM135 as a critical link between aging and age-dependent diseases. DOI: http://dx.doi.org/10.7554/eLife.19264.001 PMID:27863209

Approach and rationale to developing an IPM program: Examples of insect management in British Columbia reforestation nurseries

Treesearch

David Trotter

2002-01-01

Insects, weeds, and diseases are a significant part of the production process that nursery growers must consider in order to effectively grow the desired conifer seedling. For the pests and seedlings, the underlying theme is survival, which encompasses 3 major components: stimulus, recognition, and response (Shigo 1991). Thus, the continuation of any system depends on...

Stargardt disease: towards developing a model to predict phenotype.

PubMed

Heathfield, Laura; Lacerda, Miguel; Nossek, Christel; Roberts, Lisa; Ramesar, Rajkumar S

2013-10-01

Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype-phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype-phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families.

Digital Quantification of Goldmann Visual Fields (GVF) as a Means for Genotype-Phenotype Comparisons and Detection of Progression in Retinal Degenerations

PubMed Central

Zahid, Sarwar; Peeler, Crandall; Khan, Naheed; Davis, Joy; Mahmood, Mahdi; Heckenlively, John; Jayasundera, Thiran

2015-01-01

Purpose To develop a reliable and efficient digital method to quantify planimetric Goldmann visual field (GVF) data to monitor disease course and treatment responses in retinal degenerative diseases. Methods A novel method to digitally quantify GVF using Adobe Photoshop CS3 was developed for comparison to traditional digital planimetry (Placom 45C digital planimeter; EngineerSupply, Lynchburg, Virginia, USA). GVFs from 20 eyes from 10 patients with Stargardt disease were quantified to assess the difference between the two methods (a total of 230 measurements per method). This quantification approach was also applied to 13 patients with X-linked retinitis pigmentosa (XLRP) with mutations in RPGR. Results Overall, measurements using Adobe Photoshop were more rapidly performed than those using conventional planimetry. Photoshop measurements also exhibited less inter- and intra-observer variability. GVF areas for the I4e isopter in patients with the same mutation in RPGR who were nearby in age had similar qualitative and quantitative areas. Conclusions Quantification of GVF using Adobe Photoshop is quicker, more reliable, and less-user dependent than conventional digital planimetry. It will be a useful tool for both retrospective and prospective studies of disease course as well as for monitoring treatment response in clinical trials for retinal degenerative diseases. PMID:24664690

Digital quantification of Goldmann visual fields (GVFs) as a means for genotype-phenotype comparisons and detection of progression in retinal degenerations.

PubMed

Zahid, Sarwar; Peeler, Crandall; Khan, Naheed; Davis, Joy; Mahmood, Mahdi; Heckenlively, John R; Jayasundera, Thiran

2014-01-01

To develop a reliable and efficient digital method to quantify planimetric Goldmann visual field (GVF) data to monitor disease course and treatment responses in retinal degenerative diseases. A novel method to digitally quantify GVFs using Adobe Photoshop CS3 was developed for comparison to traditional digital planimetry (Placom 45C digital planimeter; Engineer Supply, Lynchburg, Virginia, USA). GVFs from 20 eyes from 10 patients with Stargardt disease were quantified to assess the difference between the two methods (a total of 230 measurements per method). This quantification approach was also applied to 13 patients with X-linked retinitis pigmentosa (XLRP) with mutations in RPGR. Overall, measurements using Adobe Photoshop were more rapidly performed than those using conventional planimetry. Photoshop measurements also exhibited less inter- and intraobserver variability. GVF areas for the I4e isopter in patients with the same mutation in RPGR who were nearby in age had similar qualitative and quantitative areas. Quantification of GVFs using Adobe Photoshop is quicker, more reliable, and less user dependent than conventional digital planimetry. It will be a useful tool for both retrospective and prospective studies of disease course as well as for monitoring treatment response in clinical trials for retinal degenerative diseases.

Metallothionein-1 and nitric oxide expression are inversely correlated in a murine model of Chagas disease

PubMed Central

Gonzalez-Mejia, Martha Elba; Torres-Rasgado, Enrique; Porchia, Leonardo M; Salgado, Hilda Rosas; Totolhua, José-Luis; Ortega, Arturo; Hernández-Kelly, Luisa Clara Regina; Ruiz-Vivanco, Guadalupe; Báez-Duarte, Blanca G; Pérez-Fuentes, Ricardo

2014-01-01

Chagas disease, caused by Trypanosoma cruzi, represents an endemic among Latin America countries. The participation of free radicals, especially nitric oxide (NO), has been demonstrated in the pathophysiology of seropositive individuals with T. cruzi. In Chagas disease, increased NO contributes to the development of cardiomyopathy and megacolon. Metallothioneins (MTs) are efficient free radicals scavengers of NO in vitro and in vivo. Here, we developed a murine model of the chronic phase of Chagas disease using endemic T. cruzi RyCH1 in BALB/c mice, which were divided into four groups: infected non-treated (Inf), infected N-monomethyl-L-arginine treated (Inf L-NAME), non-infected L-NAME treated and non-infected vehicle-treated. We determined blood parasitaemia and NO levels, the extent of parasite nests in tissues and liver MT-I expression levels. It was observed that NO levels were increasing in Inf mice in a time-dependent manner. Inf L-NAME mice had fewer T. cruzi nests in cardiac and skeletal muscle with decreased blood NO levels at day 135 post infection. This affect was negatively correlated with an increase of MT-I expression (r = -0.8462, p < 0.0001). In conclusion, we determined that in Chagas disease, an unknown inhibitory mechanism reduces MT-I expression, allowing augmented NO levels. PMID:24676665

Accumulation of Mutant Neuroserpin Precedes Development of Clinical Symptoms in Familial Encephalopathy with Neuroserpin Inclusion Bodies

PubMed Central

Galliciotti, Giovanna; Glatzel, Markus; Kinter, Jochen; Kozlov, Serguei V.; Cinelli, Paolo; Rülicke, Thomas; Sonderegger, Peter

2007-01-01

Intracellular protein deposition due to aggregation caused by conformational alteration is the hallmark of a number of neurodegenerative disorders, including Parkinson’s disease, tauopathies, Huntington’s disease, and familial encephalopathy with neuroserpin inclusion bodies. The latter is an autosomal dominant disorder caused by point mutations in neuroserpin resulting in its destabilization. Mutant neuroserpin polymerizes and forms intracellular aggregates that eventually lead to neurodegeneration. We generated genetically modified mice expressing the late-onset S49P-Syracuse or the early-onset S52R-Portland mutation of neuroserpin in central nervous system neurons. Mice exhibited morphological, biochemical, and clinical features resembling those found in the human disease. Analysis of brains revealed large intraneuronal inclusions composed exclusively of mutant neuroserpin, accumulating long before the development of clinical symptoms in a time-dependent manner. Clinical symptoms and amount of neuroserpin inclusions correlated with the predicted instability of the protein. The presence of inclusion bodies in subclinical mice indicates that in humans the prevalence of the disease could be higher than anticipated. In addition to shedding light on the pathophysiology of the human disorder, these mice provide an excellent model to study mechanisms of neurodegeneration or establish novel therapies for familial encephalopathy with neuroserpin inclusion bodies and other neurodegenerative diseases with intracellular protein deposition. PMID:17392169

Opportunity cost for early treatment of Chagas disease in Mexico.

PubMed

Ramsey, Janine M; Elizondo-Cano, Miguel; Sanchez-González, Gilberto; Peña-Nieves, Adriana; Figueroa-Lara, Alejandro

2014-04-01

Given current neglect for Chagas disease in public health programs in Mexico, future healthcare and economic development policies will need a more robust model to analyze costs and impacts of timely clinical attention of infected populations. A Markov decision model was constructed to simulate the natural history of a Chagas disease cohort in Mexico and to project the associated short and long-term clinical outcomes and corresponding costs. The lifetime cost for a timely diagnosed and treated Chagas disease patient is US$ 10,160, while the cost for an undiagnosed individual is US$ 11,877. The cost of a diagnosed and treated case increases 24-fold from early acute to indeterminate stage. The major cost component for lifetime cost was working days lost, between 44% and 75%, depending on the program scenario for timely diagnosis and treatment. In the long term, it is cheaper to diagnose and treat chagasic patients early, instead of doing nothing. This finding by itself argues for the need to shift current policy, in order to prioritize and attend this neglected disease for the benefit of social and economic development, which implies including treatment drugs in the national formularies. Present results are even more relevant, if one considers that timely diagnosis and treatment can arrest clinical progression and enhance a chronic patient's quality of life.

Stargardt Disease: towards developing a model to predict phenotype

PubMed Central

Heathfield, Laura; Lacerda, Miguel; Nossek, Christel; Roberts, Lisa; Ramesar, Rajkumar S

2013-01-01

Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype–phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype–phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families. PMID:23695285

Traditional Medicines and Kidney Disease in Low- and Middle-Income Countries: Opportunities and Challenges.

PubMed

Stanifer, John W; Kilonzo, Kajiru; Wang, Daphne; Su, Guobin; Mao, Wei; Zhang, Lei; Zhang, La; Nayak-Rao, Shobhana; Miranda, J Jaime

2017-05-01

Traditional medicines are a principal form of health care for many populations, particularly in low- and middle-income countries, and they have gained attention as an important means of health care coverage globally. In the context of kidney diseases, the challenges and opportunities presented by traditional medicine practices are among the most important considerations for developing effective and sustainable public health strategies. However, little is known about the practices of traditional medicines in relation to kidney diseases, especially concerning benefits and harms. Kidney diseases may be caused, treated, prevented, improved, or worsened by traditional medicines depending on the setting, the person, and the types, modes, and frequencies of traditional medicine use. Given the profound knowledge gaps, nephrology practitioners and researchers may be uniquely positioned to facilitate more optimal public health strategies through recognition and careful investigation of traditional medicine practices. Effective implementation of such strategies also will require local partnerships, including engaging practitioners and users of traditional medicines. As such, practitioners and researchers investigating kidney diseases may be uniquely positioned to bridge the cultural, social, historical, and biologic differences between biomedicine and traditional medicine, and they have opportunities to lead efforts in developing public health strategies that are sensitive to these differences. Copyright © 2017 Elsevier Inc. All rights reserved.

[Effect of major epidemics on cultural awareness].

PubMed

Spitzy, K H

1995-01-01

Mankind has been stricken with "major" epidemic diseases throughout its history. The most serious among them immediately threaten man's life e.g. plague, cholera, smallpox, typhus, and dysentery, besides, there are others which take a slower course e.g. lues, leprosy, leishmaniasis, tuberculosis, and malaria. Yet, the "lesser" epidemic diseases like diphtheria, scarlet fever, mumps, pneumococcosis, influenza, and most recently AIDS may also turn into "major" ones. Originally, man exclusively depended on his genetic makeup for protection, and being particularly prone to attacks of disease he was subject to natural selection. Thus, only one human species survived, the homo sapiens. Interbreeding achieved biologic adaptation and created a balanced genetic polymorphism. Advancing in his degree of civilization, man formed groups, developed clothing, fire, houses, and tools, and his increasing cultural awareness allowed him to migrate from the tropical climates to more temperate, and less disease-infested zones. Immigration and wars, and the accompanying infections jeopardized and diminished entire populations and eradicated highly developed cultures like that of the American Indians. The plague, coming from Asia, and lues, from America, as well as cholera, influenza, and smallpox spread around the whole globe. Fear and terror led to irrational conclusions and triggered persecutions. The attitude of accepting disease as a God-sent fate (Hiob), or a God-sent punishment suppressed reasonable measures against disease. The necessary official measures have increasingly restricted liberty, and this patronizing treatment needs to be opposed with a higher sense of responsibility. Medical art has developed from more healing towards prophylactic and predictive medicine, which prognosticates the individual susceptibility to particular infections, and other risk factors.

Pneumococcal Transmission and Disease In Silico: A Microsimulation Model of the Indirect Effects of Vaccination

PubMed Central

Nurhonen, Markku; Cheng, Allen C.; Auranen, Kari

2013-01-01

Background The degree and time frame of indirect effects of vaccination (serotype replacement and herd immunity) are key determinants in assessing the net effectiveness of vaccination with pneumococcal conjugate vaccines (PCV) in control of pneumococcal disease. Using modelling, we aimed to quantify these effects and their dependence on coverage of vaccination and the vaccine's efficacy against susceptibility to pneumococcal carriage. Methods and Findings We constructed an individual-based simulation model that explores the effects of large-scale PCV programmes and applied it in a developed country setting (Finland). A population structure with transmission of carriage taking place within relevant mixing groups (families, day care groups, schools and neighbourhoods) was considered in order to properly assess the dependency of herd immunity on coverage of vaccination and vaccine efficacy against carriage. Issues regarding potential serotype replacement were addressed by employing a novel competition structure between multiple pneumococcal serotypes. Model parameters were calibrated from pre-vaccination data about the age-specific carriage prevalence and serotype distribution. The model predicts that elimination of vaccine-type carriage and disease among those vaccinated and, due to a substantial herd effect, also among the general population takes place within 5–10 years since the onset of a PCV programme with high (90%) coverage of vaccination and moderate (50%) vaccine efficacy against acquisition of carriage. A near-complete replacement of vaccine-type carriage by non-vaccine-type carriage occurs within the same time frame. Conclusions The changed patterns in pneumococcal carriage after PCV vaccination predicted by the model are unequivocal. The overall effect on disease incidence depends crucially on the magnitude of age- and serotype-specific case-to-carrier ratios of the remaining serotypes relative to those of the vaccine types. Thus the availability of reliable data on the incidence of both pneumococcal carriage and disease is essential in assessing the net effectiveness of PCV vaccination in a given epidemiological setting. PMID:23457504

Biomarkers of exposure, sensitivity and disease

NASA Technical Reports Server (NTRS)

Brooks, A. L.

1999-01-01

PURPOSE: This review is to evaluate the use of biomarkers as an indication of past exposure to radiation or other environmental insults, individual sensitivity and risk for the development of late occurring disease. OVERVIEW: Biomarkers can be subdivided depending on their applications. Markers of exposure and dose can be used to reconstruct and predict past accidental or occupational exposures when limited or no physical measurements were available. Markers of risk or susceptibility can help identify sensitivity individuals that are at increased risk for development of spontaneous disease and may help predict the increased risk in sensitive individuals associated with environmental or therapeutic radiation exposures. Markers of disease represent the initial cellular or molecular changes that occur during disease development. Each of these types of biomarkers serves a unique purpose. OUTLINE: This paper concentrates on biomarkers of dose and exposure and provides a brief review of biomarkers of sensitivity and disease. The review of biomarkers of dose and exposure will demonstrate the usefulness of biomarkers in evaluation of physical factors associated with radiation exposure, such as LET, doserate and dose distribution. It will also evaluate the use of biomarkers to establish relationships that exist between exposure parameters such as energy deposition, environmental concentration of radioactive materials, alpha traversals and dose. In addition, the importance of biological factors on the magnitude of the biomarker response will be reviewed. Some of the factors evaluated will be the influence of species, tissue, cell types and genetic background. The review will demonstrate that markers of sensitivity and disease often have little usefulness in dose-reconstruction and, by the same token, many markers of dose or exposure may not be applicable for prediction of sensitivity or risk.

Density-dependent resistance of the gypsy moth, Lymantria dispar, to its nucleopolyhedrovirus

Treesearch

James R. Reilly; Ann E. Hajek

2007-01-01

The processes controlling disease resistance can strongly influence the population dynamics of insect outbreaks. Evidence that disease resistance is density-dependent is accumulating, but the exact form of this relationship is highly variable from species to species.

Understanding the disease of addiction.

PubMed

Detar, D Todd

2011-03-01

Addiction is a chronic brain disease. Drug addiction manifests as a compulsive obsession to use a substance despite serious detrimental and sometimes irreversible consequences. Drug addiction is not the same as drug dependency because dependency may not manifest as an addictive behavior. This problem is fundamental to understanding the disease of addiction. This article discusses the neurobiology and genetics of drug addiction. Copyright © 2011. Published by Elsevier Inc.

Modulation of morphine antinociceptive tolerance and physical dependence by co-administration of simvastatin.

PubMed

Mansouri, Mohammad Taghi; Khodayar, Mohammad Javad; Tabatabaee, Amirhossein; Ghorbanzadeh, Behnam; Naghizadeh, Bahareh

2015-10-01

Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, are widely used in the management of different diseases beyond their primary indication for lowering cholesterol. Previous studies have demonstrated the neuroprotective effects of simvastatin in different animal models. In the present study, we examined the effects of simvastatin (30, 60, 100 and 300mg/kg, p.o.) on the development and expression of morphine-induced tolerance and dependence in mice. For the induction of morphine tolerance and dependence, mice were twice daily treated with morphine (10mg/kg, s.c.) for 5 consecutive days. Tolerance was evaluated by the hot-plate test and physical dependence by naloxone challenge, on the sixth day. The results showed that oral administration of simvastatin produced antinociceptive activity in a dose-dependent way. Co-administration of simvastatin with morphine did not affect the acute morphine-induced analgesia (10mg/kg, s.c.). However, repeated co-administration of simvastatin with morphine significantly attenuated the development of tolerance to the analgesic effect of morphine and inhibited the naloxone (5mg/kg, s.c.)-precipitated withdrawal signs (jumping and body weight loss). Also, simvastatin at doses of 100 and 300mg/kg attenuated the expression of morphine-induced tolerance and dependence. These data indicated that, while simvastatin can alleviate both development and expression of morphine-induced tolerance, it cannot enhance morphine-induced antinociception. Taken together, simvastatin may be used as an adjutant therapeutic agent in combination with morphine and or other opioids in patients with severe chronic pain. Copyright © 2015 Elsevier Inc. All rights reserved.

Transgenic FingRs for Live Mapping of Synaptic Dynamics in Genetically-Defined Neurons

PubMed Central

Son, Jong-Hyun; Keefe, Matthew D.; Stevenson, Tamara J.; Barrios, Joshua P.; Anjewierden, Scott; Newton, James B.; Douglass, Adam D.; Bonkowsky, Joshua L.

2016-01-01

Tools for genetically-determined visualization of synaptic circuits and interactions are necessary to build connectomics of the vertebrate brain and to screen synaptic properties in neurological disease models. Here we develop a transgenic FingR (fibronectin intrabodies generated by mRNA display) technology for monitoring synapses in live zebrafish. We demonstrate FingR labeling of defined excitatory and inhibitory synapses, and show FingR applicability for dissecting synapse dynamics in normal and disease states. Using our system we show that chronic hypoxia, associated with neurological defects in preterm birth, affects dopaminergic neuron synapse number depending on the developmental timing of hypoxia. PMID:26728131

Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone loss.

PubMed

Zahoor, Muhammad; Westhrin, Marita; Aass, Kristin Roseth; Moen, Siv Helen; Misund, Kristine; Psonka-Antonczyk, Katarzyna Maria; Giliberto, Mariaserena; Buene, Glenn; Sundan, Anders; Waage, Anders; Sponaas, Anne-Marit; Standal, Therese

2017-12-26

Multiple myeloma (MM) is a hematologic cancer characterized by expansion of malignant plasma cells in the bone marrow. Most patients develop an osteolytic bone disease, largely caused by increased osteoclastogenesis. The myeloma bone marrow is hypoxic, and hypoxia may contribute to MM disease progression, including bone loss. Here we identified interleukin-32 (IL-32) as a novel inflammatory cytokine expressed by a subset of primary MM cells and MM cell lines. We found that high IL-32 gene expression in plasma cells correlated with inferior survival in MM and that IL-32 gene expression was higher in patients with bone disease compared with those without. IL-32 was secreted from MM cells in extracellular vesicles (EVs), and those EVs, as well as recombinant human IL-32, promoted osteoclast differentiation both in vitro and in vivo. The osteoclast-promoting activity of the EVs was IL-32 dependent. Hypoxia increased plasma-cell IL-32 messenger RNA and protein levels in a hypoxia-inducible factor 1α-dependent manner, and high expression of IL-32 was associated with a hypoxic signature in patient samples, suggesting that hypoxia may promote expression of IL-32 in MM cells. Taken together, our results indicate that targeting IL-32 might be beneficial in the treatment of MM bone disease in a subset of patients.

Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone loss

PubMed Central

Zahoor, Muhammad; Aass, Kristin Roseth; Moen, Siv Helen; Misund, Kristine; Psonka-Antonczyk, Katarzyna Maria; Giliberto, Mariaserena; Buene, Glenn; Sundan, Anders; Waage, Anders; Sponaas, Anne-Marit

2017-01-01

Multiple myeloma (MM) is a hematologic cancer characterized by expansion of malignant plasma cells in the bone marrow. Most patients develop an osteolytic bone disease, largely caused by increased osteoclastogenesis. The myeloma bone marrow is hypoxic, and hypoxia may contribute to MM disease progression, including bone loss. Here we identified interleukin-32 (IL-32) as a novel inflammatory cytokine expressed by a subset of primary MM cells and MM cell lines. We found that high IL-32 gene expression in plasma cells correlated with inferior survival in MM and that IL-32 gene expression was higher in patients with bone disease compared with those without. IL-32 was secreted from MM cells in extracellular vesicles (EVs), and those EVs, as well as recombinant human IL-32, promoted osteoclast differentiation both in vitro and in vivo. The osteoclast-promoting activity of the EVs was IL-32 dependent. Hypoxia increased plasma-cell IL-32 messenger RNA and protein levels in a hypoxia-inducible factor 1α–dependent manner, and high expression of IL-32 was associated with a hypoxic signature in patient samples, suggesting that hypoxia may promote expression of IL-32 in MM cells. Taken together, our results indicate that targeting IL-32 might be beneficial in the treatment of MM bone disease in a subset of patients. PMID:29296919

Pathological histone acetylation in Parkinson's disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition.

PubMed

Harrison, Ian F; Smith, Andrew D; Dexter, David T

2018-02-14

Parkinson's disease (PD) is associated with degeneration of nigrostriatal neurons due to intracytoplasmic inclusions composed predominantly of a synaptic protein called α-synuclein. Accumulations of α-synuclein are thought to 'mask' acetylation sites on histone proteins, inhibiting the action of histone acetyltransferase (HAT) enzymes in their equilibrium with histone deacetylases (HDACs), thus deregulating the dynamic control of gene transcription. It is therefore hypothesised that the misbalance in the actions of HATs/HDACs in neurodegeneration can be rectified with the use of HDAC inhibitors, limiting the deregulation of transcription and aiding neuronal homeostasis and neuroprotection in disorders such as PD. Here we quantify histone acetylation in the Substantia Nigra pars compacta (SNpc) in the brains of control, early and late stage PD cases to determine if histone acetylation is a function of disease progression. PD development is associated with Braak-dependent increases in histone acetylation. Concurrently, we show that as expected disease progression is associated with reduced markers of dopaminergic neurons and increased markers of activated microglia. We go on to demonstrate that in vitro, degenerating dopaminergic neurons exhibit histone hypoacetylation whereas activated microglia exhibit histone hyperacetylation. This suggests that the disease-dependent increase in histone acetylation observed in human PD cases is likely a combination of the contributions of both degenerating dopaminergic neurons and infiltrating activated microglia. The HDAC SIRT 2 has become increasingly implicated as a novel target for mediation of neuroprotection in PD: the neuronal and microglial specific effects of its inhibition however remain unclear. We demonstrate that SIRT 2 expression in the SNpc of PD brains remains relatively unchanged from controls and that SIRT 2 inhibition, via AGK2 treatment of neuronal and microglial cultures, results in neuroprotection of dopaminergic neurons and reduced activation of microglial cells. Taken together, here we demonstrate that histone acetylation is disease-dependently altered in PD, likely due the effects of dopaminergic neurodegeneration and microglial infiltration; yet SIRT 2 remains relatively unaltered with disease. Given the stable nature of SIRT 2 expression with disease and the effects of SIRT 2 inhibitor treatment on degenerating dopaminergic neurons and activated microglia detected in vitro, SIRT 2 inhibitors warrant further investigation as potential therapeutics for the treatment of the PD. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Overcoming barriers to nicotine dependence treatment.

PubMed

Ferry, L H

1999-09-01

Tobacco dependence is the most overlooked and undertreated preventable cause of chronic disease in the developed world. Three barriers to effective treatment must be overcome: the reluctance of nicotine addicts to seek help; inadequate training of health professionals to treat hard core smokers; and a health care system that does not acknowledge the need for professional treatment of nicotine addiction. Effective physicians are equipped with the knowledge and skills to identify high-risk smokers who need more assistance to quit. All smokers should be engaged in a tailored office intervention based on their needs. Adoption of simple clinical protocols can eliminate the barriers that prevent effective counseling and treatment in the office setting.

The relationship between opioid and sugar intake: Review of evidence and clinical applications

PubMed Central

Mysels, David J; Sullivan, Maria A

2011-01-01

Opioid dependence poses significant public health risks arising from associated morbidity and mortality caused by accidents, infectious disease, and social ramifications of crime and unemployment, among other complications. Opioid use, acute and chronic, is also associated with weight gain, glycemic dysregulation, and dental pathology. The literature supporting the connection between opiate use and development of preference for sweet tastes is reviewed, and further association with dental pathology, weight gain, and loss of glycemic control are considered. We discuss the impact of sweet tastes on the endogenous opioid system as well as clinical implications for analgesia and treating the opiate-dependent patient. PMID:21269006

Cholesterol: a novel regulatory role in myelin formation.

PubMed

Saher, Gesine; Quintes, Susanne; Nave, Klaus-Armin

2011-02-01

Myelin consists of tightly compacted membranes that form an insulating sheath around axons. The function of myelin for rapid saltatory nerve conduction is dependent on its unique composition, highly enriched in glycosphingolipids and cholesterol. Cholesterol emerged as the only integral myelin component that is essential and rate limiting for the development of CNS and PNS myelin. Experiments with conditional mouse mutants that lack cholesterol biosynthesis in oligodendrocytes revealed that only minimal changes of the CNS myelin lipid composition are tolerated. In Schwann cells of the PNS, protein trafficking and myelin compaction depend on cholesterol. In this review, the authors summarize the role of cholesterol in myelin biogenesis and myelin disease.

Gene expression changes in a zebrafish model of drug dependency suggest conservation of neuro-adaptation pathways.

PubMed

Kily, Layla J M; Cowe, Yuka C M; Hussain, Osman; Patel, Salma; McElwaine, Suzanne; Cotter, Finbarr E; Brennan, Caroline H

2008-05-01

Addiction is a complex psychiatric disorder considered to be a disease of the brain's natural reward reinforcement system. Repeated stimulation of the 'reward' pathway leads to adaptive changes in gene expression and synaptic organization that reinforce drug taking and underlie long-term changes in behaviour. The primitive nature of reward reinforcement pathways and the near universal ability of abused drugs to target the same system allow drug-associated reward and reinforcement to be studied in non-mammalian species. Zebrafish have proved to be a valuable model system for the study of vertebrate development and disease. Here we demonstrate that adult zebrafish show a dose-dependent acute conditioned place preference (CPP) reinforcement response to ethanol or nicotine. Repeated exposure of adult zebrafish to either nicotine or ethanol leads to a robust CPP response that persists following 3 weeks of abstinence and in the face of adverse stimuli, a behavioural indicator of the establishment of dependence. Microarray analysis using whole brain samples from drug-treated and control zebrafish identified 1362 genes that show a significant change in expression between control and treated individuals. Of these genes, 153 are common to both ethanol- and nicotine-treated animals. These genes include members of pathways and processes implicated in drug dependence in mammalian models, revealing conservation of neuro-adaptation pathways between zebrafish and mammals.

Pepino mosaic virus RNA-Dependent RNA Polymerase POL Domain Is a Hypersensitive Response-Like Elicitor Shared by Necrotic and Mild Isolates.

PubMed

Sempere, Raquel N; Gómez-Aix, Cristina; Ruíz-Ramón, Fabiola; Gómez, Pedro; Hasiów-Jaroszewska, Beata; Sánchez-Pina, María Amelia; Aranda, Miguel A

2016-04-01

Pepino mosaic virus (PepMV) is an emerging pathogen that represents a serious threat to tomato production worldwide. PepMV-induced diseases manifest with a wide range of symptoms, including systemic necrosis. Our results showed that PepMV accumulation depends on the virus isolate, tomato cultivar, and environmental conditions, and associates with the development of necrosis. Substitution of lysine for glutamic acid at position 67 in the triple gene block 3 (TGB3) protein, previously described as a necrosis determinant, led to increased virus accumulation and was necessary but not sufficient to induce systemic necrosis. Systemic necrosis both in tomato and Nicotiana benthamiana shared hypersensitive response (HR) features, allowing the assessment of the role of different genomic regions on necrosis induction. Overexpression of both TGB3 and the polymerase domain (POL) of the RNA-dependent RNA polymerase (RdRp) resulted in necrosis, although only local expression of POL triggered HR-like symptoms. Our results also indicated that the necrosis-eliciting activity of POL resides in its highly conserved "palm" domain, and that necrosis was jasmonic acid-dependent but not salicylic acid-dependent. Altogether, our data suggest that the RdRp-POL domain plays an important role in PepMV necrosis induction, with necrosis development depending on the virus accumulation level, which can be modulated by the nature of TGB3, host genotype and environmental conditions.

The Functional Genetics of Handedness and Language Lateralization: Insights from Gene Ontology, Pathway and Disease Association Analyses.

PubMed

Schmitz, Judith; Lor, Stephanie; Klose, Rena; Güntürkün, Onur; Ocklenburg, Sebastian

2017-01-01

Handedness and language lateralization are partially determined by genetic influences. It has been estimated that at least 40 (and potentially more) possibly interacting genes may influence the ontogenesis of hemispheric asymmetries. Recently, it has been suggested that analyzing the genetics of hemispheric asymmetries on the level of gene ontology sets, rather than at the level of individual genes, might be more informative for understanding the underlying functional cascades. Here, we performed gene ontology, pathway and disease association analyses on genes that have previously been associated with handedness and language lateralization. Significant gene ontology sets for handedness were anatomical structure development, pattern specification (especially asymmetry formation) and biological regulation. Pathway analysis highlighted the importance of the TGF-beta signaling pathway for handedness ontogenesis. Significant gene ontology sets for language lateralization were responses to different stimuli, nervous system development, transport, signaling, and biological regulation. Despite the fact that some authors assume that handedness and language lateralization share a common ontogenetic basis, gene ontology sets barely overlap between phenotypes. Compared to genes involved in handedness, which mostly contribute to structural development, genes involved in language lateralization rather contribute to activity-dependent cognitive processes. Disease association analysis revealed associations of genes involved in handedness with diseases affecting the whole body, while genes involved in language lateralization were specifically engaged in mental and neurological diseases. These findings further support the idea that handedness and language lateralization are ontogenetically independent, complex phenotypes.

Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer's disease pathology?

PubMed

Creegan, Rhona; Hunt, Wendy; McManus, Alexandra; Rainey-Smith, Stephanie R

2015-05-28

Alzheimer's disease (AD), the most common form of dementia, is a chronic, progressive neurodegenerative disease that manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With a global ageing population, it is predicted that there will be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Global estimates put a direct cost for treating and caring for people with dementia at $US604 billion, an estimate that is expected to increase markedly. According to recent global statistics, there are 35.6 million dementia sufferers, the number of which is predicted to double every 20 years, unless strategies are implemented to reduce this burden. Currently, there is no cure for AD; while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. A greater understanding of AD pathophysiology is paramount, and attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis, but also provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets, including nutritional ones. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestation develops.

The Functional Genetics of Handedness and Language Lateralization: Insights from Gene Ontology, Pathway and Disease Association Analyses

PubMed Central

Schmitz, Judith; Lor, Stephanie; Klose, Rena; Güntürkün, Onur; Ocklenburg, Sebastian

2017-01-01

Handedness and language lateralization are partially determined by genetic influences. It has been estimated that at least 40 (and potentially more) possibly interacting genes may influence the ontogenesis of hemispheric asymmetries. Recently, it has been suggested that analyzing the genetics of hemispheric asymmetries on the level of gene ontology sets, rather than at the level of individual genes, might be more informative for understanding the underlying functional cascades. Here, we performed gene ontology, pathway and disease association analyses on genes that have previously been associated with handedness and language lateralization. Significant gene ontology sets for handedness were anatomical structure development, pattern specification (especially asymmetry formation) and biological regulation. Pathway analysis highlighted the importance of the TGF-beta signaling pathway for handedness ontogenesis. Significant gene ontology sets for language lateralization were responses to different stimuli, nervous system development, transport, signaling, and biological regulation. Despite the fact that some authors assume that handedness and language lateralization share a common ontogenetic basis, gene ontology sets barely overlap between phenotypes. Compared to genes involved in handedness, which mostly contribute to structural development, genes involved in language lateralization rather contribute to activity-dependent cognitive processes. Disease association analysis revealed associations of genes involved in handedness with diseases affecting the whole body, while genes involved in language lateralization were specifically engaged in mental and neurological diseases. These findings further support the idea that handedness and language lateralization are ontogenetically independent, complex phenotypes. PMID:28729848