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Sample records for acquired human diseases

  1. Acquired cystic kidney disease.

    PubMed

    Levine, E

    1996-09-01

    ACKD is characterized by the development of many fluid-filled renal cysts and sometimes neoplasms in the kidneys of individuals with chronic renal failure but without a history of hereditary cystic disease. The condition is seen mainly in dialysis patients, but often begins in patients with ESRD before dialysis is started. Most patients with ACKD are asymptomatic, but the disorder may be associated with such serious complications as retroperitoneal hemorrhage and metastatic renal cell carcinoma. The diagnosis of ACKD and its complications is best achieved by CT scanning, although US and MR imaging may be useful in evaluation, particularly in patients not treated with dialysis. Cyst hemorrhage is common in ACKD and may cause flank pain and hematuria. Hemorrhagic cysts may be recognized by their CT scan, sonographic, or MR imaging features. Hemorrhagic cysts may rupture into the perinephric space causing large perinephric hematomas. These can usually be treated-conservatively. Patients with ACKD, particularly those treated with dialysis, have an increased risk of renal cell carcinoma. Renal cell carcinoma may also develop in the native kidneys of renal transplant recipients with good graft function many years after transplantation. Annual imaging of the native kidneys of all dialysis patients or of transplant recipients for the development of carcinoma is not justified, however, because it has not been shown to have a significant effect on patient outcome. Screening may, however, be useful in selected dialysis patients with good general medical condition and who have known risk factors for renal cell carcinoma including prolonged dialysis, large kidneys, ACKD, and male gender. Screening of the native kidneys of transplant recipients may be performed when they are referred for US evaluation of the renal allograft.

  2. Mycobacterial disease, immunosuppression, and acquired immunodeficiency syndrome.

    PubMed Central

    Collins, F M

    1989-01-01

    The mycobacteria are an important group of acid-fast pathogens ranging from obligate intracellular parasites such as Mycobacterium leprae to environmental species such as M. gordonae and M. fortuitum. The latter may behave as opportunistic human pathogens if the host defenses have been depleted in some manner. The number and severity of such infections have increased markedly with the emergence of the acquired immunodeficiency syndrome (AIDS) epidemic. These nontuberculous mycobacteria tend to be less virulent for humans than M. tuberculosis, usually giving rise to self-limiting infections involving the cervical and mesenteric lymph nodes of young children. However, the more virulent serovars of M. avium complex can colonize the bronchial and intestinal mucosal surfaces of healthy individuals, becoming virtual members of the commensal gut microflora and thus giving rise to low levels of skin hypersensitivity to tuberculins prepared from M. avium and M. intracellulare. Systemic disease develops when the normal T-cell-mediated defenses become depleted as a result of old age, cancer chemotherapy, or infection with human immunodeficiency virus. As many as 50% of human immunodeficiency virus antibody-positive individuals develop mycobacterial infections at some time during their disease. Most isolates of M. avium complex from AIDS patients fall into serotypes 4 and 8. The presence of these drug-resistant mycobacteria in the lungs of the AIDS patient makes their effective clinical treatment virtually impossible. More effective chemotherapeutic, prophylactic, and immunotherapeutic reagents are urgently needed to treat this rapidly increasing patient population. PMID:2680057

  3. [Acquired and congenital heart diseases during pregancy].

    PubMed

    De Feo, Stefania; Iacovoni, Attilio; Faggiano, Pompilio

    2012-05-01

    Heart diseases are the leading cause of maternal morbidity and mortality. The number of patients with congenital heart diseases reaching childbearing age, as well as the proportion of women with acquired conditions, such as ischemic heart disease, becoming pregnant is constantly increasing. All women with known heart disease should have pre-pregnancy counseling, to assess maternal and fetal risk. Women at moderate or high risk should be under the care of a specialist prenatal team with experience in managing women with heart disease during pregnancy. Conditions that are considered at particularly high risk (mortality >10%) include Marfan syndrome with dilated aortic root, severe left ventricular dysfunction, severe left heart obstructive lesions, and pulmonary hypertension. Peripartum cardiomyopathy is a rare and potentially fatal disease related to pregnancy and the postnatal period that presents with symptoms of congestion and/or hypoperfusion and may rapidly progress to acute and life-threatening heart failure. However, the majority of women with heart disease can tolerate pregnancy; therefore an adequate multidisciplinary approach with the gynecologist, anesthesiologist and cardiologist should be advocated in order to reduce maternal and fetal risks associated with pregnancy.

  4. [Acquired cystic renal disease. Association with hypernephroma].

    PubMed

    Comesaña, E; Pesqueira, D; Tardáguila, F; De la Fuente, A; Antón, I; Vidal, L; Zungri, E

    1992-02-01

    Emergence of multiple bilateral renal cysts observed in patients undergoing periodic haemodialysis is 40%. The pathology, known as Acquired Cystic Renal Disease (A.C.R.D.) presents a high association to renal cancer. Two cases of A.C.R.D. and their association with hypernephroma, one resulting in secondary retroperitoneal haemorrhage and the other in intracystic haemorrhage, are presented. Forms and diagnosis are analyzed, insisting upon the need of monitoring the patients in haemodialysis from the point of view of tumour emergence.

  5. Alzheimer's disease: An acquired neurodegenerative laminopathy

    PubMed Central

    Frost, Bess

    2016-01-01

    ABSTRACT The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a “nucleoplasmic reticulum,” into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination. PMID:27167528

  6. Alzheimer's disease: An acquired neurodegenerative laminopathy.

    PubMed

    Frost, Bess

    2016-05-01

    The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a "nucleoplasmic reticulum," into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination.

  7. Alzheimer's disease: An acquired neurodegenerative laminopathy.

    PubMed

    Frost, Bess

    2016-05-01

    The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a "nucleoplasmic reticulum," into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination. PMID:27167528

  8. Disentangling inborn and acquired immunity in human twins.

    PubMed

    Casanova, Jean-Laurent; Abel, Laurent

    2015-01-15

    The human geneticist Archibald Garrod noted in 1931 that, "It is, of necessity, no easy matter to distinguish between immunity which is inborn and that which has been acquired" (The Inborn Factors in Disease). In this issue of Cell, Brodin et al. show that the heritability of blood counts rapidly decreases with age for the lymphoid subsets responsible for adaptive immunity, unlike cells from other hematopoietic lineages.

  9. CT findings in complications of acquired renal cystic disease.

    PubMed

    Soffer, O; Miller, L R; Lichtman, J B

    1987-01-01

    A 42-year-old man with end-stage renal disease developed acquired renal cystic disease. The left kidney underwent tumorous degeneration necessitating nephrectomy. Eight months later acute hemorrhagic renal cyst rupture culminated in right nephrectomy.

  10. The thymus in acquired immune deficiency syndrome. Comparison with other types of immunodeficiency diseases, and presence of components of human immunodeficiency virus type 1.

    PubMed Central

    Schuurman, H. J.; Krone, W. J.; Broekhuizen, R.; van Baarlen, J.; van Veen, P.; Golstein, A. L.; Huber, J.; Goudsmit, J.

    1989-01-01

    The authors studied thymus specimens taken at autopsy from eight acquired immune deficiency syndrome (AIDS) patients and compared these with those taken from four patients with congenital immunodeficiency (unrelated to an intrinsic thymus defect) and seven patients after allogeneic bone marrow transplantation. In all cases, histology showed a severely involuted architecture, compatible with a debilitating disease before death. There were no major differences between thymus tissue in AIDS patients and in the other patients studied. This argues against the claim expressed in the literature that the epithelial microenvironment incurs particular HIV-1-induced injury in AIDS. This conclusion is substantiated by immunohistochemistry for HIV-1 gag and env proteins, and by hybridohistochemistry for gag/pol and env mRNA of HIV-1. Positive cells were observed only in low numbers, both inside the epithelial parenchyma and in the (expanded) perivascular areas. An interesting finding was the labeling of subcapsular/medullary epithelium in normal uninvoluted thymus by a number of antibodies to HIV-1 gag p17 and p24 proteins. Compatible with this labeling was the staining of epithelial stalks in hyperinvoluted thymuses irrespective of disease category. The previously reported cross-reactivity between HIV-1 core protein and thymosin alpha 1 cannot fully explain this observation, because the epithelium in the hyperinvoluted state is negative for thymosin alpha 1. This study confirms and extends previous reports on the endogenous presence of epitopes of retroviral antigens in thymic epithelium. Images Figure 1 Figure 2 Figure 3 PMID:2474255

  11. Behcet's disease in acquired immune deficiency syndrome.

    PubMed

    Siddiqui, Beenish; Fernandes, Denise; Chaucer, Benjamin; Chevenon, Marie; Nandi, Minesh; Saverimuttu, Jessie; Nfonoyim, Jay

    2016-01-01

    HIV/AIDS patients often present with orogenital ulcers. In the immunocompromised patient diagnosis of these ulcers pose a challenge, as there is a myriad of etiologies. We present a case of an HIV/AIDS patient with recurrent orogenital aphthosis that was confirmed to have concomitant diagnosis of Behcet's disease. Proper awareness of the causes of these ulcers is essential for prompt and effective treatment. While rare causes may be at the bottom of a differential list in an immunocompetent host, when HIV/AIDS is involved these rare causes often percolate to the top. PMID:26793479

  12. Cardiac primitive cells become committed to a cardiac fate in adult human heart with chronic ischemic disease but fail to acquire mature phenotype: genetic and phenotypic study.

    PubMed

    Nurzynska, Daria; Di Meglio, Franca; Romano, Veronica; Miraglia, Rita; Sacco, Anna Maria; Latino, Francesca; Bancone, Ciro; Della Corte, Alessandro; Maiello, Ciro; Amarelli, Cristiano; Montagnani, Stefania; Castaldo, Clotilde

    2013-01-01

    Adult human heart hosts a population of cardiac primitive CD117-positive cells (CPCs), which are responsible for physiological tissue homeostasis and regeneration. While the bona fide stem cells express telomerase, their progenies are no longer able to preserve telomeric DNA; hence the balance between their proliferation and differentiation has to be tightly controlled in order to prevent cellular senescence and apoptosis of CPCs before their maturation can be accomplished. We have examined at cellular and molecular level the proliferation, apoptosis and commitment of CPCs isolated from normal (CPC-N) and age-matched pathological adult human hearts (CPC-P) with ischemic heart disease. In the CPC-P, genes related to early stages of developmental processes, nervous system development and neurogenesis, skeletal development, bone and cartilage development were downregulated, while those involved in mesenchymal cell differentiation and heart development were upregulated, together with the transcriptional activation of TGFβ/BMP signaling pathway. In the pathological heart, asymmetric division was the prevalent type of cardiac stem cell division. The population of CPC-P consisted mainly of progenitors of cardiac cell lineages and less precursors; these cells proliferated more, but were also more susceptible to apoptosis with respect to CPC-N. These results indicate that CPCs fail to reach terminal differentiation and functional competence in pathological conditions. Adverse effects of underlying pathology, which disrupts cardiac tissue structure and composition, and cellular senescence, resulting from cardiac stem cell activation in telomere dysfunctional environment, can be responsible for such outcome.

  13. Imaging of acquired coronary diseases: From children to adults.

    PubMed

    Dehaene, A; Jacquier, A; Falque, C; Gorincour, G; Gaubert, J Y

    2016-05-01

    Acquired coronary diseases include aneurysms, fistulae, dissections, and stenosis. Aneurysms may occur secondarily to Kawasaki disease, a childhood vasculitis, the prognosis of which depends on the coronary involvement, or they may be degenerative, infectious, inflammatory, or traumatic in origin. Fistulae develop between the coronary arterial system and a pulmonary or bronchial artery, or cardiac cavity. Dissections may occur spontaneously or may be post-traumatic. These coronary abnormalities may be found incidentally or may present as complications, infarction or rupture. The goals of this article are to understand acquired childhood and adult coronary diseases and their usual means of presentation, the ways of investigating them, and the principles of their treatment. PMID:27130480

  14. Assessing the risk of laboratory-acquired meningococcal disease.

    PubMed

    Sejvar, James J; Johnson, David; Popovic, Tanja; Miller, J Michael; Downes, Frances; Somsel, Patricia; Weyant, Robbin; Stephens, David S; Perkins, Bradley A; Rosenstein, Nancy E

    2005-09-01

    Neisseria meningitidis is infrequently reported as a laboratory-acquired infection. Prompted by two cases in the United States in 2000, we assessed this risk among laboratorians. We identified cases of meningococcal disease that were possibly acquired or suspected of being acquired in a laboratory by placing an information request on e-mail discussion groups of infectious disease, microbiology, and infection control professional organizations. A probable case of laboratory-acquired meningococcal disease was defined as illness meeting the case definition for meningococcal disease in a laboratorian who had occupational exposure to an N. meningitidis isolate of the same serogroup within 14 days of illness onset. Sixteen cases of probable laboratory-acquired meningococcal disease occurring worldwide between 1985 and 2001 were identified, including six U.S. cases between 1996 and 2000. Nine cases (56%) were serogroup B; seven (44%) were serogroup C. Eight cases (50%) were fatal. All cases occurred among clinical microbiologists. In 15 cases (94%), isolate manipulation was performed without respiratory protection. We estimated that an average of three microbiologists are exposed to the 3,000 meningococcal isolates seen in U.S. laboratories yearly and calculated an attack rate of 13/100,000 microbiologists between 1996 and 2001, compared to 0.2/100,000 among U.S. adults in general. The rate and case/fatality ratio of meningococcal disease among microbiologists are higher than those in the general U.S. population. Specific risk factors for laboratory-acquired infection are likely associated with exposure to droplets or aerosols containing N. meningitidis. Prevention should focus on the implementation of class II biological safety cabinets or additional respiratory protection during manipulation of suspected meningococcal isolates.

  15. Acquired immunodeficiency syndrome and human immunodeficiency virus infection in Nevada.

    PubMed

    Jarvis, J Q; Semiatin, S L

    1991-01-01

    We summarize information from three sets of epidemiologic data: the Nevada AIDS [acquired immunodeficiency syndrome] Surveillance System, which contains information about every case identified within the state boundaries through September 1989; the human immunodeficiency virus (HIV) seroprevalence reporting systems, which currently include data on all HIV-positive reports submitted statewide to public health authorities; and surveys on the knowledge, attitudes, and behaviors of Nevadans concerning HIV-related disease. The Nevada State AIDS Task Force outlined major policy recommendations, nearly half of which concerned testing; only 2 dealt with preventing HIV transmission. Greater efforts should go into education, particularly directed toward groups at greatest risk of exposure to HIV, and to improve community-based care of infected persons.

  16. Successful treatment of acquired undescended testes with human chorionic gonadotropin.

    PubMed

    Meijer, R W; Hack, W W; Haasnoot, K

    2001-01-01

    Human chorionic gonadotrophin therapy may have its place in the management of acquired undescended testes and surgery should be reserved for those who fail to respond to therapy. Further studies are necessary to evaluate these preliminary results.

  17. Problems in veterinary ultrasonographic analysis of acquired heart disease.

    PubMed

    Bond, B R

    1991-12-01

    Echocardiography in veterinary medicine has both enhanced our ability to diagnose and treat cardiac diseases in small animals and added confusion to what we already know. Because we can actually see the heart beating and visualize blood flows within the cardiac chambers as well as measure velocities of blood flows, we have a tool that increases our non-invasive diagnostic abilities. On the other hand, the lines between different heart diseases are not always clear-cut, and the more we learn about heart disease the more we see the shades of distinction between different diseases become blurred. This chapter will look at the main abnormalities we see in veterinary medicine (mitral regurgitation, pericardial disease, and the different feline and canine cardiomyopathies) and will attempt to help the veterinary echocardiographer avoid common problems encountered in acquired heart disease as well as use echocardiographic information to gain a better understanding of the disease process occurring in animals. PMID:1839366

  18. Low-dose exposure to inorganic mercury accelerates disease and mortality in acquired murine lupus.

    PubMed

    Via, Charles S; Nguyen, Phuong; Niculescu, Florin; Papadimitriou, John; Hoover, Dennis; Silbergeld, Ellen K

    2003-08-01

    Inorganic mercury (iHg) is known to induce autoimmune disease in susceptible rodent strains. Additionally, in inbred strains of mice prone to autoimmune disease, iHg can accelerate and exacerbate disease manifestations. Despite these well-known links between iHg and autoimmunity in animal models, no association between iHg alone and autoimmune disease in humans has been documented. However, it is possible that low-level iHg exposure can interact with disease triggers to enhance disease expression or susceptibility. To address whether exposure to iHg can alter the course of subsequent acquired autoimmune disease, we used a murine model of acquired autoimmunity, lupus-like chronic graft-versus-host disease (GVHD), in which autoimmunity is induced using normal, nonautoimmune prone donor and F1 recipient mice resistant to Hg-induced autoimmunity. Our results indicate that a 2-week exposure to low-dose iHg (20 or 200 micro g/kg every other day) to donor and host mice ending 1 week before GVHD induction can significantly worsen parameters of disease severity, resulting in premature mortality. iHg pretreatment clearly worsened chronic lupus-like disease, rather than GVHD worsening iHg immunotoxicity. These results are consistent with the hypothesis that low-level, nontoxic iHg preexposure may interact with other risk factors, genetic or acquired, to promote subsequent autoimmune disease development.

  19. Autoimmunity and dysmetabolism of human acquired immunodeficiency syndrome.

    PubMed

    Huang, Yan-Mei; Hong, Xue-Zhi; Xu, Jia-Hua; Luo, Jiang-Xi; Mo, Han-You; Zhao, Hai-Lu

    2016-06-01

    Acquired immunodeficiency syndrome (AIDS) remains ill-defined by lists of symptoms, infections, tumors, and disorders in metabolism and immunity. Low CD4 cell count, severe loss of body weight, pneumocystis pneumonia, and Kaposi's sarcoma are the major disease indicators. Lines of evidence indicate that patients living with AIDS have both immunodeficiency and autoimmunity. Immunodeficiency is attributed to deficits in the skin- and mucosa-defined innate immunity, CD4 T cells and regulatory T cells, presumably relating human immunodeficiency virus (HIV) infection. The autoimmunity in AIDS is evident by: (1) overproduction of autoantibodies, (2) impaired response of CD4 cells and CD8 cells, (3) failure of clinical trials of HIV vaccines, and (4) therapeutic benefits of immunosuppression following solid organ transplantation and bone marrow transplantation in patients at risk of AIDS. Autoantibodies are generated in response to antigens such as debris and molecules de novo released from dead cells, infectious agents, and catabolic events. Disturbances in metabolic homeostasis occur at the interface of immunodeficiency and autoimmunity in the development of AIDS. Optimal treatments favor therapeutics targeting on the regulation of metabolism to restore immune homeostasis.

  20. Human oestriasis acquired in Florence and review on human myiasis in Italy.

    PubMed

    Zammarchi, Lorenzo; Giorni, Andrea; Gabrielli, Simona; Strohmeyer, Marianne; Cancrini, Gabriella; Bartoloni, Alessandro

    2014-06-01

    Myiases-causing flies are widely observed in tropical countries, whereas in Italy, a temperate country, their epidemiology and clinical presentation are poorly known. We report three cases of human conjunctival myiasis recently observed at our hospital, and the results of a review of the literature on human myiasis in Italy. In August 2012, a case of Oestrus ovis conjunctival myiasis acquired in the city centre of Florence, Italy was diagnosed at our hospital. In the early fall of 2013, two additional cases, acquired in the neighbouring areas, occurred. The review of literature showed that, up to the middle of 1990s, myiasis in Italy was mainly an occupational disease of shepherds, caused by O. ovis. Recently, cases of travel acquired furuncular myiasis emerged, together with "opportunistic" autochthonous cases of wound myiasis in patients with underlying health conditions. Considering the causative agents of human of myiasis in Italy, among the 703 autochthonous cases reported, 98.1% were caused by O. ovis, while among the 42 imported cases described, 59.5% were due to Cordylobia spp. and 40.5% to Dermatobia hominis. Our findings suggest that O. ovis conjunctival myiasis may still be observed in urban setting in Italy. Health care providers should know and implement the basic rules of entomoprophylaxis for myiasis in the facilities where they are working and use these indications to educate patients and care givers in both pretravel care and geriatric outpatient settings.

  1. Acquired Cell-Mediated Immunodepression in Acute Chagas' Disease

    PubMed Central

    Teixeira, Antonio R. L.; Teixeira, Glória; Macêdo, Vanize; Prata, Aluizio

    1978-01-01

    In this study two groups of patients with acute Chagas' disease were identified. Group one consisted of five patients with apparent acute Chagas' disease. These patients showed symptoms and signals of an acute illness, such as high fever and enlarged spleen. One of these patients developed severe myocarditis and heart failure. Group two consisted of seven patients with inapparent acute Chagas' disease. This was a nonclinical entity, not perceived by the patient who did not seek medical care. The diagnosis was made by the shift of a serologic test which indicates the presence of immunoglobulin M antibodies to Trypanosoma cruzi. The patients with apparent acute Chagas' disease showed positive delayed-type skin response to T. cruzi antigen. Also, their leukocytes showed significant inhibition of migration in the presence of this antigen. By contrast, the patients with the inapparent acute Chagas' disease did not show positive delayed-type skin response to T. cruzi antigen and no significant inhibition was observed when their cells migrated in the presence of this antigen. Of interest, none of these patients was capable of developing contact sensitivity to 2,4-dinitrochlorobenzene. However, three out of five patients with the apparent acute disease and all the normal control subjects showed positive contact reaction after sensitization to this drug. The results of these experiments would suggest that the thymus-derived (T)-lymphocyte function is depressed in patients with the clinically inapparent acute Chagas' disease. This immunodepression seems to be acquired in the course of the T. cruzi infection because all patients showed positive delayed-type skin response to at least one ubiquitous microbial extract, thus indicating previously normal T-cell function. We hypothesize that T. cruzi antigens may directly stimulate T cells with the concomitant release of factors that might become supressive for T-cell responses. Furthermore, the suppressive effect might interfere

  2. Fulminant community-acquired infectious diseases: diagnostic problems.

    PubMed

    Levin, S; Goodman, L J; Fuhrer, J

    1986-09-01

    The processes presented here do not represent an all-inclusive list of fulminant infectious diseases. Some of the more common acute, overwhelming infections of the central nervous system and lungs are covered elsewhere in this issue. We have selected less common, potentially catastrophic syndromes that might be recognized earlier if certain historical clues, physical findings, or laboratory abnormalities are appreciated. Specific and effective therapy is available for most of the diseases we have chosen. Meningitis due to Naegleria fowleri, a free-living ameba that may invade the central nervous system through the cribriform plate in persons swimming in brackish water, and hemorrhagic mediastinitis due to inhalation of Bacillus anthracis, which is acquired in occupational exposure to goat's hair, wool, or an animal with anthrax, are other examples but are lacking in proven effective therapy. Although most physicians quickly consider exotic and overwhelming infections in the severely compromised patient, fewer recognize this risk in the diabetic, cirrhotic, or healthy person with a unique occupational or travel history. During the present epidemic of AIDS, previous exposure to the HTLV-3 virus must be considered in all severely ill patients. The proper use of new diagnostic tests may permit the physician to intercede effectively if these life-threatening diseases are suspected. PMID:3736273

  3. Acquired immune heterogeneity and its sources in human helminth infection

    PubMed Central

    BOURKE, C. D.; MAIZELS, R. M.; MUTAPI, F.

    2011-01-01

    SUMMARY Similarities in the immunobiology of different parasitic worm infections indicate that co-evolution of humans and helminths has shaped a common anti-helminth immune response. However, recent in vitro and immuno-epidemiological studies highlight fundamental differences and plasticity within host-helminth interactions. The ‘trade-off’ between immunity and immunopathology inherent in host immune responses occurs on a background of genetic polymorphism, variable exposure patterns and infection history. For the parasite, variation in life-cycle and antigen expression can influence the effector responses directed against them. This is particularly apparent when comparing gastrointestinal and tissue-dwelling helminths. Furthermore, insights into the impact of anti-helminthic treatment and co-infection on acquired immunity suggest that immune heterogeneity arises not from hosts and parasites in isolation, but also from the environment in which immune responses develop. Large-scale differences observed in the epidemiology of human helminthiases are a product of complex host-parasite-environment interactions which, given potential for exposure to parasite antigens in utero, can arise even before a parasite interacts with its human host. This review summarizes key differences identified in human acquired immune responses to nematode and trematode infections of public health importance and explores the factors contributing to these variations. PMID:20946693

  4. Human cytotrophoblasts acquire aneuploidies as they differentiateto an invasive phenotype

    SciTech Connect

    Weier, Jingly F.; Weier, Heinz-Ulrich G.; Jung, Christine J.; Gormley, Matthew; Zhou, Yuan; Chu, Lisa W.; Genbacev, Olga; Wright, AlexiA.; Fisher, Susan J.

    2004-12-15

    Through an unusual differentiation process, human trophoblast progenitors (cytotrophoblasts) give rise to tumor-like cells that invade the uterus. By an unknown mechanism, invasive cytotrophoblasts exhibit permanent cell cycle withdrawal. Here we report molecular cytogenetic data showing that {approx} 20 to 60 percent of these interphase cells had acquired aneusomies involving chromosomes X, Y, o r16. The incidence positively correlated with gestational age and differentiation to an invasive phenotype. Scoring 12 chromosomes in flow-sorted cytotrophoblasts showed that more than 95 percent of the cells were hyperdiploid. Thus, aneuploidy appears to be an important component of normal placentation, perhaps limiting the proliferative and invasive potential of cytotrophoblasts within the uterus.

  5. ACQUIRED PES CAVUS IN CHARCOT-MARIE-TOOTH DISEASE

    PubMed Central

    Carvalho Maranho, Daniel Augusto; Volpon, José Batista

    2015-01-01

    Hereditary motor and sensory neuropathies, especially Charcot-Marie-Tooth disease, are frequently expressed with an acquired cavusvarus foot which is characterized by a fixed increase of the plantar arch and hindfoot inversion. Diagnosis of the underlying condition achieved through careful patient assessment and local evaluations is the keystone for decision-making about the adequate treatment. The cavus may present as an isolated deformity of the forefoot, hindfoot or it may be a combination of both locations. Related deformities, mainly the varus and toe clawing require appropriate evaluation; clinical characteristics such as severity of the deformity, impairment of the muscular power, flexibility and patient's age are important characteristics in the treatment decision. Conservative treatment of the cavusvarus foot with physiotherapy, insoles and shoe modifications are reserved to young patients and mild deformities. However, there is a tendency of the deformity to become more severe over time because of the progressive feature of the underlying neurological condition. So, the surgical treatment by using classical techniques is performed in early stages. Most importantly is the identification of the primary and main components of each deformity to properly correct them, if possible. Muscular transfers are used to treat the dynamic unbalance, retracted structures should be either divided or lengthened and localized osteotomies should be preferred over arthrodeses, which are reserved for stiff and severely deformed feet in adults. PMID:27077056

  6. ACQUIRED PES CAVUS IN CHARCOT-MARIE-TOOTH DISEASE.

    PubMed

    Carvalho Maranho, Daniel Augusto; Volpon, José Batista

    2009-01-01

    Hereditary motor and sensory neuropathies, especially Charcot-Marie-Tooth disease, are frequently expressed with an acquired cavusvarus foot which is characterized by a fixed increase of the plantar arch and hindfoot inversion. Diagnosis of the underlying condition achieved through careful patient assessment and local evaluations is the keystone for decision-making about the adequate treatment. The cavus may present as an isolated deformity of the forefoot, hindfoot or it may be a combination of both locations. Related deformities, mainly the varus and toe clawing require appropriate evaluation; clinical characteristics such as severity of the deformity, impairment of the muscular power, flexibility and patient's age are important characteristics in the treatment decision. Conservative treatment of the cavusvarus foot with physiotherapy, insoles and shoe modifications are reserved to young patients and mild deformities. However, there is a tendency of the deformity to become more severe over time because of the progressive feature of the underlying neurological condition. So, the surgical treatment by using classical techniques is performed in early stages. Most importantly is the identification of the primary and main components of each deformity to properly correct them, if possible. Muscular transfers are used to treat the dynamic unbalance, retracted structures should be either divided or lengthened and localized osteotomies should be preferred over arthrodeses, which are reserved for stiff and severely deformed feet in adults.

  7. Trade-offs between acquired and innate immune defenses in humans

    PubMed Central

    McDade, Thomas W.; Georgiev, Alexander V.; Kuzawa, Christopher W.

    2016-01-01

    Immune defenses provide resistance against infectious disease that is critical to survival. But immune defenses are costly, and limited resources allocated to immunity are not available for other physiological or developmental processes. We propose a framework for explaining variation in patterns of investment in two important subsystems of anti-pathogen defense: innate (non-specific) and acquired (specific) immunity. The developmental costs of acquired immunity are high, but the costs of maintenance and activation are relatively low. Innate immunity imposes lower upfront developmental costs, but higher operating costs. Innate defenses are mobilized quickly and are effective against novel pathogens. Acquired responses are less effective against novel exposures, but more effective against secondary exposures due to immunological memory. Based on their distinct profiles of costs and effectiveness, we propose that the balance of investment in innate versus acquired immunity is variable, and that this balance is optimized in response to local ecological conditions early in development. Nutritional abundance, high pathogen exposure and low signals of extrinsic mortality risk during sensitive periods of immune development should all favor relatively higher levels of investment in acquired immunity. Undernutrition, low pathogen exposure, and high mortality risk should favor innate immune defenses. The hypothesis provides a framework for organizing prior empirical research on the impact of developmental environments on innate and acquired immunity, and suggests promising directions for future research in human ecological immunology. PMID:26739325

  8. Hospital-acquired infections: diseases with increasingly limited therapies.

    PubMed Central

    Swartz, M N

    1994-01-01

    About 5% of patients admitted to acute-care hospitals acquire nosocomial infections. A variety of factors contribute: increasing age of patients; availability, for treatment of formerly untreatable diseases, of extensive surgical and intensive medical therapies; and frequent use of antimicrobial drugs capable of selecting a resistant microbial flora. Nosocomial infections due to resistant organisms have been a problem ever since infections due to penicillinase-producing Staphylococcus aureus were noted within a few years of the introduction of penicillin. By the 1960s aerobic Gram-negative bacilli had assumed increasing importance as nosocomial pathogens, and many strains were resistant to available antimicrobials. During the 1980s the principal organisms causing nosocomial bloodstream infections were coagulase-negative staphylococci, aerobic Gram-negative bacilli, S. aureus, Candida spp., and Enterococcus spp. Coagulase-negative staphylococci and S. aureus are often methicillin-resistant, requiring parenteral use of vancomycin. Prevalence of vancomycin resistance among enterococcal isolates from patients in intensive care units has increased, likely due to increased use of this drug. Plasmid-mediated gentamicin resistance in up to 50% of enterococcal isolates, along with enhanced penicillin resistance in some strains, leaves few therapeutic options. The emergence of Enterobacteriaceae with chromosomal or plasmid-encoded extended spectrum beta-lactamases presents a world-wide problem of resistance to third generation cephalosporins. Control of these infections rests on (i) monitoring infections with such resistant organisms in an ongoing fashion, (ii) prompt institution of barrier precautions when infected or colonized patients are identified, and (iii) appropriate use of antimicrobials through implementation of antibiotic control programs. Images PMID:8146133

  9. Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in Older Adults.

    PubMed

    Scott, Jake; Goetz, Matthew Bidwell

    2016-08-01

    Improved survival with combination antiretroviral therapy has led to a dramatic increase in the number of human immunodeficiency virus (HIV)-infected individuals 50 years of age or older such that by 2020 more than 50% of HIV-infected persons in the United States will be above this age. Recent studies confirm that antiretroviral therapy should be offered to all HIV-infected patients regardless of age, symptoms, CD4+ cell count, or HIV viral load. However, when compared with HIV-uninfected populations, even with suppression of measurable HIV replication, older individuals are at greater risk for cardiovascular disease, malignancies, liver disease, and other comorbidities.

  10. Herd immunity acquired indirectly from interactions between the ecology of infectious diseases, demography and economics.

    PubMed

    Bonds, Matthew H; Rohani, Pejman

    2010-03-01

    Patterns of morbidity and mortality around the globe are determined by interactions between infectious diseases and systematic human socioeconomic processes. The most obvious of these patterns is that the greatest burdens of infectious diseases are found among the poor, who lack the basic resources for disease prevention and treatment. Yet, it is becoming increasingly clear that many infectious diseases are themselves causes of poverty owing to their effects on labour productivity. A particularly subtle phenomenon that receives little attention in the epidemiology literature and is especially important for poor communities is the role of the birth rate as an important direct cause of high disease burdens. Because of their high rates of transmission and life-long immunity, the persistence of many child diseases such as measles relies on high rates of reproduction as their source of susceptible individuals. Thus, there are significant direct health benefits of lower fertility rates, which are further enhanced by interactions with economic processes. Indeed, fertility, poverty and disease all interact with each other in important and predictable ways that can be built into traditional disease ecology models. We present such a model here that provides insights into the long-term effect of policy interventions. For example, because of indirect income effects, herd immunity may be acquired with lower vaccine coverage than previously thought. Reductions in the disease burden can also occur through lower fertility. Our model thus provides a disease ecology framework that is useful for the analysis of demographic transitions.

  11. Human disease genes.

    PubMed

    Jimenez-Sanchez, G; Childs, B; Valle, D

    2001-02-15

    The complete human genome sequence will facilitate the identification of all genes that contribute to disease. We propose that the functional classification of disease genes and their products will reveal general principles of human disease. We have determined functional categories for nearly 1,000 documented disease genes, and found striking correlations between the function of the gene product and features of disease, such as age of onset and mode of inheritance. As knowledge of disease genes grows, including those contributing to complex traits, more sophisticated analyses will be possible; their results will yield a deeper understanding of disease and an enhanced integration of medicine with biology.

  12. Oxfendazole treatment of sheep with naturally acquired hydatid disease.

    PubMed

    Dueger, E L; Moro, P L; Gilman, R H

    1999-09-01

    A blinded, randomized placebo-controlled trial assessed the efficacy and safety of oxfendazole for the treatment of ovine hydatid disease. Cyst fertility and parasite viability were measured following daily, weekly, and monthly treatment schedules with 30 mg of oxfendazole per kg of body weight. The 12-week trial was conducted in 215 adult sheep in the central Peruvian Andes and was masked for both treatment group and scheduling. In this trial oxfendazole significantly reduced protoscolex viability relative to controls in all treatment groups. In the daily, weekly, and monthly groups, 100, 97, and 78% of sheep, respectively, were either cured or improved following treatment, compared to 35% cured or improved animals in the control group. However, daily dosing at 30 mg of oxfendazole per kg proved highly toxic to sheep, resulting in a 24% death rate in the daily group as compared to a 4 to 6% mortality rate in all other groups. If found safe in humans, oxfendazole may prove to be a useful and inexpensive treatment for cestode infections in humans. This study suggests that a staggered dosing regimen of oxfendazole, and possibly other benzimidazoles, may be as efficacious as daily treatment regimens for hydatidosis while decreasing both the cost and adverse effects associated with daily dosing.

  13. Neuropathological and biochemical criteria to identify acquired Creutzfeldt-Jakob disease among presumed sporadic cases.

    PubMed

    Kobayashi, Atsushi; Parchi, Piero; Yamada, Masahito; Mohri, Shirou; Kitamoto, Tetsuyuki

    2016-06-01

    As an experimental model of acquired Creutzfeldt-Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock-in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrP(Sc) ). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrP(Sc) in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft-associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion-contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrP(Sc) , represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases. PMID:26669818

  14. Neuropathological and biochemical criteria to identify acquired Creutzfeldt-Jakob disease among presumed sporadic cases.

    PubMed

    Kobayashi, Atsushi; Parchi, Piero; Yamada, Masahito; Mohri, Shirou; Kitamoto, Tetsuyuki

    2016-06-01

    As an experimental model of acquired Creutzfeldt-Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock-in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrP(Sc) ). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrP(Sc) in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft-associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion-contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrP(Sc) , represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases.

  15. ACOG Committee Opinion No. 536: Human immunodeficiency virus and acquired immunodeficiency syndrome and women of color.

    PubMed

    2012-09-01

    In the United States, most new cases of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) occur among women of color (primarily African American and Hispanic women). Most women of color acquire the disease from heterosexual contact, often from a partner who has undisclosed risk factors for HIV infection. Safe sex practices, especially consistent condom use, must be emphasized for all women, including women of color. A combination of testing, education, and brief behavioral interventions can help reduce the rate of HIV infection and its complications among women of color. In addition,biomedical interventions such as early treatment of patients infected with HIV and pre-exposure antiretroviral prophylaxis of high-risk individuals offer promise for future reductions in infections.

  16. Laboratory-acquired human glanders--Maryland, May 2000.

    PubMed

    2000-06-23

    On May 5, 2000, the Baltimore City Health Department was notified by hospital infection-control staff of a serious systemic febrile illness in a microbiologist whose research at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) involved several pathogenic bacteria, including Burkholderia mallei, the causative agent of glanders. This report summarizes the first human case of glanders in the United States since 1945, and emphasizes the importance of considering occupational exposures among laboratory workers with a febrile illness, the difficulty of characterizing unusual agents, including potential agents of biological terrorism such as glanders using routine laboratory techniques, the appropriate isolation practices for patients who may be infected by these agents, and laboratory safety.

  17. Langerhans cell precursors acquire RANK/CD265 in prenatal human skin.

    PubMed

    Schöppl, Alice; Botta, Albert; Prior, Marion; Akgün, Johnnie; Schuster, Christopher; Elbe-Bürger, Adelheid

    2015-01-01

    The skin is the first barrier against foreign pathogens and the prenatal formation of a strong network of various innate and adaptive cells is required to protect the newborn from perinatal infections. While many studies about the immune system in healthy and diseased adult human skin exist, our knowledge about the cutaneous prenatal/developing immune system and especially about the phenotype and function of antigen-presenting cells such as epidermal Langerhans cells (LCs) in human skin is still scarce. It has been shown previously that LCs in healthy adult human skin express receptor activator of NF-κB (RANK), an important molecule prolonging their survival. In this study, we investigated at which developmental stage LCs acquire this important molecule. Immunofluorescence double-labeling of cryostat sections revealed that LC precursors in prenatal human skin either do not yet [10-11 weeks of estimated gestational age (EGA)] or only faintly (13-15 weeks EGA) express RANK. LCs express RANK at levels comparable to adult LCs by the end of the second trimester. Comparable with adult skin, dermal antigen-presenting cells at no gestational age express this marker. These findings indicate that epidermal leukocytes gradually acquire RANK during gestation - a phenomenon previously observed also for other markers on LCs in prenatal human skin.

  18. Langerhans cell precursors acquire RANK/CD265 in prenatal human skin

    PubMed Central

    Schöppl, Alice; Botta, Albert; Prior, Marion; Akgün, Johnnie; Schuster, Christopher; Elbe-Bürger, Adelheid

    2015-01-01

    The skin is the first barrier against foreign pathogens and the prenatal formation of a strong network of various innate and adaptive cells is required to protect the newborn from perinatal infections. While many studies about the immune system in healthy and diseased adult human skin exist, our knowledge about the cutaneous prenatal/developing immune system and especially about the phenotype and function of antigen-presenting cells such as epidermal Langerhans cells (LCs) in human skin is still scarce. It has been shown previously that LCs in healthy adult human skin express receptor activator of NF-κB (RANK), an important molecule prolonging their survival. In this study, we investigated at which developmental stage LCs acquire this important molecule. Immunofluorescence double-labeling of cryostat sections revealed that LC precursors in prenatal human skin either do not yet [10–11 weeks of estimated gestational age (EGA)] or only faintly (13–15 weeks EGA) express RANK. LCs express RANK at levels comparable to adult LCs by the end of the second trimester. Comparable with adult skin, dermal antigen-presenting cells at no gestational age express this marker. These findings indicate that epidermal leukocytes gradually acquire RANK during gestation – a phenomenon previously observed also for other markers on LCs in prenatal human skin. PMID:25722033

  19. Antigen-Specific Acquired Immunity in Human Brucellosis: Implications for Diagnosis, Prognosis, and Vaccine Development

    PubMed Central

    Cannella, Anthony P.; Tsolis, Renee M.; Liang, Li; Felgner, Philip L.; Saito, Mayuko; Sette, Alessandro; Gotuzzo, Eduardo; Vinetz, Joseph M.

    2012-01-01

    Brucella spp., are Gram negative bacteria that cause disease by growing within monocyte/macrophage lineage cells. Clinical manifestations of brucellosis are immune mediated, not due to bacterial virulence factors. Acquired immunity to brucellosis has been studied through observations of naturally infected hosts (cattle, goats), mouse models (mice), and human infection. Even though Brucella spp. are known for producing mechanisms that evade the immune system, cell-mediated immune responses drive the clinical manifestations of human disease after exposure to Brucella species, as high antibody responses are not associated with protective immunity. The precise mechanisms by which cell-mediated immune responses confer protection or lead to disease manifestations remain undefined. Descriptive studies of immune responses in human brucellosis show that TH1 (interferon-γ-producing T cells) are associated with dominant immune responses, findings consistent with animal studies. Whether these T cell responses are protective, or determine the different clinical responses associated with brucellosis is unknown, especially with regard to undulant fever manifestations, relapsing disease, or are associated with responses to distinct sets of Brucella spp. antigens are unknown. Few data regarding T cell responses in terms of specific recognition of Brucella spp. protein antigens and peptidic epitopes, either by CD4+ or CD8+ T cells, have been identified in human brucellosis patients. Additionally because current attenuated Brucella vaccines used in animals cause human disease, there is a true need for a recombinant protein subunit vaccine for human brucellosis, as well as for improved diagnostics in terms of prognosis and identification of unusual forms of brucellosis. This review will focus on current understandings of antigen-specific immune responses induced Brucella peptidic epitopes that has promise for yielding new insights into vaccine and diagnostics development, and for

  20. Acquired heart conditions in adults with congenital heart disease: a growing problem.

    PubMed

    Tutarel, Oktay

    2014-09-01

    The number of adults with congenital heart disease is increasing due to the great achievements in the field of paediatric cardiology, congenital heart surgery and intensive care medicine over the last decades. Mortality has shifted away from the infant and childhood period towards adulthood. As congenital heart disease patients get older, a high prevalence of cardiovascular risk factors is encountered similar to the general population. Consequently, the contribution of acquired morbidities, especially acquired heart conditions to patient outcome, is becoming increasingly important. Therefore, to continue the success story of the last decades in the treatment of congenital heart disease and to further improve the outcome of these patients, more attention has to be given to the prevention, detection and adequate therapy of acquired heart conditions. The aim of this review is to give an overview about acquired heart conditions that may be encountered in adults with congenital heart disease.

  1. [Anesthesia for non-cardiac surgery in children with congenital and acquired heart diseases].

    PubMed

    Le Bel, S

    2013-01-01

    The goals of this review are to recall some pathophysiological principles at work in most of congenital heart diseases; to specify factors to be considered when defining perioperative risk for a child with an acquired or congenital heart disease; to describe an anaesthetic management strategy in the context of some specific heart diseases.

  2. Zygomycetes in Human Disease

    PubMed Central

    Ribes, Julie A.; Vanover-Sams, Carolyn L.; Baker, Doris J.

    2000-01-01

    The Zygomycetes represent relatively uncommon isolates in the clinical laboratory, reflecting either environmental contaminants or, less commonly, a clinical disease called zygomycosis. There are two orders of Zygomycetes containing organisms that cause human disease, the Mucorales and the Entomophthorales. The majority of human illness is caused by the Mucorales. While disease is most commonly linked to Rhizopus spp., other organisms are also associated with human infection, including Mucor, Rhizomucor, Absidia, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum spp. Although Mortierella spp. do cause disease in animals, there is no longer sufficient evidence to suggest that they are true human pathogens. The spores from these molds are transmitted by inhalation, via a variety of percutaneous routes, or by ingestion of spores. Human zygomycosis caused by the Mucorales generally occurs in immunocompromised hosts as opportunistic infections. Host risk factors include diabetes mellitus, neutropenia, sustained immunosuppressive therapy, chronic prednisone use, iron chelation therapy, broad-spectrum antibiotic use, severe malnutrition, and primary breakdown in the integrity of the cutaneous barrier such as trauma, surgical wounds, needle sticks, or burns. Zygomycosis occurs only rarely in immunocompetent hosts. The disease manifestations reflect the mode of transmission, with rhinocerebral and pulmonary diseases being the most common manifestations. Cutaneous, gastrointestinal, and allergic diseases are also seen. The Mucorales are associated with angioinvasive disease, often leading to thrombosis, infarction of involved tissues, and tissue destruction mediated by a number of fungal proteases, lipases, and mycotoxins. If the diagnosis is not made early, dissemination often occurs. Therapy, if it is to be effective, must be started early and requires combinations of antifungal drugs, surgical intervention, and reversal of the underlying risk

  3. The human disease network.

    PubMed

    Goh, Kwang-Il; Cusick, Michael E; Valle, David; Childs, Barton; Vidal, Marc; Barabási, Albert-László

    2007-05-22

    A network of disorders and disease genes linked by known disorder-gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes. PMID:17502601

  4. Heart failure in congenital heart disease: a confluence of acquired and congenital.

    PubMed

    Fahed, Akl C; Roberts, Amy E; Mital, Seema; Lakdawala, Neal K

    2014-01-01

    Heart failure (HF) is a common cause of morbidity and mortality in congenital heart disease (CHD), with increasing prevalence because of improved treatment options and outcomes. Genetic factors and acquired postnatal factors in CHD might play a major role in the progression to HF. This article proposes 3 routes that lead to HF in CHD: rare monogenic entities that cause both CHD and HF; severe CHD lesions in which acquired hemodynamic effects of CHD or surgery result in HF; and, most commonly, a combined effect of complex genetics in overlapping pathways and acquired stressors caused by the primary lesion.

  5. Nongenital human papillomavirus disease.

    PubMed

    Mayeaux, E J; Khan, Michelle J

    2013-06-01

    Human papillomavirus (HPV) is the most common viral cause of cancer, and is responsible for 5% of cancers worldwide. Following demonstration of the causative link between HPV and cervical cancer, HPV has been shown to be associated with several anogenital malignancies and with oral pharyngeal cancers. HPV-related anal and oral pharyngeal disease is rising in incidence and includes anal warts and neoplasia, recurrent respiratory papillomatosis, and oral pharyngeal neoplasia. This article presents an overview of the epidemiology, clinical manifestations, diagnosis, and treatment of nongenital HPV-related disease.

  6. RF Device for Acquiring Images of the Human Body

    NASA Technical Reports Server (NTRS)

    Gaier, Todd C.; McGrath, William R.

    2010-01-01

    A safe, non-invasive method for forming images through clothing of large groups of people, in order to search for concealed weapons either made of metal or not, has been developed. A millimeter wavelength scanner designed in a unique, ring-shaped configuration can obtain a full 360 image of the body with a resolution of less than a millimeter in only a few seconds. Millimeter waves readily penetrate normal clothing, but are highly reflected by the human body and concealed objects. Millimeter wave signals are nonionizing and are harmless to human tissues when used at low power levels. The imager (see figure) consists of a thin base that supports a small-diameter vertical post about 7 ft (=2.13 m) tall. Attached to the post is a square-shaped ring 2 in. (=5 cm) wide and 3 ft (=91 cm) on a side. The ring is oriented horizontally, and is supported halfway along one side by a connection to a linear bearing on the vertical post. A planar RF circuit board is mounted to the inside of each side of the ring. Each circuit board contains an array of 30 receivers, one transmitter, and digitization electronics. Each array element has a printed-circuit patch antenna coupled to a pair of mixers by a 90 coupler. The mixers receive a reference local oscillator signal to a subharmonic of the transmitter frequency. A single local oscillator line feeds all 30 receivers on the board. The resulting MHz IF signals are amplified and carried to the edge of the board where they are demodulated and digitized. The transmitted signal is derived from the local oscillator at a frequency offset determined by a crystal oscillator. One antenna centrally located on each side of the square ring provides the source illumination power. The total transmitted power is less than 100 mW, resulting in an exposure level that is completely safe to humans. The output signals from all four circuit boards are fed via serial connection to a data processing computer. The computer processes the approximately 1-MB

  7. Legionnaires' Disease acquired within the homes of two patients: link to the home water supply

    SciTech Connect

    Stout, J.E.; Yu, V.L.; Muraca, P.

    1987-03-06

    Two patients with sporadic community-acquired legionnaires' disease are described. Legionella pneumophila was isolated from sputum specimens, and seroconversion of antibody titers was demonstrated for both patients. Legionella pneumophila was also recovered from the residential water supply of both patients. In each case, the serogroup of the environmental organism matched that of the infecting organism. In one patient, serogroup 3 was isolated - a rare cause of legionnaires' disease, and in the second case, monoclonal antibody testing confirmed that the serogroup 1 organisms isolated from sputum and residential water supply samples were identical. The incubation period of legionnaires' disease is presumed to be up to two weeks. Because of medical problems, both patients had been confined to their homes for the entire two weeks before the onset of symptoms. This is the first report that links acquisition of community-acquired legionnaires' disease to contaminated water supplies within the homes of susceptible patients.

  8. Epidemiological characteristics of human prion diseases.

    PubMed

    Chen, Cao; Dong, Xiao-Ping

    2016-01-01

    Human prion diseases are a group of transmissible, progressive, and invariably fatal neurodegenerative disorders, which include Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. Human prion diseases affect approximately 1-2 persons per million worldwide annually, occurring in sporadic, inherited, and acquired forms. These diseases have attracted both scientific and public attention not only because of their mysterious pathogen, but also due to their considerable threat to public health since the emergence of the variant CJD.There are still no specific therapeutic and prophylactic interventions available for prion diseases, thus active surveillance of human prion diseases is critical for disease control and prevention. Since 1993, CJD surveillance systems have been established in many countries and regions, and several long-term multinational cooperative projects have been conducted.In this paper, the epidemiological characteristics of various human prion diseases and the active surveillance systems pertaining to them in different countries and regions are summarized and reviewed. PMID:27251305

  9. A case of multicentric Castleman's disease in HIV infection with the rare complication of acquired angioedema.

    PubMed

    Fernando, I; Scott, G

    2014-06-01

    Multicentric Castleman's disease (MCD), a polyclonal lymphoproliferative disorder of unknown aetiology, is a well-recognised complication of HIV disease. We present a case of MCD in an HIV-positive patient that is unusual on two counts: our patient's MCD first presented in the context of an immune restoration inflammatory syndrome (IRIS), following the initiation of highly active antiretroviral therapy (HAART). In addition, her MCD was associated with the unusual complication of acquired angioedema (AAE), which resolved following treatment of the MCD. While AAE is frequently found to have an underlying diagnosis of a lymphoproliferative disease, this is the first reported case linking AAE to MCD.

  10. The use of recombinant activated factor VII in congenital and acquired von Willebrand disease.

    PubMed

    Franchini, Massimo; Veneri, Dino; Lippi, Giuseppe

    2006-11-01

    Recombinant activated factor VII (NovoSeven), a novel hemostatic agent originally developed for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors, has been recently employed with benefit for the management of hemorrhages in other nonhemophilic congenital and acquired hemostatic abnormalities. This review focuses on the use of this drug in acquired and congenital von Willebrand disease. The analysis of the literature data shows that recombinant activated factor VII is an effective agent for the treatment of refractory bleeding in von Willebrand disease patients and for the treatment or prevention of bleeding in those patients with alloantibodies or autoantibodies against von Willebrand factor. Further studies are needed, however, to assess its safety and to optimize the dosages and regimens of therapy in such patients.

  11. 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

  12. First experimental in vivo model of enhanced dengue disease severity through maternally acquired heterotypic dengue antibodies.

    PubMed

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

    2014-04-01

    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

  13. Pro- and anti-inflammatory cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome.

    PubMed

    Breen, Elizabeth Crabb

    2002-09-01

    In persons with human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS), the immune system becomes dysfunctional in many ways. There is both immunodeficiency due to the loss of CD4-positive T helper cells and hyperactivity as a result of B-cell activation. Likewise, both decreases and increases are seen in the production and/or activity of cytokines. Cytokine changes in HIV infection have been assessed by a variety of techniques, ranging from determination of cytokine gene expression at the mRNA level to secretion of cytokine proteins in vivo and in vitro. Changes in cytokine levels in HIV-infected persons can affect the function of the immune system, and have the potential to directly impact the course of HIV disease by enhancing or suppressing HIV replication. In particular, the balance between the pro-inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha, which up-regulate HIV expression, and IL-10, which can act both as an anti-inflammatory cytokine and a B-cell stimulatory factor, may play an important role in the progression to AIDS. In light of its ability to suppress the production of pro-inflammatory cytokines and, under some conditions, suppress HIV replication, increased IL-10 may be viewed as beneficial in slowing HIV disease progression. However, an association between increased IL-10 and the development of AIDS-associated B-cell lymphoma highlights the bifunctional nature of IL-10 as both an anti-inflammatory and B-cell-stimulatory cytokine that could have beneficial and detrimental effects on the course of HIV infection and AIDS.

  14. CT of acquired cystic kidney disease and renal tumors in long-term dialysis patients

    SciTech Connect

    Levine, E.; Grantham, J.J.; Slusher, S.L.; Greathouse, J.L.; Krohn, B.P.

    1984-01-01

    The kidneys of long term dialysis patients frequently demonstrate multiple small acquired cysts and renal cell tumors on pathologic examination. The original kidneys of 30 long-term dialysis patients and six renal transplant patients were evaluated by computed tomography to determine the incidence of these abnormalities. Among dialysis patients, 43.3% had diffuse bilateral cysts, while 16.7% had occasional cysts (fewer than five per kidney), and 40% showed no renal cysts. Seven solid renal tumors were detected in four dialysis patients with renal cysts. Acquired cystic kidney disease tends to result in renal enlargement, is more common in patients who have been maintained on dialysis for prolonged periods, and may lead to spontaneous renal hemorrhage. The six transplant patients showed no evidence of renal cysts, and all had markedly shrunken kidneys. Acquired cystic disease and renal cell tumors in the original kidneys of dialysis patients may be due to biologically active substances that are not cleared effectively by dialysis but that are removed by normally functioning transplant kidneys.

  15. Zebrafish Models of Human Liver Development and Disease

    PubMed Central

    Wilkins, Benjamin J.; Pack, Michael

    2016-01-01

    The liver performs a large number of essential synthetic and regulatory functions that are acquired during fetal development and persist throughout life. Their disruption underlies a diverse group of heritable and acquired diseases that affect both pediatric and adult patients. Although experimental analyses used to study liver development and disease are typically performed in cell culture models or rodents, the zebrafish is increasingly used to complement discoveries made in these systems. Forward and reverse genetic analyses over the past two decades have shown that the molecular program for liver development is largely conserved between zebrafish and mammals, and that the zebrafish can be used to model heritable human liver disorders. Recent work has demonstrated that zebrafish can also be used to study the mechanistic basis of acquired liver diseases. Here, we provide a comprehensive summary of how the zebrafish has contributed to our understanding of human liver development and disease. PMID:23897685

  16. Gut epithelial barrier dysfunction in human immunodeficiency virus-hepatitis C virus coinfected patients: Influence on innate and acquired immunity

    PubMed Central

    Márquez, Mercedes; Fernández Gutiérrez del Álamo, Clotilde; Girón-González, José Antonio

    2016-01-01

    Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus (HIV)-infected patients have several non-acquired immunodeficiency syndrome (AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus (HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed. PMID:26819512

  17. In the world of Dolly, when does a human embryo acquire respect?

    PubMed

    Cameron, C; Williamson, R

    2005-04-01

    For most of the 20th century, it was possible to regard fertilisation as the identifiable point when life begins, because this moment could be defined unequivocally and was thought to be the single most essential biological step in the establishment of a new human entity. Since the successful reproductive cloning of Dolly and other mammals, it is clear that any human cell has the potential to supply the full genome of an embryo, and hence a person, without going through fertilisation. At what point in time do such embryos acquire the respect accorded to human beings? The authors argue that the time of implantation is the most useful point at which the potential and the intention to create a new person are translated into reality, because from that point a new life develops. Implantation differentiates a somatic cell in culture (which is not due respect) from a human entity that has acquired its own identity and developmental potential. The authors examine the value of quickening or viability as alternative developmental stages in the process of acquiring respect for the Dolly embryo.

  18. In the world of Dolly, when does a human embryo acquire respect?

    PubMed

    Cameron, C; Williamson, R

    2005-04-01

    For most of the 20th century, it was possible to regard fertilisation as the identifiable point when life begins, because this moment could be defined unequivocally and was thought to be the single most essential biological step in the establishment of a new human entity. Since the successful reproductive cloning of Dolly and other mammals, it is clear that any human cell has the potential to supply the full genome of an embryo, and hence a person, without going through fertilisation. At what point in time do such embryos acquire the respect accorded to human beings? The authors argue that the time of implantation is the most useful point at which the potential and the intention to create a new person are translated into reality, because from that point a new life develops. Implantation differentiates a somatic cell in culture (which is not due respect) from a human entity that has acquired its own identity and developmental potential. The authors examine the value of quickening or viability as alternative developmental stages in the process of acquiring respect for the Dolly embryo. PMID:15800362

  19. Massive renal and retroperitoneal hemorrhage in a case of acquired renal cystic disease with atypical epithelial cell proliferation.

    PubMed

    Verani, R; Wagner, E; Thompson, C

    1988-07-01

    We present a case of acquired renal cystic disease in a patient with end-stage renal disease (ESRD) secondary to systemic lupus erythematosus who was dialysis dependent for 5 years. Renal hemorrhage and neoplastic transformation of the cyst epithelium are the two major complications of acquired renal cystic disease, and were present in this patient. The full clinical significance of the acquired renal cystic lesion is still unclear, although the possibility of renal tumors and massive renal and retroperitoneal hemorrhage should be considered in the long-term dialysis population.

  20. Prevalence of obesity among patients with congenital and acquired heart disease.

    PubMed

    Shustak, Rachel J; McGuire, Sharda B; October, Tessie W; Phoon, Colin K L; Chun, Anne J L

    2012-01-01

    Overweight and obesity rates have risen dramatically in the United States, with subsequent detrimental comorbidity risks. The rates for obesity among children with congenital and acquired heart disease have rarely been reported. A retrospective cross-sectional study was conducted to determine the prevalence of overweight and obesity in children with heart disease and to identify subgroups at increased risk. A total of 795 cases were identified from a chart review of patients presenting to an urban center's Pediatric Cardiology Program between 1 January and 31 December 2006. A body mass index (BMI) at the 85th percentile or higher was defined as overweight, and a BMI at the 95th percentile or higher was defined as obese. Subjects with comorbidities affecting body habitus were excluded from the study. Overall, overweight and obesity rates were similar to national data. No significant differences in overweight or obesity rates were detected between heart disease and non-heart disease groups (P = 0.50). According to multivariate analysis, Hispanic ethnicity and male gender were the only predictors of obesity. This study shows that children with heart disease are not immune to the common predictors of obesity such as gender and ethnicity and that the future care of children with heart disease should include general discussions about the risks for obesity.

  1. Proteomics in human Parkinson's disease research.

    PubMed

    Licker, Virginie; Kövari, Enikö; Hochstrasser, Denis F; Burkhard, Pierre R

    2009-11-01

    During the last decades, considerable advances in the understanding of specific mechanisms underlying neurodegeneration in Parkinson's disease have been achieved, yet neither definite etiology nor unifying sequence of molecular events has been formally established. Current unmet needs in Parkinson's disease research include exploring new hypotheses regarding disease susceptibility, occurrence and progression, identifying reliable diagnostic, prognostic and therapeutic biomarkers, and translating basic research into appropriate disease-modifying strategies. The most popular view proposes that Parkinson's disease results from the complex interplay between genetic and environmental factors and mechanisms believed to be at work include oxidative stress, mitochondrial dysfunction, excitotoxicity, iron deposition and inflammation. More recently, a plethora of data has accumulated pinpointing an abnormal processing of the neuronal protein alpha-synuclein as a pivotal mechanism leading to aggregation, inclusions formation and degeneration. This protein-oriented scenario logically opens the door to the application of proteomic strategies to this field of research. We here review the current literature on proteomics applied to Parkinson's disease research, with particular emphasis on pathogenesis of sporadic Parkinson's disease in humans. We propose the view that Parkinson's disease may be an acquired or genetically-determined brain proteinopathy involving an abnormal processing of several, rather than individual neuronal proteins, and discuss some pre-analytical and analytical developments in proteomics that may help in verifying this concept.

  2. [Human prion diseases in the Czech Republic].

    PubMed

    Rohan, Z; Rusina, R; Marešová, M; Matěj, R

    2015-09-01

    Human prion diseases are a group of very rare diseases with a unique pathogenesis and, due to an inauspicious prognosis and unavailability of therapy, with fatal consequences. The etiopathogenetic background is the presence of pathologically misfolded prion protein, highly resistant to denaturation, the aggregation and presence of which in the brain tissue causes irreversible neuronal damage. The most frequent prion disease in humans is Creutzfeldt-Jakob disease (CJD) which occurs in sporadic, hereditary/familial, or acquired/infectious/iatrogenic forms. A new form of CJD, variant CJD, is considered to be linked to dietary exposure to beef products from cattle infected with bovine spongiform encephalopathy (BSE) and to infection via blood transfusion. The clinical picture of these diseases is characterized by a rapidly progressing dementia, cerebellar and extrapyramidal symptoms, and rather specific MRI, EEG, and CSF findings. Clinically, the diagnosis is described as possible or probable prion disease and needs to be confirmed by neuropathological or immunological investigation of the brain tissue. Epidemiological data from the Czech Republic spanning the last decade are presented. PMID:26448298

  3. Early developmental exposures shape trade-offs between acquired and innate immunity in humans

    PubMed Central

    Georgiev, Alexander V.; Kuzawa, Christopher W.; McDade, Thomas W.

    2016-01-01

    Background and objectives Life history theory predicts resource allocation trade-offs between competing functions and processes. We test the hypothesis that relative investment towards innate versus acquired immunity in humans is subject to such trade-offs and that three types of early developmental exposures are particularly salient in shaping adult immunophenotype: (i) pathogen exposure, (ii) nutritional resources; and (iii) extrinsic mortality cues. Methodology We quantified one aspect each of innate and acquired immune function, via C-reactive protein and Epstein–Barr virus antibodies, respectively, in a sample of 1248 men and women from the Philippines (ca. 21.5 years old). Early developmental exposures were assessed via long-term data collected prospectively since participants’ birth (1983–4). We calculated a standardized ratio to assess relative bias towards acquired versus innate immune function and examined its relationship to a suite of predictors via multiple regression. Results In partial support of our predictions, some of the measures of higher pathogen exposure, greater availability of nutritional resources, and lower extrinsic mortality cues in early life were associated with a bias toward acquired immunity in both men and women. The immune profile of women, in particular, appeared to be more sensitive to early life pathogen exposures than those of men. Finally, contrary to prediction, women exhibited a greater relative investment toward innate, not acquired, immunity. Conclusions and implications Early environments can exert considerable influence on the development of immunity. They affect trade-offs between innate and acquired immunity, which show adaptive plasticity and may differ in their influence in men and women. PMID:27530543

  4. Cranial CT in acquired immunodeficiency syndrome: spectrum of diseases and optimal contrast enhancement technique.

    PubMed

    Post, M J; Kursunoglu, S J; Hensley, G T; Chan, J C; Moskowitz, L B; Hoffman, T A

    1985-11-01

    A retrospective review of cranial CT scans obtained over a 4 year period in patients with acquired immunodeficiency syndrome (AIDS) and documented central nervous system (CNS) pathology is presented. The spectrum of diseases and the value of CT in detecting new, recurrent, and superimposed disease processes were determined. Fifty-one AIDS patients with confirmed CNS pathology were identified. Six of them had two coexistent diseases. Opportunistic infections predominated, especially Toxoplasma encephalitis and cryptococcal meningitis, while tumor was seen infrequently. Initial CT was positive in 76% of cases. In contrast to meningeal processes, where it was not very effective, CT was very sensitive in detecting most parenchymal disease processes. Characteristic although not pathognomonic CT patterns were found for certain diseases. Improvement or resolution of CT abnormalities in patients on medical therapy for Toxoplasma encephalitis correlated well with clinical improvement. Recurrence of CT abnormalities correlated well with medical noncompliance. The optimal contrast enhancement technique for detecting CNS pathology and for monitoring the effectiveness of medical therapy was also evaluated by a prospective study in which both immediate (IDD) and 1 hr delayed (DDD) double-dose contrast CT scans were compared. The examination found to be diagnostically superior in 30 of the 41 IDD/DDD studies was the delayed scan. It is recommended that CT be used routinely and with the 1 hr DDD scan to evaluate and follow AIDS patients with neurologic symptoms and/or signs.

  5. Inclusion body disease of cranes: comparison of pathologic findings in cranes with acquired vs. experimentally induced disease

    USGS Publications Warehouse

    Schuh, J.C.; Sileo, L.; Siegfried, L.M.; Yuill, Thomas M.

    1986-01-01

    Inclusion body disease of cranes was the cause of death in 17 immature and mature cranes of 5 different species in Wisconsin. A herpesvirus of unknown origin was the apparent cause. An isolate of this herpesvirus was used to experimentally infect 3 species of cranes. Macroscopic and microscopic lesions associated with naturally acquired and experimentally induced disease were essentially identical. Multifocal hepatic and splenic necrosis was found in all cranes evaluated. Necrosis of the gastrointestinal tract, thymus, and bursa of Fabricius also was seen in some of the cranes. Eosinophilic intranuclear inclusion bodies often were commonly associated with hepatic lesions, sometimes with the splenic lesions, and rarely with the thymic or gastrointestinal tract lesions. The lesions of this inclusion body disease were similar to those reported for cranes in Austria from which a crane herpesvirus was isolated.

  6. Monocyte/macrophage trafficking in acquired immunodeficiency syndrome encephalitis: lessons from human and nonhuman primate studies.

    PubMed

    Fischer-Smith, Tracy; Bell, Christie; Croul, Sidney; Lewis, Mark; Rappaport, Jay

    2008-08-01

    Here the authors discuss evidence in human and animal models supporting two opposing views regarding the pathogenesis of human immunodeficiency virus (HIV) in the central nervous system (CNS): (1) HIV infection in the CNS is a compartmentalized infection, with the virus-infected macrophages entering the CNS early, infecting resident microglia and astrocytes, and achieving a state of latency with evolution toward a fulminant CNS infection late in the course of disease; or alternatively, (2) events in the periphery lead to altered monocyte/macrophage (MPhi) homeostasis, with increased CNS invasion of infected and/or uninfected MPhis. Here the authors have reevaluated evidence presented in the favor of the latter model, with a discussion of phenotypic characteristics distinguishing normal resident microglia with those accumulating in HIV encephalitis (HIVE). CD163 is normally expressed by perivascular MPhi s but not resident microglia in normal CNS of humans and rhesus macaques. In agreement with other studies, the authors demonstrate expression of CD163 by brain MPhi s in HIVE and simian immunodeficiency virus encephalitis (SIVE). CNS tissues from HIV-sero positive individuals with HIVE or HIV-associated progressive multifocal leukoencephalopathy (PML) were also examined. In HIVE, the authors further demonstrate colocalization of CD163 and CD16 (Fcgamma III recptor) gene expression, the latter marker associated with HIV infection of monocyte in vivo and permissivity of infection. Indeed, CD163(+) MPhis and microglia are often productively infected in HIVE CNS. In SIV infected rhesus macaques, CD163(+) cells accumulate perivascularly, within nodular lesions and the parenchyma in animals with encephalitis. Likewise, parenchymal microglia and perivascular MPhi s are CD163(+) in HIVE. In contrast to HIVE, CD163(+)perivascular and parenchymal MPhi s in HIV-associated PML were only associated with areas of demyelinating lesions. Interestingly, SIV-infected rhesus macaques

  7. Human immunodeficiency virus and acquired immunodeficiency syndrome: correlation but not causation.

    PubMed Central

    Duesberg, P H

    1989-01-01

    AIDS is an acquired immunodeficiency syndrome defined by a severe depletion of T cells and over 20 conventional degenerative and neoplastic diseases. In the U.S. and Europe, AIDS correlates to 95% with risk factors, such as about 8 years of promiscuous male homosexuality, intravenous drug use, or hemophilia. Since AIDS also correlates with antibody to a retrovirus, confirmed in about 40% of American cases, it has been hypothesized that this virus causes AIDS by killing T cells. Consequently, the virus was termed human immunodeficiency virus (HIV), and antibody to HIV became part of the definition of AIDS. The hypothesis that HIV causes AIDS is examined in terms of Koch's postulates and epidemiological, biochemical, genetic, and evolutionary conditions of viral pathology. HIV does not fulfill Koch's postulates: (i) free virus is not detectable in most cases of AIDS; (ii) virus can only be isolated by reactivating virus in vitro from a few latently infected lymphocytes among millions of uninfected ones; (iii) pure HIV does not cause AIDS upon experimental infection of chimpanzees or accidental infection of healthy humans. Further, HIV violates classical conditions of viral pathology. (i) Epidemiological surveys indicate that the annual incidence of AIDS among antibody-positive persons varies from nearly 0 to over 10%, depending critically on nonviral risk factors. (ii) HIV is expressed in less than or equal to 1 of every 10(4) T cells it supposedly kills in AIDS, whereas about 5% of all T cells are regenerated during the 2 days it takes the virus to infect a cell. (iii) If HIV were the cause of AIDS, it would be the first virus to cause a disease only after the onset of antiviral immunity, as detected by a positive "AIDS test." (iv) AIDS follows the onset of antiviral immunity only after long and unpredictable asymptomatic intervals averaging 8 years, although HIV replicates within 1 to 2 days and induces immunity within 1 to 2 months. (v) HIV supposedly causes AIDS

  8. Mouse models of human disease

    PubMed Central

    Perlman, Robert L.

    2016-01-01

    The use of mice as model organisms to study human biology is predicated on the genetic and physiological similarities between the species. Nonetheless, mice and humans have evolved in and become adapted to different environments and so, despite their phylogenetic relatedness, they have become very different organisms. Mice often respond to experimental interventions in ways that differ strikingly from humans. Mice are invaluable for studying biological processes that have been conserved during the evolution of the rodent and primate lineages and for investigating the developmental mechanisms by which the conserved mammalian genome gives rise to a variety of different species. Mice are less reliable as models of human disease, however, because the networks linking genes to disease are likely to differ between the two species. The use of mice in biomedical research needs to take account of the evolved differences as well as the similarities between mice and humans. PMID:27121451

  9. An unusually long-lasting outbreak of community-acquired Legionnaires' disease, 2005-2008, Italy.

    PubMed

    Scaturro, M; Fontana, S; Crippa, S; Caporali, M G; Seyler, T; Veschetti, E; Villa, G; Rota, M C; Ricci, M L

    2015-08-01

    An unusually long-lasting community-acquired outbreak of Legionnaires' disease (LD) occurred in the inhabitants of a town in northern Italy from 2005 to 2008. Overall, 43 cases were diagnosed including five deaths. Hundreds of water samples were collected for Legionella isolation but only two clinical samples were obtained. Clinical strains were ST23 as were environmental isolates detected in most Legionella-positive patients' homes and those from a public fountain. Although no Legionella was found in the municipal water mains, a continuous chlorination was applied in 2008. This action resulted in a halving of cases, although incidence remained tenfold higher than the Italian average incidence until the end of 2013, when it dropped to the expected rate. Retrospective analyses of prevalent wind direction suggested that a hidden cooling tower could have been the main cause of this uncommon outbreak, highlighting the importance of implementation of cooling tower registers in supporting LD investigations. PMID:25427871

  10. Vulvar carcinoma in a 12-year-old girl with vertically acquired human immunodeficiency virus infection.

    PubMed

    Giaquinto, C; Del Mistro, A; De Rossi, A; Bertorelle, R; Giacomet, V; Ruga, E; Minucci, D

    2000-10-01

    We report the first case of a girl with vertically acquired human immunodeficiency virus (HIV) infection, who developed invasive squamous cell carcinoma of the vulva at 12 years of age. Lesions resembling bowenoid papulosis covered the perianal area as well. She underwent a nonmutilating surgical excision of the infiltrating lesion. More than 3 years later, her clinical condition is excellent, although dysplastic, noninfiltrating multifocal lesions persist. This case highlights the need to perform careful periodic genital examinations in all HIV-infected children and adolescents born to HIV-positive mothers.

  11. The Urine Urokinase Concentration in End Stage Renal Disease with Acquired Renal Cyst

    PubMed Central

    Hong, Sae Yong; Yang, Dong Ho; Lee, Byoung Ho; Ki, Eun Kyong; Chung, Kwang Hoe

    1991-01-01

    To see whether there was any difference in the urine urokinase concentration between acquired cystic kidney disease (ACKD) group and control (non cyst) group in end stage renal disease patients (ESRD), we evaluated fifty ESRD patients who had been maintained on chronic hemodialysis for various period. The urine urokinase concentration was higher in the ACKD group (17.5±14.7 unit/ml, range 13.5–47.0 unit/ml, n=9) than the control group (4.1±3.4 unit/ml, range 0.5–12.0 unit/ml, n=36) (p<0.001), and polycyst group (2.6±1.8 unit/ml, range 1.0–5.1 unit/ml, n=5) (p<0.01). But there was no difference between the control group and polycyst group. In the control group and the ACKD group, there was a direct relation between the dialysis duration and the urokinase concentration and the longer the dialysis duration, the higher the urine urokinase concentration (r squared=0.424, p=0.0001). The hemodialysis duration was longer in the ACKD group (42±17.0 months) than the control group (20.0±12.5 months) (p<0.005). These findings suggest that urokinase may be responsible for cystogenic degeneration in ESRD. PMID:1807367

  12. Simian virus 40-induced disease in rhesus monkeys with simian acquired immunodeficiency syndrome.

    PubMed Central

    Horvath, C. J.; Simon, M. A.; Bergsagel, D. J.; Pauley, D. R.; King, N. W.; Garcea, R. L.; Ringler, D. J.

    1992-01-01

    Simian virus 40 (SV40) disease was diagnosed in four rhesus monkeys that died with SIV-induced acquired immunodeficiency syndrome (AIDS). One juvenile monkey seroconverted for SV40 6 months after inoculation with SIV and developed severe bilateral tubulointerstitial nephritis. In contrast, progressive multifocal leukoencephalopathy (PML) occurred in two adult monkeys that were seropositive for SV40 before SIV inoculation, as well as a third adult that was naturally infected with SIV and seropositive for SV40 5 years before death. Large intranuclear inclusions containing abundant polyomavirus particles were limited to either renal tubular epithelial cells or oligodendrocytes. In situ DNA hybridization for SV40 large T antigen further demonstrated that SV40 nucleic acid was localized to either kidney or brain tissue. By immunohistochemical analysis, areas of central nervous system inflammation and demyelination were shown to contain CD68+ macrophages (gitter cells), aggregates of CD8+ T lymphocytes, and numerous gemistocytic astrocytes that labeled for glial fibrillary acidic protein. These observations indicate that rhesus monkeys with SIV-induced AIDS are predisposed to polyomaviral disease, in which SV40 nucleic acid is observed in renal tissue in primary infections and brain tissue after viral reactivation. Furthermore, this organ-specific replication suggests that tissue-tropic strains of SV40 may develop in immunodeficient monkeys. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:1376560

  13. Acquired cystic disease-associated renal cell carcinoma: further characterization of the morphologic and immunopathologic features.

    PubMed

    Ahn, Soomin; Kwon, Ghee Young; Cho, Yong Mee; Jun, Sun-Young; Choi, Chan; Kim, Hyun-Jung; Park, Yong Wook; Park, Weon Seo; Shim, Jung Won

    2013-12-01

    Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is a subtype of renal cell carcinoma (RCC) with unique morphologic features found exclusively in the background of end-stage renal disease. We analyzed the clinicopathologic features and immumoreactive profiles of 12 cases of ACD-RCC to further characterize this recently recognized entity. Review of histologic slides was performed in conjunction with immunohistochemical staining directed to the contemporary diagnostic antibodies and the putative target therapy-related markers. Histologically, the tumors showed characteristic inter-or intracellular microlumens and eosinophilic tumor cells. Intratumoral hemosiderin deposition and degenerating foamy tumor cells were consistent findings which were not previously described. Immunohistochemically, all the tumors were positive for alpha-methylacyl-CoA-racemase, CD10, pan-cytokeratin, PTEN (phosphatase and tensin homolog deleted on chromosome 10) and c-met, while negative for carbonic anhydrase-9, CD57, CD68, c-kit, pax-2, platelet-derived growth factor receptor (PDGFR)-α or vascular endothelial growth factor receptor (VEGFR)-2. Heterogenous staining was found for CK7 and kidney-specific cadherin. Positive reaction to c-met suggests its utility as a plausible therapeutic target in ACD-RCC. Thus, we present the unique morphologic and immunopathologic features of ACD-RCC, which may be helpful in both diagnostic and therapeutic aspects. PMID:23471757

  14. DNA analysis in human disease.

    PubMed Central

    Wright, A F

    1986-01-01

    The analysis of human DNA using recombinant DNA technology is fast becoming an integral part of the diagnosis, assessment, and prevention of inherited and somatic genetic disease. The rationale underlying these methods of analysis is discussed, and the nature and extent of mutational change in heritable disorders and neoplastic development is outlined. PMID:3543064

  15. The Unspecific Side of Acquired Immunity Against Infectious Disease: Causes and Consequences

    PubMed Central

    Muraille, Eric

    2016-01-01

    Acquired immunity against infectious disease (AIID) has long been considered as strictly dependent on the B and T lymphocytes of the adaptive immune system. Consequently, AIID has been viewed as highly specific to the antigens expressed by pathogens. However, a growing body of data motivates revision of this central paradigm of immunology. Unrelated past infection, vaccination, and chronic infection have been found to induce cross-protection against numerous pathogens. These observations can be partially explained by the poly-specificity of antigenic T and B receptors, the Mackaness effect and trained immunity. In addition, numerous studies highlight the importance of microbiota composition on resistance to infectious disease via direct competition or modulation of the immune response. All of these data support the idea that a non-negligible part of AIID in nature can be nonspecific to the pathogens encountered and even of the antigens expressed by pathogens. As this protection may be dependent on the private T and B repertoires produced by the random rearrangement of genes, past immune history, chronic infection, and microbiota composition, it is largely unpredictable at the individual level. However, we can reasonably expect that a better understanding of the underlying mechanisms will allow us to statistically predict cross-protection at the population level. From an evolutionary perspective, selection of immune mechanisms allowing for partially nonspecific AIID would appear to be advantageous against highly polymorphic and rapidly evolving pathogens. This new emerging paradigm may have several important consequences on our understanding of individual infectious disease susceptibility and our conception of tolerance, vaccination and therapeutic strategies against infection and cancer. It also underscores the importance of viewing the microbiota and persisting infectious agents as integral parts of the immune system. PMID:26793171

  16. Animal models for human diseases.

    PubMed

    Rust, J H

    1982-01-01

    The use of animal models for the study of human disease is, for the most part, a recent development. This discussion of the use of animal models for human diseases directs attention to the sterile period, early advances, some personal experiences, the human as the model, biological oddities among common laboratory animals, malignancies in laboratory animals, problems created by federal regulations, cancer tests with animals, and what the future holds in terms of the use of animal models as an aid to understanding human disease. In terms of early use of animal models, there was a school of rabbis, some of whom were also physicians, in Babylon who studied and wrote extensively on ritual slaughter and the suitability of birds and beasts for food. Considerable detailed information on animal pathology, physiology, anatomy, and medicine in general can be found in the Soncino Babylonian Talmudic Translations. The 1906 edition of the "Jewish Encyclopedia," has been a rich resource. Although it has not been possible to establish what diseases of animals were studied and their relationship to the diseases of humans, there are fascinating clues to pursue, despite the fact that these were sterile years for research in medicine. The quotation from the Talmud is of interest: "The medical knowledge of the Talmudist was based upon tradition, the dissection of human bodies, observation of disease and experiments upon animals." A bright light in the lackluster years of medical research was provided by Galen, considered the originator of research in physiology and anatomy. His dissection of animals and work on apes and other lower animals were models for human anatomy and physiology and the bases for many treatises. Yet, Galen never seemed to suggest that animals could serve as models for human diseases. Most early physicians who can be considered to have been students of disease developed their medical knowledge by observing the sick under their care. 1 early medical investigator

  17. Conditional Lineage Ablation to Model Human Diseases

    NASA Astrophysics Data System (ADS)

    Lee, Paul; Morley, Gregory; Huang, Qian; Fischer, Avi; Seiler, Stephanie; Horner, James W.; Factor, Stephen; Vaidya, Dhananjay; Jalife, Jose; Fishman, Glenn I.

    1998-09-01

    Cell loss contributes to the pathogenesis of many inherited and acquired human diseases. We have developed a system to conditionally ablate cells of any lineage and developmental stage in the mouse by regulated expression of the diphtheria toxin A (DTA) gene by using tetracycline-responsive promoters. As an example of this approach, we targeted expression of DTA to the hearts of adult mice to model structural abnormalities commonly observed in human cardiomyopathies. Induction of DTA expression resulted in cell loss, fibrosis, and chamber dilatation. As in many human cardiomyopathies, transgenic mice developed spontaneous arrhythmias in vivo, and programmed electrical stimulation of isolated-perfused transgenic hearts demonstrated a strikingly high incidence of spontaneous and inducible ventricular tachycardia. Affected mice showed marked perturbations of cardiac gap junction channel expression and localization, including a subset with disorganized epicardial activation patterns as revealed by optical action potential mapping. These studies provide important insights into mechanisms of arrhythmogenesis and suggest that conditional lineage ablation may have wide applicability for studies of disease pathogenesis.

  18. Pigeons acquire multiple categories in parallel via associative learning: A parallel to human word learning?

    PubMed Central

    Wasserman, Edward A.; Brooks, Daniel I.; McMurray, Bob

    2014-01-01

    Might there be parallels between category learning in animals and word learning in children? To examine this possibility, we devised a new associative learning technique for teaching pigeons to sort 128 photographs of objects into 16 human language categories. We found that pigeons learned all 16 categories in parallel, they perceived the perceptual coherence of the different object categories, and they generalized their categorization behavior to novel photographs from the training categories. More detailed analyses of the factors that predict trial-by-trial learning implicated a number of factors that may shape learning. First, we found considerable trial-by-trial dependency of pigeons’ categorization responses, consistent with several recent studies that invoke this dependency to claim that humans acquire words via symbolic or inferential mechanisms; this finding suggests that such dependencies may also arise in associative systems. Second, our trial-by-trial analyses divulged seemingly irrelevant aspects of the categorization task, like the spatial location of the report responses, which influenced learning. Third, those trial-by-trial analyses also supported the possibility that learning may be determined both by strengthening correct stimulus-response associations and by weakening incorrect stimulus-response associations. The parallel between all these findings and important aspects of human word learning suggests that associative learning mechanisms may play a much stronger part in complex human behavior than is commonly believed. PMID:25497520

  19. Proteins aggregation and human diseases

    NASA Astrophysics Data System (ADS)

    Hu, Chin-Kun

    2015-04-01

    Many human diseases and the death of most supercentenarians are related to protein aggregation. Neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), frontotemporallobar degeneration, etc. Such diseases are due to progressive loss of structure or function of neurons caused by protein aggregation. For example, AD is considered to be related to aggregation of Aβ40 (peptide with 40 amino acids) and Aβ42 (peptide with 42 amino acids) and HD is considered to be related to aggregation of polyQ (polyglutamine) peptides. In this paper, we briefly review our recent discovery of key factors for protein aggregation. We used a lattice model to study the aggregation rates of proteins and found that the probability for a protein sequence to appear in the conformation of the aggregated state can be used to determine the temperature at which proteins can aggregate most quickly. We used molecular dynamics and simple models of polymer chains to study relaxation and aggregation of proteins under various conditions and found that when the bending-angle dependent and torsion-angle dependent interactions are zero or very small, then protein chains tend to aggregate at lower temperatures. All atom models were used to identify a key peptide chain for the aggregation of insulin chains and to find that two polyQ chains prefer anti-parallel conformation. It is pointed out that in many cases, protein aggregation does not result from protein mis-folding. A potential drug from Chinese medicine was found for Alzheimer's disease.

  20. Is community-acquired pneumonia an independent risk factor for cardiovascular disease?

    PubMed

    Singanayagam, A; Singanayagam, A; Elder, D H J; Chalmers, J D

    2012-01-01

    Community-acquired pneumonia (CAP) is the most frequent infectious cause of death in western countries. The high mortality rate in CAP is commonly related to comorbid conditions such as cardiovascular disease. Clinical studies in both primary and secondary care settings have identified an increase in short- and long-term risk of cardiovascular events and death from vascular events following acute respiratory infections. The mechanism remains to be fully established, but it has been suggested that the inflammatory state in patients affected by CAP acts to promote platelet activation and thrombosis, and to narrow coronary arteries through vasoconstriction. Acute infections destabilise vascular endothelium and create an imbalance between myocardial oxygen supply and demand, leading to an increased risk of cardiovascular events. Acute infections have been shown to have both systemic effects and local effects on coronary vessels. These effects are mediated through both the host response to infection and, in some cases, direct effects of bacterial infection or bacterial products. In this review, we discuss the link between CAP and increased risk of cardiovascular events, drawing on existing evidence from clinical and mechanistic studies. Further studies into and increased awareness of this association is warranted to promote novel ways of protecting high-risk patients. PMID:21737556

  1. Outer Surface Protein A Protects Lyme Disease Spirochetes from Acquired Host Immunity in the Tick Vector▿

    PubMed Central

    Battisti, James M.; Bono, James L.; Rosa, Patricia A.; Schrumpf, Merry E.; Schwan, Tom G.; Policastro, Paul F.

    2008-01-01

    The Lyme disease spirochete Borrelia burgdorferi alters the expression of outer surface protein (osp) genes as the bacterium cycles between ticks and mammals. OspA is produced as borreliae enter the tick vector and remains a major surface antigen during midgut colonization. To elucidate the role of OspA in the vector, we created an insertional deletion of ospA in strain B31-A3. The ospA mutant infects mice when it is injected intradermally and is acquired by larval ticks fed on these mice, where it persists through the molt to the nymph stage. Bacterial survival rates in artificially infected tick larvae fed on naïve mice were compared with those in the vector fed on immune mice. The ospA mutant proliferates in larvae if it is exposed to blood from naïve mice, but it declines in density after larval feeding if the blood is from immune mice. When uninfected larvae are fed on B-cell-deficient mice infected with the ospA mutant, larvae show borrelial densities and persistence that are significantly greater than those fed on infected, immunocompetent mice. We conclude that OspA serves a critical antibody-shielding role during vector blood meal uptake from immune hosts and is not required for persistence in the tick vector. PMID:18779341

  2. Domestically Acquired Legionnaires’ Disease: Two Case Reports and a Review of the Pertinent Literature

    PubMed Central

    Erdoğan, Haluk; Arslan, Hande

    2016-01-01

    Background: Legionella species may colonize in home water systems and cause Legionnaires’ disease (LD). We herein report two cases of sporadic LD associated with the solar energy-heated hot water systems of the patients’ houses. Case Report: A 60-year-old woman with chronic bronchitis and diabetes mellitus presented with a high fever, abdominal pain, and diarrhea. Physical examination revealed rales, and her chest radiograph showed a homogeneous density in the left lung. The Legionella urinary antigen test was positive, and an indirect fluorescent antibody test revealed a serum antibody titer of 1/520 for L. pneumophila serogroup 1. In the second case, a 66-year-old man with diabetes mellitus was treated for pneumonia at another hospital. After the patient’s general condition worsened and he required mechanical ventilation, he was referred to our hospital. The Legionella urinary antigen test was positive. Neither of the patients had been hospitalized or travelled within the previous month. Both patients used hot water storage tanks heated by solar energy; both also used an electrical device in the bathroom to heat the water when solar energy alone was insufficient. The hot water samples from the residences of both patients were positive for L. pneumophila sero-group 1. Conclusion: These cases show that domestic hot water systems heated by solar energy must be considered a possible source of community-acquired LD. PMID:27308081

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-06-01

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

  5. A novel ELISA-based diagnosis of acquired von Willebrand disease with increased VWF proteolysis.

    PubMed

    Rauch, Antoine; Caron, Claudine; Vincent, Flavien; Jeanpierre, Emmanuelle; Ternisien, Catherine; Boisseau, Pierre; Zawadzki, Christophe; Fressinaud, Edith; Borel-Derlon, Annie; Hermoire, Sylvie; Paris, Camille; Lavenu-Bombled, Cécile; Veyradier, Agnès; Ung, Alexandre; Vincentelli, André; van Belle, Eric; Lenting, Peter J; Goudemand, Jenny; Susen, Sophie

    2016-05-01

    Von Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speed-dependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWD-patients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWF-proteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis. PMID:26791163

  6. Rac GTPases in Human Diseases

    PubMed Central

    Pai, Sung-Yun; Kim, Chaekyun; Williams, David A.

    2010-01-01

    Rho GTPases are members of the Ras superfamily of GTPases that regulate a wide variety of cellular functions. While Rho GTPase pathways have been implicated in various pathological conditions in humans, to date coding mutations in only the hematopoietic specific GTPase, RAC2, have been found to cause a human disease, a severe phagocytic immunodeficiency characterized by life-threatening infections in infancy. Interestingly, the phenotype was predicted by a mouse knock-out of RAC2 and resembles leukocyte adhesion deficiency (LAD). Here we review Rho GTPases with a specific focus on Rac GTPases. In particular, we discuss a new understanding of the unique and overlapping roles of Rac2 in blood cells that has developed since the generation of mice deficient in Rac1, Rac2 and Rac3 proteins. We propose that Rac2 mutations leading to disease be termed LAD type IV. PMID:21178276

  7. Nicotinamide Phosphoribosyltransferase in Human Diseases

    PubMed Central

    Zhang, Li Qin; Heruth, Daniel P.; Ye, Shui Qing

    2011-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) was first reported as a pre-B-cell colony enhancing factor in 1994 with little notice, but it has received increasing attention in recent years due to accumulating evidence indicating that NAMPT is a pleiotropic protein such as a growth factor, a cytokine, an enzyme and a visfatin. Now, NAMPT has been accepted as an official name of this protein. Because of NAMPT’s multiple functions in a variety of physiological processes, their dysregulations have been implicated in the pathogenesis of a number of human diseases or conditions such as acute lung injury, aging, atherosclerosis, cancer, diabetes, rheumatoid arthritis and sepsis. This review will cover the current understanding of NAMPT’s structure and functions with an emphasis on recent progress of nicotinamide phosphoribosyltransferase’s pathological roles in various human diseases and conditions. Future directions on exploring its Terra incognita will be offered in the end. PMID:22140607

  8. Brazilian response to the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic among injection drug users.

    PubMed

    Mesquita, Fábio; Doneda, Denise; Gandolfi, Denise; Nemes, Maria Inês Battistella; Andrade, Tarcísio; Bueno, Regina; Piconez e Trigueiros, Daniela

    2003-12-15

    The Brazilian response to the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic is being observed all over the world because of its success. Understanding the role of injection drug users (IDUs) in the epidemic and the political response thereto is a key factor in the control of the epidemic in Brazil. This paper summarizes some of the most important analyses of the Brazilian response to the HIV/AIDS epidemic among and from IDUs. Key elements of the response include the support of the Brazilian Universal Public Health System, the provision of universal access to highly active antiretroviral therapy, and the creation of harm reduction projects that are politically and financially supported by the federal government. The response among and from IDUs is a key element in overall control of the HIV/AIDS epidemic. The response to the epidemic among and from IDUs has been headed in the correct direction since its beginning and is now being intensively expanded.

  9. A possible mechanism of acquired acid resistance of human dental enamel by laser irradiation.

    PubMed

    Oho, T; Morioka, T

    1990-01-01

    A possible mechanism of acquired acid resistance of lased enamel was proposed on the basis of the investigations of optical properties, compositional and structural changes and permeability of lased and unlased human dental enamel. Lased enamel showed a high positive birefringence, suggesting the formation of 'microspaces' in enamel. No new products were found, though a decrease of lattice strain and a slight a-axis contraction were recognized in lased enamel compared with unlased enamel. The contents of water, carbonate and organic substances were reduced in lased enamel. Gradual changes of birefringence were observed in lased enamel during treatment with acid solutions, and this change was attributed to mineralization of the microspaces. The ions released by an acid decalcification would be trapped in the microspaces in lased enamel, whereas such ions diffuse to the surrounding solution in unlased enamel.

  10. Spinal cord toxoplasmosis in human immunodeficiency virus infection/acquired immunodeficiency syndrome.

    PubMed

    García-García, Concepción; Castillo-Álvarez, Federico; Azcona-Gutiérrez, José M; Herraiz, María J; Ibarra, Valvanera; Oteo, José A

    2015-05-01

    Neurological complications in patients with human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) are still common, even in the era of highly active antiretroviral therapy. Opportunistic infections, immune reconstitution, the virus itself, antiretroviral drugs and neurocognitive disorders have to be considered when establishing the differential diagnosis. Toxoplasmic encephalitis remains the major cause of space-occupying lesions in the brain of patients with HIV/AIDS; however, spinal cord involvement has been reported infrequently. Here, we review spinal cord toxoplasmosis in HIV infection and illustrate the condition with a recent case from our hospital. We suggest that most patients with HIV/AIDS and myelitis with enhanced spine lesions, multiple brain lesions and positive serology for Toxoplasma gondii should receive immediate empirical treatment for toxoplasmosis, and a biopsy should be performed in those cases without clinical improvement or with deterioration.

  11. Recent multistate outbreaks of human salmonella infections acquired from turtles: a continuing public health challenge.

    PubMed

    Harris, Julie R; Neil, Karen P; Behravesh, Casey Barton; Sotir, Mark J; Angulo, Frederick J

    2010-02-15

    The federal ban in the United States on the sale of turtles with shell lengths <4 inches that was established in 1975 has reduced the number of turtle-associated human Salmonella infections during subsequent years, especially among children. Although numerous sporadic turtle-associated Salmonella infections in humans have been reported since the ban went into effect, outbreaks were not reported until recently. Since 2006, 3 multistate outbreaks of turtle-associated Salmonella infections have been documented in the United States. This review examines the history of turtle-associated human Salmonella infections in the United States and discusses reasons why an increase in turtle-associated salmonellosis may be occurring and how challenges in enforcement of the ban affect disease control. Additional steps should be considered by the public health community, state governments, and enforcement agencies to prevent turtle-associated Salmonella infections in humans. PMID:20085463

  12. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder

    PubMed Central

    Frye, R E; Melnyk, S; MacFabe, D F

    2013-01-01

    Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels—a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of

  13. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder.

    PubMed

    Frye, R E; Melnyk, S; Macfabe, D F

    2013-01-01

    Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels-a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial

  14. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder.

    PubMed

    Frye, R E; Melnyk, S; Macfabe, D F

    2013-01-01

    Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels-a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial

  15. Cross-reactive acquired immunity influences transmission success of the Lyme disease pathogen, Borrelia afzelii.

    PubMed

    Jacquet, Maxime; Durand, Jonas; Rais, Olivier; Voordouw, Maarten J

    2015-12-01

    Cross-reactive acquired immunity in the vertebrate host induces indirect competition between strains of a given pathogen species and is critical for understanding the ecology of mixed infections. In vector-borne diseases, cross-reactive antibodies can reduce pathogen transmission at the vector-to-host and the host-to-vector lifecycle transition. The highly polymorphic, immunodominant, outer surface protein C (OspC) of the tick-borne spirochete bacterium Borrelia afzelii induces a strong antibody response in the vertebrate host. To test how cross-immunity in the vertebrate host influences tick-to-host and host-to-tick transmission, mice were immunized with one of two strain-specific recombinant OspC proteins (A3, A10), challenged via tick bite with one of the two B. afzelii ospC strains (A3, A10), and infested with xenodiagnostic ticks. Immunization with a given rOspC antigen protected mice against homologous strains carrying the same major ospC group allele but provided little or no cross-protection against heterologous strains carrying a different major ospC group allele. There were cross-immunity effects on the tick spirochete load but not on the probability of host-to-tick transmission. The spirochete load in ticks that had fed on mice with cross-immune experience was reduced by a factor of two compared to ticks that had fed on naive control mice. In addition, strain-specific differences in mouse spirochete load, host-to-tick transmission, tick spirochete load, and the OspC-specific IgG response revealed the mechanisms that determine variation in transmission success between strains of B. afzelii. This study shows that cross-immunity in infected vertebrate hosts can reduce pathogen load in the arthropod vector with potential consequences for vector-to-host pathogen transmission.

  16. Cross-reactive acquired immunity influences transmission success of the Lyme disease pathogen, Borrelia afzelii.

    PubMed

    Jacquet, Maxime; Durand, Jonas; Rais, Olivier; Voordouw, Maarten J

    2015-12-01

    Cross-reactive acquired immunity in the vertebrate host induces indirect competition between strains of a given pathogen species and is critical for understanding the ecology of mixed infections. In vector-borne diseases, cross-reactive antibodies can reduce pathogen transmission at the vector-to-host and the host-to-vector lifecycle transition. The highly polymorphic, immunodominant, outer surface protein C (OspC) of the tick-borne spirochete bacterium Borrelia afzelii induces a strong antibody response in the vertebrate host. To test how cross-immunity in the vertebrate host influences tick-to-host and host-to-tick transmission, mice were immunized with one of two strain-specific recombinant OspC proteins (A3, A10), challenged via tick bite with one of the two B. afzelii ospC strains (A3, A10), and infested with xenodiagnostic ticks. Immunization with a given rOspC antigen protected mice against homologous strains carrying the same major ospC group allele but provided little or no cross-protection against heterologous strains carrying a different major ospC group allele. There were cross-immunity effects on the tick spirochete load but not on the probability of host-to-tick transmission. The spirochete load in ticks that had fed on mice with cross-immune experience was reduced by a factor of two compared to ticks that had fed on naive control mice. In addition, strain-specific differences in mouse spirochete load, host-to-tick transmission, tick spirochete load, and the OspC-specific IgG response revealed the mechanisms that determine variation in transmission success between strains of B. afzelii. This study shows that cross-immunity in infected vertebrate hosts can reduce pathogen load in the arthropod vector with potential consequences for vector-to-host pathogen transmission. PMID:26384476

  17. Acquired cystic kidney disease in children undergoing continuous ambulatory peritoneal dialysis. Kyushu Pediatric Nephrology Study Group.

    PubMed

    1999-08-01

    Our cross-sectional study aims to elucidate the prevalence of acquired cystic kidney disease (ACKD), time of occurrence of ACKD, relationship between the prevalence of ACKD and duration of dialysis, progression of cysts, and ACKD-related complications in 54 children undergoing continuous ambulatory peritoneal dialysis (CAPD). ACKD was defined as four or more cysts detected in each kidney by ultrasonography, computed tomography (CT), or magnetic resonance imaging. The presence of less than four cysts was diagnosed as solitary cysts (SCs). Noncystic primary disease was present as glomerulonephritis in 23 patients (42.6%); hypoplastic kidney, 7 patients (13.0%); reflux nephropathy, 6 patients (11.1%); and other, 18 patients (33.3%). ACKD was evident in 16 patients (29.6%) during the 57.9 +/- 39.8 months after the start of CAPD. Nine patients (16. 7%) had SCs. SCs and ACKD were detected initially in patients with 1 and 3 years of CAPD, respectively. The mean duration of CAPD for patients with ACKD (96.1 +/- 36.6 months) differed from that of patients with SCs (49.8 +/- 29.9 months) and no cysts (38.3 +/- 25.8 months). The groups were classified according to time after the start of CAPD: 0 to 4 years (n = 33), 5 to 9 years (n = 16), and longer than 10 years (n = 5). The prevalence of ACKD among these three groups was 9.1%, 50%, and 80%, respectively, and this prevalence increased significantly with increasing duration of CAPD. Of 15 patients examined two to four times by ultrasonography or CT, the number and size of cysts increased in 7 patients with ACKD and 2 patients with SC. Two patients with many and large cysts experienced gross hematuria, and one of those patients had intracystic and retroperitoneal bleeding caused by cyst rupture. No solid mass lesion was found by imaging diagnostic modalities in the 54 patients. In conclusion, the prevalence of ACKD in children undergoing CAPD is just as high as that in adults. The prevalence of ACKD and number and size of

  18. Human cord blood CD34+ progenitor cells acquire functional cardiac properties through a cell fusion process.

    PubMed

    Avitabile, Daniele; Crespi, Alessia; Brioschi, Chiara; Parente, Valeria; Toietta, Gabriele; Devanna, Paolo; Baruscotti, Mirko; Truffa, Silvia; Scavone, Angela; Rusconi, Francesca; Biondi, Andrea; D'Alessandra, Yuri; Vigna, Elisa; Difrancesco, Dario; Pesce, Maurizio; Capogrossi, Maurizio C; Barbuti, Andrea

    2011-05-01

    The efficacy of cardiac repair by stem cell administration relies on a successful functional integration of injected cells into the host myocardium. Safety concerns have been raised about the possibility that stem cells may induce foci of arrhythmia in the ischemic myocardium. In a previous work (36), we showed that human cord blood CD34(+) cells, when cocultured on neonatal mouse cardiomyocytes, exhibit excitation-contraction coupling features similar to those of cardiomyocytes, even though no human genes were upregulated. The aims of the present work are to investigate whether human CD34(+) cells, isolated after 1 wk of coculture with neonatal ventricular myocytes, possess molecular and functional properties of cardiomyocytes and to discriminate, using a reporter gene system, whether cardiac differentiation derives from a (trans)differentiation or a cell fusion process. Umbilical cord blood CD34(+) cells were isolated by a magnetic cell sorting method, transduced with a lentiviral vector carrying the enhanced green fluorescent protein (EGFP) gene, and seeded onto primary cultures of spontaneously beating rat neonatal cardiomyocytes. Cocultured EGFP(+)/CD34(+)-derived cells were analyzed for their electrophysiological features at different time points. After 1 wk in coculture, EGFP(+) cells, in contact with cardiomyocytes, were spontaneously contracting and had a maximum diastolic potential (MDP) of -53.1 mV, while those that remained isolated from the surrounding myocytes did not contract and had a depolarized resting potential of -11.4 mV. Cells were then resuspended and cultured at low density to identify EGFP(+) progenitor cell derivatives. Under these conditions, we observed single EGFP(+) beating cells that had acquired an hyperpolarization-activated current typical of neonatal cardiomyocytes (EGFP(+) cells, -2.24 ± 0.89 pA/pF; myocytes, -1.99 ± 0.63 pA/pF, at -125 mV). To discriminate between cell autonomous differentiation and fusion, EGFP(+)/CD34

  19. Acquired immune response to oncogenic human papillomavirus associated with prophylactic cervical cancer vaccines.

    PubMed

    Einstein, Mark H

    2008-04-01

    Human papillomavirus (HPV) is a common infection among women and a necessary cause of cervical cancer. Oncogenic HPV types infecting the anogenital tract have the potential to induce natural immunity, but at present we do not clearly understand the natural history of infection in humans and the mechanisms by which the virus can evade the host immune response. Natural acquired immune responses against HPV may be involved in the clearance of infection, but persistent infection with oncogenic virus types leads to the development of precancerous lesions and cancer. B cell responses are important for viral neutralization, but antibody responses in patients with cervical cancer are poor. Prophylactic vaccines targeting oncogenic virus types associated with cervical cancer have the potential to prevent up to 80% of cervical cancers by targeting HPV types 16 and 18. Clinical data show that prophylactic vaccines are effective in inducing antibody responses and in preventing persistent infection with HPV, as well as the subsequent development of high-grade cervical intraepithelial neoplasia. This article reviews the known data regarding natural immune responses to HPV and those developed by prophylactic vaccination.

  20. Aleutian Mink Disease Virus and Humans

    PubMed Central

    d’Amore, Francesco; Baandrup, Ulrik; Clausen, Michael Roost; Gottschalck, Elisabeth; Aasted, Bent

    2009-01-01

    Reports of a possible relationship between Aleutian mink disease parvovirus (AMDV) and human infection are rare. However, 2 mink farmers with vascular disease and microangiopathy similar to that in mink with Aleutian disease were found to have AMDV-specific antibodies and AMDV DNA. These findings raise the suspicion that AMDV may play a role in human disease. PMID:19961696

  1. Aleutian mink disease virus and humans.

    PubMed

    Jepsen, Jørgen R; d'Amore, Francesco; Baandrup, Ulrik; Clausen, Michael Roost; Gottschalck, Elisabeth; Aasted, Bent

    2009-12-01

    Reports of a possible relationship between Aleutian mink disease parvovirus (AMDV) and human infection are rare. However, 2 mink farmers with vascular disease and microangiopathy similar to that in mink with Aleutian disease were found to have AMDV-specific antibodies and AMDV DNA. These findings raise the suspicion that AMDV may play a role in human disease. PMID:19961696

  2. Human Microbiota and Ophthalmic Disease

    PubMed Central

    Lu, Louise J.; Liu, Ji

    2016-01-01

    The human ocular surface, consisting of the cornea and conjunctiva, is colonized by an expansive, diverse microbial community. Molecular-based methods, such as 16S rRNA sequencing, has allowed for more comprehensive and precise identification of the species composition of the ocular surface microbiota compared to traditional culture-based methods. Evidence suggests that the normal microbiota plays a protective immunological role in preventing the proliferation of pathogenic species and thus, alterations in the homeostatic microbiome may be linked to ophthalmic pathologies. Further investigation of the ocular surface microbiome, as well as the microbiome of other areas of the body such as the oral mucosa and gut, and their role in the pathophysiology of diseases is a significant, emerging field of research, and may someday enable the development of novel probiotic approaches for the treatment and prevention of ophthalmic diseases. PMID:27698616

  3. Human Microbiota and Ophthalmic Disease

    PubMed Central

    Lu, Louise J.; Liu, Ji

    2016-01-01

    The human ocular surface, consisting of the cornea and conjunctiva, is colonized by an expansive, diverse microbial community. Molecular-based methods, such as 16S rRNA sequencing, has allowed for more comprehensive and precise identification of the species composition of the ocular surface microbiota compared to traditional culture-based methods. Evidence suggests that the normal microbiota plays a protective immunological role in preventing the proliferation of pathogenic species and thus, alterations in the homeostatic microbiome may be linked to ophthalmic pathologies. Further investigation of the ocular surface microbiome, as well as the microbiome of other areas of the body such as the oral mucosa and gut, and their role in the pathophysiology of diseases is a significant, emerging field of research, and may someday enable the development of novel probiotic approaches for the treatment and prevention of ophthalmic diseases.

  4. Acquired immunodeficiency syndrome (AIDS): a commentary on the international aspects of the disease.

    PubMed

    Potts, M

    1988-02-01

    By the beginning of 1987 there were 1100 heterosexual cases of AIDS in the US, and by 1991 an estimated 1/4 million US citizens will have AIDS, or will have already died from it. The situation in the 3rd World is even more grim. In parts of Africa the annual incidence of HIV infection is approaching 1%. Up to 12% of pregnant women in urban hospitals in Zaire carry the virus, and 25-88% of the prostitutes in some of the large cities in sub-Sahara Africa have the disease. Already, 5-10 million people around the world may be carrying HIV. Like the influenza virus, HIV can change its protein coat rapidly. The victim can appear perfectly healthy and still spread the disease. In countries with low maternal mortality, it could become the most common cause of maternal death. If people are to adopt safe sex practices, they must be convinced that they are at risk, that a lethal disease can be asymptomatic but ineffective for many years. They must know that safety practices--including the use of condoms, and perhaps especially spermicidally lubricated condoms--offer worthwhile protection. If any link in this chain is broken, individuals will not adopt such voluntary practices. There are no known political or geographical barriers to human copulation; now is the time to act, particularly in countries with a low or no prevalence of AIDS. Obstetricians must fight AIDS with the same commitment to preventative medicine that they bring to good obstetrics and good family planning.

  5. CNVs, Aneuploidies and Human Disease

    PubMed Central

    Martin, Christa L.; Kirkpatrick, Brianne E.; Ledbetter, David H.

    2015-01-01

    In the perinatal setting, chromosome imbalances cause a wide range of clinically significant disorders and increase risk for other particular phenotypes. As technologies have improved to detect increasingly smaller deletions and duplications, collectively referred to as copy number variants (CNVs), we are learning the significant role that these types of genomic variants play in human disease and their relatively high frequency in ~1% of all pregnancies. In this overview, we will highlight key aspects of CNV detection and interpretation used during the course of clinical care in the prenatal and neonatal periods. Since CNVs are one of the most frequent causes of a broad spectrum of human disorders, early diagnosis and accurate interpretation is important to implement timely interventions and targeted clinical management. PMID:26042902

  6. Aluminium and human breast diseases.

    PubMed

    Darbre, P D; Pugazhendhi, D; Mannello, F

    2011-11-01

    The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between breasts and between tissue samples from the same breast. We have recently found increased levels of aluminium in noninvasively collected nipple aspirate fluids taken from breast cancer patients (mean 268 ± 28 μg/l) compared with control healthy subjects (mean 131 ± 10 μg/l) providing evidence of raised aluminium levels in the breast microenvironment when cancer is present. The measurement of higher levels of aluminium in type I human breast cyst fluids (median 150 μg/l) compared with human serum (median 6 μg/l) or human milk (median 25 μg/l) warrants further investigation into any possible role of aluminium in development of this benign breast disease. Emerging evidence for aluminium in several breast structures now requires biomarkers of aluminium action in order to ascertain whether the presence of aluminium has any biological impact. To this end, we report raised levels of proteins that modulate iron homeostasis (ferritin, transferrin) in parallel with raised aluminium in nipple aspirate fluids in vivo, and we report overexpression of mRNA for several S100 calcium binding proteins following long-term exposure of MCF-7 human breast cancer cells in vitro to aluminium chlorhydrate.

  7. Aluminium and human breast diseases.

    PubMed

    Darbre, P D; Pugazhendhi, D; Mannello, F

    2011-11-01

    The human breast is exposed to aluminium from many sources including diet and personal care products, but dermal application of aluminium-based antiperspirant salts provides a local long-term source of exposure. Recent measurements have shown that aluminium is present in both tissue and fat of the human breast but at levels which vary both between breasts and between tissue samples from the same breast. We have recently found increased levels of aluminium in noninvasively collected nipple aspirate fluids taken from breast cancer patients (mean 268 ± 28 μg/l) compared with control healthy subjects (mean 131 ± 10 μg/l) providing evidence of raised aluminium levels in the breast microenvironment when cancer is present. The measurement of higher levels of aluminium in type I human breast cyst fluids (median 150 μg/l) compared with human serum (median 6 μg/l) or human milk (median 25 μg/l) warrants further investigation into any possible role of aluminium in development of this benign breast disease. Emerging evidence for aluminium in several breast structures now requires biomarkers of aluminium action in order to ascertain whether the presence of aluminium has any biological impact. To this end, we report raised levels of proteins that modulate iron homeostasis (ferritin, transferrin) in parallel with raised aluminium in nipple aspirate fluids in vivo, and we report overexpression of mRNA for several S100 calcium binding proteins following long-term exposure of MCF-7 human breast cancer cells in vitro to aluminium chlorhydrate. PMID:22099158

  8. Prevention and treatment of human immunodeficiency virus/acquired immunodeficiency syndrome in resource-limited settings.

    PubMed Central

    Hogan, Daniel R.; Salomon, Joshua A.

    2005-01-01

    Strategies for confronting the epidemic of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) have included a range of different approaches that focus on prevention and treatment. However, debate persists over what levels of emphasis are appropriate for the different components of the global response. This paper presents an overview of this debate and briefly summarizes the evidence on a range of interventions designed to prevent the spread of HIV infection, paying particular attention to voluntary counselling and testing, treatment for sexually transmitted infections and prevention of mother-to-child transmission. We also review the experience with antiretroviral therapy to date in terms of response rates and survival rates, adherence, drug resistance, behavioural change and epidemiological impact. Although various studies have identified strategies with proven effectiveness in reducing the risks of HIV infection and AIDS mortality, considerable uncertainties remain. Successful integration of treatment and prevention of HIV/AIDS will require a balanced approach and rigorous monitoring of the impact of programmes in terms of both individual and population outcomes. PMID:15744406

  9. Persistence and Fitness of Multidrug-Resistant Human Immunodeficiency Virus Type 1 Acquired in Primary Infection

    PubMed Central

    Brenner, Bluma G.; Routy, Jean-Pierre; Petrella, Marco; Moisi, Daniela; Oliveira, Maureen; Detorio, Mervi; Spira, Bonnie; Essabag, Vidal; Conway, Brian; Lalonde, Richard; Sekaly, Rafick-Pierre; Wainberg, Mark A.

    2002-01-01

    This study examines the persistence and fitness of multidrug-resistant (MDR) viruses acquired during primary human immunodeficiency virus infection (PHI). In four individuals, MDR infections persisted over the entire study period, ranging from 36 weeks to 5 years, in the absence of antiretroviral therapy. In stark contrast, identified source partners in two cases showed expected outgrowth of wild-type (WT) virus within 12 weeks of treatment interruption. In the first PHI case, triple-class MDR resulted in low plasma viremia (1.6 to 3 log copies/ml) over time compared with mean values obtained for an untreated PHI group harboring WT infections (4.1 to 4.3 log copies/ml). Increasing viremia in PHI patient 1 at week 52 was associated with the de novo emergence of a protease inhibitor-resistant variant through a recombination event involving the original MDR virus. MDR infections in two other untreated PHI patients yielded viremia levels typical of the untreated WT group. A fourth patient's MDR infection yielded low viremia (<50 to 500 copies/ml) for 5 years despite his having phenotypic resistance to all antiretroviral drugs in his treatment regimen. In two of these PHI cases, a rebound to higher levels of plasma viremia only occurred when the M184V mutation in reverse transcriptase could no longer be detected and, in a third case, nondetection of M184V was associated with an inability to isolate virus. To further evaluate the fitness of MDR variants acquired in PHI, MDR and corresponding WT viruses were isolated from index and source partners, respectively. Although MDR viral infectivity (50% tissue culture infective dose) was comparable to that observed for WT viruses, MDR infections in each case demonstrated 2-fold and 13- to 23-fold reductions in p24 antigen and reverse transcriptase enzymatic activity, respectively. In dual-infection competition assays, MDR viruses consistently demonstrated a marked replicative disadvantage compared with WT virus. These results

  10. Sexually transmitted disease (STD) and acquired immunodeficiency syndrome (AIDS) in South East Asia.

    PubMed

    Ismail, R

    1999-01-01

    This article reports on the prevalence of AIDS and sexually transmitted diseases (STDs) in Southeast Asia. The spread of HIV infection in this region has been predicted to be worse than that of Africa. The high-prevalence countries are Thailand, Cambodia, and Myanmar, where prevalence rates in the population at risk (15-49 year olds) are up to 2%; while low prevalence countries with rates of 0.1% include the Philippines, Indonesia, Laos, Brunei, and Singapore. Heterosexual transmission in Southeast Asia is the main mode of spread of HIV. Another route is through migration, rural-to-urban or international migration of people seeking jobs; with concurrent loneliness and anonymity, they become vulnerable to STDs and HIV infection. Intravenous drug use poses an increasing risk of transmission. The unavailability of data in some countries makes it difficult to evaluate the extent of the epidemic or if there's an impending epidemic. There are a number of caveats to the data compilation from various countries. These include the following: under-reporting of cases; underdiagnosis; missed diagnosis; and differences in the time of data collection. It is clear that poverty, illiteracy, and poor access to educational information in most countries in this region facilitate the rapid spread of HIV. These coupled with lack of primary health care services, and in most instances, enormously high cost of drugs make the pain and suffering due to the HIV/AIDS epidemic a human disaster far worse than the ravages of war. PMID:10330595

  11. Sexually transmitted disease (STD) and acquired immunodeficiency syndrome (AIDS) in South East Asia.

    PubMed

    Ismail, R

    1999-01-01

    This article reports on the prevalence of AIDS and sexually transmitted diseases (STDs) in Southeast Asia. The spread of HIV infection in this region has been predicted to be worse than that of Africa. The high-prevalence countries are Thailand, Cambodia, and Myanmar, where prevalence rates in the population at risk (15-49 year olds) are up to 2%; while low prevalence countries with rates of 0.1% include the Philippines, Indonesia, Laos, Brunei, and Singapore. Heterosexual transmission in Southeast Asia is the main mode of spread of HIV. Another route is through migration, rural-to-urban or international migration of people seeking jobs; with concurrent loneliness and anonymity, they become vulnerable to STDs and HIV infection. Intravenous drug use poses an increasing risk of transmission. The unavailability of data in some countries makes it difficult to evaluate the extent of the epidemic or if there's an impending epidemic. There are a number of caveats to the data compilation from various countries. These include the following: under-reporting of cases; underdiagnosis; missed diagnosis; and differences in the time of data collection. It is clear that poverty, illiteracy, and poor access to educational information in most countries in this region facilitate the rapid spread of HIV. These coupled with lack of primary health care services, and in most instances, enormously high cost of drugs make the pain and suffering due to the HIV/AIDS epidemic a human disaster far worse than the ravages of war.

  12. Treatment of human papillomavirus infection with interferon alpha and ribavirin in a patient with acquired aplastic anemia.

    PubMed

    Mosa, Clara; Trizzino, Antonino; Trizzino, Angela; Di Marco, Floriana; D'Angelo, Paolo; Farruggia, Piero

    2014-06-01

    Genital warts caused by human papillomavirus (HPV) are the most frequent sexually transmitted infection. We describe a case of severe perianal and genital HPV infection in a patient with acquired aplastic anemia, unresponsive to traditional therapies and treated effectively with a combination of interferon and ribavirin. PMID:24661930

  13. The Best Time to Acquire New Skills: Age-Related Differences in Implicit Sequence Learning across the Human Lifespan

    ERIC Educational Resources Information Center

    Janacsek, Karolina; Fiser, Jozsef; Nemeth, Dezso

    2012-01-01

    Implicit skill learning underlies obtaining not only motor, but also cognitive and social skills through the life of an individual. Yet, the ontogenetic changes in humans' implicit learning abilities have not yet been characterized, and, thus, their role in acquiring new knowledge efficiently during development is unknown. We investigated such…

  14. What High School Students Who Are Mildly Mentally Retarded Know about the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome.

    ERIC Educational Resources Information Center

    Cobb, Hazel B.; Horn, Charles J., Jr.

    Alabama high school students (N=309) with mild mental retardation completed a questionnaire concerning their knowledge, attitudes, and sources of information about human immune deficiency virus/acquired immune deficiency syndrome (HIV/AIDS). Students demonstrated some basic knowledge of HIV/AIDS, and expressed some concern about getting AIDS. They…

  15. Health Administrator Perspectives on Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Prevention and Services at Historically Black Colleges and Universities

    ERIC Educational Resources Information Center

    Warren-Jeanpiere, Lari; Jones, Sandra; Sutton, Madeline Y.

    2011-01-01

    Objective: Due to the disproportionate impact of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) among African American young adults, the authors explored (1) number of historically black college and university (HBCU) campuses with existing HIV prevention policies and services and (2) perceived barriers for implementing…

  16. The Role of Acquired Immunity in the Spread of Human Papillomavirus (HPV): Explorations with a Microsimulation Model

    PubMed Central

    Matthijsse, Suzette M.; van Rosmalen, Joost; Hontelez, Jan A. C.; Bakker, Roel; de Kok, Inge M. C. M.; van Ballegooijen, Marjolein; de Vlas, Sake J.

    2015-01-01

    Background Knowledge of the natural history of human papillomavirus (HPV), in particular the role of immunity, is crucial in estimating the (cost-) effectiveness of HPV vaccination and cervical cancer screening strategies, because naturally acquired immunity after clearing an infection may already protect part of the risk population against new HPV infections. Methods We used STDSIM, an established stochastic microsimulation model, quantified to the Netherlands. We explored different assumptions regarding the natural history of HPV-16 and HPV-18, and estimated the transmission probabilities and durations of acquired immunity necessary to reproduce age-specific prevalence. Results A model without acquired immunity cannot reproduce the age-specific patterns of HPV. Also, it is necessary to assume a high degree of individual variation in the duration of infection and acquired immunity. According to the model estimates, on average 20% of women are immune for HPV-16 and 15% for HPV-18. After an HPV-16 infection, 50% are immune for less than 1 year, whereas 20% exceed 30 years. For HPV-18, up to 12% of the individuals are immune for less than 1 year, and about 50% over 30 years. Almost half of all women will never acquire HPV-16 or HPV-18. Conclusions Acquired immunity likely plays a major role in HPV epidemiology, but its duration shows substantial variation. Combined with the lifetime risk, this explains to a large extent why many women will never develop cervical cancer. PMID:25642941

  17. Endosomal phosphoinositides and human diseases.

    PubMed

    Nicot, Anne-Sophie; Laporte, Jocelyn

    2008-08-01

    Phosphoinositides (PIs) are lipid second messengers implicated in signal transduction and membrane trafficking. Seven distinct PIs can be synthesized by phosphorylation of the inositol ring of phosphatidylinositol (PtdIns), and their metabolism is accurately regulated by PI kinases and phosphatases. Two of the PIs, PtdIns3P and PtdIns(3,5)P(2), are present on intracellular endosomal compartments, and several studies suggest that they have a role in membrane remodeling and trafficking. We refer to them as 'endosomal PIs'. An increasing number of human genetic diseases including myopathy and neuropathies are associated to mutations in enzymes regulating the turnover of these endosomal PIs. The PtdIns3P and PtdIns(3,5)P(2) 3-phosphatase myotubularin gene is mutated in X-linked centronuclear myopathy, whereas its homologs MTMR2 and MTMR13 and the PtdIns(3,5)P(2) 5-phosphatase SAC3/FIG4 are implicated in Charcot-Marie-Tooth peripheral neuropathies. Mutations in the gene encoding the PtdIns3P 5-kinase PIP5K3/PIKfyve have been found in patients affected with François-Neetens fleck corneal dystrophy. This review presents the roles of the endosomal PIs and their regulators and proposes defects of membrane remodeling as a common pathological mechanism for the corresponding diseases.

  18. Tight junctions and human diseases.

    PubMed

    Sawada, Norimasa; Murata, Masaki; Kikuchi, Keisuke; Osanai, Makoto; Tobioka, Hirotoshi; Kojima, Takashi; Chiba, Hideki

    2003-09-01

    Tight junctions are intercellular junctions adjacent to the apical end of the lateral membrane surface. They have two functions, the barrier (or gate) function and the fence function. The barrier function of tight junctions regulates the passage of ions, water, and various macromolecules, even of cancer cells, through paracellular spaces. The barrier function is thus relevant to edema, jaundice, diarrhea, and blood-borne metastasis. On the other hand, the fence function maintains cell polarity. In other words, tight junctions work as a fence to prevent intermixing of molecules in the apical membrane with those in the lateral membrane. This function is deeply involved in cancer cell biology, in terms of loss of cell polarity. Of the proteins comprising tight junctions, integral membrane proteins occludin, claudins, and JAMs have been recently discovered. Of these molecules, claudins are exclusively responsible for the formation of tight-junction strands and are connected with the actin cytoskeleton mediated by ZO-1. Thus, both functions of tight junctions are dependent on the integrity of the actin cytoskeleton as well as ATP. Mutations in the claudin14 and the claudin16 genes result in hereditary deafness and hereditary hypomagnesemia, respectively. Some pathogenic bacteria and viruses target and affect the tight-junction function, leading to diseases. In this review, the relationship between tight junctions and human diseases is summarized.

  19. Acquired hyperpigmentations*

    PubMed Central

    Cestari, Tania Ferreira; Dantas, Lia Pinheiro; Boza, Juliana Catucci

    2014-01-01

    Cutaneous hyperpigmentations are frequent complaints, motivating around 8.5% of all dermatological consultations in our country. They can be congenital, with different patterns of inheritance, or acquired in consequence of skin problems, systemic diseases or secondary to environmental factors. The vast majority of them are linked to alterations on the pigment melanin, induced by different mechanisms. This review will focus on the major acquired hyperpigmentations associated with increased melanin, reviewing their mechanisms of action and possible preventive measures. Particularly prominent aspects of diagnosis and therapy will be emphasized, with focus on melasma, post-inflammatory hyperpigmentation, periorbital pigmentation, dermatosis papulosa nigra, phytophotodermatoses, flagellate dermatosis, erythema dyschromicum perstans, cervical poikiloderma (Poikiloderma of Civatte), acanthosis nigricans, cutaneous amyloidosis and reticulated confluent dermatitis PMID:24626644

  20. Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome.

    PubMed

    Monaco, Cynthia L; Gootenberg, David B; Zhao, Guoyan; Handley, Scott A; Ghebremichael, Musie S; Lim, Efrem S; Lankowski, Alex; Baldridge, Megan T; Wilen, Craig B; Flagg, Meaghan; Norman, Jason M; Keller, Brian C; Luévano, Jesús Mario; Wang, David; Boum, Yap; Martin, Jeffrey N; Hunt, Peter W; Bangsberg, David R; Siedner, Mark J; Kwon, Douglas S; Virgin, Herbert W

    2016-03-01

    Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression. PMID:26962942

  1. Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome.

    PubMed

    Monaco, Cynthia L; Gootenberg, David B; Zhao, Guoyan; Handley, Scott A; Ghebremichael, Musie S; Lim, Efrem S; Lankowski, Alex; Baldridge, Megan T; Wilen, Craig B; Flagg, Meaghan; Norman, Jason M; Keller, Brian C; Luévano, Jesús Mario; Wang, David; Boum, Yap; Martin, Jeffrey N; Hunt, Peter W; Bangsberg, David R; Siedner, Mark J; Kwon, Douglas S; Virgin, Herbert W

    2016-03-01

    Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.

  2. Acquired Epidermodysplasia Verruciformis Associated with Human Papilloma Virus Type 14 in a Small Bowel Transplanted Child--A Case Report.

    PubMed

    Hirschman, Derek; Tacastacas, Joselin; Rady, Peter L; Tyring, Stephen K; Cooper, Kevin; Honda, Kord

    2016-01-01

    A 3-year-old African American girl taking sirolimus and tacrolimus for a small bowel transplantation presented with hypopigmented macules and papules throughout her trunk. A biopsy diagnosed epidermodysplasia verruciformis (EV) that was found to be associated with human papillomavirus (HPV) type 14 according to polymerase chain reaction analysis. There are few cases of acquired EV in the setting of organ transplantation. Although there is no standardized treatment for acquired EV, prevention and surveillance for transformation to squamous cell carcinoma are primary concerns.

  3. Human natural chimerism: an acquired character or a vestige of evolution?

    PubMed

    Rinkevich, B

    2001-06-01

    Analysis on five common classes of human natural chimeras (cytomictical, whole body, fetal-maternal, germ cell, and tumor chimeras) reveals that (1) they initiate only during pregnancy, (2) the most common class are chimeras which contain maternal cells, and (3) the primary mechanisms that are involved in their formation and establishment are still elusive. These classes of natural chimerism, are involved only with maladaptive phenomena such as malignancy and autoimmune diseases and without any documented benefit. A recent review has challenged the accepted dogma that the evolution of immunity is pathogen-directed and asserted that preserving individuality from littering the soma and the germline by conspecific alien cells might have been the original function of the innate immunity. Following this tenet, I propose here that human natural chimerism is a by-product of the new role evolved from primitive components of immunity to "educate" the developing embryo with the armamentarium of effector mechanisms, dedicated to purge the individual from pervasive somatic and germline variants, and is not a vestige of evolution.

  4. [The deterministic concept of human diseases].

    PubMed

    Petlenko, V P; Strukov, A I; Khmel'nitskiĭ, O K

    1984-01-01

    Human disease is a complex systemic event, the theoretical analysis of which requires application of the methodological appratus of investigation. As such, the authors used the concept of Marxist-Leninist determinism. The latter is a system of universal interconnections and causative dependence of natural events, society, and human diseases in particular. Analysis of human diseases from the position of the Marxist-Leninist theory of determinism is one of the basic problems of the theory of pathology. A logical analysis of evolutionary, systemic, morphological and causative determinism is given which characterizes on the whole human diseases. PMID:6391430

  5. miR-146b antagomir-treated human Tregs acquire increased GVHD inhibitory potency.

    PubMed

    Lu, Yunjie; Hippen, Keli L; Lemire, Amanda L; Gu, Jian; Wang, Weizhi; Ni, Xuhao; Ranganathan, Parvathi; Levine, Bruce L; Riley, James L; June, Carl H; Turka, Laurence A; Munn, David H; Garzon, Ramiro; Lu, Ling; Blazar, Bruce R

    2016-09-01

    CD4(+)CD25(+)FoxP3(+) thymic-derived regulatory T cells (tTregs) are indispensable for maintaining immune system equilibrium. Adoptive transfer of tTregs is an effective means of suppressing graft-versus-host disease (GVHD) in murine models and in early human clinical trials. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an ubiquitin-conjugating enzyme that mediates nuclear factor κB (NF-κB) activation, plays an essential role in modulating regulatory T cell survival and function. MicroRNAs (miRNAs) are noncoding RNAs, which mediate RNA silencing and posttranscriptional gene repression. By performing comprehensive TaqMan Low Density Array miRNA assays, we identified 10 miRNAs differentially regulated in human tTreg compared with control T cells. One candidate, miR-146b, is preferentially and highly expressed in human naive tTregs compared with naive CD4 T cells. miRNA prediction software revealed that TRAF6 was the one of the top 10 scored mRNAs involved tTreg function with the highest probability as a potential miR-146b target. Antagomir-mediated knockdown of miRNA-146b, but not another miRNA-146 family member (miRNA-146a), enhanced TRAF6 expression. TRAF6, in turn, increases NF-κB activation, which is essential for tTreg function as well as Foxp3 protein and antiapoptotic gene expression, and downregulates proapoptotic gene expression. miR-146b knockdown increased the nuclear localization and expression of genes regulated by NF-κB, which was associated with enhanced tTreg survival, proliferation, and suppressive function measured in vitro and in vivo. TRAF6 inhibition had the opposite effects. We conclude that an miR-146b-TRAF6-NF-κB-FoxP3 signaling pathway restrains regulatory T cell survival, proliferation, and suppressor function. In vitro exposure of human tTregs to miR-146b antagomirs can be exploited to improve the clinical efficacy of human adoptive tTreg transfer in a GVHD setting. PMID:27485827

  6. Nonspecific interstitial pneumonitis: a common cause of pulmonary disease in the acquired immunodeficiency syndrome

    SciTech Connect

    Suffredini, A.F.; Ognibene, F.P.; Lack, E.E.; Simmons, J.T.; Brenner, M.; Gill, V.J.; Lane, H.C.; Fauci, A.S.; Parrillo, J.E.; Masur, H.

    1987-07-01

    During a 4.4-year period, nonspecific interstitial pneumonitis was seen in 41 of 110 (38%) patients with the acquired immunodeficiency syndrome and accounted for 32% (48/152) of all episodes of clinical pneumonitis. Diffuse alveolar damage was typically a feature of nonspecific interstitial pneumonitis, but neither lung biopsy nor bronchoalveolar lavage detected a pathogen. Of these 41 patients, 13 had no associated pulmonary tumor and had not been exposed to pulmonary toxins, whereas 28 patients had either concurrent pulmonary Kaposi sarcoma, previous experimental therapies, or a history of pneumocystis pneumonia or drug abuse. Of these 41, 23 had normal chest radiographs. The clinical features of patients with nonspecific interstitial pneumonitis were similar to those of patients with pneumocystis pneumonia, although histologic findings showed less severe alveolar damage in patients with nonspecific interstitial pneumonitis (p less than 0.001). Pathologic evaluation and clinical follow-up suggest that many clinical episodes of pneumonitis in patients with the acquired immunodeficiency syndrome are due to nonspecific interstitial pneumonitis of unknown cause.

  7. Rabbit Models for Studying Human Infectious Diseases

    PubMed Central

    Peng, Xuwen; Knouse, John A; Hernon, Krista M

    2015-01-01

    Using an appropriate animal model is crucial for mimicking human disease conditions, and various facets including genetics, anatomy, and pathophysiology should be considered before selecting a model. Rabbits (Oryctolagus cuniculus) are well known for their wide use in production of antibodies, eye research, atherosclerosis and other cardiovascular diseases. However, a systematic description of the rabbit as primary experimental models for the study of various human infectious diseases is unavailable. This review focuses on the human infectious diseases for which rabbits are considered a classic or highly appropriate model, including AIDS (caused by HIV1), adult T-cell leukemia–lymphoma (human T-lymphotropic virus type 1), papilloma or carcinoma (human papillomavirus) , herpetic stromal keratitis (herpes simplex virus type 1), tuberculosis (Mycobacterium tuberculosis), and syphilis (Treponema pallidum). In addition, particular aspects of the husbandry and care of rabbits used in studies of human infectious diseases are described. PMID:26678367

  8. Rabbit Models for Studying Human Infectious Diseases.

    PubMed

    Peng, Xuwen; Knouse, John A; Hernon, Krista M

    2015-12-01

    Using an appropriate animal model is crucial for mimicking human disease conditions, and various facets including genetics, anatomy, and pathophysiology should be considered before selecting a model. Rabbits (Oryctolagus cuniculus) are well known for their wide use in production of antibodies, eye research, atherosclerosis and other cardiovascular diseases. However, a systematic description of the rabbit as primary experimental models for the study of various human infectious diseases is unavailable. This review focuses on the human infectious diseases for which rabbits are considered a classic or highly appropriate model, including AIDS (caused by HIV1), adult T-cell leukemia-lymphoma (human T-lymphotropic virus type 1), papilloma or carcinoma (human papillomavirus) , herpetic stromal keratitis (herpes simplex virus type 1), tuberculosis (Mycobacterium tuberculosis), and syphilis (Treponema pallidum). In addition, particular aspects of the husbandry and care of rabbits used in studies of human infectious diseases are described. PMID:26678367

  9. Cognition and Instruction: Recent Theories of Human Competence and How It Is Acquired.

    ERIC Educational Resources Information Center

    Resnick, Lauren B.

    This paper outlines the current state of knowledge about how intellectual competence is acquired. Implications resulting from recent changes in the psychology of learning and development are beginning to revitalize the science of learning and instruction. Four broad topics illustrate the links between instructional experiments, fundamental…

  10. Fasciculations in human hereditary disease.

    PubMed

    Finsterer, Josef; Aliyev, Rahim

    2015-06-01

    Fasciculations are a manifestation of peripheral nerve hyperexcitability in addition to myokymia, neuromyotonia, cramps, or tetany. Fasciculations occur in hereditary and non-hereditary diseases. Among the hereditary diseases, fasciculations are most frequently reported in familial amyotrophic lateral sclerosis (FALS), and spinal muscular atrophy (SMA). Among the non-hereditary diseases, fasciculations occur most frequently in peripheral nerve hyperexcitability syndromes (Isaac's syndrome, voltage-gated potassium channelopathy, cramp fasciculation syndrome, Morvan syndrome). If the cause of fasciculations remains unknown, they are called benign. Systematically reviewing the literature about fasciculations in hereditary disease shows that fasciculations can be a phenotypic feature in bulbospinal muscular atrophy (BSMA), GM2-gangliosidosis, triple-A syndrome, or hereditary neuropathy. Additionally, fasciculations have been reported in familial amyloidosis, spinocerebellar ataxias, Huntington's disease, Rett syndrome, central nervous system disease due to L1-cell adhesion molecule (L1CAM) mutations, Fabry's disease, or Gerstmann-Sträussler disease. Rarely, fasciculations may be a phenotypic feature in patients with mitochondrial disorders or other myopathies. Fasciculations are part of the phenotype in much more genetic disorders than commonly assumed. Fasciculations not only occur in motor neuron disease, but also in hereditary neuropathy, spinocerebellar ataxia, GM2-gangliosidosis, Huntington's disease, Rett syndrome, Fabry's disease, Gerstmann-Sträussler disease, mitochondrial disorders, or muscular dystrophies. PMID:25073774

  11. Does biodiversity protect humans against infectious disease?

    PubMed

    Wood, Chelsea L; Lafferty, Kevin D; DeLeo, Giulio; Young, Hillary S; Hudson, Peter J; Kuris, Armand M

    2014-04-01

    Control of human infectious disease has been promoted as a valuable ecosystem service arising from the conservation of biodiversity. There are two commonly discussed mechanisms by which biodiversity loss could increase rates of infectious disease in a landscape. First, loss of competitors or predators could facilitate an increase in the abundance of competent reservoir hosts. Second, biodiversity loss could disproportionately affect non-competent, or less competent reservoir hosts, which would otherwise interfere with pathogen transmission to human populations by, for example, wasting the bites of infected vectors. A negative association between biodiversity and disease risk, sometimes called the "dilution effect hypothesis," has been supported for a few disease agents, suggests an exciting win-win outcome for the environment and society, and has become a pervasive topic in the disease ecology literature. Case studies have been assembled to argue that the dilution effect is general across disease agents. Less touted are examples in which elevated biodiversity does not affect or increases infectious disease risk for pathogens of public health concern. In order to assess the likely generality of the dilution effect, we review the association between biodiversity and public health across a broad variety of human disease agents. Overall, we hypothesize that conditions for the dilution effect are unlikely to be met for most important diseases of humans. Biodiversity probably has little net effect on most human infectious diseases but, when it does have an effect, observation and basic logic suggest that biodiversity will be more likely to increase than to decrease infectious disease risk.

  12. Inheriting vice, acquiring virtue: hereditary disease and moral hygiene in eighteenth-century France.

    PubMed

    Quinlan, Sean M

    2006-01-01

    This essay examines the medical debates over hereditary disease and moral hygiene in France between 1748 and 1790. During this time, which was marked by two formal academic exchanges about pathological inheritance, doctors critically studied the existence of hereditary diseases--including syphilis, arthritis, phthisis, scrofula, rickets, gout, stones, epilepsy, and insanity--and the problems that heredity might pose for curing and preventing these diseases. Amid public debate, doctors first treated heredity with formal skepticism and then embraced the idea. Their changing attitudes stemmed less from epistemological or cognitive reasons than from new cultural beliefs about gender, domesticity, and demographic policy. Fearing moral degeneracy and demographic decline, they argued that a number of social pathologies were truly hereditary and that these diseases spread within the family itself. These beliefs were seemingly confirmed by new clinical studies on tuberculosis. Though doctors conceded that hereditary diseases might limit Enlightenment hopes to perfect society, they also suggested that sexual hygiene and physical education could cure hereditary degeneracy and transcend genealogy and descent. Consequently, they stressed that physical regeneration was a dynamic process, one that stretched from the conjugal bed to weaning and beyond. Rather than accepting the accidents of birth, physicians believed that their patients could self-consciously overcome inherited defects and thus regenerate themselves and even all of society itself. Heredity thus gave doctors an idiom with which to diagnose a felt social crisis and to prescribe appropriate hygienic responses.

  13. The Human Phenotypic Disease Network

    NASA Astrophysics Data System (ADS)

    Hidalgo, Cesar; Blumm, Nicholas; Barabasi, Albert-Laszlo; Christakis, Nicholas

    2008-03-01

    We study the evolution of patient illness using a network summarizing the disease associations extracted from 32 million Medicare claims recorded from 13 million elders using the ICD9-CM format. We find that the evolution of patients' illness is accurately described by a process in which once a patient develops a particular disease, subsequent disease are seen to occur among diseases lying close by in the network. In addition, we find that patients affected with diseases with high network connectivity are more likely to die during a follow-up period of eight years.

  14. Parasitic diseases in humans transmitted by vectors.

    PubMed

    Cholewiński, Marcin; Derda, Monika; Hadaś, Edward

    2015-01-01

    Despite the considerable progress of medicine, parasitic diseases still pose a great threat to human health and life. Among parasitic diseases, those transmitted by vectors, mainly arthropods, play a particular role. These diseases occur most frequently in the poorest countries and affect a vast part of the human population. They include malaria, babesiosis, trypanosomiasis, leishmaniasis and filariasis. This study presents those vector-transmitted diseases that are responsible for the greatest incidence and mortality of people on a global scale. Attention is focused primarily on diseases transmitted by mosquitoes, flies, Hemiptera and ticks.

  15. Hooked! Modeling human disease in zebrafish.

    PubMed

    Santoriello, Cristina; Zon, Leonard I

    2012-07-01

    Zebrafish have been widely used as a model system for studying developmental processes, but in the last decade, they have also emerged as a valuable system for modeling human disease. The development and function of zebrafish organs are strikingly similar to those of humans, and the ease of creating mutant or transgenic fish has facilitated the generation of disease models. Here, we highlight the use of zebrafish for defining disease pathways and for discovering new therapies. PMID:22751109

  16. OrthoDisease: a database of human disease orthologs.

    PubMed

    O'Brien, Kevin P; Westerlund, Isabelle; Sonnhammer, Erik L L

    2004-08-01

    One of the greatest promises of genome sequencing projects is to further the understanding of human diseases and to develop new therapies. Model organism genomes have been sequenced in parallel to human genomes to provide effective tools for the investigation of human gene function. Many of their genes share a common ancestry and function with human genes, and this is particularly true for orthologous genes. Here we present OrthoDisease, a comprehensive database of model organism genes that are orthologous to human disease genes. OrthoDisease was constructed by applying the Inparanoid ortholog detection algorithm to disease genes derived from the Online Mendelian Inheritance in Man database (OMIM). Pairwise whole genome/proteome comparisons between Homo sapiens and six other organisms were performed to identify ortholog clusters. OMIM numbers were extracted from the OMIM Morbid Map and were converted to gene sequences using the Locuslink mim2loc and loc2acc tables. These were mapped to Inparanoid ortholog clusters using Blast. The number of ortholog clusters in OrthoDisease with each respective species is currently: M. musculus, 1,354; D. melanogaster, 724; C. elegans, 533; A. thaliana, 398; S. cerevisiae, 290; and E. coli, 153. The database is accessible online at http://orthodisease.cgb.ki.se, and can be searched with disease or protein names. The web interface presents all ortholog clusters that include a selected disease gene. A capability to download the entire dataset is also provided.

  17. Acquired resistance to gemcitabine and cross-resistance in human pancreatic cancer clones.

    PubMed

    Yoneyama, Hiroshi; Takizawa-Hashimoto, Asako; Takeuchi, Osamu; Watanabe, Yukiko; Atsuda, Koichiro; Asanuma, Fumiki; Yamada, Yoshinori; Suzuki, Yukio

    2015-01-01

    The efficacy of gemcitabine (GEM), a standard treatment agent for pancreatic cancer, is insufficient because of primary or acquired resistance to this drug. Patients with tumors intrinsically sensitive to GEM gradually acquire resistance and require a shift to second agents, which are associated with the risk of cross-resistance. However, whether cross-resistance is actually present has long been disputed. Using six GEM-resistant and four highly GEM-resistant clones derived from the pancreatic cancer cell line BxPC-3, we determined the resistance of each clone and parent cell line to GEM and four anticancer agents (5-FU, CDDP, CPT-11, and DTX). The GEM-resistant clones had different resistances to GEM and other agents, and did not develop a specific pattern of cross-resistance. This result shows that tumor cells are heterogeneous. However, all highly GEM-resistant clones presented overexpression of ribonucleotide reductase subunit M1 (RRM1), a target enzyme for metabolized GEM, and showed cross-resistance with 5-FU. The expression level of RRM1 was high; therefore, resistance to GEM was high. We showed that a tumor cell acquired resistance to GEM, and cross-resistance developed in one clone. These results suggest that only cells with certain mechanisms for high-level resistance to GEM survive against selective pressure applied by highly concentrated GEM. RRM1 may be one of the few factors that can induce high resistance to GEM and a suitable therapeutic target for GEM-resistant pancreatic cancer.

  18. Benzothiadiazole, a novel class of inducers of systemic acquired resistance, activates gene expression and disease resistance in wheat.

    PubMed Central

    Görlach, J; Volrath, S; Knauf-Beiter, G; Hengy, G; Beckhove, U; Kogel, K H; Oostendorp, M; Staub, T; Ward, E; Kessmann, H; Ryals, J

    1996-01-01

    Systemic acquired resistance is an important component of the disease resistance repertoire of plants. In this study, a novel synthetic chemical, benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester (BTH), was shown to induce acquired resistance in wheat. BTH protected wheat systemically against powdery mildew infection by affecting multiple steps in the life cycle of the pathogen. The onset of resistance was accompanied by the induction of a number of newly described wheat chemically induced (WCI) genes, including genes encoding a lipoxygenase and a sulfur-rich protein. With respect to both timing and effectiveness, a tight correlation existed between the onset of resistance and the induction of the WCI genes. Compared with other plant activators, such as 2,6-dichloroisonicotinic acid and salicylic acid, BTH was the most potent inducer of both resistance and gene induction. BTH is being developed commercially as a novel type of plant protection compound that works by inducing the plant's inherent disease resistance mechanisms. PMID:8624439

  19. CLINICAL APPROACH TO THE DIAGNOSTIC EVALUATION OF HERDITARY AND ACQUIRED NEUROMUSCULAR DISEASES

    PubMed Central

    McDonald, Craig M.

    2012-01-01

    SYNOPSIS In the context of a neuromuscular disease diagnostic evaluation, the clinician still must be able to obtain a relevant patient and family history and perform focused general, musculoskeletal, neurologic and functional physical examinations to direct further diagnostic evaluations. Laboratory studies for hereditary neuromuscular diseases include relevant molecular genetic studies. The EMG and nerve conduction studies remain an extension of the physical examination and help to guide further diagnostic studies such as molecular genetic studies, and muscle and nerve biopsies. All diagnostic information needs to be interpreted not in isolation, but within the context of relevant historical information, family history, physical examination findings, and laboratory data, electrophysiologic findings, pathologic findings, and molecular genetic findings if obtained. PMID:22938875

  20. Tissue Specificity of Human Disease Module

    PubMed Central

    Kitsak, Maksim; Sharma, Amitabh; Menche, Jörg; Guney, Emre; Ghiassian, Susan Dina; Loscalzo, Joseph; Barabási, Albert-László

    2016-01-01

    Genes carrying mutations associated with genetic diseases are present in all human cells; yet, clinical manifestations of genetic diseases are usually highly tissue-specific. Although some disease genes are expressed only in selected tissues, the expression patterns of disease genes alone cannot explain the observed tissue specificity of human diseases. Here we hypothesize that for a disease to manifest itself in a particular tissue, a whole functional subnetwork of genes (disease module) needs to be expressed in that tissue. Driven by this hypothesis, we conducted a systematic study of the expression patterns of disease genes within the human interactome. We find that genes expressed in a specific tissue tend to be localized in the same neighborhood of the interactome. By contrast, genes expressed in different tissues are segregated in distinct network neighborhoods. Most important, we show that it is the integrity and the completeness of the expression of the disease module that determines disease manifestation in selected tissues. This approach allows us to construct a disease-tissue network that confirms known and predicts unexpected disease-tissue associations. PMID:27748412

  1. Genetically Engineered Pig Models for Human Diseases

    PubMed Central

    Prather, Randall S.; Lorson, Monique; Ross, Jason W.; Whyte, Jeffrey J.; Walters, Eric

    2015-01-01

    Although pigs are used widely as models of human disease, their utility as models has been enhanced by genetic engineering. Initially, transgenes were added randomly to the genome, but with the application of homologous recombination, zinc finger nucleases, and transcription activator-like effector nuclease (TALEN) technologies, now most any genetic change that can be envisioned can be completed. To date these genetic modifications have resulted in animals that have the potential to provide new insights into human diseases for which a good animal model did not exist previously. These new animal models should provide the preclinical data for treatments that are developed for diseases such as Alzheimer's disease, cystic fibrosis, retinitis pigmentosa, spinal muscular atrophy, diabetes, and organ failure. These new models will help to uncover aspects and treatments of these diseases that were otherwise unattainable. The focus of this review is to describe genetically engineered pigs that have resulted in models of human diseases. PMID:25387017

  2. Azithromycin Dose To Maximize Efficacy and Suppress Acquired Drug Resistance in Pulmonary Mycobacterium avium Disease

    PubMed Central

    Deshpande, Devyani; Pasipanodya, Jotam G.

    2016-01-01

    Mycobacterium avium complex is now the leading mycobacterial cause of chronic pneumonia in the United States. Macrolides and ethambutol form the backbone of the regimen used in the treatment of pulmonary disease. However, therapy outcomes remain poor, with microbial cure rates of 4% in cavitary disease. The treatment dose of azithromycin has mostly been borrowed from that used to treat other bacterial pneumonias; there are no formal dose-response studies in pulmonary M. avium disease and the optimal dose is unclear. We utilized population pharmacokinetics and pharmacokinetics/pharmacodynamics-derived azithromycin exposures associated with optimal microbial kill or resistance suppression to perform 10,000 patient Monte Carlo simulations of dose effect studies for daily azithromycin doses of 0.5 to 10 g. The currently recommended dose of 500 mg per day achieved the target exposures in 0% of patients. Exposures associated with optimal kill and resistance suppression were achieved in 87 and 54% of patients, respectively, only by the very high dose of 8 g per day. The azithromycin susceptibility breakpoint above which patients failed therapy on the very high doses of 8 g per day was an MIC of 16 mg/liter, suggesting a critical concentration of 32 mg/liter, which is 8-fold lower than the currently used susceptibility breakpoint of 256 mg/liter. If the standard dose of 500 mg a day were used, then the critical concentration would fall to 2 mg/liter, 128-fold lower than 256 mg/liter. The misclassification of resistant isolates as susceptible could explain the high failure rates of current doses. PMID:26810646

  3. Chemopreventative effects of tetrahydrocurcumin on human diseases.

    PubMed

    Wu, Jia-Ching; Tsai, Mei-Ling; Lai, Ching-Shu; Wang, Ying-Jan; Ho, Chi-Tang; Pan, Min-Hsiung

    2014-01-01

    Chemoprevention is a relatively new and promising strategy to prevent human degenerative diseases, including cancer, and is defined as the use of natural dietary compounds and/or synthetic substances to block, inhibit, reverse, or retard the progress of human diseases. Tetrahydrocurcumin (THC) is a major metabolite of curcumin (extracted from the roots of the Curcuma longa Linn). THC has been demonstrated to prevent oxidative stress and inflammation, to act against neurodegeneration, and to possess anti-cancer activity. In this review, we summarize the current knowledge and underlying molecular mechanisms of the chemopreventative activities of THC and its potential effects on the development of various human diseases. PMID:24220621

  4. Chemopreventative effects of tetrahydrocurcumin on human diseases.

    PubMed

    Wu, Jia-Ching; Tsai, Mei-Ling; Lai, Ching-Shu; Wang, Ying-Jan; Ho, Chi-Tang; Pan, Min-Hsiung

    2014-01-01

    Chemoprevention is a relatively new and promising strategy to prevent human degenerative diseases, including cancer, and is defined as the use of natural dietary compounds and/or synthetic substances to block, inhibit, reverse, or retard the progress of human diseases. Tetrahydrocurcumin (THC) is a major metabolite of curcumin (extracted from the roots of the Curcuma longa Linn). THC has been demonstrated to prevent oxidative stress and inflammation, to act against neurodegeneration, and to possess anti-cancer activity. In this review, we summarize the current knowledge and underlying molecular mechanisms of the chemopreventative activities of THC and its potential effects on the development of various human diseases.

  5. Human migration and infectious diseases.

    PubMed

    Soto, S M

    2009-01-01

    Emerging infectious diseases (EID) are defined as diseases that have appeared recently or that have recently increased in their frequency, geographical distribution or both. Commercial globalisation, population movements and environmental changes are the main factors favouring the international spread of microorganisms. Transport and communication development constitutes also a remarkable factor in the worldwide dispersion of microorganisms. The mass movement of large numbers of people creates new opportunities for the spread and establishment of common or novel infectious diseases. A surveillance system to detect emergent and re-emergent infections, a rapid responsiveness of healthcare systems and laboratories, vector control, and the provision of healthcare education programmes to inform the population of how to avoid infections are needed in order to stop the spread of infectious diseases. PMID:19220349

  6. Human migration and infectious diseases.

    PubMed

    Soto, S M

    2009-01-01

    Emerging infectious diseases (EID) are defined as diseases that have appeared recently or that have recently increased in their frequency, geographical distribution or both. Commercial globalisation, population movements and environmental changes are the main factors favouring the international spread of microorganisms. Transport and communication development constitutes also a remarkable factor in the worldwide dispersion of microorganisms. The mass movement of large numbers of people creates new opportunities for the spread and establishment of common or novel infectious diseases. A surveillance system to detect emergent and re-emergent infections, a rapid responsiveness of healthcare systems and laboratories, vector control, and the provision of healthcare education programmes to inform the population of how to avoid infections are needed in order to stop the spread of infectious diseases.

  7. Stem cell differentiation and human liver disease

    PubMed Central

    Zhou, Wen-Li; Medine, Claire N; Zhu, Liang; Hay, David C

    2012-01-01

    Human stem cells are scalable cell populations capable of cellular differentiation. This makes them a very attractive in vitro cellular resource and in theory provides unlimited amounts of primary cells. Such an approach has the potential to improve our understanding of human biology and treating disease. In the future it may be possible to deploy novel stem cell-based approaches to treat human liver diseases. In recent years, efficient hepatic differentiation from human stem cells has been achieved by several research groups including our own. In this review we provide an overview of the field and discuss the future potential and limitations of stem cell technology. PMID:22563188

  8. [Choice of optimal perfusion flow rate during surgical correction of combined acquired heart diseases].

    PubMed

    Len'kin, A I; Zakharov, V I; Smetkin, A A; Len'kin, P I; Kirov, M Iu

    2013-01-01

    Cardiac output during the use of cardiopulmonary bypass (CPB) is defined by perfusion flow rate, which is calculated by multiplying the perfusion index (PI) on the body surface area. To date, there is no clear definition of an optimal PI and flow rate of perfusion. 60 patients operated with CPB were enrolled in the prospective study to determine the relations between different modes of perfusion and oxygen transport during surgical correction of combined valvular heart disease. Calculation of the CPB flow rate was based on PI 2.5 and 3.0 l/min/m2. Results of the study demonstrate that perfusion based on PI 2.5 l/min/m2 provides more stable oxygen transport parameters and reduces the time of ICU stay in comparison with the flow rate based on PI 3.0 l/min/m2.

  9. Bacillary angiomatosis associated with extensive esophageal polyposis: a new mucocutaneous manifestation of acquired immunodeficiency disease (AIDS).

    PubMed

    Chang, A D; Drachenberg, C I; James, S P

    1996-10-01

    Bacillary angiomatosis is a rare infection that has been associated with human immunodeficiency virus infection. The causative organism is Rochalimaea henselae and contact with cats is a risk factor. We present a case of a 37-yr-old man who had recent prolonged exposure to a cat and presented with fever, iron deficiency anemia, and guaiac-positive stools who had biopsy-proven bacillary angiomatosis skin lesions and on esophagogastroduodenoscopy had multiple, diffuse, friable, polypoid lesions in the esophagus. The histology of the esophageal polyps was identical to the skin lesions, and the polyps disappeared after treatment with erythromycin. Bacillary angiomatosis should be included in the differential diagnosis of infectious upper gastrointestinal manifestations associated with AIDS.

  10. Human genome project and sickle cell disease.

    PubMed

    Norman, Brenda J; Miller, Sheila D

    2011-01-01

    Sickle cell disease is one of the most common genetic blood disorders in the United States that affects 1 in every 375 African Americans. Sickle cell disease is an inherited condition caused by abnormal hemoglobin in the red blood cells. The Human Genome Project has provided valuable insight and extensive research advances in the understanding of the human genome and sickle cell disease. Significant progress in genetic knowledge has led to an increase in the ability for researchers to map and sequence genes for diagnosis, treatment, and prevention of sickle cell disease and other chronic illnesses. This article explores some of the recent knowledge and advances about sickle cell disease and the Human Genome Project.

  11. Global change and human susceptibility to disease

    SciTech Connect

    Daily, G.C.; Ehrlich, P.R.

    1996-12-31

    Although the loss of good health is inherently unpredictable, human behavior at the individual and societal levels profoundly influences the incidence and evolution of disease. In this review, the authors define the human epidemiological environment and describe key biophysical, economic, sociocultural, and political factors that shape it. The potential impact upon the epidemiological environment of biophysical aspects of global change--changes in the size; mobility, and geographic distribution of the human population; land conversion; agricultural intensification; and climate change--is then examined. Human vulnerability to disease is strongly and deleteriously influenced by many of these ongoing, intensifying alterations. The authors then examine threats to human defenses against disease, including immune suppression, loss of biodiversity and indigenous knowledge, and the evolution of antibiotic resistance. Effective responses will require greatly enhanced attention by and collaboration among experts in diverse academic disciplines, in the private sector, and in government worldwide. 157 refs.

  12. Human myiasis in New Zealand: imported and indigenously-acquired cases: the species of concern and clinical aspects.

    PubMed

    Derraik, Jose G B; Heath, Allen C G; Rademaker, Marius

    2010-09-10

    Reports of myiasis in humans in New Zealand are somewhat rare, and little attention has been paid to this issue in the local medical literature. A number of Diptera (fly) families present in New Zealand have been associated with cases of human myiasis: Calliphoridae (7 species), Fanniidae (2 species), Muscidae (3 species), Oestridae (4 species), Phoridae (3 species), Psychodidae (1 species), Sarcophagidae (2 species), Stratiomyidae (1 species) and Syrphidae (1 species). Despite these numbers, there have only been 6 published records and we obtained further 16 unpublished reports of myiasis acquired in New Zealand. Records of imported myiasis in humans are also rare, with only 2 published and 6 unpublished cases obtained. As many medical practitioners are unaware of myiasis or encounter it rarely, we provide a brief discussion of the clinical features and treatment. PMID:20930889

  13. Atypical prion diseases in humans and animals.

    PubMed

    Tranulis, Michael A; Benestad, Sylvie L; Baron, Thierry; Kretzschmar, Hans

    2011-01-01

    Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep, have long been recognized, our understanding of their epidemiology and pathogenesis is still in its early stages. Progress is hampered by the lengthy incubation periods and the lack of effective ways of monitoring and characterizing these agents. Protease-resistant conformers of the prion protein (PrP), known as the "scrapie form" (PrP(Sc)), are used as disease markers, and for taxonomic purposes, in correlation with clinical, pathological, and genetic data. In humans, prion diseases can arise sporadically (sCJD) or genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE) causing variant CJD (vCJD). Person-to-person spread of human prion disease has only been known to occur following cannibalism (kuru disease in Papua New Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In contrast, scrapie in small ruminants and chronic wasting disease (CWD) in cervids behave as infectious diseases within these species. Recently, however, so-called atypical forms of prion diseases have been discovered in sheep (atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble sporadic or genetic human prion diseases and might be their animal equivalents. This hypothesis also raises the significant public health question of possible epidemiological links between these diseases and their counterparts in humans. PMID:21598097

  14. Physiochemical basis of human degenerative disease

    PubMed Central

    Lipinski, Boguslaw

    2015-01-01

    The onset of human degenerative diseases in humans, including type 2 diabetes, cardiovascular disease, neurological disorders, neurodevelopmental disease and neurodegenerative disease has been shown to be related to exposures to persistent organic pollutants, including polychlorinated biphenyls, chlorinated pesticides, polybrominated diphenyl ethers and others, as well as to polynuclear aromatic hydrocarbons, phthalates, bisphenol-A and other aromatic lipophilic species. The onset of these diseases has also been related to exposures to transition metal ions. A physiochemical mechanism for the onset of degenerative environmental disease dependent upon exposure to a combination of lipophilic aromatic hydrocarbons and transition metal ions is proposed here. The findings reported here also, for the first time, explain why aromatic hydrocarbons exhibit greater toxicity than aliphatic hydrocarbons of equal carbon numbers. PMID:27486355

  15. Vertically acquired hepatitis C virus infection: Correlates of transmission and disease progression

    PubMed Central

    Tovo, Pier-Angelo; Calitri, Carmelina; Scolfaro, Carlo; Gabiano, Clara; Garazzino, Silvia

    2016-01-01

    The worldwide prevalence of hepatitis C virus (HCV) infection in children is 0.05%-0.4% in developed countries and 2%-5% in resource-limited settings, where inadequately tested blood products or un-sterile medical injections still remain important routes of infection. After the screening of blood donors, mother-to-child transmission (MTCT) of HCV has become the leading cause of pediatric infection, at a rate of 5%. Maternal HIV co-infection is a significant risk factor for MTCT and anti-HIV therapy during pregnancy seemingly can reduce the transmission rate of both viruses. Conversely, a high maternal viral load is an important, but not preventable risk factor, because at present no anti-HCV treatment can be administered to pregnant women to block viral replication. Caution is needed in adopting obstetric procedures, such as amniocentesis or internal fetal monitoring, that can favor fetal exposure to HCV contaminated maternal blood, though evidence is lacking on the real risk of single obstetric practices. Mode of delivery and type of feeding do not represent significant risk factors for MTCT. Therefore, there is no reason to offer elective caesarean section or discourage breast-feeding to HCV infected parturients. Information on the natural history of vertical HCV infection is limited. The primary infection is asymptomatic in infants. At least one quarter of infected children shows a spontaneous viral clearance (SVC) that usually occurs within 6 years of life. IL-28B polymorphims and genotype 3 infection have been associated with greater chances of SVC. In general, HCV progression is mild or moderate in children with chronic infection who grow regularly, though cases with marked liver fibrosis or hepatic failure have been described. Non-organ specific autoantibodies and cryoglobulins are frequently found in children with chronic infection, but autoimmune diseases or HCV associated extrahepatic manifestations are rare. PMID:26819507

  16. Robust spectral analysis of videocapsule images acquired from celiac disease patients

    PubMed Central

    2011-01-01

    Background Dominant frequency (DF) analysis of videocapsule endoscopy images is a new method to detect small intestinal periodicities that may result from mechanical rhythms such as peristalsis. Longer periodicity is related to greater image texture at areas of villous atrophy in celiac disease. However, extraneous features and spatiotemporal phase shift may mask DF rhythms. Method The robustness of Fourier and ensemble averaging spectral analysis to compute DF was tested. Videocapsule images from the distal duodenum of 11 celiac patients (frame rate 2/s and pixel resolution 576 × 576) were analyzed. For patients 1, 2, ... 11, respectively, a total of 10, 11, ..., 20 sequential images were extracted from a randomly selected time epoch. Each image sequence was artificially repeated to 200 frames, simulating periodicities of 0.2, 0.18, ..., 0.1Hz, respectively. Random white noise at four different levels, spatiotemporal phase shift, and frames with air bubbles were added. Power spectra were constructed pixel-wise over 200 frames, and an average spectrum was computed from the 576 × 576 individual spectra. The largest spectral peak in the average spectrum was the estimated DF. Error was defined as the absolute difference between actual DF and estimated DF. Results For Fourier analysis, the mean absolute error between estimated and actual DF was 0.032 ± 0.052Hz. Error increased with greater degree of random noise imposed. In contrast, all ensemble average estimates precisely predicted the simulated DF. Conclusions The ensemble average DF estimate of videocapsule images with simulated periodicity is robust to noise and spatiotemporal phase shift as compared with Fourier analysis. Accurate estimation of DF eliminates the need to impose complex masking, extraction, and/or corrective preprocessing measures. PMID:21906318

  17. Evolutionary Response to Human Infectious Diseases

    ERIC Educational Resources Information Center

    Armelagos, George J.; Dewey, John R.

    1970-01-01

    Gives an overview of human history, relating cultural changes with resulting changes in population density and in ecological balance to patterns of infectious diseases in man. Discusses mechanisms of evolution of resistance. Suggests that in populations where infectious diseases can be controlled, attention should shift to degenerative diseases…

  18. Human Echinococcosis: A Neglected Disease

    PubMed Central

    da Silva, António Menezes

    2010-01-01

    Echinococcosis is among the most neglected parasitic diseases. Development of new drugs and other treatment modalities receives very little attention, if any. In most developed countries, Cystic Echinococcosis (CE) is an imported disease of very low incidence and prevalence and is found almost exclusively in migrants from endemic regions. In endemic regions, predominantly settings with limited resources, patient numbers are high. Whole communities do not have access to appropriate treatment. The choice of treatment modalities is limited because of poor infrastructure and shortage of equipment and drugs. In this context, CE meets the criteria for a neglected disease. Furthermore, the terminology related to the designations around the parasite, its evolution and some therapeutic procedures is not uniform and sometimes inappropriate terms and wrong designations are used based on incorrect concepts. Although all of us know the different aspects of the disease it is pertinent to remember some important points and, above all, to clarify some aspects concerning the hydatid cyst's nomenclature in order to understand better the therapeutic options in the liver locations, particularly the different surgical approaches. PMID:20862339

  19. Melanized Fungi in Human Disease

    PubMed Central

    Revankar, Sanjay G.; Sutton, Deanna A.

    2010-01-01

    Summary: Melanized or dematiaceous fungi are associated with a wide variety of infectious syndromes. Many are soil organisms and are generally distributed worldwide, though certain species appear to have restricted geographic ranges. Though they are uncommon causes of disease, melanized fungi have been increasingly recognized as important pathogens, with most reports occurring in the past 20 years. The spectrum of diseases with which they are associated has also broadened and includes allergic disease, superficial and deep local infections, pneumonia, brain abscess, and disseminated infection. For some infections in immunocompetent individuals, such as allergic fungal sinusitis and brain abscess, they are among the most common etiologic fungi. Melanin is a likely virulence factor for these fungi. Diagnosis relies on careful microscopic and pathological examination, as well as clinical assessment of the patient, as these fungi are often considered contaminants. Therapy varies depending upon the clinical syndrome. Local infection may be cured with excision alone, while systemic disease is often refractory to therapy. Triazoles such as voriconazole, posaconazole, and itraconazole have the most consistent in vitro activity. Further studies are needed to better understand the pathogenesis and optimal treatment of these uncommon infections. PMID:20930077

  20. Global biogeography of human infectious diseases.

    PubMed

    Murray, Kris A; Preston, Nicholas; Allen, Toph; Zambrana-Torrelio, Carlos; Hosseini, Parviez R; Daszak, Peter

    2015-10-13

    The distributions of most infectious agents causing disease in humans are poorly resolved or unknown. However, poorly known and unknown agents contribute to the global burden of disease and will underlie many future disease risks. Existing patterns of infectious disease co-occurrence could thus play a critical role in resolving or anticipating current and future disease threats. We analyzed the global occurrence patterns of 187 human infectious diseases across 225 countries and seven epidemiological classes (human-specific, zoonotic, vector-borne, non-vector-borne, bacterial, viral, and parasitic) to show that human infectious diseases exhibit distinct spatial grouping patterns at a global scale. We demonstrate, using outbreaks of Ebola virus as a test case, that this spatial structuring provides an untapped source of prior information that could be used to tighten the focus of a range of health-related research and management activities at early stages or in data-poor settings, including disease surveillance, outbreak responses, or optimizing pathogen discovery. In examining the correlates of these spatial patterns, among a range of geographic, epidemiological, environmental, and social factors, mammalian biodiversity was the strongest predictor of infectious disease co-occurrence overall and for six of the seven disease classes examined, giving rise to a striking congruence between global pathogeographic and "Wallacean" zoogeographic patterns. This clear biogeographic signal suggests that infectious disease assemblages remain fundamentally constrained in their distributions by ecological barriers to dispersal or establishment, despite the homogenizing forces of globalization. Pathogeography thus provides an overarching context in which other factors promoting infectious disease emergence and spread are set.

  1. Ertapenem as initial antimicrobial monotherapy for patients with chronic obstructive pulmonary disease hospitalized with typical community-acquired pneumonia.

    PubMed

    Friedland, Ian R; McCarroll, Kathleen A; DiNubile, Mark J; Woods, Gail L

    2004-01-01

    This report describes a post-hoc analysis of two large studies of typical community-acquired pneumonia (CAP) in hospitalized patients, focusing on demographics, disease characteristics, and outcome in patients with and without chronic obstructive pulmonary disease (COPD). In both studies, ertapenem 1 g IV daily was compared with ceftriaxone 1 g IV daily as initial antimicrobial therapy. Clinically improving patients could be switched to oral antibiotic therapy after 3 days. Of the 857 patients treated in both studies, 264 (31%) had COPD. The proportions of patients who were male, were >/=65 years of age, had a Pneumonia Severity Index of IV/V, or had Haemophilus influenzae isolated in a baseline culture were higher in patients with COPD. Streptococcus pneumoniae was the most common pathogen both in patients with and without COPD. Clinical response rates in assessable patients 7-14 days after completion of therapy for the combined treatment groups were 90% (187/208) for patients with COPD and 93% (424/456) for those without COPD (odds ratio 0.7 [95% CI, 0.4-1.2], P = 0.17). Of assessable COPD patients, 109/121 (90%) treated with ertapenem and 78/87 (90%) treated with ceftriaxone achieved a favorable clinical response (odds ratio 1.0 [95% CI, 0.6-1.8], P = 0.94). The outcome in patients with or without COPD was similar regardless of therapy. In patients with COPD as well as in the overall study population, the efficacy of ertapenem as initial antimicrobial monotherapy for patients with serious typical community-acquired pneumonia was comparable to that of ceftriaxone.

  2. TOXICOGENOMICS AND HUMAN DISEASE RISK ASSESSMENT

    EPA Science Inventory


    Toxicogenomics and Human Disease Risk Assessment.

    Complete sequencing of human and other genomes, availability of large-scale gene
    expression arrays with ever-increasing numbers of genes displayed, and steady
    improvements in protein expression technology can hav...

  3. [Primary human demodicosis. A disease sui generis].

    PubMed

    Hsu, C-K; Zink, A; Wei, K-J; Dzika, E; Plewig, G; Chen, W

    2015-03-01

    Human Demodex mites (Demodex folliculorum and Demodex brevis) are unique in that they are an obligate human ectoparasite that can inhabit the pilosebaceous unit lifelong without causing obvious host immune response in most cases. The mode of symbiosis between humans and human Demodex mites is unclear, while the pathogenicity of human Demodex mites in many inflammatory skin diseases is now better understood. Primary human demodicosis is a skin disease sui generis not associated with local or systemic immunosuppression. Diagnosis is often underestimated and differentiation from folliculitis, papulopustular rosacea and perioral dermatitis is not always straightforward. Dependent on the morphology and degree of inflammation, the clinical manifestations can be classified into spinulate, papulopustular, nodulocystic, crustic and fulminant demodicosis. Therapy success can be achieved only with acaricides/arachidicides. The effective doses, optimal regimen and antimicrobial resistance remain to be determined. PMID:25744530

  4. Cis-regulatory mutations in human disease

    PubMed Central

    2009-01-01

    Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few. PMID:19641089

  5. Addressing Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in Advanced Practice Nursing Education.

    ERIC Educational Resources Information Center

    Nokes, Kathleen M.; Stein, Gary L.

    1997-01-01

    A survey of 23 advanced practice nursing programs showed only 3 had HIV-specific graduate-level nursing courses. Recommendations were made for HIV-specific courses, integration of HIV content into other courses, use of Centers for Disease Control and Occupational Safety and Health Administration guidelines, and subspecialties in HIV nursing. (SK)

  6. U.S-acquired human rabies with symptom onset and diagnosis abroad, 2012.

    PubMed

    2012-10-01

    On July 8, 2012, a U.S. resident was admitted to a hospital in Dubai, United Arab Emirates, for evaluation of right arm spasticity, anxiety, and malaise. By the next day, the patient had become comatose following a period of agitation. On July 31, he died. Investigators from CDC, state, and local health departments determined that the patient acquired rabies from contact in March with a bat in California. Person-to-person transmission of rabies has been documented in cases of organ and tissue transplantation and is theoretically possible if infectious saliva or tears are introduced into fresh open wounds or onto mucous membranes. Once symptoms begin, rabies is almost always fatal. While he was potentially infectious, during June 11-July 31, the patient traveled on eight international flights through six countries. To date, 59 persons have been identified as contacts, and 23 persons have been administered postexposure prophylaxis (PEP); no secondary cases have been identified. Bites or scratches from bats or other animals suspected of having rabies should be regarded seriously; victims should promptly seek consultation with public health practitioners and medical-care providers. This report highlights the need for collaboration to 1) identify persons who potentially had contact with infectious materials from a person infected with rabies, 2) conduct a risk assessment, and 3) provide prophylaxis to all those with a reasonable risk for contact with infectious materials (e.g., tears, saliva, or neural tissue from a person with rabies contacting open wounds or mucous membranes of an uninfected person).

  7. Recombinant human soluble thrombomodulin is active against hemophagocytic lymphohistiocytosis associated with acquired immunodeficiency syndrome.

    PubMed

    Chi, SungGi; Ikezoe, Takayuki; Takeuchi, Asako; Takaoka, Masato; Yokoyama, Akihito

    2013-11-01

    A 39-year-old man was admitted to our hospital to initiate highly active anti-retroviral therapy (HAART) for documented acquired immune deficiency syndrome. The HIV load was 2.5 million copies/mL and the CD4-positive lymphocyte count was only 52 cells/µL at presentation. The HAART regimen consisted of lamivudine and abacavir as the backbone, plus raltegravir and lopinavir/ritonavir as the base. The day after initiating HAART, his body temperature rose to 102.4 °F (39.1 °C), accompanied by elevated levels of liver enzymes, neutropenia, coagulopathies, and an extremely high serum ferritin level, prompting us to suspect hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulation (DIC). To correct the coagulation abnormalities, recombinant thrombomodulin (rTM) was initiated at 375 U/kg. Surprisingly, fever resolved almost immediately, in parallel with dramatic decreases in serum levels of ferritin and liver enzymes and prompt normalization of coagulopathy with only two doses of rTM. The patient subsequently developed amebiasis, which was successfully treated using metronidazole. In summary, the use of rTM dramatically improved not only DIC, but also HLH, suggesting potent anti-inflammatory effects of the agent. Although further clinical reports and trials are needed, rTM appears to provide an additional therapeutic option in the management of HLH.

  8. Evolution of the human hand: approaches to acquiring, analysing and interpreting the anatomical evidence

    PubMed Central

    MARZKE, MARY W.; MARZKE, R. F.

    2000-01-01

    The discovery of fossil hand bones from an early human ancestor at Olduvai Gorge in 1960, at the same level as primitive stone tools, generated a debate about the role of tools in the evolution of the human hand that has raged to the present day. Could the Olduvai hand have made the tools? Did the human hand evolve as an adaptation to tool making and tool use? The debate has been fueled by anatomical studies comparing living and fossil human and nonhuman primate hands, and by experimental observations. These have assessed the relative abilities of apes and humans to manufacture the Oldowan tools, but consensus has been hampered by disagreements about how to translate experimental data from living species into quantitative models for predicting the performance of fossil hands. Such models are now beginning to take shape as new techniques are applied to the capture, management and analysis of data on kinetic and kinematic variables ranging from hand joint structure, muscle mechanics, and the distribution and density of bone to joint movements and muscle recruitment during manipulative behaviour. The systematic comparative studies are highlighting a functional complex of features in the human hand facilitating a distinctive repertoire of grips that are apparently more effective for stone tool making than grips characterising various nonhuman primate species. The new techniques are identifying skeletal variables whose form may provide clues to the potential of fossil hominid hands for one-handed firm precision grips and fine precision manoeuvering movements, both of which are essential for habitual and effective tool making and tool use. PMID:10999274

  9. Neuroimaging findings in human prion disease

    PubMed Central

    Macfarlane, R G; Wroe, S J; Collinge, J; Yousry, T A; Jäger, H R

    2007-01-01

    Imaging occupies an important role in the investigation of dementia and neurodegenerative disease. The role of imaging in prion disease used to be one of exclusion of other conditions. Over the past decade, the non‐invasive nature of MRI, the improved range of magnetic resonance sequences and the availability of clinical and neuropathological correlation have led to a more prominent position of MRI and its inclusion in the diagnostic criteria for variant Creutzfeldt–Jakob disease. As experience of imaging in human prion disease increases, patterns of change related to strain and genotype may improve the diagnostic potential of imaging in the future, may reduce the need for more invasive testing and prove useful in future therapeutic trials. This paper reviews the current knowledge of imaging appearances in human prion disease. PMID:17135459

  10. Transformation of sweet orange [Citrus sinensis (L.) Osbeck] with pthA-nls for acquiring resistance to citrus canker disease.

    PubMed

    Yang, Li; Hu, Chunhua; Li, Na; Zhang, Jiayin; Yan, Jiawen; Deng, Ziniu

    2011-01-01

    The COOH terminal of pthA encoding three nuclear localizing signals (NLS) was amplified by polymerase chain reaction (PCR) from the plasmid of Xanthomonas axonopodis pv. citri, the pathogen of citrus canker disease. Then the sense and antisense strands of the nls were cloned into pBI121 vector. pthA-nls driven by the CaMV35 s promoter was transferred into sweet orange via Agrobacterium -mediated transformation. Successful integration was confirmed by PCR and Southern blotting, and 12 sense-nls (nls (+)) and 9 antisense-nls (nls (-)) transgenic clones were obtained. The expression of nls fragment was analyzed by RT-PCR, Real time q-PCR and Western blotting, in which the specific NLS protein was detected only in nls (+) transgenic clones. In an in vitro assay, when pin-puncture inoculation was performed with 2.5 × 10(7) cfu/ml of bacterial solution, the nls (+) transgenic clones showed no typical lesion development, while typical symptoms were observed in the wild types and the nls (-) transgenic clones. In vivo assay results indicated that the nls (+) transgenic clones showed less disease incidence, in comparison with the wild types and the nls (-) transgenic clones, when pin-puncture inoculation was performed with 10(4)-10(5) cfu/ml. The minimum disease incidence was 23.3% for 'Sucarri' sweet orange and 33.3% for 'Bingtang' sweet orange. When 10(4)-10(7) cfu/ml of pathogen was spray inoculated, the nls (+) transgenic clones did not show any symptom, and even the concentration raised to 10(9) cfu/ml, the disease incidence was 20-80%, while the wild types and the nls (-) transgenic clones had 100% disease development with whatever concentration of inoculum. Two transgenic clones were confirmed to be resistant to citrus canker disease in the repeated inoculation. The results suggested that the transformation of nls sense strands may offer an effective way to acquire resistance to citrus canker disease.

  11. The Impact of Evolutionary Driving Forces on Human Complex Diseases: A Population Genetics Approach.

    PubMed

    Saeb, Amr T M; Al-Naqeb, Dhekra

    2016-01-01

    Investigating the molecular evolution of human genome has paved the way to understand genetic adaptation of humans to the environmental changes and corresponding complex diseases. In this review, we discussed the historical origin of genetic diversity among human populations, the evolutionary driving forces that can affect genetic diversity among populations, and the effects of human movement into new environments and gene flow on population genetic diversity. Furthermore, we presented the role of natural selection on genetic diversity and complex diseases. Then we reviewed the disadvantageous consequences of historical selection events in modern time and their relation to the development of complex diseases. In addition, we discussed the effect of consanguinity on the incidence of complex diseases in human populations. Finally, we presented the latest information about the role of ancient genes acquired from interbreeding with ancient hominids in the development of complex diseases. PMID:27313952

  12. The Impact of Evolutionary Driving Forces on Human Complex Diseases: A Population Genetics Approach

    PubMed Central

    Saeb, Amr T. M.; Al-Naqeb, Dhekra

    2016-01-01

    Investigating the molecular evolution of human genome has paved the way to understand genetic adaptation of humans to the environmental changes and corresponding complex diseases. In this review, we discussed the historical origin of genetic diversity among human populations, the evolutionary driving forces that can affect genetic diversity among populations, and the effects of human movement into new environments and gene flow on population genetic diversity. Furthermore, we presented the role of natural selection on genetic diversity and complex diseases. Then we reviewed the disadvantageous consequences of historical selection events in modern time and their relation to the development of complex diseases. In addition, we discussed the effect of consanguinity on the incidence of complex diseases in human populations. Finally, we presented the latest information about the role of ancient genes acquired from interbreeding with ancient hominids in the development of complex diseases. PMID:27313952

  13. Malassezia skin diseases in humans.

    PubMed

    Difonzo, E M; Faggi, E; Bassi, A; Campisi, E; Arunachalam, M; Pini, G; Scarfì, F; Galeone, M

    2013-12-01

    Although Malassezia yeasts are a part of the normal microflora, under certain conditions they can cause superficial skin infection, such as pityriasis versicolor (PV) and Malassezia folliculitis. Moreover the yeasts of the genus Malassezia have been associated with seborrheic dermatitis and dandruff, atopic dermatitis, psoriasis, and, less commonly, with confluent and reticulated papillomatosis, onychomycosis, and transient acantholytic dermatosis. The study of the clinical role of Malassezia species has been surrounded by controversy due to the relative difficulty in isolation, cultivation, and identification. This review focuses on the clinical, mycologic, and immunologic aspects of the various skin diseases associated with Malassezia. Moreover, since there exists little information about the epidemiology and ecology of Malassezia species in the Italian population and the clinical significance of these species is not fully distinguished, we will report data about a study we carried out. The aim of our study was the isolation and the identification of Malassezia species in PV-affected skin and non-affected skin in patients with PV and in clinically healthy individuals without any Malassezia associated skin disease. PMID:24442041

  14. The Neuropathology of Obesity: Insights from Human Disease

    PubMed Central

    Lee, Edward B.; Mattson, Mark P.

    2013-01-01

    Obesity, a pathologic state defined by excess adipose tissue, is a significant public health problem as it affects a large proportion of individuals and is linked with increased risk for numerous chronic diseases. Obesity is the result of fundamental changes associated with modern society including overnutrition and sedentary lifestyles. Proper energy homeostasis is dependent on normal brain function as the master metabolic regulator which integrates peripheral signals, modulates autonomic outflow and controls feeding behavior. Therefore, many human brain diseases are associated with obesity. This review explores the neuropathology of obesity by examining brain diseases which either cause or are influenced by obesity. First, several genetic and acquired brain diseases are discussed as a means to understand the central regulation of peripheral metabolism. These diseases range from monogenetic causes of obesity (leptin deficiency, MC4R deficiency, Bardet-Biedl syndrome and others) to complex neurodevelopmental disorders (Prader-Willi syndrome and Sim1 deficiency) and neurodegenerative conditions (frontotemporal dementia and Gourmand’s syndrome) and serve to highlight the central regulatory mechanisms which have evolved to maintain energy homeostasis. Next, to examine the effect of obesity on the brain, chronic neuropathologic conditions (epilepsy, multiple sclerosis and Alzheimer’s disease) are discussed as examples of obesity leading to maladaptive processes which exacerbate chronic disease. Thus obesity is associated with multiple pathways including abnormal metabolism, altered hormonal signaling and increased inflammation which act in concert to promote downstream neuropathology. Finally, the effect of anti-obesity interventions is discussed in terms of brain structure and function. Together, understanding human diseases and anti-obesity interventions leads to insights into the bidirectional interaction between peripheral metabolism and central brain function

  15. Salicylic acid and systemic acquired resistance play a role in attenuating crown gall disease caused by Agrobacterium tumefaciens.

    PubMed

    Anand, Ajith; Uppalapati, Srinivasa Rao; Ryu, Choong-Min; Allen, Stacy N; Kang, Li; Tang, Yuhong; Mysore, Kirankumar S

    2008-02-01

    We investigated the effects of salicylic acid (SA) and systemic acquired resistance (SAR) on crown gall disease caused by Agrobacterium tumefaciens. Nicotiana benthamiana plants treated with SA showed decreased susceptibility to Agrobacterium infection. Exogenous application of SA to Agrobacterium cultures decreased its growth, virulence, and attachment to plant cells. Using Agrobacterium whole-genome microarrays, we characterized the direct effects of SA on bacterial gene expression and showed that SA inhibits induction of virulence (vir) genes and the repABC operon, and differentially regulates the expression of many other sets of genes. Using virus-induced gene silencing, we further demonstrate that plant genes involved in SA biosynthesis and signaling are important determinants for Agrobacterium infectivity on plants. Silencing of ICS (isochorismate synthase), NPR1 (nonexpresser of pathogenesis-related gene 1), and SABP2 (SA-binding protein 2) in N. benthamiana enhanced Agrobacterium infection. Moreover, plants treated with benzo-(1,2,3)-thiadiazole-7-carbothioic acid, a potent inducer of SAR, showed reduced disease symptoms. Our data suggest that SA and SAR both play a major role in retarding Agrobacterium infectivity. PMID:18156296

  16. Acquired hemophilia A associated with IgG4-related lung disease in a patient with autoimmune pancreatitis.

    PubMed

    Sugino, Keishi; Gocho, Kyoko; Ishida, Fumiaki; Kikuchi, Naoshi; Hirota, Nao; Sato, Keita; Sano, Go; Isobe, Kazutoshi; Sakamoto, Susumu; Takai, Yujiro; Hata, Yoshinobu; Shibuya, Kazutoshi; Uekusa, Toshimasa; Kurosaki, Atsuko; Homma, Sakae

    2012-01-01

    Immunoglobulin G4 (IgG4)-related lung diseases can occur in patients with autoimmune pancreatitis (AIP). However, the causal relationship between AIP and acquired hemophilia A (AH) is unknown. We herein report the first case of AH associated with IgG4-related lung disease that developed in a patient with AIP. A 65-year-old asymptomatic man with a history of AIP and sclerosing cholangitis diagnosed at the age of 57 was admitted to our hospital due to an abnormal reticulonodular shadow on chest X-ray. An examination of lung biopsy specimens revealed IgG4-positive plasma cell infiltration in the interstitium. The serum IgG4 level was elevated. One year later, the patient developed a progressive severe hematoma in the left femoral muscle. On admission, laboratory examinations revealed severe anemia with a markedly prolonged activated partial prothrombin time, a decreased level of factor VIII (FVIII) activity, and the existence of anti-FVIII antibodies. These findings were consistent with a diagnosis of AH. No relapse has been observed over the past 25 months, during which time, corticosteroid therapy has been continuously administered.

  17. The Lebanese Society for Infectious Diseases and Clinical Microbiology (LSIDCM) guidelines for adult community-acquired pneumonia (Cap) in Lebanon.

    PubMed

    Moghnieh, Rima; Yared Sakr, Nadine; Kanj, Souha S; Musharrafieh, Umayya; Husni, Rula; Jradeh, Mona; Al-Awar, Ghassan; Matar, Madona; Jureij, Wafa; Antoine, Saad; Azar, Eid; Abi Hanna, Pierre; Minari, Afaf; Hammoud, Jamale; Kfoury, Joumana; Mahfouz, Tahsin; Abou Chakra, Diaa; Zaatari, Mohamad; Tabbarah, Zuhayr A

    2014-01-01

    Adult community-acquired pneumonia (CAP) is a common cause of morbidity and mortality which is managed by different disciplines in a heterogeneous fashion. Development of consensus guidelines to standardize these wide variations in care has become a prime objective. The Lebanese Society of Infectious Diseases and Clinical Microbiology (LSIDCM) convened to set Lebanese national guidelines for the management of CAP since it is a major and a prevalent disease affecting the Lebanese population. These guidelines, besides being helpful in direct clinical practice, play a major role in establishing stewardship programs in hospitals in an effort to contain antimicrobial resistance on the national level. These guidelines are intended for primary care practitioners and emergency medicine physicians. They constitute an appropriate starting point for specialists' consultation being based on the available local epidemiological and resistance data. This document includes the following: 1/ Rationale and scope of the guidelines; 2/ Microbiology of CAP based on Lebanese data; 3/ Clinical presentation and diagnostic workup of CAP; 4/ Management and prevention strategies based on the IDSA/ATS Consensus Guidelines, 2007, and the ESCMID Guidelines, 2011, and tailored to the microbiological data in Lebanon; 5/ Comparison to regional guidelines. The recommendations made in this document were graded based on the strength of the evidence as in the 2007 IDSA/ATS Consensus Guidelines. Hopefully, these guidelines will be an important step towards standardization of CAP care in Lebanon and set the agenda for further research in this area.

  18. Reading-related oculomotor testing and training protocols for acquired brain injury in humans.

    PubMed

    Han, Ying; Ciuffreda, Kenneth J; Kapoor, Neera

    2004-11-01

    Many individuals with acquired brain injury (ABI) report reading problems of oculomotor origin. These may include frequent loss of place, skipping of lines and difficulty shifting to the next line of print. We describe two protocols for the testing and training of reading-related eye movements in adult individuals with ABI (traumatic brain injury [TBI] and stroke with hemianopia), who experience oculomotor-based symptoms when reading. These protocols use objective eye movement recording techniques and computer-based stimulus presentation and analysis. One protocol tests and the other trains basic horizontal and vertical versional eye movements (fixation, saccades and pursuit), as well as reading eye movements using simulated single and multiple line dynamic arrays. In addition, a reading rating-scale questionnaire is administered before and after completion of training to assess subjective reading improvement. In all paradigms, the target consists of a 0.5 degrees luminous square, which is displayed on a computer monitor positioned 40 cm from the subject along the midline. All testing and training are conducted under binocular viewing conditions with optical correction in place. There are two modes of training: normal internal oculomotor visual feedback either alone (4 weeks) or in conjunction with external oculomotor auditory feedback (4 weeks) administered in a counterbalanced manner within each diagnostic group. Training is performed 1 h, twice weekly for the 8 weeks. Oculomotor testing is conducted before, midway and after training. Following training, reading-related eye movements and reading ability improved as assessed both subjectively and objectively. These protocols provide a systematic approach to the quantitative and comprehensive testing and training of reading-related eye movement skills and behaviors in the ABI population manifesting oculomotor-based reading dysfunctions. Furthermore, the training protocol results in the rapid remediation of the eye

  19. Animal models of human disease: inflammation.

    PubMed

    Webb, David R

    2014-01-01

    Animals have been used as models to study inflammation and autoimmunity for more than 80 years. During that time it has been understood that although the use of such models is an important and necessary part of understanding human disease, they inevitably display significant differences from the human disease state. Since our understanding of human inflammation and autoimmunity is necessarily incomplete, it may be concluded that the animal models will also be reflective of the state of knowledge regarding such diseases. Nevertheless, animal models of rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis have been successfully used to enhance the understanding of the human disease and have made significant contributions to the development of powerful new therapies. However, there are exceptions. One of the most persistent has been the study of sepsis where the animal models have been woefully inadequate in uncovering targets for drug discovery and have led to repeated clinical failures. As will be explained, only by using newly developed genomics tools has it been possible to uncover the differences between sepsis in mice and sepsis in man. It is concluded that approaches using the newer genomic and proteomic data derived from human tissues, will make possible the development of animal models with more predictive power as aids to drug discovery.

  20. Th17 cells in human disease

    PubMed Central

    Tesmer, Laura A.; Lundy, Steven K.; Sarkar, Sujata; Fox, David A.

    2012-01-01

    Summary Our understanding of the role of T cells in human disease is undergoing revision as a result of the discovery of T-helper 17 (Th17) cells, a unique CD4+ T-cell subset characterized by production of interleukin-17 (IL-17). IL-17 is a highly inflammatory cytokine with robust effects on stromal cells in many tissues. Recent data in humans and mice suggest that Th17 cells play an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma. Initial reports also propose a role for Th17 cells in tumorigenesis and transplant rejection. Important differences, as well as many similarities, are emerging when the biology of Th17 cells in the mouse is compared with corresponding phenomena in humans. As our understanding of human Th17 biology grows, the mechanisms underlying many diseases are becoming more apparent, resulting in a new appreciation for both previously known and more recently discovered cytokines, chemokines, and feedback mechanisms. Given the strong association between excessive Th17 activity and human disease, new therapeutic approaches targeting Th17 cells are highly promising, but the potential safety of such treatments may be limited by the role of these cells in normal host defenses against infection. PMID:18613831

  1. The complement system in human cardiometabolic disease.

    PubMed

    Hertle, E; Stehouwer, C D A; van Greevenbroek, M M J

    2014-10-01

    The complement system has been implicated in obesity, fatty liver, diabetes and cardiovascular disease (CVD). Complement factors are produced in adipose tissue and appear to be involved in adipose tissue metabolism and local inflammation. Thereby complement links adipose tissue inflammation to systemic metabolic derangements, such as low-grade inflammation, insulin resistance and dyslipidaemia. Furthermore, complement has been implicated in pathophysiological mechanisms of diet- and alcohol induced liver damage, hyperglycaemia, endothelial dysfunction, atherosclerosis and fibrinolysis. In this review, we summarize current evidence on the role of the complement system in several processes of human cardiometabolic disease. C3 is the central component in complement activation, and has most widely been studied in humans. C3 concentrations are associated with insulin resistance, liver dysfunction, risk of the metabolic syndrome, type 2 diabetes and CVD. C3 can be activated by the classical, the lectin and the alternative pathway of complement activation; and downstream activation of C3 activates the terminal pathway. Complement may also be activated via extrinsic proteases of the coagulation, fibrinolysis and the kinin systems. Studies on the different complement activation pathways in human cardiometabolic disease are limited, but available evidence suggests that they may have distinct roles in processes underlying cardiometabolic disease. The lectin pathway appeared beneficial in some studies on type 2 diabetes and CVD, while factors of the classical and the alternative pathway were related to unfavourable cardiometabolic traits. The terminal complement pathway was also implicated in insulin resistance and liver disease, and appears to have a prominent role in acute and advanced CVD. The available human data suggest a complex and potentially causal role for the complement system in human cardiometabolic disease. Further, preferably longitudinal studies are needed to

  2. Acquired Cystic Kidney Disease

    MedlinePlus

    ... Griffin Rodgers, Director of the NIDDK Clinical Trials Current research studies and how you can volunteer Community Outreach and Health Fairs Science-based information and tips for planning an outreach effort or community event For Health Care Professionals Patient and provider resources ...

  3. Acquired Cystic Kidney Disease

    MedlinePlus

    ... Fax: 813–636–8122 Email: info@aakp.org Internet: www.aakp.org American Kidney Fund 6110 Executive ... Fax: 301–881–0898 Email: helpline@kidneyfund.org Internet: www.kidneyfund.org Life Options Rehabilitation Resource Center ...

  4. Zoonotic diseases and human health: the human influenza example.

    PubMed

    Schoub, Barry D

    2012-06-20

    Over the past few decades a large number of new and emerging infectious diseases have been recognised in humans, partly because of improved diagnostic technologies and increased awareness and also, partly because of dynamic ecological changes between human hosts and their exposure to animals and the environment (Coker et al. 2011). Some 177 new pathogenic organisms have been recognised to be 'emerging', that is, have newly arisen or been newly introduced into human populations; almost three quarters of these, 130 (73%), have come from zoonotic origins (Cascio et al. 2011; Cutler, Fooks & Van Der Poel 2010; Taylor, Latham & Woolhouse 2001; Woolhouse & Gowtage-Sequeria 2005). One of the most prevalent and important human infectious disease is influenza, a disease responsible globally for a quarter million deaths annually. In the USA alone the toll from influenza is estimated at 36 000 deaths and 226 000 hospitalisations, and it ranks as the most important cause of vaccine preventable mortality in that country (CDC 2010). The epidemiological behaviour of human influenza clearly defines it as an emerging infectious disease and the recent understanding of its zoonotic origins has contributed much to the understanding of its behaviour in humans (Fauci 2006).

  5. Oxidants and human disease: some new concepts

    SciTech Connect

    Halliwell, B.

    1987-11-01

    Oxidant species such as superoxide radical (O/sub 2//sup -/), hydrogen peroxide (H/sub 2/O/sub 2/), hydroxyl radical (HO.), and lipid peroxides (LOOH) are becoming increasingly implicated in human disease. However, the question of whether such oxidants are a major cause of tissue injury in human disease or are merely produced during such injury has been difficult to answer because of inadequate experimental techniques, and possibly because of an overemphasis on lipid peroxidation as a mechanism of oxidant injury. Recent developments in methodology, in the authors understanding of the primary mechanism of oxidant toxicity to cells, and in concepts of antioxidant protection are reviewed. Good evidence now exists for some role of oxidant damage to tissues in the pathology of several human diseases, including rheumatoid arthritis, reperfusion injury, immune injury to lung and kidney, and cerebral trauma or ischemia. These have led to promising suggestions for new therapeutic approaches.

  6. Newborn human skin fibroblasts senesce in vitro without acquiring adult growth factor requirements

    SciTech Connect

    Wharton, W.

    1984-01-01

    Cultures of human fibroblasts were prepared from chest skin obtained either from newborns (less than 3 months old) or adults (more than 35 years old) and maintained in vitro until they senesced. Adult cells grew logarithmically in medium supplemented with whole blood serum but not with platelet-poor plasma. Early passage cells obtained from newborns grew equally well in either plasma- or serum-supplemented medium. The difference in growth factor requirements between adult and newborn cells persisted through the lifespan of the cells; i.e., newborn cells did not develop adult hormonal requirements when maintained in culture. Thus, in vitro cellular aging can be distinguished from some types of differentiation.

  7. Avian influenza: potential impact on sub-Saharan military populations with high rates of human immunodeficiency virus/acquired immunodeficiency syndrome.

    PubMed

    Feldman, Robert L; Nickell, Kent

    2007-07-01

    Several sub-Saharan militaries have large percentages of troops with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. With the arrival of avian influenza in Africa, the potential exists that some of those soldiers might also become infected with H5N1, the virus responsible for the disease. Two possible scenarios have been postulated regarding how such a coinfection of HIV and H5N1 might present. (1) Soldiers already weakened by HIV/acquired immunodeficiency syndrome rapidly succumb to H5N1. The cause of death is a "cytokine storm," essentially a runaway inflammatory response. (2) The weakened immune system prevents the cytokine storm from occurring; however, H5N1 is still present, replicating, and being shed, leading to the infection of others. A cytokine storm is particularly dangerous for individuals of military age, as evidenced by the large number of soldiers who died during the 1918 influenza epidemic. If large numbers of sub-Saharan soldiers suffer a similar fate from avian influenza, then military and political instability could develop.

  8. Engineering large animal models of human disease.

    PubMed

    Whitelaw, C Bruce A; Sheets, Timothy P; Lillico, Simon G; Telugu, Bhanu P

    2016-01-01

    The recent development of gene editing tools and methodology for use in livestock enables the production of new animal disease models. These tools facilitate site-specific mutation of the genome, allowing animals carrying known human disease mutations to be produced. In this review, we describe the various gene editing tools and how they can be used for a range of large animal models of diseases. This genomic technology is in its infancy but the expectation is that through the use of gene editing tools we will see a dramatic increase in animal model resources available for both the study of human disease and the translation of this knowledge into the clinic. Comparative pathology will be central to the productive use of these animal models and the successful translation of new therapeutic strategies.

  9. Functional annotation of HOT regions in the human genome: implications for human disease and cancer.

    PubMed

    Li, Hao; Chen, Hebing; Liu, Feng; Ren, Chao; Wang, Shengqi; Bo, Xiaochen; Shu, Wenjie

    2015-06-26

    Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait-associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis. Additionally, genetic risk variants are disproportionally enriched in HOT regions compared with LOT (low-occupancy target) regions in both disease-relevant and cancer cells. Importantly, this enrichment is biased toward disease- or cancer-specific cell types. Furthermore, we observed that cancer cells generally acquire cancer-specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis, and therapy.

  10. The Disease and Gene Annotations (DGA): an annotation resource for human disease.

    PubMed

    Peng, Kai; Xu, Wei; Zheng, Jianyong; Huang, Kegui; Wang, Huisong; Tong, Jiansong; Lin, Zhifeng; Liu, Jun; Cheng, Wenqing; Fu, Dong; Du, Pan; Kibbe, Warren A; Lin, Simon M; Xia, Tian

    2013-01-01

    Disease and Gene Annotations database (DGA, http://dga.nubic.northwestern.edu) is a collaborative effort aiming to provide a comprehensive and integrative annotation of the human genes in disease network context by integrating computable controlled vocabulary of the Disease Ontology (DO version 3 revision 2510, which has 8043 inherited, developmental and acquired human diseases), NCBI Gene Reference Into Function (GeneRIF) and molecular interaction network (MIN). DGA integrates these resources together using semantic mappings to build an integrative set of disease-to-gene and gene-to-gene relationships with excellent coverage based on current knowledge. DGA is kept current by periodically reparsing DO, GeneRIF, and MINs. DGA provides a user-friendly and interactive web interface system enabling users to efficiently query, download and visualize the DO tree structure and annotations as a tree, a network graph or a tabular list. To facilitate integrative analysis, DGA provides a web service Application Programming Interface for integration with external analytic tools.

  11. Human placenta-derived mesenchymal stem cells acquire neural phenotype under the appropriate niche conditions.

    PubMed

    Martini, Maristela Maria; Jeremias, Talita da Silva; Kohler, Maria Cecília; Marostica, Lucas Lourenço; Trentin, Andréa Gonçalves; Alvarez-Silva, Marcio

    2013-02-01

    Mesenchymal stem cells (MSCs) are multipotent stem cells with clinical interest. It has been reported that MSCs can be isolated from the human term placenta. We investigated the ability of human placenta-derived MSCs to differentiate into a neural phenotype in coculture assays with astrocytes obtained from neonatal rats. Placenta-derived MSCs were cocultured on a confluent monolayer of astrocytes obtained from the rat cerebellum to evaluate the differences in morphology. The extracellular matrix (ECM) produced by astrocytes as well as the growth factors produced by the astrocyte-conditioned medium were evaluated. The expression of the neural markers glial fibrillate acid protein (GFAP) and Nestin was studied in MSCs by immunocytochemistry. MSCs were able to respond to the astrocyte niche in coculture assays. They expressed the neural markers GFAP, Nestin, or β-Tubulin III, followed by an outgrowth of cell processes. The ECM from astrocytes was not effective in inducing the neural phenotype in MSCs, although the expression of β-Tubulin III was observed. When MSCs were cocultured with cerebellar astrocytes from newborn rats, a neural phenotype was achieved. This was determined by immunocytochemistry to GFAP, Nestin, or β-Tubulin III and by morphological changes. It was achieved without the addition of exogenous differentiation factors. This demonstrates that placenta-derived MSCs may be able to differentiate into neural cell types when in direct contact with a neural environment.

  12. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes

    NASA Technical Reports Server (NTRS)

    Romanov, S. R.; Kozakiewicz, B. K.; Holst, C. R.; Stampfer, M. R.; Haupt, L. M.; Tlsty, T. D.

    2001-01-01

    Senescence and genomic integrity are thought to be important barriers in the development of malignant lesions. Human fibroblasts undergo a limited number of cell divisions before entering an irreversible arrest, called senescence. Here we show that human mammary epithelial cells (HMECs) do not conform to this paradigm of senescence. In contrast to fibroblasts, HMECs exhibit an initial growth phase that is followed by a transient growth plateau (termed selection or M0; refs 3-5), from which proliferative cells emerge to undergo further population doublings (approximately 20-70), before entering a second growth plateau (previously termed senescence or M1; refs 4-6). We find that the first growth plateau exhibits characteristics of senescence but is not an insurmountable barrier to further growth. HMECs emerge from senescence, exhibit eroding telomeric sequences and ultimately enter telomere-based crisis to generate the types of chromosomal abnormalities seen in the earliest lesions of breast cancer. Growth past senescent barriers may be a pivotal event in the earliest steps of carcinogenesis, providing many genetic changes that predicate oncogenic evolution. The differences between epithelial cells and fibroblasts provide new insights into the mechanistic basis of neoplastic transformation.

  13. [Regulatory B cells in human autoimmune diseases].

    PubMed

    Miyagaki, Tomomitsu

    2015-01-01

    B cells have been generally considered to be positive regulators of immune responses because of their ability to produce antigen-specific antibodies and to activate T cells through antigen presentation. Impairment of B cell development and function may cause autoimmune diseases. Recently, specific B cell subsets that can negatively regulate immune responses have been described in mouse models of a wide variety of autoimmune diseases. The concept of those B cells, termed regulatory B cells, is now recognized as important in the murine immune system. Among several regulatory B cell subsets, IL-10-producing regulatory B cells are the most widely investigated. On the basis of discoveries from studies of such mice, human regulatory B cells that produce IL-10 in most cases are becoming an active area of research. There have been emerging data suggesting the importance of human regulatory B cells in various diseases. Revealing the immune regulation mechanisms of human regulatory B cells in human autoimmune diseases could lead to the development of novel B cell targeted therapies. This review highlights the current knowledge on regulatory B cells, mainly IL-10-producing regulatory B cells, in clinical research using human samples. PMID:26725860

  14. Estrogen receptors and human disease: an update

    PubMed Central

    Burns, Katherine A.

    2016-01-01

    A myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERβ. As we reviewed previously, given the widespread role for estrogen in normal human physiology, it is not surprising that estrogen is implicated in the development or progression of a number of diseases. In this review, we are giving a 5-year update of the literature regarding the influence of estrogens on a number of human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. A large number of sophisticated experimental studies have provided insights into human disease, but for this review, the literature citations were limited to articles published after our previous review (Deroo and Korach in J Clin Invest 116(3):561–570, 2006) and will focus in most cases on human data and clinical trials. We will describe the influence in which estrogen’s action, through one of or both of the ERs, mediates the aforementioned human disease states. PMID:22648069

  15. Mouse homologues of human hereditary disease.

    PubMed Central

    Searle, A G; Edwards, J H; Hall, J G

    1994-01-01

    Details are given of 214 loci known to be associated with human hereditary disease, which have been mapped on both human and mouse chromosomes. Forty two of these have pathological variants in both species; in general the mouse variants are similar in their effects to the corresponding human ones, but exceptions include the Dmd/DMD and Hprt/HPRT mutations which cause little, if any, harm in mice. Possible reasons for phenotypic differences are discussed. In most pathological variants the gene product seems to be absent or greatly reduced in both species. The extensive data on conserved segments between human and mouse chromosomes are used to predict locations in the mouse of over 50 loci of medical interest which are mapped so far only on human chromosomes. In about 80% of these a fairly confident prediction can be made. Some likely homologies between mapped mouse loci and unmapped human ones are also given. Sixty six human and mouse proto-oncogene and growth factor gene homologies are also listed; those of confirmed location are all in known conserved segments. A survey of 18 mapped human disease loci and chromosome regions in which the manifestation or severity of pathological effects is thought to be the result of genomic imprinting shows that most of the homologous regions in the mouse are also associated with imprinting, especially those with homologues on human chromosomes 11p and 15q. Useful methods of accelerating the production of mouse models of human hereditary disease include (1) use of a supermutagen, such as ethylnitrosourea (ENU), (2) targeted mutagenesis involving ES cells, and (3) use of gene transfer techniques, with production of 'knockout mutations'. PMID:8151633

  16. Wombats acquired scabies from humans and/or dogs from outside Australia.

    PubMed

    Andriantsoanirina, V; Ariey, F; Izri, A; Bernigaud, C; Fang, F; Guillot, J; Chosidow, O; Durand, R

    2015-06-01

    According to previous studies, Sarcoptes mites of wombats were relatively recently introduced into Australia by colonizers and/or their dogs. However, that affirmation has been called into question due to apparent flaws in the design of the phylogenetic studies. With the aim of providing a definitive answer to this question, a part of the mitochondrial gene coding for 12S rRNA of S. scabiei mites from 23 humans and one dog collected in France was sequenced and a phylogenetic analysis including the sequences previously deposited in Genbank was performed. Phylogenetic analysis did not show host segregation or geographical isolation of the mites. Conversely, the present work suggested that mange in wombats is indeed due to the introduction of S. scabiei into Australia by immigrating individuals and/or their companion animals. PMID:25813454

  17. Septic arthritis in patients with acquired immunodeficiency syndrome with human immunodeficiency virus infection.

    PubMed

    Rivera, J; Monteagudo, I; Lopez-Longo, J; Sanchez-Atrio, A

    1992-12-01

    We have evaluated the presence and characteristics of septic arthritis in intravenous (iv) drug users with human immunodeficiency virus (HIV) infection. Sixteen patients with both HIV infection and septic arthritis were studied and compared with 5 patients with septic arthritis but no HIV infection. Clinical profile, laboratory findings at the time of onset, localization, causative organisms, mean hospitalization time and presence of complications were the same in HIV positive and HIV negative patients. Staphylococcus aureus was the most commonly isolated organism in both groups. We conclude that septic arthritis in HIV infected iv drug users is not uncommon, it is produced by the same organisms and presents similar characteristics to the ones found in iv drug users without HIV infection. Therefore, the presence of HIV infection does not appear to modify the characteristics of septic arthritis.

  18. Wombats acquired scabies from humans and/or dogs from outside Australia.

    PubMed

    Andriantsoanirina, V; Ariey, F; Izri, A; Bernigaud, C; Fang, F; Guillot, J; Chosidow, O; Durand, R

    2015-06-01

    According to previous studies, Sarcoptes mites of wombats were relatively recently introduced into Australia by colonizers and/or their dogs. However, that affirmation has been called into question due to apparent flaws in the design of the phylogenetic studies. With the aim of providing a definitive answer to this question, a part of the mitochondrial gene coding for 12S rRNA of S. scabiei mites from 23 humans and one dog collected in France was sequenced and a phylogenetic analysis including the sequences previously deposited in Genbank was performed. Phylogenetic analysis did not show host segregation or geographical isolation of the mites. Conversely, the present work suggested that mange in wombats is indeed due to the introduction of S. scabiei into Australia by immigrating individuals and/or their companion animals.

  19. Self-renewal and pluripotency acquired through somatic reprogramming to human cancer stem cells.

    PubMed

    Nagata, Shogo; Hirano, Kunio; Kanemori, Michele; Sun, Liang-Tso; Tada, Takashi

    2012-01-01

    Human induced pluripotent stem cells (iPSCs) are reprogrammed by transient expression of transcription factors in somatic cells. Approximately 1% of somatic cells can be reprogrammed into iPSCs, while the remaining somatic cells are differentially reprogrammed. Here, we established induced pluripotent cancer stem-like cells (iCSCs) as self-renewing pluripotent cell clones. Stable iCSC lines were established from unstable induced epithelial stem cell (iESC) lines through re-plating followed by embryoid body formation and serial transplantation. iCSCs shared the expression of pluripotent marker genes with iPSCs, except for REX1 and LIN28, while exhibited the expression of somatic marker genes EMP1 and PPARγ. iESCs and iCSCs could generate teratomas with high efficiency by implantation into immunodeficient mice. The second iCSCs isolated from dissociated cells of teratoma from the first iCSCs were stably maintained, showing a gene expression profile similar to the first iCSCs. In the first and second iCSCs, transgene-derived Oct4, Sox2, Klf4, and c-Myc were expressed. Comparative global gene expression analyses demonstrated that the first iCSCs were similar to iESCs, and clearly different from human iPSCs and somatic cells. In iCSCs, gene expression kinetics of the core pluripotency factor and the Myc-related factor were pluripotent type, whereas the polycomb complex factor was somatic type. These findings indicate that pluripotent tumorigenicity can be conferred on somatic cells through up-regulation of the core pluripotency and Myc-related factors, prior to establishment of the iPSC molecular network by full reprogramming through down-regulation of the polycomb complex factor.

  20. Properties of Adenyl Cyclase from Human Jejunal Mucosa during Naturally Acquired Cholera and Convalescence

    PubMed Central

    Chen, Lincoln C.; Rohde, Jon E.; Sharp, Geoffrey W. G.

    1972-01-01

    The enterotoxin of Vibrio cholerae causes copious fluid production throughout the lenght of the small intestine. As this is thought to be mediated by stimulation of adenyl cyclase, a study has been made of the activity and properties of this enzyme in jejunal biopsy tissue taken from patients during the diarrheal phase of cholera and after recovery. Adenyl cyclase activity during cholera was increased more than twofold relative to the enzyme in convalescence. Under both conditions stimulation by prostaglandin E1 (PGE1) and by fluoride was observed. The responsiveness to PGE1 was not altered in cholera; the total activity of the fluoride-stimulated enzyme was similar, a finding that suggests cholera toxin stimulates pre-existing enzyme in the intestinal cell. The enzymes during cholera and convalescence were similar in all other properties examined. Optimal Mg++ concentration was 10 mM; Mn++ at 5 mM stimulated the enzyme but could not replace Mg++ except in the presence of 10 mM fluoride. Calcium was markedly inhibitory at concentrations greater than 10-4 M. The pH optimum was 7.5 and the Michaelis constant (Km) for ATP concentration approximated 10-4 M. Thus the interaction of cholera toxin with human intestinal adenyl cyclase does not alter the basic properties of the enzyme. When biopsy specimens were maintained intact in oxygenated Ringer's solution at 0°C, no loss of activity was observed at 1½ and 3 hr. In contrast, when the cells were homogenized, rapid loss of activity, with a half-life of 90 min was seen even at 0°C. Consequently for comparative assays of human jejunal adenyl cyclase, strict control of the experimental conditions is required. It was under such conditions that a twofold increase in basal adenyl cyclase activity during cholera was observed. Images PMID:4335441

  1. A Comparison of Human Neutrophils Acquired from Four Experimental Models of Inflammation

    PubMed Central

    Motwani, Madhur P.; Day, Richard M.; Gilroy, Derek W.; O’Brien, Alastair J.

    2016-01-01

    Defects in neutrophil function have been implicated in a wide spectrum of clinical conditions. Several models are employed to study activated human neutrophils akin to those found at a site of inflammation. These include whole blood (WB) ex vivo stimulation with lipopolysaccharide (LPS) and in vivo techniques: cantharidin blister, skin windows and intra-dermal injection of UV-killed E.coli (UVKEc). Neutrophils obtained from these have never been compared. We compared the activation status of neutrophils from each technique in order to inform the optimal model for use in human studies. Healthy male volunteers were randomised to undergo one of the four techniques (n = 5/group). LPS: WB stimulated with 1ng/ml of LPS for 4 hours. Cantharidin: 12.5μl of 0.1% cantharidin elicited a single blister, aspirated at 24 hours. Skin windows: four 6mm mechanical-suction blisters created, de-roofed and an exudate-collection chamber placed over the windows for 4 hours before aspiration. UVKEc: 1.5 x 107 UVKEc injected intra-dermally. A single 10mm mechanical-suction blister formed and aspirated at 4 hours. Unstimulated WB used as the control. Flow cytometry was used to determine activation status using CD16, CD11b, CD54, CD62L and CD88. Functional status was assessed with a phagocytosis assay. The pattern of neutrophil activation was similar in all models. Neutrophil CD11b was elevated in all models, most markedly in UVKEc (p<0.0001), and CD54 was also elevated but only significant in the LPS model (p = 0.001). CD62L was significantly reduced in all 4 models (p<0.0001) and CD88 was also suppressed in all. There were no changes in CD16 in any model, neither was there any significant difference in the phagocytic capacity of the neutrophils. In summary, there are no significant differences in activation marker expression or phagocytic capacity in the neutrophils obtained from each technique. Therefore we believe whole blood stimulation is the best model in experimentally challenging

  2. Hospital-acquired Clostridium difficile-associated disease in the intensive care unit setting: epidemiology, clinical course and outcome

    PubMed Central

    Marra, Alexandre R; Edmond, Michael B; Wenzel, Richard P; Bearman, Gonzalo ML

    2007-01-01

    Background Clostridium difficile-associated disease (CDAD) is a serious nosocomial infection, however few studies have assessed CDAD outcome in the intensive care unit (ICU). We evaluated the epidemiology, clinical course and outcome of hospital-acquired CDAD in the critical care setting. Methods We performed a historical cohort study on 58 adults with a positive C. difficile cytotoxin assay result occurring in intensive care units. Results Sixty-two percent of patients had concurrent infections, 50% of which were bloodstream infections. The most frequently prescribed antimicrobials prior to CDAD were anti-anaerobic agents (60.3%). Septic shock occurred in 32.8% of CDAD patients. The in-hospital mortality was 27.6%. Univariate analysis revealed that SOFA score, at least one organ failure and age were predictors of mortality. Charlson score ≥3, gender, concurrent infection, and number of days with diarrhea before a positive C. difficile toxin assay were not significant predictors of mortality on univariate analysis. Independent predictors for death were SOFA score at infection onset (per 1-point increment, OR 1.40; CI95 1.13–1.75) and age (per 1-year increment, OR 1.10; CI95 1.02–1.19). Conclusion In ICU patients with CDAD, advanced age and increased severity of illness at the onset of infection, as measured by the SOFA score, are independent predictors of death. PMID:17517130

  3. Epidemiology of invasive fungal infections in patients with acquired immunodeficiency syndrome at a reference hospital for infectious diseases in Brazil.

    PubMed

    de Oliveira, Renata Buccheri; Atobe, Jane Harumi; Souza, Simone Aparecida; de Castro Lima Santos, Daniel Wagner

    2014-08-01

    Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20-25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres.

  4. Comparative Genomics Suggests That the Human Pathogenic Fungus Pneumocystis jirovecii Acquired Obligate Biotrophy through Gene Loss

    PubMed Central

    Cissé, Ousmane H.; Pagni, Marco; Hauser, Philippe M.

    2014-01-01

    Pneumocystis jirovecii is a fungal parasite that colonizes specifically humans and turns into an opportunistic pathogen in immunodeficient individuals. The fungus is able to reproduce extracellularly in host lungs without eliciting massive cellular death. The molecular mechanisms that govern this process are poorly understood, in part because of the lack of an in vitro culture system for Pneumocystis spp. In this study, we explored the origin and evolution of the putative biotrophy of P. jirovecii through comparative genomics and reconstruction of ancestral gene repertoires. We used the maximum parsimony method and genomes of related fungi of the Taphrinomycotina subphylum. Our results suggest that the last common ancestor of Pneumocystis spp. lost 2,324 genes in relation to the acquisition of obligate biotrophy. These losses may result from neutral drift and affect the biosyntheses of amino acids and thiamine, the assimilation of inorganic nitrogen and sulfur, and the catabolism of purines. In addition, P. jirovecii shows a reduced panel of lytic proteases and has lost the RNA interference machinery, which might contribute to its genome plasticity. Together with other characteristics, that is, a sex life cycle within the host, the absence of massive destruction of host cells, difficult culturing, and the lack of virulence factors, these gene losses constitute a unique combination of characteristics which are hallmarks of both obligate biotrophs and animal parasites. These findings suggest that Pneumocystis spp. should be considered as the first described obligate biotrophs of animals, whose evolution has been marked by gene losses. PMID:25062922

  5. Telomerase activity and telomere length in human tumor cells with acquired resistance to anticancer agents.

    PubMed

    Smith, V; Dai, F; Spitz, M; Peters, G J; Fiebig, H H; Hussain, A; Burger, A M

    2009-11-01

    Telomeres and telomerase are targets for anticancer drug development and specific inhibitors are currently under clinical investigation. However, it has been reported that standard cytotoxic agents can affect telomere length and telomerase activity suggesting that they also have of a role in drug resistance. in this study, telomere lengths and telomerase activity as well as drug efflux pump expression, glutathione (GSH) levels and polyadenosine-ribose polymerase (PARP) cleavage were assessed in a panel of human tumor cell lines made resistant to vindesine, gemcitabine and cisplatin. these included two lung cancer cell lines resistant to vindesine (LXFL 529L/Vind, LXFA 526L/Vind), a renal cancer cell line (RXF944L/Gem) and an ovarian cancer cell line (AG6000) resistant to gemcitabine, and one resistant to cisplatin (ADDP). The resistant clones were compared to their parental lines and evaluated for cross resistance to other cytotoxic agents. Several drug specific resistance patterns were found, and various complex patterns of cross resistance emerged from some cell lines, but these mechanisms of resistance could not be related to drug efflux pump expression, GSH levels or pARp cleavage. However, all displayed changes in telomerase activity and/or telomere length. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics.

  6. Arabidopsis ENHANCED DISEASE SUSCEPTIBILITY1 promotes systemic acquired resistance via azelaic acid and its precursor 9-oxo nonanoic acid.

    PubMed

    Wittek, Finni; Hoffmann, Thomas; Kanawati, Basem; Bichlmeier, Marlies; Knappe, Claudia; Wenig, Marion; Schmitt-Kopplin, Philippe; Parker, Jane E; Schwab, Wilfried; Vlot, A Corina

    2014-11-01

    Systemic acquired resistance (SAR) is a form of inducible disease resistance that depends on salicylic acid and its upstream regulator ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1). Although local Arabidopsis thaliana defence responses activated by the Pseudomonas syringae effector protein AvrRpm1 are intact in eds1 mutant plants, SAR signal generation is abolished. Here, the SAR-specific phenotype of the eds1 mutant is utilized to identify metabolites that contribute to SAR. To this end, SAR bioassay-assisted fractionation of extracts from the wild type compared with eds1 mutant plants that conditionally express AvrRpm1 was performed. Using high-performance liquid chromatography followed by mass spectrometry, systemic immunity was associated with the accumulation of 60 metabolites, including the putative SAR signal azelaic acid (AzA) and its precursors 9-hydroperoxy octadecadienoic acid (9-HPOD) and 9-oxo nonanoic acid (ONA). Exogenous ONA induced SAR in systemic untreated leaves when applied at a 4-fold lower concentration than AzA. The data suggest that in planta oxidation of ONA to AzA might be partially responsible for this response and provide further evidence that AzA mobilizes Arabidopsis immunity in a concentration-dependent manner. The AzA fragmentation product pimelic acid did not induce SAR. The results link the C9 lipid peroxidation products ONA and AzA with systemic rather than local resistance and suggest that EDS1 directly or indirectly promotes the accumulation of ONA, AzA, or one or more of their common precursors possibly by activating one or more pathways that either result in the release of these compounds from galactolipids or promote lipid peroxidation.

  7. Relationship between the Use of Inhaled Steroids for Chronic Respiratory Diseases and Early Outcomes in Community-Acquired Pneumonia

    PubMed Central

    Almirall, Jordi; Bolíbar, Ignasi; Serra-Prat, Mateu; Palomera, Elisabet; Roig, Jordi; Hospital, Imma; Carandell, Eugenia; Agustí, Mercè; Ayuso, Pilar; Estela, Andreu; Torres, Antoni

    2013-01-01

    Background The role of inhaled steroids in patients with chronic respiratory diseases is a matter of debate due to the potential effect on the development and prognosis of community-acquired pneumonia (CAP). We assessed whether treatment with inhaled steroids in patients with chronic bronchitis, COPD or asthma and CAP may affect early outcome of the acute pneumonic episode. Methods Over 1-year period, all population-based cases of CAP in patients with chronic bronchitis, COPD or asthma were registered. Use of inhaled steroids were registered and patients were followed up to 30 days after diagnosis to assess severity of CAP and clinical course (hospital admission, ICU admission and mortality). Results Of 473 patients who fulfilled the selection criteria, inhaled steroids were regularly used by 109 (23%). In the overall sample, inhaled steroids were associated with a higher risk of hospitalization (OR=1.96, p = 0.002) in the bivariate analysis, but this effect disappeared after adjusting by other severity-related factors (adjusted OR=1.08, p=0.787). This effect on hospitalization also disappeared when considering only patients with asthma (OR=1.38, p=0.542), with COPD alone (OR=4.68, p=0.194), but a protective effect was observed in CB patients (OR=0.15, p=0.027). Inhaled steroids showed no association with ICU admission, days to clinical recovery and mortality in the overall sample and in any disease subgroup. Conclusions Treatment with inhaled steroids is not a prognostic factor in COPD and asthmatic patients with CAP, but could prevent hospitalization for CAP in patients with clinical criteria of chronic bronchitis. PMID:24039899

  8. The First World War years of Sydney Domville Rowland: an early case of possible laboratory-acquired meningococcal disease.

    PubMed

    Wever, Peter C; Hodges, A J

    2016-08-01

    Sydney Domville Rowland was a bacteriologist and staff member at the Lister Institute of Preventive Medicine when the First World War broke out in 1914. Following a request to the Director of the Lister Institute to staff and equip a mobile field laboratory as quickly as possible, Rowland was appointed to take charge of No. 1 Mobile Laboratory and took up a temporary commission at the rank of Lieutenant in the Royal Army Medical Corps. On 9 October 1914, Rowland set out for the European mainland and was subsequently attached to General Headquarters in Saint-Omer, France (October 1914-June 1915), No. 10 Casualty Clearing Station in Lijssenthoek, Belgium (June 1915-February 1916, during which period he was promoted Major), and No. 26 General Hospital in Étaples, France (February 1916-March 1917). His research focused on gas gangrene, typhoid fever, trench fever, wound infection and cerebrospinal fever. In February of 1917, while engaged in identifying meningococcal carriers, Rowland contracted cerebrospinal meningitis to which he succumbed at age 44 on 6 March 1917. His untimely death might have been caused by laboratory-acquired meningococcal disease, especially since Rowland's work with Neisseria meningitidis isolates had extended beyond routine laboratory techniques and included risk procedures like immunisation of rabbits with pathogenic strains isolated from cerebrospinal fluid. Currently, microbiology laboratory workers who are routinely exposed to N. meningitidis isolates are recognised as a population at increased risk for meningococcal disease, for which reason recommended preventive measures include vaccination and handling of isolates within a class II biosafety cabinet. PMID:27084843

  9. The First World War years of Sydney Domville Rowland: an early case of possible laboratory-acquired meningococcal disease.

    PubMed

    Wever, Peter C; Hodges, A J

    2016-08-01

    Sydney Domville Rowland was a bacteriologist and staff member at the Lister Institute of Preventive Medicine when the First World War broke out in 1914. Following a request to the Director of the Lister Institute to staff and equip a mobile field laboratory as quickly as possible, Rowland was appointed to take charge of No. 1 Mobile Laboratory and took up a temporary commission at the rank of Lieutenant in the Royal Army Medical Corps. On 9 October 1914, Rowland set out for the European mainland and was subsequently attached to General Headquarters in Saint-Omer, France (October 1914-June 1915), No. 10 Casualty Clearing Station in Lijssenthoek, Belgium (June 1915-February 1916, during which period he was promoted Major), and No. 26 General Hospital in Étaples, France (February 1916-March 1917). His research focused on gas gangrene, typhoid fever, trench fever, wound infection and cerebrospinal fever. In February of 1917, while engaged in identifying meningococcal carriers, Rowland contracted cerebrospinal meningitis to which he succumbed at age 44 on 6 March 1917. His untimely death might have been caused by laboratory-acquired meningococcal disease, especially since Rowland's work with Neisseria meningitidis isolates had extended beyond routine laboratory techniques and included risk procedures like immunisation of rabbits with pathogenic strains isolated from cerebrospinal fluid. Currently, microbiology laboratory workers who are routinely exposed to N. meningitidis isolates are recognised as a population at increased risk for meningococcal disease, for which reason recommended preventive measures include vaccination and handling of isolates within a class II biosafety cabinet.

  10. Immune-competent human skin disease models.

    PubMed

    Bergers, Lambert I J C; Reijnders, Christianne M A; van den Broek, Lenie J; Spiekstra, Sander W; de Gruijl, Tanja D; Weijers, Ester M; Gibbs, Susan

    2016-09-01

    All skin diseases have an underlying immune component. Owing to differences in animal and human immunology, the majority of drugs fail in the preclinical or clinical testing phases. Therefore animal alternative methods that incorporate human immunology into in vitro skin disease models are required to move the field forward. This review summarizes the progress, using examples from fibrosis, autoimmune diseases, psoriasis, cancer and contact allergy. The emphasis is on co-cultures and 3D organotypic models. Our conclusion is that current models are inadequate and future developments with immune-competent skin-on-chip models based on induced pluripotent stem cells could provide a next generation of skin models for drug discovery and testing.

  11. Commentary: is Alzheimer's disease uniquely human?

    PubMed Central

    Finch, Caleb E.; Austad, Steven N.

    2015-01-01

    That Alzheimer's disease (AD) might be a human-specific disease was hypothesized by Rapoport in 1989. Apes and humans share an identical amyloid beta (Aβ) peptide amino acid sequence and accumulate considerable Aβ deposits after age 40 years, an age when amyloid plaques are uncommon in humans. Despite their early Aβ buildup, ape brains have not shown evidence dystrophic neurites near plaques. Aging great ape brains also have few neurofibrillary tangles, with one exception of 1 obese chimpanzee euthanized after a stroke who displayed abundant neurofibrillary tangles, but without the typical AD distribution. We discuss the need for more exacting evaluation of neuron density with age, and note husbandry issues that may allow great apes to live to greater ages. We remain reserved about expectations for fully developed AD-like pathology in the great apes of advanced ages and cautiously support Rapoport's hypothesis. PMID:25533426

  12. Long-Term Outcome After Ablation of Right Atrial Tachyarrhythmias After the Surgical Repair of Congenital and Acquired Heart Disease.

    PubMed

    Anguera, Ignasi; Dallaglio, Paolo; Macías, Rosa; Jiménez-Candil, Javier; Peinado, Rafael; García-Seara, Javier; Arcocha, Mari Fe; Herreros, Benito; Quesada, Aurelio; Hernández-Madrid, Antonio; Alvarez, Miguel; Filgueiras, David; Matía, Roberto; Cequier, Angel; Sabaté, Xavier

    2015-06-15

    Atrial myopathy, atriotomies, and fibrotic scars are the pathophysiological substrate of lines of conduction block, promoting atrial macroreentry. The aim of this study was to determine the acute and long-term outcome of radiofrequency catheter ablation (RFCA) for right atrial tachyarrhythmia (AT) in adults after cardiac surgery for congenital heart disease (CHD) and acquired heart disease (AHD) and predictors of these outcomes. Clinical records of adults after surgery for heart disease undergoing RFCA of right-sided AT were analyzed retrospectively. Multivariate analyses identified clinical and procedural factors predicting acute and long-term outcomes. A total of 372 patients (69% men; age 61 ± 15 years) after surgical repair of CHD (n = 111) or AHD (n = 261) were studied. Cavotricuspid isthmus-dependent atrial flutter (CTI-AFL) was observed in 300 patients and non-CTI-AFL in 72 patients. Ablation was successful in 349 cases (94%). During a mean follow-up of 51 ± 30 months, recurrences were observed in 24.5% of patients. Multivariate analysis showed that non-CTI-AFL (hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.1 to 2.9) and CHD (HR 1.75, 95% CI 1.07 to 2.9) were independent predictors of long-term recurrences. Multivariate analysis showed that female gender (HR 2.29, 95% CI 1.6 to 3.3), surgery for AHD (HR 95% 2.31, 95% CI 1.5 to 3.7), and left atrial dilatation (HR 2.1, 95% CI 1.3 to 3.2) were independent predictors of long-term atrial fibrillation. In conclusion, RFCA of right-sided AT after cardiac surgery is associated with high acute success rates and significant long-term recurrences. Non-CTI-dependent AFL and surgery for CHD are at higher risk of recurrence. Atrial fibrillation is common during follow-up, particularly in patients with AHD and enlarged left atrium. PMID:25896151

  13. 'Laminopathies': A wide spectrum of human diseases

    SciTech Connect

    Worman, Howard J. . E-mail: hjw14@columbia.edu; Bonne, Gisele

    2007-06-10

    Mutations in genes encoding the intermediate filament nuclear lamins and associated proteins cause a wide spectrum of diseases sometimes called 'laminopathies.' Diseases caused by mutations in LMNA encoding A-type lamins include autosomal dominant Emery-Dreifuss muscular dystrophy and related myopathies, Dunnigan-type familial partial lipodystrophy, Charcot-Marie-Tooth disease type 2B1 and developmental and accelerated aging disorders. Duplication in LMNB1 encoding lamin B1 causes autosomal dominant leukodystrophy and mutations in LMNB2 encoding lamin B2 are associated with acquired partial lipodystrophy. Disorders caused by mutations in genes encoding lamin-associated integral inner nuclear membrane proteins include X-linked Emery-Dreifuss muscular dystrophy, sclerosing bone dysplasias, HEM/Greenberg skeletal dysplasia and Pelger-Huet anomaly. While mutations and clinical phenotypes of 'laminopathies' have been carefully described, data explaining pathogenic mechanisms are only emerging. Future investigations will likely identify new 'laminopathies' and a combination of basic and clinical research will lead to a better understanding of pathophysiology and the development of therapies.

  14. Safety and Efficacy of Antimicrobial Peptides against Naturally Acquired Leishmaniasis

    PubMed Central

    Alberola, J.; Rodríguez, A.; Francino, O.; Roura, X.; Rivas, L.; Andreu, D.

    2004-01-01

    Leishmaniases, which are important causes of morbidity and mortality in humans and dogs, are extremely difficult to treat. Antimicrobial peptides are rarely used as alternative treatments for naturally acquired parasitic diseases. Here we report that the acylated synthetic antimicrobial peptide Oct-CA(1-7)M(2-9) is safe and effective for treating naturally acquired canine leishmaniasis. PMID:14742227

  15. Drug repurposing and human parasitic protozoan diseases

    PubMed Central

    Andrews, Katherine T.; Fisher, Gillian; Skinner-Adams, Tina S.

    2014-01-01

    Parasitic diseases have an enormous health, social and economic impact and are a particular problem in tropical regions of the world. Diseases caused by protozoa and helminths, such as malaria and schistosomiasis, are the cause of most parasite related morbidity and mortality, with an estimated 1.1 million combined deaths annually. The global burden of these diseases is exacerbated by the lack of licensed vaccines, making safe and effective drugs vital to their prevention and treatment. Unfortunately, where drugs are available, their usefulness is being increasingly threatened by parasite drug resistance. The need for new drugs drives antiparasitic drug discovery research globally and requires a range of innovative strategies to ensure a sustainable pipeline of lead compounds. In this review we discuss one of these approaches, drug repurposing or repositioning, with a focus on major human parasitic protozoan diseases such as malaria, trypanosomiasis, toxoplasmosis, cryptosporidiosis and leishmaniasis. PMID:25057459

  16. Acquired color vision deficiency.

    PubMed

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.

  17. Cholestasis: human disease and experimental animal models.

    PubMed

    Rodríguez-Garay, Emilio Alberto

    2003-01-01

    Cholestasis may result from a failure in bile secretion in hepatocytes or ductular cells, or from a blockade to the free bile flow. Human cholestasis may be induced by many drugs, being antibiotics the more common. Other types of cholestasis seen in humans are a group of familial cholestatic disorders, obstructive cholestasis, primary biliary cirrhosis, extrahepatic biliary atresia, primary sclerosing cholangitis, cholestasis of pregnancy, oral contraceptive-induced cholestasis, and sepsis-induced cholestasis. Experimental animal models allow the understanding of pathophysiological mechanisms involved and their clinical correlates. The most common experimental models of intrahepatic cholestasis are estrogen-induced, endotoxin-induced and drug-induced cholestasis. A well known model of extrahepatic biliary obstruction is common bile duct ligation. Drug-induced cholestasis were described using different drugs. On this regard, alpha naphthylisothiocyanate treatment has been extensively used, permitting to describe not only cholestatic alterations but also compensatory mechanisms. Congenital defficiency of transport proteins also were studied in natural rat models of cholestasis. The experimental animal models allow to define down-regulated alterations of hepatocyte transport proteins, and up-regulated ones acting as compensatory mechanisms. In conclusion, animal model and transport protein studies are necessary for the progressive understanding of congenital and acquired human cholestasis, and regulatory mechanisms that operate on liver cells.

  18. Human endogenous retroviruses in neurologic disease.

    PubMed

    Christensen, Tove

    2016-01-01

    Endogenous retroviruses are pathogenic - in other species than the human. Disease associations for Human Endogenous RetroViruses (HERVs) are emerging, but so far an unequivocal pathogenetic cause-effect relationship has not been established. A role for HERVs has been proposed in neurological and neuropsychiatric diseases as diverse as multiple sclerosis (MS) and schizophrenia (SCZ). Particularly for MS, many aspects of the activation and involvement of specific HERV families (HERV-H/F and HERV-W/MSRV) have been reported, both for cells in the circulation and in the central nervous system. Notably envelope genes and their gene products (Envs) appear strongly associated with the disease. For SCZ, for ALS, and for HIV-associated dementia (HAD), indications are accumulating for involvement of the HERV-K family, and also HERV-H/F and/or HERV-W. Activation is reasonably a prerequisite for causality as most HERV sequences remain quiescent in non-pathological conditions, so the importance of regulatory pathways and epigenetics involved in regulating HERV activation, derepression, and also involvement of retroviral restriction factors, is emerging. HERV-directed antiretrovirals have potential as novel therapeutic paradigms in neurologic disease, particularly in MS. The possible protective or ameliorative effects of antiretroviral therapy in MS are substantiated by reports that treatment of HIV infection may be associated with a significantly decreased risk of MS. Further studies of HERVs, their role in neurologic diseases, and their potential as therapeutic targets are essential. PMID:26818266

  19. Unsolved issues related to human mitochondrial diseases.

    PubMed

    Lombès, Anne; Auré, Karine; Bellanné-Chantelot, Christine; Gilleron, Mylène; Jardel, Claude

    2014-05-01

    Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed. Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.

  20. Successful treatment of bowenoid papulosis in a 9-year-old girl with vertically acquired human immunodeficiency virus.

    PubMed

    Godfrey, James C; Vaughan, Mary C; Williams, Judith V

    2003-07-01

    A 9-year-old black girl with vertically acquired human immunodeficiency virus (HIV) and no history of condyloma acuminata presented with a 4-year history of enlarging and spreading dark brown flat papules in the perineum. Some of the lesions were confluent and extended from the clitoris to the labia majora and posteriorly to the buttocks and perianal region. A biopsy of one of the lesions showed bowenoid features. Our patient had a normal Pap smear, but vaginal and cervical biopsy specimens revealed human papillomavirus type 16. Therapy with topical imiquimod cream every other day was started, but little improvement was noted after 2 months. Application of 25% podophyllin every 4 to 8 weeks was added, and improvement was noted within 1 month. After 1 year of treatment, the patient had complete resolution of all lesions, and she has had no further appearance of lesions. Our case emphasizes the need for increased awareness of the potential for development of bowenoid papulosis in HIV-positive children as well as the successful treatment of our patient with topical therapy alone.

  1. Epstein-Barr and human immunodeficiency viruses in acquired immunodeficiency syndrome-related primary central nervous system lymphoma.

    PubMed Central

    Morgello, S.

    1992-01-01

    The prevalence of Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV) in acquired immunodeficiency syndrome (AIDS)-related primary central nervous system (CNS) lymphoma was examined. Deoxyribonucleic acid (DNA) extracted from 12 formalin-fixed, paraffin-embedded tumors was used as substrate for the polymerase chain reaction (PCR). Targets for amplification were the EBNA-1 region of EBV, the gag region of HIV, and a single copy cellular sequence as a control. The cases studied were autopsy and surgical specimens collected between the years 1985 and 1989. By the working formulation for non-Hodgkin's lymphomas, five had large cell, four had mixed large and small cleaved cell, two had small cleaved cell, and one had an unclassified histology. Epstein-Barr virus was detected in 6 of 12 tumors studied. Human immunodeficiency virus was not detected in any of the tumors. The presence of EBV was not correlated with any particular histologic tumor type. It is concluded that EBV, not HIV, can be detected in a large percentage (50%) of AIDS-related primary central nervous system (CNS) lymphomas. This viral association may be significant in light of the demonstrated ability of EBV to induce lymphoid tumors in experimental mammalian systems. Images Figure 1 Figure 2 PMID:1323221

  2. Human papilloma virus and cervical preinvasive disease

    PubMed Central

    Bari, M; Iancu, G; Popa, F

    2009-01-01

    Cervical cancer lesions represent a major threat to the health of the women worldwide. Human Papillomavirus (HPV) is responsible for 99.7% of cervical cancer cases, the infectious etiology giving the possibility of preventing cervical cancer by vaccination. The most aggressive HPV types are 16 and 18, which cause about 70% of cases of invasive cancer. The vaccination is recommended to the girls aged 11–12. The diagnosis and the treatment of cervical preinvasive disease allow the doctor to prevent the development of the invasive disease. PMID:20108750

  3. The Mitochondrial Proteome and Human Disease

    PubMed Central

    Calvo, Sarah E.; Mootha, Vamsi K.

    2015-01-01

    For nearly three decades, the sequence of the human mitochondrial genome (mtDNA) has provided a molecular framework for understanding maternally inherited diseases. However, the vast majority of human mitochondrial disorders are caused by nuclear defects, which is not surprising since the mtDNA encodes only 13 proteins. Advances in genomics, mass spectrometry, and computation have only recently made it possible to systematically identify the complement of over 1,000 proteins that comprise the mammalian mitochondrial proteome. Here, we review recent progress in characterizing the mitochondrial proteome and highlight insights into its complexity, tissue heterogeneity, evolutionary origins, and biochemical versatility. We then discuss how this proteome is being used to discover the genetic basis of respiratory chain disorders as well as to expand our definition of mitochondrial disease. Finally, we explore future prospects and challenges for using the mitochondrial proteome as a foundation for systems analysis of the organelle. PMID:20690818

  4. [Human hantavirus diseases - still neglected zoonoses?].

    PubMed

    Vrbovská, V; Chalupa, P; Straková, P; Hubálek, Z; Rudolf, I

    2015-10-01

    Hantavirus disease is the most common rodent-borne viral infection in the Czech Republic, with a mean annual incidence of 0.02 cases per 100 000 population and specific antibodies detected in 1% of the human population. Four hantaviruses (Puumala, Dobrava-Belgrade, Tula, and Seewis) circulate in this country, of which Puumala virus (responsible for a mild form of hemorrhagic fever with renal syndrome called nephropathia epidemica) and Dobrava-Belgrade virus (causing haemorrhagic fever with renal syndrome) have been proven to cause human disease. The aim of this study is to provide a comprehensive review of the hantaviruses occurring in the Czech Republic, based on the literature published during the past three decades, including their geographical distribution and clinical symptoms. The recent detection of Tula virus in an immunocompromised person as well as reports of Seoul virus infections in Europe highlight the possible emergence of neglected hantavirus infections in the foreseeable future. PMID:26795222

  5. [Human hantavirus diseases - still neglected zoonoses?].

    PubMed

    Vrbovská, V; Chalupa, P; Straková, P; Hubálek, Z; Rudolf, I

    2015-10-01

    Hantavirus disease is the most common rodent-borne viral infection in the Czech Republic, with a mean annual incidence of 0.02 cases per 100 000 population and specific antibodies detected in 1% of the human population. Four hantaviruses (Puumala, Dobrava-Belgrade, Tula, and Seewis) circulate in this country, of which Puumala virus (responsible for a mild form of hemorrhagic fever with renal syndrome called nephropathia epidemica) and Dobrava-Belgrade virus (causing haemorrhagic fever with renal syndrome) have been proven to cause human disease. The aim of this study is to provide a comprehensive review of the hantaviruses occurring in the Czech Republic, based on the literature published during the past three decades, including their geographical distribution and clinical symptoms. The recent detection of Tula virus in an immunocompromised person as well as reports of Seoul virus infections in Europe highlight the possible emergence of neglected hantavirus infections in the foreseeable future.

  6. Molecular biology of human muscle disease

    SciTech Connect

    Dunne, P.W.; Epstein, H.F. )

    1991-01-01

    The molecular revolution that is transforming the entire biomedical field has had far-reaching impact in its application to inherited human muscle disease. The gene for Duchenne muscular dystrophy was one of the first cloned without knowledge of the defective protein product. This success was based upon the availability of key chromosomal aberrations that provided molecular landmarks for the disease locus. Subsequent discoveries regarding the mode of expression for this gene, the structure and localization of its protein product dystrophin, and molecular diagnosis of affected and carrier individuals constitute a paradigm for investigation of human genetics. Finding the gene for myotonic muscular dystrophy is requiring the brute force approach of cloning several million bases of DNA, identifying expressed sequences, and characterizing candidate genes. The gene that causes hypertrophic cardiomyopathy has been found serendipitously to be one of the genetic markers on chromosome 14, the {beta} myosin heavy chain.

  7. The nuclear envelopathies and human diseases

    PubMed Central

    2009-01-01

    The nuclear envelope (NE) consists of two membrane layers that segregate the nuclear from the cytoplasmic contents. Recent progress in our understanding of nuclear-lamina associated diseases has revealed intriguing connections between the envelope components and nuclear processes. Here, we review the functions of the nuclear envelope in chromosome organization, gene expression, DNA repair and cell cycle progression, and correlate deficiencies in envelope function with human pathologies. PMID:19849840

  8. A Genomic Approach to Human Autoimmune Diseases

    PubMed Central

    Pascual, Virginia; Chaussabel, Damien; Banchereau, Jacques

    2010-01-01

    The past decade has seen an explosion in the use of DNA-based microarrays. These techniques permit to assess RNA abundance on a genome-wide scale. Medical applications emerged in the field of cancer, with studies of both solid tumors and hematological malignancies leading to the development of tests that are now used to personalize therapeutic options. Microarrays have also been used to analyze the blood transcriptome in a wide range of diseases. In human autoimmune diseases, these studies are showing potential for identifying therapeutic targets as well as biomarkers for diagnosis, assessment of disease activity and response to treatment. More quantitative and sensitive high throughput RNA profiling methods are starting to be available and will be necessary for transcriptome analyses to become routine tests in the clinical setting. We expect this to crystallize within the coming decade, as they become part of the personalized medicine armamentarium. PMID:20192809

  9. Leukocyte chemoattractant receptors in human disease pathogenesis.

    PubMed

    Zabel, Brian A; Rott, Alena; Butcher, Eugene C

    2015-01-01

    Combinations of leukocyte attractant ligands and cognate heptahelical receptors specify the systemic recruitment of circulating cells by triggering integrin-dependent adhesion to endothelial cells, supporting extravasation, and directing specific intratissue localization via gradient-driven chemotaxis. Chemoattractant receptors also control leukocyte egress from lymphoid organs and peripheral tissues. In this article, we summarize the fundamental mechanics of leukocyte trafficking, from the evolution of multistep models of leukocyte recruitment and navigation to the regulation of chemoattractant availability and function by atypical heptahelical receptors. To provide a more complete picture of the migratory circuits involved in leukocyte trafficking, we integrate a number of nonchemokine chemoattractant receptors into our discussion. Leukocyte chemoattractant receptors play key roles in the pathogenesis of autoimmune diseases, allergy, inflammatory disorders, and cancer. We review recent advances in our understanding of chemoattractant receptors in disease pathogenesis, with a focus on genome-wide association studies in humans and the translational implications of mechanistic studies in animal disease models.

  10. The Genetics of Human Skin Disease

    PubMed Central

    DeStefano, Gina M.; Christiano, Angela M.

    2014-01-01

    The skin is composed of a variety of cell types expressing specific molecules and possessing different properties that facilitate the complex interactions and intercellular communication essential for maintaining the structural integrity of the skin. Importantly, a single mutation in one of these molecules can disrupt the entire organization and function of these essential networks, leading to cell separation, blistering, and other striking phenotypes observed in inherited skin diseases. Over the past several decades, the genetic basis of many monogenic skin diseases has been elucidated using classical genetic techniques. Importantly, the findings from these studies has shed light onto the many classes of molecules and essential genetic as well as molecular interactions that lend the skin its rigid, yet flexible properties. With the advent of the human genome project, next-generation sequencing techniques, as well as several other recently developed methods, tremendous progress has been made in dissecting the genetic architecture of complex, non-Mendelian skin diseases. PMID:25274756

  11. Animal model of human disease: lymphocytic gastritis.

    PubMed

    Rubio, C A; Jarlnäs, M; Johnson, L

    1993-01-01

    Gastric specimens from 102 belonging to 11 different species were reviewed. Of the 11 species, only the gastric mucosa of pigs contained a large number of lymphocytes in the surface and in the foveolar epithelium (mean 82 lymphocytes/1000 epithelial cells, range 62-128 lymphocytes. The gastric specimens of the remaining 10 species revealed none or occasional lymphocytes in the surface or the foveolar epithelium. The occurrence of intraepithelial lymphocytes in the gastric mucosa of pigs mimics the human disease known as "lymphocytic gastritis". Since the etiology of this disease remains unknown, the apparently endemic nature of lymphocytic gastritis in pigs offer an alternative to investigate the possible cause(s), as well as the mechanism of, this disease.

  12. Mitochondria: impaired mitochondrial translation in human disease.

    PubMed

    Boczonadi, Veronika; Horvath, Rita

    2014-03-01

    Defects of the mitochondrial protein synthesis cause a subgroup of mitochondrial diseases, which are usually associated with decreased activities of multiple respiratory chain (RC) enzymes. The clinical presentations of these disorders are often disabling, progressive or fatal, affecting the brain, liver, skeletal muscle, heart and other organs. Currently there are no effective cures for these disorders and treatment is at best symptomatic. The diagnosis in patients with multiple respiratory chain complex defects is particularly difficult because of the massive number of nuclear genes potentially involved in intra-mitochondrial protein synthesis. Many of these genes are not yet linked to human disease. Whole exome sequencing rapidly changed the diagnosis of these patients by identifying the primary defect in DNA, and preventing the need for invasive and complex biochemical testing. Better understanding of the mitochondrial protein synthesis apparatus will help us to explore disease mechanisms and will provide clues for developing novel therapies.

  13. The genetics of human skin disease.

    PubMed

    DeStefano, Gina M; Christiano, Angela M

    2014-10-01

    The skin is composed of a variety of cell types expressing specific molecules and possessing different properties that facilitate the complex interactions and intercellular communication essential for maintaining the structural integrity of the skin. Importantly, a single mutation in one of these molecules can disrupt the entire organization and function of these essential networks, leading to cell separation, blistering, and other striking phenotypes observed in inherited skin diseases. Over the past several decades, the genetic basis of many monogenic skin diseases has been elucidated using classical genetic techniques. Importantly, the findings from these studies has shed light onto the many classes of molecules and essential genetic as well as molecular interactions that lend the skin its rigid, yet flexible properties. With the advent of the human genome project, next-generation sequencing techniques, as well as several other recently developed methods, tremendous progress has been made in dissecting the genetic architecture of complex, non-Mendelian skin diseases. PMID:25274756

  14. Gene therapy for human genetic disease?

    PubMed

    Friedmann, T; Roblin, R

    1972-03-01

    In our view, gene therapy may ameliorate some human genetic diseases in the future. For this reason, we believe that research directed at the development of techniques for gene therapy should continue. For the foreseeable future, however, we oppose any further attempts at gene therapy in human patients because (i) our understanding of such basic processes as gene regulation and genetic recombination in human cells is inadequate; (ii) our understanding of the details of the relation between the molecular defect and the disease state is rudimentary for essentially all genetic diseases; and (iii) we have no information on the short-range and long-term side effects of gene therapy. We therefore propose that a sustained effort be made to formulate a complete set of ethicoscientific criteria to guide the development and clinical application of gene therapy techniques. Such an endeavor could go a long way toward ensuring that gene therapy is used in humans only in those instances where it will prove beneficial, and toward preventing its misuse through premature application. Two recent papers have provided new demonstrations of directed genetic modification of mammalian cells. Munyon et al. (44) restored the ability to synthesize the enzyme thymidine kinase to thymidine kinase-deficient mouse cells by infection with ultraviolet-irradiated herpes simplex virus. In their experiments the DNA from herpes simplex virus, which contains a gene coding for thymidine kinase, may have formed a hereditable association with the mouse cells. Merril et al. (45) reported that treatment of fibroblasts from patients with galactosemia with exogenous DNA caused increased activity of a missing enzyme, alpha-D-galactose-l-phosphate uridyltransferase. They also provided some evidence that the change persisted after subculturing the treated cells. If this latter report can be confirmed, the feasibility of directed genetic modification of human cells would be clearly demonstrated, considerably

  15. MicroRNAs in common human diseases.

    PubMed

    Li, Yu; Kowdley, Kris V

    2012-10-01

    MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that have attracted tremendous attention from the biological and biomedical research communities over the past decade. With over 1900 miRNAs discovered in humans to date, many of them have already been implicated in common human disorders. Facilitated by high-throughput genomics and bioinformatics in conjunction with traditional molecular biology techniques and animal models, miRNA research is now positioned to make the transition from laboratories to clinics to deliver profound benefits to public health. Herein, we overview the progress of miRNA research related to human diseases, as well as the potential for miRNA to becoming the next generation of diagnostics and therapeutics.

  16. Acquired lymphangiectasis.

    PubMed

    Celis, A V; Gaughf, C N; Sangueza, O P; Gourdin, F W

    1999-01-01

    Acquired lymphangiectasis is a dilatation of lymphatic vessels that can result as a complication of surgical intervention and radiation therapy for malignancy. Acquired lymphangiectasis shares clinical and histologic features with the congenital lesion, lymphangioma circumscriptum. Diagnosis and treatment of these vesiculo-bullous lesions is important because they may be associated with pain, chronic drainage, and cellulitis. We describe two patients who had these lesions after treatment for cancer and review the pertinent literature. Although a number of treatment options are available, we have found CO2 laser ablation particularly effective. PMID:9932832

  17. Acquired von Willebrand disease during CentriMag support is associated with high prevalence of bleeding during support and after transition to heart replacement therapy.

    PubMed

    Morrison, Kerry A; Jorde, Ulrich P; Garan, Arthur R; Takayama, Hiroo; Naka, Yoshifumi; Uriel, Nir

    2014-01-01

    The Levitronix CentriMag is a magnetically levitated centrifugal-flow pump that can be implanted rapidly in the operating room for both right and left ventricular support. Recently, continuous-flow pumps have been associated with excessive bleeding, which can be at least partially explained by acquired von Willebrand disease (vWD). We investigated whether acquired vWD occurs during CentriMag support and determined the frequency of bleeding complications during device support as well as after transition to long-term support. We found that acquired vWD is common early post CentriMag implantation and is associated with frequent bleeding events and high requirement of blood products.

  18. Human autoimmune diseases: a comprehensive update.

    PubMed

    Wang, Lifeng; Wang, Fu-Sheng; Gershwin, M Eric

    2015-10-01

    There have been significant advances in our understanding of human autoimmunity that have led to improvements in classification and diagnosis and, most importantly, research advances in new therapies. The importance of autoimmunity and the mechanisms that lead to clinical disease were first recognized about 50 years ago following the pioneering studies of Macfarlane Burnett and his Nobel Prize-winning hypothesis of the 'forbidden clone'. Such pioneering efforts led to a better understanding not only of autoimmunity, but also of lymphoid cell development, thymic education, apoptosis and deletion of autoreactive cells. Contemporary theories suggest that the development of an autoimmune disease requires a genetic predisposition and environmental factors that trigger the immune pathways that lead, ultimately, to tissue destruction. Despite extensive research, there are no genetic tools that can be used clinically to predict the risk of autoimmune disease. Indeed, the concordance of autoimmune disease in identical twins is 12-67%, highlighting not only a role for environmental factors, but also the potential importance of stochastic or epigenetic phenomena. On the other hand, the identification of cytokines and chemokines, and their cognate receptors, has led to novel therapies that block pathological inflammatory responses within the target organ and have greatly improved the therapeutic effect in patients with autoimmune disease, particularly rheumatoid arthritis. Further advances involving the use of multiplex platforms for diagnosis and identification of new therapeutic agents should lead to major breakthroughs within the next decade. PMID:26212387

  19. International military human immunodeficiency virus/acquired immunodeficiency syndrome policies and programs: strengths and limitations in current practice.

    PubMed

    Yeager, R; Hendrix, C W; Kingma, S

    2000-02-01

    A survey was conducted to evaluate military human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) policies and programs in 119 countries. Ninety-eight percent of the 62 respondents provide prevention education, 95% in group settings but only 53% individually. Predeployment briefings are more common than postdeployment briefings. Condoms are promoted more often than provided. Seventy-eight respondents report some form of mandatory HIV testing, and 58% perform mandatory recruit testing, with recruitment denied to HIV-positive individuals in 17%. Counseling accompanies mandatory testing less than voluntary testing. In-service care for AIDS patients is universal. Many military prevention programs can be improved through postdeployment briefings and proactive interventions involving education, condom distribution, and counseling combined with testing. Mandatory testing is often inconsistent with stated goals, and AIDS care policies may strain military budgets. Testing based on cost-benefit assessments may increase efficiency in military HIV control. Military budgets may benefit from greater civil-military cost sharing in AIDS care. PMID:10709366

  20. International military human immunodeficiency virus/acquired immunodeficiency syndrome policies and programs: strengths and limitations in current practice.

    PubMed

    Yeager, R; Hendrix, C W; Kingma, S

    2000-02-01

    A survey was conducted to evaluate military human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) policies and programs in 119 countries. Ninety-eight percent of the 62 respondents provide prevention education, 95% in group settings but only 53% individually. Predeployment briefings are more common than postdeployment briefings. Condoms are promoted more often than provided. Seventy-eight respondents report some form of mandatory HIV testing, and 58% perform mandatory recruit testing, with recruitment denied to HIV-positive individuals in 17%. Counseling accompanies mandatory testing less than voluntary testing. In-service care for AIDS patients is universal. Many military prevention programs can be improved through postdeployment briefings and proactive interventions involving education, condom distribution, and counseling combined with testing. Mandatory testing is often inconsistent with stated goals, and AIDS care policies may strain military budgets. Testing based on cost-benefit assessments may increase efficiency in military HIV control. Military budgets may benefit from greater civil-military cost sharing in AIDS care.

  1. New clinical and histological patterns of acute disseminated histoplasmosis in human immunodeficiency virus-positive patients with acquired immunodeficiency syndrome.

    PubMed

    Ollague Sierra, Jose E; Ollague Torres, Jose M

    2013-04-01

    Histoplasmosis has attained increasing relevance in the past 3 decades because of the appearance of the human immunodeficiency virus (HIV). In most immunocompetent persons, the infection is asymptomatic or can produce a respiratory condition with symptoms and radiological images similar to those observed in pulmonary tuberculosis; in non-HIV+ immunocompromised patients, it can cause respiratory symptoms or evolve into a disseminated infection. The same can occur in acquired immunodeficiency syndrome (AIDS) patients. We have observed a series of HIV+ patients with AIDS who presented with cutaneous histoplasmosis and in whom the clinical and histopathological features were highly unusual, including variable mucocutaneous lesions that were difficult to diagnose clinically. These patients displayed unusual, previously undescribed, histological patterns, including lichenoid pattern, nodular pseudomyxoid pattern, pyogenic granuloma-like pattern, perifollicular pattern, and superficial (S), mid (M), and deep perivascular dermatitis; and more commonly encountered patterns, such as histiocytic lobular panniculitis and focal nodular dermatitis. The novel histopathological patterns of cutaneous involvement by histoplasmosis seen in these patients resembled other common inflammatory and infectious conditions and required a high level of suspicion and the application of special stains for organisms for confirmation. These new, clinical, and histological findings do not seem to be commonly encountered in HIV- patients infected with the fungus but seem to be displayed most prominently in HIV+ patients with AIDS.

  2. Rapid Tests and the Diagnosis of Visceral Leishmaniasis and Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Coinfection.

    PubMed

    Barbosa Júnior, Walter Lins; Ramos de Araújo, Paulo Sérgio; Dias de Andrade, Luiz; Aguiar Dos Santos, Ana Maria; Lopes da Silva, Maria Almerice; Dantas-Torres, Filipe; Medeiros, Zulma

    2015-11-01

    After the emergence of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), the number of visceral leishmaniasis (VL)-HIV/AIDS coinfections has increased worldwide. Herein, we assessed the usefulness of an rK39-based immunochromatographic test (rK39 ICT) (DiaMed-IT LEISH(®); DiaMed AG, Cressier-sur-Morat, Switzerland) and a latex agglutination test (KAtex; Kalon Biological, Guildford, United Kingdom) for urinary antigen detection to diagnose VL in 15 HIV/AIDS patients from northeastern Brazil. VL diagnosis was based on clinical findings, cytology, serology, parasite DNA, and/or urinary antigen detection. VL was confirmed in seven out of 15 HIV/AIDS patients. Only three patients were positive in bone marrow cytology, three patients were conventional polymerase chain reaction (PCR) positive, while six were real-time PCR positive. All patients were direct agglutination test (DAT) (Royal Tropical Institute, Amsterdam, The Netherlands) positive; of these, four were positive by rK39 ICT and five by KAtex. Large-scale studies are needed to validate the use of the KAtex in the national public health laboratory network in Brazil, aiming at improving the diagnosis of VL in HIV/AIDS patients in this country.

  3. Rapid Tests and the Diagnosis of Visceral Leishmaniasis and Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome Coinfection.

    PubMed

    Barbosa Júnior, Walter Lins; Ramos de Araújo, Paulo Sérgio; Dias de Andrade, Luiz; Aguiar Dos Santos, Ana Maria; Lopes da Silva, Maria Almerice; Dantas-Torres, Filipe; Medeiros, Zulma

    2015-11-01

    After the emergence of the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), the number of visceral leishmaniasis (VL)-HIV/AIDS coinfections has increased worldwide. Herein, we assessed the usefulness of an rK39-based immunochromatographic test (rK39 ICT) (DiaMed-IT LEISH(®); DiaMed AG, Cressier-sur-Morat, Switzerland) and a latex agglutination test (KAtex; Kalon Biological, Guildford, United Kingdom) for urinary antigen detection to diagnose VL in 15 HIV/AIDS patients from northeastern Brazil. VL diagnosis was based on clinical findings, cytology, serology, parasite DNA, and/or urinary antigen detection. VL was confirmed in seven out of 15 HIV/AIDS patients. Only three patients were positive in bone marrow cytology, three patients were conventional polymerase chain reaction (PCR) positive, while six were real-time PCR positive. All patients were direct agglutination test (DAT) (Royal Tropical Institute, Amsterdam, The Netherlands) positive; of these, four were positive by rK39 ICT and five by KAtex. Large-scale studies are needed to validate the use of the KAtex in the national public health laboratory network in Brazil, aiming at improving the diagnosis of VL in HIV/AIDS patients in this country. PMID:26416105

  4. 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.

  5. Human genome sequencing in health and disease.

    PubMed

    Gonzaga-Jauregui, Claudia; Lupski, James R; Gibbs, Richard A

    2012-01-01

    Following the "finished," euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges.

  6. Cell mechanics and human disease states

    NASA Astrophysics Data System (ADS)

    Suresh, Subra

    2006-03-01

    This presentation will provide summary of our very recent studies exploring the effects of biochemical factors, influenced by foreign organisms or in vivo processes, on intracellular structural reorganization, single-cell mechanical response and motility of a population of cells in the context of two human diseases: malaria induced by Plasmodium falciparum merozoites that invade red blood cells, and gastrointestinal cancer metastasis involving epithelial cells. In both cases, particular attention will be devoted to systematic changes induced in specific molecular species in response to controlled alterations in disease state. The role of critical proteins in influencing the mechanical response of human red bloods during the intra-erythrocytic development of P. falciparum merozoites has also been assessed quantitatively using specific protein knock-out experiments by recourse to gene inactivation methods. Single-cell mechanical response characterization entails such tools as optical tweezers and mechanical plate stretchers whereas cell motility assays and cell-population biorheology characterization involves microfluidic channels. The experimental studies are accompanied by three-dimensional computational simulations at the continuum and mesoscopic scales of cell deformation. An outcome of such combined experimental and computational biophysical studies is the realization of how chemical factors influence single-cell mechanical response, cytoadherence, the biorheology of a large population of cells through microchannels representative of in vivo conditions, and the onset and progression of disease states.

  7. The Human Microbiome and Surgical Disease

    PubMed Central

    Morowitz, Michael J.; Babrowski, Trissa; Carlisle, Erica M.; Olivas, Andrea; Romanowski, Kathleen S.; Seal, John B.; Liu, Donald C.; Alverdy, John C.

    2015-01-01

    Objective The purpose of this review article is to summarize what is currently known about microbes associated with the human body and to provide examples of how this knowledge impacts the care of surgical patients. Background Pioneering research over the past decade has demonstrated that human beings live in close, constant contact with dynamic communities of microbial organisms. This new reality has wide-ranging implications for the care of surgical patients. Methods and Results Recent advances in the culture-independent study of the human microbiome are reviewed. To illustrate the translational relevance of these studies to surgical disease, we discuss in detail what is known about the role of microbes in the pathogenesis of obesity, gastrointestinal malignancies, Crohn disease, and perioperative complications including surgical site infections and sepsis. The topics of mechanical bowel preparation and perioperative antibiotics are also discussed. Conclusions Heightened understanding of the microbiome in coming years will likely offer opportunities to refine the prevention and treatment of a wide variety of surgical conditions. PMID:21422915

  8. The Microbiota, Chemical Symbiosis, and Human Disease

    PubMed Central

    Redinbo, Matthew R.

    2014-01-01

    Our understanding of mammalian-microbial mutualism has expanded by combing microbial sequencing with evolving molecular and cellular methods, and unique model systems. Here, the recent literature linking the microbiota to diseases of three of the key mammalian mucosal epithelial compartments – nasal, lung and gastrointestinal (GI) tract – is reviewed with a focus on new knowledge about the taxa, species, proteins and chemistry that promote health and impact progression toward disease. The information presented is further organized by specific diseases now associated with the microbiota:, Staphylococcus aureus infection and rhinosinusitis in the nasal-sinus mucosa; cystic fibrosis (CF), chronic obstructive pulmonary disorder (COPD), and asthma in the pulmonary tissues. For the vast and microbially dynamic GI compartment, several disorders are considered, including obesity, atherosclerosis, Crohn’s disease, ulcerative colitis, drug toxicity, and even autism. Our appreciation of the chemical symbiosis ongoing between human systems and the microbiota continues to grow, and suggest new opportunities for modulating this symbiosis using designed interventions. PMID:25305474

  9. Human brain disease recreated in mice

    SciTech Connect

    Marx, J.

    1990-12-14

    In the early 1980s, neurologist Stanley Prusiner suggested that scrapie, an apparently infectious degenerative brain disease of sheep, could be transmitted by prions, infectious particles made just of protein - and containing no nucleic acids. But prion research has come a long way since then. In 1985, the cloning of the gene encoding the prion protein proved that it does in fact exist. And the gene turned out to be widely expressed in the brains of higher organisms, a result suggesting that the prion protein has a normal brain function that can somehow be subverted, leading to brain degeneration. Then studies done during the past 2 years suggested that specific mutations in the prion gene might cause two similar human brain diseases, Gerstmann-Straeussler-Scheinker syndrome (GSS) and Creutzfelt-Jakob disease. Now, Prusiner's group at the University of California, San Francisco, has used genetic engineering techniques to recreate GSS by transplanting the mutated prion gene into mice. Not only will the animal model help neurobiologists answer the many remaining questions about prions and how they work, but it may also shed some light on other neurodegenerative diseases as well.

  10. Consensus on context-specific strategies for reducing the stigma of human immunodeficiency virus/acquired immunodeficiency syndrome in Zambézia Province, Mozambique

    PubMed Central

    Mukolo, Abraham; Torres, Isabel; Bechtel, Ruth M.; Sidat, Mohsin; Vergara, Alfredo E.

    2014-01-01

    Stigma has been implicated in poor outcomes of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) care. Reducing stigma is important for HIV prevention and long-term treatment success. Although stigma reduction interventions are conducted in Mozambique, little is known about the current nature of stigma and the efficacy and effectiveness of stigma reduction initiatives. We describe action research to generate consensus on critical characteristics of HIV stigma and anti-stigma interventions in Zambézia Province, Mozambique. Qualitative data gathering methods, including indepth key-informant interviews, community interviews and consensus group sessions, were utilized. Delphi methods and the strategic options development analysis technique were used to synthesize qualitative data. Key findings are that stigma enacted by the general public might be declining in tandem with the HIV/AIDS epidemic in Mozambique, but there is likely excessive residual fear of HIV disease and community attitudes that sustain high levels of perceived stigma. HIV-positive women accessing maternal and child health services appear to shoulder a disproportionate burden of stigma. Unintentional biases among healthcare providers are currently the critical frontier of stigmatization, but there are few interventions designed to address them. Culturally sensitive psychotherapies are needed to address psychological distress associated with internalized stigma and these interventions should complement current supports for voluntary counseling and testing. While advantageous for defining stakeholder priorities for stigma reduction efforts, confirmatory quantitative studies of these consensus positions are needed before the launch of specific interventions. PMID:24527744

  11. Consensus on context-specific strategies for reducing the stigma of human immunodeficiency virus/acquired immunodeficiency syndrome in Zambézia Province, Mozambique.

    PubMed

    Mukolo, Abraham; Torres, Isabel; Bechtel, Ruth M; Sidat, Mohsin; Vergara, Alfredo E

    2013-01-01

    Stigma has been implicated in poor outcomes of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) care. Reducing stigma is important for HIV prevention and long-term treatment success. Although stigma reduction interventions are conducted in Mozambique, little is known about the current nature of stigma and the efficacy and effectiveness of stigma reduction initiatives. We describe action research to generate consensus on critical characteristics of HIV stigma and anti-stigma interventions in Zambézia Province, Mozambique. Qualitative data gathering methods, including in-depth key-informant interviews, community interviews and consensus group sessions, were utilized. Delphi methods and the strategic options development analysis technique were used to synthesize qualitative data. Key findings are that stigma enacted by the general public might be declining in tandem with the HIV/AIDS epidemic in Mozambique, but there is likely excessive residual fear of HIV disease and community attitudes that sustain high levels of perceived stigma. HIV-positive women accessing maternal and child health services appear to shoulder a disproportionate burden of stigma. Unintentional biases among healthcare providers are currently the critical frontier of stigmatization, but there are few interventions designed to address them. Culturally sensitive psychotherapies are needed to address psychological distress associated with internalized stigma and these interventions should complement current supports for voluntary counseling and testing. While advantageous for defining stakeholder priorities for stigma reduction efforts, confirmatory quantitative studies of these consensus positions are needed before the launch of specific interventions.

  12. A controlled study of funding for human immunodeficiency virus/acquired immunodeficiency syndrome as resource capacity building in the health system in Rwanda.

    PubMed

    Shepard, Donald S; Zeng, Wu; Amico, Peter; Rwiyereka, Angelique K; Avila-Figueroa, Carlos

    2012-05-01

    Because human inmmunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) receives more donor funding globally than that for all other diseases combined, some critics allege this support undermines general health care. This empirical study evaluates the impact of HIV/AIDS funding on the primary health care system in Rwanda. Using a quasi-experimental design, we randomly selected 25 rural health centers (HCs) that started comprehensive HIV/AIDS services from 2002 through 2006 as the intervention group. Matched HCs with no HIV/AIDS services formed the control group. The analysis compared growth in inputs and services between intervention and control HCs with a difference-in-difference analysis in a random-effects model. Intervention HCs performed better than control HCs in most services (seven of nine), although only one of these improvements (Bacille Calmette-Guérin vaccination) reached or approached statistical significance. In conclusion, this six-year controlled study found no adverse effects of the expansion of HIV/AIDS services on non-HIV services among rural health centers in Rwanda.

  13. Recursion-based depletion of human immunodeficiency virus-specific naive CD4(+) T cells may facilitate persistent viral replication and chronic viraemia leading to acquired immunodeficiency syndrome.

    PubMed

    Tsukamoto, Tetsuo; Yamamoto, Hiroyuki; Okada, Seiji; Matano, Tetsuro

    2016-09-01

    Although antiretroviral therapy has made human immunodeficiency virus (HIV) infection a controllable disease, it is still unclear how viral replication persists in untreated patients and causes CD4(+) T-cell depletion leading to acquired immunodeficiency syndrome (AIDS) in several years. Theorists tried to explain it with the diversity threshold theory in which accumulated mutations in the HIV genome make the virus so diverse that the immune system will no longer be able to recognize all the variants and fail to control the viraemia. Although the theory could apply to a number of cases, macaque AIDS models using simian immunodeficiency virus (SIV) have shown that failed viral control at the set point is not always associated with T-cell escape mutations. Moreover, even monkeys without a protective major histocompatibility complex (MHC) allele can contain replication of a super infected SIV following immunization with a live-attenuated SIV vaccine, while those animals are not capable of fighting primary SIV infection. Here we propose a recursion-based virus-specific naive CD4(+) T-cell depletion hypothesis through thinking on what may happen in individuals experiencing primary immunodeficiency virus infection. This could explain the mechanism for impairment of virus-specific immune response in the course of HIV infection.

  14. Recursion-based depletion of human immunodeficiency virus-specific naive CD4(+) T cells may facilitate persistent viral replication and chronic viraemia leading to acquired immunodeficiency syndrome.

    PubMed

    Tsukamoto, Tetsuo; Yamamoto, Hiroyuki; Okada, Seiji; Matano, Tetsuro

    2016-09-01

    Although antiretroviral therapy has made human immunodeficiency virus (HIV) infection a controllable disease, it is still unclear how viral replication persists in untreated patients and causes CD4(+) T-cell depletion leading to acquired immunodeficiency syndrome (AIDS) in several years. Theorists tried to explain it with the diversity threshold theory in which accumulated mutations in the HIV genome make the virus so diverse that the immune system will no longer be able to recognize all the variants and fail to control the viraemia. Although the theory could apply to a number of cases, macaque AIDS models using simian immunodeficiency virus (SIV) have shown that failed viral control at the set point is not always associated with T-cell escape mutations. Moreover, even monkeys without a protective major histocompatibility complex (MHC) allele can contain replication of a super infected SIV following immunization with a live-attenuated SIV vaccine, while those animals are not capable of fighting primary SIV infection. Here we propose a recursion-based virus-specific naive CD4(+) T-cell depletion hypothesis through thinking on what may happen in individuals experiencing primary immunodeficiency virus infection. This could explain the mechanism for impairment of virus-specific immune response in the course of HIV infection. PMID:27515208

  15. Proteomics in human disease: cancer, heart and infectious diseases.

    PubMed

    Jungblut, P R; Zimny-Arndt, U; Zeindl-Eberhart, E; Stulik, J; Koupilova, K; Pleissner, K P; Otto, A; Müller, E C; Sokolowska-Köhler, W; Grabher, G; Stöffler, G

    1999-07-01

    In recent years, genomics has increased the understanding of many diseases. Proteomics is a rapidly growing research area that encompasses both genetic and environmental factors. The protein composition represents the functional status of a biological compartment. The five approaches presented here resulted in the detection of disease-associated proteins. Calgranulin B was upregulated in colorectal cancer, and hepatoma-derived aldose reductase-like protein was reexpressed in a rat model during hepatocarcinogenesis. In these two investigations, attention was focused on one protein, obviously differing in amount, directly after two-dimensional electrophoresis (2-DE). Additional methods, such as enzyme activity measurements and immunohistochemistry, confirmed the disease association of the two candidates resulting from 2-DE subtractive analysis. The following three investigations take advantage of the holistic potential of the 2-DE approach. The comparison of 2-DE patterns from dilated cardiomyopathy patients with those of controls revealed 25 statistically significant intensity differences, from which 12 were identified by amino acid analysis, Edman degradation or matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). A human myocardial 2-DE database was constructed, containing 3300 protein spots and 150 identified protein species. The number of identified proteins was limited by the capacity of our group, rather than by the principle of feasibility. Another field where proteomics proves to be a valuable tool in identifying proteins of importance for diagnosis is proteome analysis of pathogenic microorganisms such as Borrelia burgdorferi (Lyme disease) and Toxoplasma gondii (toxoplasmosis). Sera from patients with early or late symptoms of Lyme borreliosis contained antibodies of various classes against about 80 antigens each, containing the already described antigens OspA, B and C, flagellin, p83/100, and p39. Similarly, antibody reactivity to

  16. Mitophagy: Mechanisms and Role in Human Disease

    PubMed Central

    Springer, Maya Z.; Macleod, Kay F.

    2016-01-01

    Mitophagy is a selective form of macro-autophagy in which mitochondria are specifically targeted for autophagic degradation. Mitophagy plays an important role in cellular homeostasis by eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to stress. Cells execute mitophagy through several non-redundant mechanisms, including the PINK1/Parkin partnership that modulates turnover of depolarized mitochondria and stress-induced BNIP3, NIX and FUNDC1 molecular adaptors that interact directly with LC3 to promote mitophagy. These pathways are deregulated in human diseases, including cancer, neurodegeneration, metabolic disorders, muscle atrophy, ageing and inflammation, reflecting the importance of mitophagy as a cellular housekeeping function. PMID:27453450

  17. Gene Conversion in Human Genetic Disease

    PubMed Central

    Chen, Jian-Min; Férec, Claude; Cooper, David N.

    2010-01-01

    Gene conversion is a specific type of homologous recombination that involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’. We have recently reviewed the molecular mechanisms underlying gene conversion, explored the key part that this process has played in fashioning extant human genes, and performed a meta-analysis of gene-conversion events known to have caused human genetic disease. Here we shall briefly summarize some of the latest developments in the study of pathogenic gene conversion events, including (i) the emerging idea of minimal efficient sequence homology (MESH) for homologous recombination, (ii) the local DNA sequence features that appear to predispose to gene conversion, (iii) a mechanistic comparison of gene conversion and transient hypermutability, and (iv) recently reported examples of pathogenic gene conversion events. PMID:24710102

  18. The role of nurses in the human immunodeficiency virus/acquired immune deficiency syndrome policy process in Botswana.

    PubMed

    Phaladze, N A

    2003-03-01

    In Botswana, there is dearth of literature on the role of nursing in health-care policy and resource allocation and yet nurses constitute the majority (85%) of health manpower. The health-care delivery system depends mostly on nurses for service provision. There were two main purposes of this study: first, to gather descriptive data from major key players (with particular emphasis on nurses) concerning knowledge of the policy process and resource allocation for management and care of clients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) in Botswana; and, second, to identify nurse characteristics (e.g. position, education, experience, job category) associated with motivation to influence health-care policy in HIV/AIDS management and care in Botswana. A policy process conceptual framework was used to guide data collection and analysis. A case-study research method was used to conduct in-depth interviews from a purposive sample of 19 policy makers, and a survey questionnaire was used to collect data from a purposive sample of 95 registered nurses from six study sites in Botswana. The study findings indicate minimal participation of nurses in health-care policy process and resource allocation. The demographic variable of position was a predictor of the involvement of nurses in policy and in budgetary decisions. Both survey and interview data indicated that this minimal participation of nurses in the policy process resulted in implementation problems, thus compromising service provision. Implications of the findings for the nursing profession, nursing practice and policy, which address the importance of nurses' involvement, are discussed. PMID:12581124

  19. Differences in miRNA expression profiles between GIST and leiomyoma in human samples acquired by submucosal tunneling biopsy

    PubMed Central

    Fujita, Koji; Kobara, Hideki; Mori, Hirohito; Fujihara, Shintaro; Chiyo, Taiga; Matsunaga, Tae; Nishiyama, Noriko; Ayaki, Maki; Yachida, Tatsuo; Morishita, Asahiro; Fujiwara, Masao; Okano, Keiichi; Suzuki, Yasuyuki; Iwama, Hisakazu; Masaki, Tsutomu

    2015-01-01

    Background and study aims: Small gastrointestinal stromal tumors (GISTs) rarely have malignant potential with poor prognosis. Using conventional imaging to differentiate between small GISTs and leiomyoma, which often have similar characteristics, is difficult but essential in daily practice. Although some studies have reported on the utility of serum c-kit as a biomarker for non-small GIST and specific miRNA, clinical aspects of such testing are controversial. The aim of this study was to identify differences between small GIST and leiomyoma through the investigation of miRNA expression patterns in human cases. Patients and methods: MiRNA expression was examined in nine GIST (less than low risk, mean 18 mm in size) samples and seven leiomyoma samples acquired by a novel sampling method, submucosal tunneling biopsy (STB), which produces tumor specimens of submucosal tumor (SMT) without contamination of sufficient size to be examined under direct vision. Total RNA was extracted from these tissues and analyzed for miRNA expression patterns by microarray. Subsequently, real-time quantitative polymerase chain reaction (qPCR) were used to confirm specific miRNA overexpression, comparing GISTs with leiomyomas. Results: Microarray analysis revealed upregulation of the miR-140 family up to 20 times higher in GISTs than in leiomyomas. Real-time qPCR revealed that the expression level of miR-140-5 p in GISTs was 27.86 times higher than in leiomyomas; miR-140-3 p was 12.24 times higher as well. Conclusions: The STB method provided suitable SMT samples for miRNA analysis. MiR-140 family members may serve as specific biomarkers to distinguish GIST from leiomyoma. PMID:26716134

  20. Vitamin D status in a Brazilian cohort of adolescents and young adults with perinatally acquired human immunodeficiency virus infection.

    PubMed

    Schtscherbyna, Annie; Gouveia, Carla; Pinheiro, Maria Fernanda Miguens Castelar; Luiz, Ronir Raggio; Farias, Maria Lucia Fleiuss; Machado, Elizabeth Stankiewicz

    2016-02-01

    The purpose was to determine the prevalence and related factors of vitamin D (VitD) insufficiency in adolescents and young adults with perinatally acquired human immunodeficiency virus. A cohort of 65 patients (17.6 ± 2 years) at the Federal University of Rio de Janeiro, Brazil, were examined for pubertal development, nutrition, serum parathormone and serum 25-hydroxyvitamin D [s25(OH)D]. s25(OH)D levels < 30 ng/mL (< 75 nmol/L) were defined as VitD insufficiency. CD4+ T-cell counts and viral load, history of worst clinical status, immunologic status as nadir, current immunologic status, and antiretroviral (ART) regimen were also evaluated as risk factors for VitD insufficiency. Mean s25(OH)D was 37.7 ± 13.9 ng/mL and 29.2% had VitD insufficiency. There was no difference between VitD status and gender, age, nutritional status, clinical and immunological classification, and type of ART. Only VitD consumption showed tendency of association with s25(OH)D (p = 0.064). Individuals analysed in summer/autumn season had a higher s25(OH)D compared to the ones analysed in winter/spring (42.6 ± 14.9 vs. 34.0 ± 11.9, p = 0.011). Although, the frequency of VitD insufficiency did not differ statistically between the groups (summer/autumn 17.9% vs. winter/spring 37.8%, p = 0.102), we suggest to monitor s25(OH)D in seropositive adolescents and young adults, especially during winter/spring months, even in sunny regions.

  1. Vitamin D status in a Brazilian cohort of adolescents and young adults with perinatally acquired human immunodeficiency virus infection

    PubMed Central

    Schtscherbyna, Annie; Gouveia, Carla; Pinheiro, Maria Fernanda Miguens Castelar; Luiz, Ronir Raggio; Farias, Maria Lucia Fleiuss; Machado, Elizabeth Stankiewicz

    2016-01-01

    The purpose was to determine the prevalence and related factors of vitamin D (VitD) insufficiency in adolescents and young adults with perinatally acquired human immunodeficiency virus. A cohort of 65 patients (17.6 ± 2 years) at the Federal University of Rio de Janeiro, Brazil, were examined for pubertal development, nutrition, serum parathormone and serum 25-hydroxyvitamin D [s25(OH)D]. s25(OH)D levels < 30 ng/mL (< 75 nmol/L) were defined as VitD insufficiency. CD4+ T-cell counts and viral load, history of worst clinical status, immunologic status as nadir, current immunologic status, and antiretroviral (ART) regimen were also evaluated as risk factors for VitD insufficiency. Mean s25(OH)D was 37.7 ± 13.9 ng/mL and 29.2% had VitD insufficiency. There was no difference between VitD status and gender, age, nutritional status, clinical and immunological classification, and type of ART. Only VitD consumption showed tendency of association with s25(OH)D (p = 0.064). Individuals analysed in summer/autumn season had a higher s25(OH)D compared to the ones analysed in winter/spring (42.6 ± 14.9 vs. 34.0 ± 11.9, p = 0.011). Although, the frequency of VitD insufficiency did not differ statistically between the groups (summer/autumn 17.9% vs. winter/spring 37.8%, p = 0.102), we suggest to monitor s25(OH)D in seropositive adolescents and young adults, especially during winter/spring months, even in sunny regions. PMID:26872341

  2. Orchitis and human immunodeficiency virus type 1 infected cells in reproductive tissues from men with the acquired immune deficiency syndrome.

    PubMed Central

    Pudney, J.; Anderson, D.

    1991-01-01

    Mechanisms underlying human immunodeficiency virus type 1 (HIV-1) infection of the male reproductive tract and the sexual transmission of HIV-1 through semen are poorly understood. To address these issues, the authors performed morphologic and immunocytochemical analyses of reproductive tissues obtained at autopsy from 43 male acquired immune deficiency syndrome (AIDS) patients. Monoclonal antibodies recognizing different subpopulations of white blood cells were used to detect leukocyte infiltration and map the location of potential lymphocytic/monocytic HIV-1 host cells and immunocytochemistry and in situ hybridization techniques were used to detect HIV-1-infected cells in the testis, excurrent ducts, and prostate. Distinct pathologic changes were observed in a majority of testes of AIDS patients that included azoospermia, hyalinization of the boundary wall of seminiferous tubules, and lymphocytic infiltration of the interstitium. The reproductive excurrent ducts and prostate appeared morphologically normal except for the presence of focal accumulations of white blood cells in the connective tissue stroma. In the testis many white blood cells were shown to be CD4+, indicating the presence of abundant host cells (T-helper/inducer lymphocytes and macrophages) for HIV-1. Furthermore macrophages and cells of lymphocytic morphology were observed migrating across the boundary walls of hyalinized seminiferous in tubules to enter the lumen. In 9 of the 23 cases tested for HIV-1 protein expression by immunocytochemistry. HIV-1 + cells of lymphocytic/monocytic morphology were found in the seminiferous tubules and interstitium of the testis, epididymal epithelium, and connective tissue of the epididymis and prostate. One patient with epididymal blockage had accumulations of HIV-1-antigen-positive cells of macrophages morphology in the distended lumen of the efferent ducts. There was no evidence of active HIV-1 infection in germ cells or Sertoli cells of the seminiferous

  3. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... acquired CJD. CJD belongs to a family of human and animal diseases known as the transmissible spongiform ... CJD is the most common of the known human TSEs. Other human TSEs include kuru, fatal familial ...

  4. HIV and the spectrum of human disease.

    PubMed

    Lucas, Sebastian; Nelson, Ann Marie

    2015-01-01

    Infection with the human immunodeficiency virus (HIV) causes systemic T cell destruction and reduced cell-mediated immunity that leads to a wide range of opportunistic infections and cancers. Second, it directly damages many tissues - gut, brain, lung - through mononuclear cell infection and activation. Third, through immune activation and effects on endothelia, it can cause more subtle systemic organ damage, such as chronic cardiovascular, hepatic, pulmonary and central nervous system disease. Antiretroviral treatment has enabled HIV-infected persons to live with chronic infection, although with some side-effects and mortality, including reactions due to the immune reconstitution inflammatory syndrome (IRIS). As cohorts of infected people get older, age-related diseases will combine with chronic HIV infection to produce disabilities whose scale is not yet understood. HIV is detectable in tissues by immunohistochemistry when infection loads are high, such as at first presentation. Pathologists should proactively consider HIV disease in routine diagnostic work, so as to identify more HIV-infected patients and enable their optimal management.

  5. Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases.

    PubMed

    Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

    2012-01-01

    The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

  6. Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases

    NASA Astrophysics Data System (ADS)

    Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

    2012-10-01

    The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

  7. Assessment of protection from systemic infection or disease afforded by low to intermediate titers of passively acquired neutralizing antibody against bovine viral diarrhea virus in calves.

    PubMed

    Bolin, S R; Ridpath, J F

    1995-06-01

    Colostrum-deprived calves (n = 24) were fed various amounts of colostrum, colostrum substitute, or milk replacer to establish a range in titer of passively acquired viral neutralizing antibody in serum. The calves were then challenge exposed intranasally with a virulent, noncytopathic bovine viral diarrhea virus (BVDV-890). After viral challenge exposure, calves were monitored for fever, leukopenia, thrombocytopenia, and diarrhea. In addition, viral isolation and viral titration were performed on specimens of nasal secretions, buffy coat cells, and serum obtained from the calves. Fever and systemic spread of virus were detected in calves that had viral neutralizing titer of 256 or lower. Calves that had viral neutralizing titer lower than 16 developed severe clinical disease manifested by fever, leukopenia, thrombocytopenia, and diarrhea. Severity and duration of signs of disease decreased as titers of passively acquired viral neutralizing antibody increased. These results indicate that low to intermediate titers of passively acquired viral neutralizing antibody were not sufficient to fully protect calves from virulent bovine viral diarrhea virus.

  8. Surveillance for Travel and Domestically Acquired Multidrug-Resistant Human Shigella Infections-Pennsylvania, 2006-2014.

    PubMed

    Li, Yu Lung; Tewari, Deepanker; Yealy, Courtney C; Fardig, David; M'ikanatha, Nkuchia M

    2016-01-01

    Shigellosis is a leading cause of enteric infections in the United States. We compared antimicrobial resistance in Shigella infections related to overseas travel (travel-associated) and in those acquired domestically by analyzing antimicrobial resistance patterns, geographic distributions, and pulsed-field gel electrophoresis (PFGE) patterns. We tested samples (n = 204) from a collection of isolates recovered from patients in Pennsylvania between 2006 and 2014. Isolates were grouped into travel- and non-travel-associated categories. Eighty-one (79.4%) of the Shigella isolates acquired during international travel were resistant to multiple antibiotics compared to 53 (52.1%) of the infections transmitted in domestic settings. A majority (79.4%) of isolates associated with international travel demonstrated resistance to aminoglycosides and tetracyclines, whereas 47 (46.1%) of the infections acquired domestically were resistant to tetracycline. Almost all isolates (92.2%) transmitted in domestic settings were resistant to aminoglycosides, and 5 isolates from adult male patients were resistant to azithromycin, a drug often used for empiric treatment of severe shigellosis. Twenty (19.6%) isolates associated with illnesses acquired during overseas travel in 4 countries were resistant to quinolones. One S. sonnei PFGE pattern was traced to a multidrug-resistant isolate acquired overseas that had caused a multistate outbreak of shigellosis, suggesting global dissemination of a drug-resistant species. Resistance to certain drugs-for example, tetracycline-increased in both overseas- and domestic-acquired infections during the study period. The prevalence of resistance to macrolides (azithromycin) and third-generation cephalosporins (ceftriaxone) was less than 1%; however, efforts to better monitor changes in drug resistance over time combined with increased antimicrobial stewardship are essential at the local, national, and global levels. PMID:27314654

  9. Cystic renal cell carcinoma and acquired renal cystic disease associated with consumption of chaparral tea: a case report.

    PubMed

    Smith, A Y; Feddersen, R M; Gardner, K D; Davis, C J

    1994-12-01

    Nordihydroguaiaretic acid is an antioxidant used experimentally to induce cystic renal disease in rats. It may be extracted from the leaves of the creosote bush, which are consumed as chaparral tea in the southwestern United States. We report a case of cystic renal disease and cystic adenocarcinoma of the kidney associated with a history of protracted consumption of chaparral tea.

  10. Human papillomavirus molecular biology and disease association

    PubMed Central

    Egawa, Nagayasu; Griffin, Heather; Kranjec, Christian; Murakami, Isao

    2015-01-01

    Summary Human papillomaviruses (HPVs) have evolved over millions of years to propagate themselves in a range of different animal species including humans. Viruses that have co‐evolved slowly in this way typically cause chronic inapparent infections, with virion production in the absence of apparent disease. This is the case for many Beta and Gamma HPV types. The Alpha papillomavirus types have however evolved immunoevasion strategies that allow them to cause persistent visible papillomas. These viruses activate the cell cycle as the infected epithelial cell differentiates in order to create a replication competent environment that allows viral genome amplification and packaging into infectious particles. This is mediated by the viral E6, E7, and E5 proteins. High‐risk E6 and E7 proteins differ from their low‐risk counterparts however in being able to drive cell cycle entry in the upper epithelial layers and also to stimulate cell proliferation in the basal and parabasal layers. Deregulated expression of these cell cycle regulators underlies neoplasia and the eventual progression to cancer in individuals who cannot resolve high‐risk HPV infection. Most work to date has focused on the study of high‐risk HPV types such as HPV 16 and 18, which has led to an understanding of the molecular pathways subverted by these viruses. Such approaches will lead to the development of better strategies for disease treatment, including targeted antivirals and immunotherapeutics. Priorities are now focused toward understanding HPV neoplasias at sites other than the cervix (e.g. tonsils, other transformation zones) and toward understanding the mechanisms by which low‐risk HPV types can sometimes give rise to papillomatosis and under certain situations even cancers. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25752814

  11. Human papillomavirus molecular biology and disease association.

    PubMed

    Doorbar, John; Egawa, Nagayasu; Griffin, Heather; Kranjec, Christian; Murakami, Isao

    2015-03-01

    Human papillomaviruses (HPVs) have evolved over millions of years to propagate themselves in a range of different animal species including humans. Viruses that have co-evolved slowly in this way typically cause chronic inapparent infections, with virion production in the absence of apparent disease. This is the case for many Beta and Gamma HPV types. The Alpha papillomavirus types have however evolved immunoevasion strategies that allow them to cause persistent visible papillomas. These viruses activate the cell cycle as the infected epithelial cell differentiates in order to create a replication competent environment that allows viral genome amplification and packaging into infectious particles. This is mediated by the viral E6, E7, and E5 proteins. High-risk E6 and E7 proteins differ from their low-risk counterparts however in being able to drive cell cycle entry in the upper epithelial layers and also to stimulate cell proliferation in the basal and parabasal layers. Deregulated expression of these cell cycle regulators underlies neoplasia and the eventual progression to cancer in individuals who cannot resolve high-risk HPV infection. Most work to date has focused on the study of high-risk HPV types such as HPV 16 and 18, which has led to an understanding of the molecular pathways subverted by these viruses. Such approaches will lead to the development of better strategies for disease treatment, including targeted antivirals and immunotherapeutics. Priorities are now focused toward understanding HPV neoplasias at sites other than the cervix (e.g. tonsils, other transformation zones) and toward understanding the mechanisms by which low-risk HPV types can sometimes give rise to papillomatosis and under certain situations even cancers.

  12. MicroRNAs in Human Diseases: From Autoimmune Diseases to Skin, Psychiatric and Neurodegenerative Diseases.

    PubMed

    Ha, Tai-You

    2011-10-01

    MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression via degradation or translational repression of their target messenger RNAs (mRNAs). Recent studies have clearly demonstrated that miRNAs play critical roles in several biologic processes, including cell cycle, differentiation, cell development, cell growth, and apoptosis and that miRNAs are highly expressed in regulatory T (Treg) cells and a wide range of miRNAs are involved in the regulation of immunity and in the prevention of autoimmunity. It has been increasingly reported that miRNAs are associated with various human diseases like autoimmune disease, skin disease, neurological disease and psychiatric disease. Recently, the identification of mi- RNAs in skin has added a new dimension in the regulatory network and attracted significant interest in this novel layer of gene regulation. Although miRNA research in the field of dermatology is still relatively new, miRNAs have been the subject of much dermatological interest in skin morphogenesis and in regulating angiogenesis. In addition, miRNAs are moving rapidly onto center stage as key regulators of neuronal development and function in addition to important contributions to neurodegenerative disorder. Moreover, there is now compelling evidence that dysregulation of miRNA networks is implicated in the development and onset of human neruodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Tourette's syndrome, Down syndrome, depression and schizophrenia. In this review, I briefly summarize the current studies about the roles of miRNAs in various autoimmune diseases, skin diseases, psychoneurological disorders and mental stress.

  13. Arsenic: toxicity, oxidative stress and human disease.

    PubMed

    Jomova, K; Jenisova, Z; Feszterova, M; Baros, S; Liska, J; Hudecova, D; Rhodes, C J; Valko, M

    2011-03-01

    Arsenic (As) is a toxic metalloid element that is present in air, water and soil. Inorganic arsenic tends to be more toxic than organic arsenic. Examples of methylated organic arsenicals include monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)]. Reactive oxygen species (ROS)-mediated oxidative damage is a common denominator in arsenic pathogenesis. In addition, arsenic induces morphological changes in the integrity of mitochondria. Cascade mechanisms of free radical formation derived from the superoxide radical, combined with glutathione-depleting agents, increase the sensitivity of cells to arsenic toxicity. When both humans and animals are exposed to arsenic, they experience an increased formation of ROS/RNS, including peroxyl radicals (ROO•), the superoxide radical, singlet oxygen, hydroxyl radical (OH•) via the Fenton reaction, hydrogen peroxide, the dimethylarsenic radical, the dimethylarsenic peroxyl radical and/or oxidant-induced DNA damage. Arsenic induces the formation of oxidized lipids which in turn generate several bioactive molecules (ROS, peroxides and isoprostanes), of which aldehydes [malondialdehyde (MDA) and 4-hydroxy-nonenal (HNE)] are the major end products. This review discusses aspects of chronic and acute exposures of arsenic in the etiology of cancer, cardiovascular disease (hypertension and atherosclerosis), neurological disorders, gastrointestinal disturbances, liver disease and renal disease, reproductive health effects, dermal changes and other health disorders. The role of antioxidant defence systems against arsenic toxicity is also discussed. Consideration is given to the role of vitamin C (ascorbic acid), vitamin E (α-tocopherol), curcumin, glutathione and antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase in their protective roles against arsenic-induced oxidative stress.

  14. Wolbachia endosymbionts and human disease control.

    PubMed

    Slatko, Barton E; Luck, Ashley N; Dobson, Stephen L; Foster, Jeremy M

    2014-07-01

    Most human filarial nematode parasites and arthropods are hosts for a bacterial endosymbiont, Wolbachia. In filaria, Wolbachia are required for normal development, fertility and survival, whereas in arthropods, they are largely parasitic and can influence development and reproduction, but are generally not required for host survival. Due to their obligate nature in filarial parasites, Wolbachia have been a target for drug discovery initiatives using several approaches including diversity and focused library screening and genomic sequence analysis. In vitro and in vivo anti-Wolbachia antibiotic treatments have been shown to have adulticidal activity, a long sought goal of filarial parasite drug discovery. In mosquitoes, it has been shown that the presence of Wolbachia can inhibit the transmission of certain viruses, such as Dengue, Chikungunya, Yellow Fever, West Nile, as well as the infectivity of the malaria-causing protozoan, Plasmodium and filarial nematodes. Furthermore, Wolbachia can cause a form of conditional sterility that can be used to suppress populations of mosquitoes and additional medically important insects. Thus Wolbachia, a pandemic endosymbiont offers great potential for elimination of a wide-variety of devastating human diseases. PMID:25046729

  15. Wolbachia endosymbionts and human disease control.

    PubMed

    Slatko, Barton E; Luck, Ashley N; Dobson, Stephen L; Foster, Jeremy M

    2014-07-01

    Most human filarial nematode parasites and arthropods are hosts for a bacterial endosymbiont, Wolbachia. In filaria, Wolbachia are required for normal development, fertility and survival, whereas in arthropods, they are largely parasitic and can influence development and reproduction, but are generally not required for host survival. Due to their obligate nature in filarial parasites, Wolbachia have been a target for drug discovery initiatives using several approaches including diversity and focused library screening and genomic sequence analysis. In vitro and in vivo anti-Wolbachia antibiotic treatments have been shown to have adulticidal activity, a long sought goal of filarial parasite drug discovery. In mosquitoes, it has been shown that the presence of Wolbachia can inhibit the transmission of certain viruses, such as Dengue, Chikungunya, Yellow Fever, West Nile, as well as the infectivity of the malaria-causing protozoan, Plasmodium and filarial nematodes. Furthermore, Wolbachia can cause a form of conditional sterility that can be used to suppress populations of mosquitoes and additional medically important insects. Thus Wolbachia, a pandemic endosymbiont offers great potential for elimination of a wide-variety of devastating human diseases.

  16. Lymphoma in acquired generalized lipodystrophy.

    PubMed

    Brown, Rebecca J; Chan, Jean L; Jaffe, Elaine S; Cochran, Elaine; DePaoli, Alex M; Gautier, Jean-Francois; Goujard, Cecile; Vigouroux, Corinne; Gorden, Phillip

    2016-01-01

    Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin. AGL is associated with high risk for lymphoma, especially PTCL. Autoimmunity likely contributes to this risk. Lymphoma developed with or without metreleptin, suggesting metreleptin does not directly cause lymphoma development; a theoretical role of metreleptin in lymphoma progression remains possible. For most patients with AGL and severe metabolic complications, the proven benefits of metreleptin on metabolic disease will likely outweigh theoretical risks of metreleptin in lymphoma development or progression.

  17. Attitudes of Baccalaureate Nursing Students toward Persons with Acquired Immunodeficiency Syndrome According to Mode of Human Immunodeficiency Virus Transmission.

    ERIC Educational Resources Information Center

    West, Andrea M.; And Others

    1996-01-01

    Nursing students (n=236) completed the AIDS Knowledge Scale and AIDS Attitude Scale. Results showed most stigma attached to AIDS acquired through drug use or sexual contact, the least through maternal transmission or blood transfusion. Demographic characteristics did not influence attitudes. (SK)

  18. Real time three-dimensional echocardiography for quantification of ventricular volumes, mass, and function in children with congenital and acquired heart diseases.

    PubMed

    Balluz, Rula; Liu, Liwen; Zhou, Xiaodong; Ge, Shuping

    2013-04-01

    Quantitative measurement of left ventricular (LV) volumes, mass, and function is one of the most common and important indications for echocardiography. These measurements are among the most powerful tools for diagnosis and prognosis of congenital and acquired heart diseases and for assessment of medical, percutaneous, and surgical interventions. Awareness is also growing of the importance of right ventricular (RV) volume, mass, and function in many cardiopulmonary diseases. Furthermore, there are challenges and opportunities to measure the volume, mass, and function of complex chambers such as the left atrium, right atrium, and the univentricular heart. As echocardiography continues to be the imaging modality of choice for these measurements, the strengths and limitations of M-mode, two-dimensional (2D), and recently three-dimensional (3D) echocardiographic (3DE) methodologies for accurate and reproducible measurement of these indices have been extensively investigated for congenital and acquired heart diseases. Evidence suggests that 3DE provides improved accuracy and reproducibility over 2D methods for measurement of LV volume and function calculation in adults and in children. Data have accumulated on the utility of 3DE for measuring chamber volumes and function for the RV and for the single ventricle, which may become more widely used in clinical and research arenas in the future. Finally, new advanced modes of analysis such as 3D strain and synchrony analysis by 3DE are promising methodologies that warrant further investigation.

  19. Food Security in Households of People Living With Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome: A Cross-sectional Study in a Subdivision of Darjeeling District, West Bengal

    PubMed Central

    2016-01-01

    Objectives: Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) adversely impacts food security in households of people living with HIV/AIDS (PLWHA). Little research has focused on food insecurity among PLWHA in India. The purpose of this study was to identify the prevalence of and factors relating to food security in households of PLWHA in the Siliguri subdivision of Darjeeling, West Bengal, India. Methods: A cross-sectional community-based study was carried out among 173 PLWHA residing in Siliguri and registered at the Anti-retroviral Therapy Centre of North Bengal Medical College & Hospital. Data was collected at the household level with interviews of PLWHA using a food security survey instrument. We analyzed the associations using logistic regression. Results: The prevalence of household food security among the participants was 50.9% (88/173). Five years or more of schooling, higher socioeconomic class and males were found to be significantly associated with a higher likelihood of food security. A later stage of the disease and the presence of other family members with HIV/AIDS were significantly associated with a lower likelihood of food security. The major coping strategies to deal with food insecurity in the acute phase HIV infection included borrowing money (56.1%), followed by spousal support, loans from microfinance institutions, banks, or money lenders, borrowing food, or selling agricultural products. Conclusions: The present study revealed that only about half of households with PLWHA were food secure. Prior interventions relating to periods of food and economic crisis as well as strategies for sustaining food security and economic status are needed in this area. PMID:27499166

  20. Influence of the home environment on the prevention of mother to child transmission of human immunodeficiency virus/acquired immune-deficiency syndrome in South Africa.

    PubMed

    Sewnunan, A; Modiba, L M

    2015-01-01

    The human immunodeficiency virus and acquired immune-deficiency syndrome (HIV/AIDS) is still a 'family crises' which marks the beginning of the deterioration of the family unit and the trauma in the emotional, psychological and material lives of both the mother and child. In South African context where the majority of HIV-positive mothers are young single women who live in extended families, disclosure to the sexual partner alone is not an adequate condition for the success of prevention of mother to child transmission (PMTCT). In South Africa, close to one in three women who attend antenatal clinics are HIV positive. KwaZulu-Natal is one of the worst affected provinces, where as many as 40-60% of pregnant women attending antenatal services are living with HIV infection. The study sought to investigate the link between the home environment and its contribution to the success of the programme on PMTCT of HIV/AIDS. A qualitative, explorative, descriptive and contextual study was used in this study to explore whether the home environment for the support system is available for the HIV-positive women on the PMTCT programme. The population of this study included all women who have undergone counselling and tested HIV positive and who have joined the programme on PMTCT of HIV/AIDS in a specific hospital in KwaZulu-Natal Province. Although 14 women agreed to participate in the study, only 10 women were interviewed as saturation was attained. Data were collected using semi-structured interview schedule. Interviews were audio-taped and field notes were taken. Content analysis was used and it was done manually. This study revealed that one of the major issues still surrounding HIV/AIDS and PMTCT is that of non-disclosure, selective disclosure and the stigma and discrimination that surrounds this disease. PMID:26694631

  1. Influence of the home environment on the prevention of mother to child transmission of human immunodeficiency virus/acquired immune-deficiency syndrome in South Africa.

    PubMed

    Sewnunan, A; Modiba, L M

    2015-01-01

    The human immunodeficiency virus and acquired immune-deficiency syndrome (HIV/AIDS) is still a 'family crises' which marks the beginning of the deterioration of the family unit and the trauma in the emotional, psychological and material lives of both the mother and child. In South African context where the majority of HIV-positive mothers are young single women who live in extended families, disclosure to the sexual partner alone is not an adequate condition for the success of prevention of mother to child transmission (PMTCT). In South Africa, close to one in three women who attend antenatal clinics are HIV positive. KwaZulu-Natal is one of the worst affected provinces, where as many as 40-60% of pregnant women attending antenatal services are living with HIV infection. The study sought to investigate the link between the home environment and its contribution to the success of the programme on PMTCT of HIV/AIDS. A qualitative, explorative, descriptive and contextual study was used in this study to explore whether the home environment for the support system is available for the HIV-positive women on the PMTCT programme. The population of this study included all women who have undergone counselling and tested HIV positive and who have joined the programme on PMTCT of HIV/AIDS in a specific hospital in KwaZulu-Natal Province. Although 14 women agreed to participate in the study, only 10 women were interviewed as saturation was attained. Data were collected using semi-structured interview schedule. Interviews were audio-taped and field notes were taken. Content analysis was used and it was done manually. This study revealed that one of the major issues still surrounding HIV/AIDS and PMTCT is that of non-disclosure, selective disclosure and the stigma and discrimination that surrounds this disease.

  2. Histoplasmosis in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS): multicenter study of outcomes and factors associated with relapse.

    PubMed

    Myint, Thein; Anderson, Albert M; Sanchez, Alejandro; Farabi, Alireza; Hage, Chadi; Baddley, John W; Jhaveri, Malhar; Greenberg, Richard N; Bamberger, David M; Rodgers, Mark; Crawford, Timothy N; Wheat, L Joseph

    2014-01-01

    Although discontinuation of suppressive antifungal therapy for acquired immunodeficiency syndrome (AIDS)-associated histoplasmosis is accepted for patients with immunologic recovery, there have been no published studies of this approach in clinical practice, and minimal characterization of individuals who relapse with this disease. We performed a multicenter retrospective cohort study to determine the outcome in AIDS patients following discontinuation of suppressive antifungal therapy for histoplasmosis. Ninety-seven patients were divided into a physician-discontinued suppressive therapy group (PD) (38 patients) and a physician-continued suppressive therapy group (PC) (59 patients). The 2 groups were not statistically different at baseline, but at discontinuation of therapy and at the most recent follow-up there were significant differences in adherence to therapy, human immunodeficiency virus (HIV) RNA, and urinary Histoplasma antigen concentration. There was no relapse or death attributed to histoplasmosis in the PD group compared with 36% relapse (p < 0.0001) and 5% death (p = 0.28) in the PC group. Relapse occurred in 53% of the nonadherent patients but not in the adherent patients (p < 0.0001). Sixty-seven percent of patients with initial central nervous system (CNS) histoplasmosis relapsed compared to 15% of patients without CNS involvement (p = 0.0004), which may be accounted for by nonadherence. In addition, patients with antigenuria above 2.0 ng/mL at 1-year follow-up were 12.82 times (95% confidence interval, 2.91-55.56) more likely to relapse compared to those with antigenuria below 2.0 ng/mL. Discontinuation of antifungal therapy was safe in adherent patients who completed at least 1 year of antifungal treatment, and had CD4 counts >150 cells/mL, HIV RNA <400 c/mL, Histoplasma antigenuria <2 ng/mL (equivalent to <4.0 units in second-generation method), and no CNS histoplasmosis.

  3. Continuous administration of bevacizumab plus capecitabine, even after acquired resistance to bevacizumab, restored anti-angiogenic and antitumor effect in a human colorectal cancer xenograft model

    PubMed Central

    Iwai, Toshiki; Sugimoto, Masamichi; Harada, Suguru; Yorozu, Keigo; Kurasawa, Mitsue; Yamamoto, Kaname

    2016-01-01

    Vascular endothelial growth factor (VEGF)-neutralizing therapy with bevacizumab has become increasingly important for treating colorectal cancer. It was demonstrated that second-line chemotherapy together with bevacizumab after disease progression (PD) on first-line therapy including bevacizumab showed clinical benefits in metastatic colorectal and breast cancers (ML18147 trial, TANIA trial). One of the rationales for these trials was that the refractoriness to first-line therapy is caused by resistance to not so much bevacizumab as to the chemotherapeutic agents. Nevertheless, resistance to bevacizumab cannot be ruled out because VEGF-independent angiogenesis has been reported to be a mechanism of resistance to anti-VEGF therapy. In this study, we used a xenograft model with the human colon cancer HT-29 cells to investigate the mechanisms underlying the effect of continued administration of bevacizumab plus capecitabine even after resistance to bevacizumab was acquired. The combination of capecitabine plus bevacizumab exhibited significantly stronger antitumor and anti-angiogenic activities than did monotherapy with either agent. Capecitabine treatment significantly increased the intratumoral VEGF level compared with the control group; however, the combination with bevacizumab neutralized the VEGF. Among angiogenic factors other than VEGF, intratumoral galectin-3, which reportedly promotes angiogenesis both dependent on, and independently of VEGF, was significantly decreased in the capecitabine group and the combination group compared with the control group. In an in vitro experiment, 5-fluorouracil (5-FU), an active metabolite of capecitabine, inhibited galectin-3 production by HT-29 cells. These results suggested that capecitabine has a dual mode of action: namely, inhibition of tumor cell growth and inhibition of galectin-3 production by tumor cells. Thus, capecitabine and bevacizumab may work in a mutually complementary manner in tumor angiogenesis inhibition

  4. Community-acquired pneumonia.

    PubMed

    Falguera, M; Ramírez, M F

    2015-11-01

    This article not only reviews the essential aspects of community-acquired pneumonia for daily clinical practice, but also highlights the controversial issues and provides the newest available information. Community-acquired pneumonia is considered in a broad sense, without excluding certain variants that, in recent years, a number of authors have managed to delineate, such as healthcare-associated pneumonia. The latter form is nothing more than the same disease that affects more frail patients, with a greater number of risk factors, both sharing an overall common approach. PMID:26186969

  5. Community-acquired pneumonia.

    PubMed

    Falguera, M; Ramírez, M F

    2015-11-01

    This article not only reviews the essential aspects of community-acquired pneumonia for daily clinical practice, but also highlights the controversial issues and provides the newest available information. Community-acquired pneumonia is considered in a broad sense, without excluding certain variants that, in recent years, a number of authors have managed to delineate, such as healthcare-associated pneumonia. The latter form is nothing more than the same disease that affects more frail patients, with a greater number of risk factors, both sharing an overall common approach.

  6. [Comment on the intervention of Traditional Chinese Medicine on survival rates of patients living with human immunodeficiency virus and acquired immune deficiency syndrome].

    PubMed

    Li, Qiang; Liu, Zhibin; Yang, Jiping; Guo, Huijun; Xu, Liran

    2016-06-01

    Despite many differences between Traditional Chinese Medicine (TCM) and conventional medicine, the use of TCM in the treatment of human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) is increasingly recognized and accepted by patients. Recent research findings on the benefits of Chinese herbal medicine on long-term survival in patients with HIV/AIDS are encouraging and hopeful, but inconclusive. More research is needed.

  7. Disease emergence and resurgence: the wildlife-human connection

    USGS Publications Warehouse

    Friend, Milton

    2006-01-01

    In 2000, the Global Outbreak Alert and Response Network (GOARN) was organized as a global disease watchdog group to coordinate disease outbreak information and health crisis response. The World Health Organization (WHO) is the headquarters for this network.2 Understandably, the primary focus for WHO is human health. However, diseases such as the H5N1 avian influenza epizootic in Asian bird populations demonstrate the need for integrating knowledge about disease emergence in animals and in humans.

  8. Human Lyme disease vaccines: past and future concerns.

    PubMed

    Nardelli, Dean T; Munson, Erik L; Callister, Steven M; Schell, Ronald F

    2009-05-01

    The development of a vaccine for Lyme disease was intensely pursued in the 1990s. However, citing a lack of demand, the first human Lyme disease vaccine was withdrawn from the market less than 5 years after its approval. The public's concerns about the vaccine's safety also likely contributed to the withdrawal of the vaccine. Nearly a decade later, no vaccine for human Lyme disease exists. The expansion of Lyme disease's endemic range, as well as the difficulty of diagnosing infection and the disease's steady increase in incidence in the face of proven preventative measures, make the pursuit of a Lyme disease vaccine a worthwhile endeavor. Many believe that the negative public perception of the Lyme disease vaccine will have tarnished any future endeavors towards its development. Importantly, many of the drawbacks of the Lyme disease vaccine were apparent or foreseeable prior to its approval. These pitfalls must be confronted before the construction of a new, effective and safe human Lyme disease vaccine.

  9. Drosophila as a model for human neurodegenerative disease.

    PubMed

    Bilen, Julide; Bonini, Nancy M

    2005-01-01

    Among many achievements in the neurodegeneration field in the past decade, two require special attention due to the huge impact on our understanding of molecular and cellular pathogenesis of human neurodegenerative diseases. First is defining specific mutations in familial neurodegenerative diseases and second is modeling these diseases in easily manipulable model organisms including the fruit fly, nematode, and yeast. The power of these genetic systems has revealed many genetic factors involved in the various pathways affected, as well as provided potential drug targets for therapeutics. This review focuses on fruit fly models of human neurodegenerative diseases, with emphasis on how fly models have provided new insights into various aspects of human diseases.

  10. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression

    PubMed Central

    Munawwar, Arshi; Singh, Sarman

    2016-01-01

    Of eight human herpesviruses (HHVs), often, only herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) find mention in medical literature as both of these viruses are commonly associated with genital lesions and oral ulcers, commonly known as cold sores. However, role of human herpesviruses as copathogens and in aggravation and in the transmission of other human diseases, especially the Acquired immunodeficiency syndrome (HIV/AIDS) has only very recently been recognized. Therefore, screening and treating subclinical HHV infections may offer slowing of HIV infection, disease progression, and its transmission. Beside HSV-1 and HSV-2, HHV-3 a causative agent of herpes zoster remained one of the first manifestations of HIV disease before the era of highly active antiretroviral therapy (HAART). HHV-5 also known as human Cytomegalovirus infection remains a significant risk factor for HIV-associated mortality and morbidity even in HAART era. It is proposed that Cytomegalovirus viremia could be a better predictor of HIV disease progression than CD4+ T-lymphocyte count. The role of HHV-4 or Epstein–Burr virus and HHV-6, HHV-7, and HHV-8 is still being investigated in HIV disease progression. This review provides insight into the current understanding about these 8 HHVs, their co-pathogenesis, and role in HIV/AIDS disease progression. The review also covers recent literature in favor and against administering anti-HHV treatment along with HAART for slower AIDS progression and interrupted sexual transmission. PMID:27013807

  11. [Community acquired pneumonia in children: Treatment of complicated cases and risk patients. Consensus statement by the Spanish Society of Paediatric Infectious Diseases (SEIP) and the Spanish Society of Paediatric Chest Diseases (SENP)].

    PubMed

    Moreno-Pérez, D; Andrés Martín, A; Tagarro García, A; Escribano Montaner, A; Figuerola Mulet, J; García García, J J; Moreno-Galdó, A; Rodrigo Gonzalo de Lliria, C; Saavedra Lozano, J

    2015-09-01

    The incidence of community-acquired pneumonia complications has increased during the last decade. According to the records from several countries, empyema and necrotizing pneumonia became more frequent during the last few years. The optimal therapeutic approach for such conditions is still controversial. Both pharmacological management (antimicrobials and fibrinolysis), and surgical management (pleural drainage and video-assisted thoracoscopic surgery), are the subject of continuous assessment. In this paper, the Spanish Society of Paediatric Infectious Diseases and the Spanish Society of Paediatric Chest Diseases have reviewed the available evidence. Consensus treatment guidelines are proposed for complications of community-acquired pneumonia in children, focusing on parapneumonic pleural effusion. Recommendations are also provided for the increasing population of patients with underlying diseases and immunosuppression.

  12. [Community acquired pneumonia in children: Treatment of complicated cases and risk patients. Consensus statement by the Spanish Society of Paediatric Infectious Diseases (SEIP) and the Spanish Society of Paediatric Chest Diseases (SENP)].

    PubMed

    Moreno-Pérez, D; Andrés Martín, A; Tagarro García, A; Escribano Montaner, A; Figuerola Mulet, J; García García, J J; Moreno-Galdó, A; Rodrigo Gonzalo de Lliria, C; Saavedra Lozano, J

    2015-09-01

    The incidence of community-acquired pneumonia complications has increased during the last decade. According to the records from several countries, empyema and necrotizing pneumonia became more frequent during the last few years. The optimal therapeutic approach for such conditions is still controversial. Both pharmacological management (antimicrobials and fibrinolysis), and surgical management (pleural drainage and video-assisted thoracoscopic surgery), are the subject of continuous assessment. In this paper, the Spanish Society of Paediatric Infectious Diseases and the Spanish Society of Paediatric Chest Diseases have reviewed the available evidence. Consensus treatment guidelines are proposed for complications of community-acquired pneumonia in children, focusing on parapneumonic pleural effusion. Recommendations are also provided for the increasing population of patients with underlying diseases and immunosuppression. PMID:25617977

  13. Consanguinity, human evolution, and complex diseases

    PubMed Central

    Bittles, A. H.; Black, M. L.

    2010-01-01

    There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F ≥ 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is ≈3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates. PMID:19805052

  14. Human polyoma viruses and disease with emphasis on clinical BK and JC.

    PubMed

    Boothpur, Raghavender; Brennan, Daniel C

    2010-04-01

    Polyoma viruses are ubiquitous infecting many different mammalian species including humans. There are five known human polyoma viruses. JC virus and BK virus are two polyoma viruses identified nearly three decades ago. Recently WU, KI and Merkel cell polyoma viruses have been isolated from humans. The exact role of these three newly discovered viruses in human disease is not known. Most human polyoma disease is caused by BK and JC viruses which are usually acquired in childhood. Approximately 50-80% of humans have seropositivity to these viruses. Clinically apparent diseases in immunocompetent hosts are extremely rare. These viruses remain latent possibly in the lymphoid organs, neuronal tissue, and kidney and under the circumstances of severe immunosuppression both these viruses reactivate. Neurotropic JC virus reaches the brain and causes progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system with a high mortality rate. BK virus is urotheliotropic and its reactivation causes a form of interstitial nephritis, known as BK or polyoma virus associated nephropathy which is associated with high graft loss if not recognized early. There are no known effective antiviral agents for any of the polyoma viruses.

  15. Risk of Newly Detected Infections and Cervical Abnormalities in Women Seropositive for Naturally Acquired Human Papillomavirus Type 16/18 Antibodies: Analysis of the Control Arm of PATRICIA

    PubMed Central

    Castellsagué, Xavier; Naud, Paulo; Chow, Song-Nan; Wheeler, Cosette M.; Germar, Maria Julieta V.; Lehtinen, Matti; Paavonen, Jorma; Jaisamrarn, Unnop; Garland, Suzanne M.; Salmerón, Jorge; Apter, Dan; Kitchener, Henry; Teixeira, Julio C.; Skinner, S. Rachel; Limson, Genara; Szarewski, Anne; Romanowski, Barbara; Aoki, Fred Y.; Schwarz, Tino F.; Poppe, Willy A. J.; Bosch, F. Xavier; de Carvalho, Newton S.; Peters, Klaus; Tjalma, Wiebren A. A.; Safaeian, Mahboobeh; Raillard, Alice; Descamps, Dominique; Struyf, Frank; Dubin, Gary; Rosillon, Dominique; Baril, Laurence

    2014-01-01

    Background. We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681). Methods. Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15–25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463]). Results. High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242–794), 204 (95% CI, 129–480), and 480 (95% CI, 250–5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively. Conclusions. Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type. PMID:24610876

  16. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

    PubMed

    Kalil, Andre C; Metersky, Mark L; Klompas, Michael; Muscedere, John; Sweeney, Daniel A; Palmer, Lucy B; Napolitano, Lena M; O'Grady, Naomi P; Bartlett, John G; Carratalà, Jordi; El Solh, Ali A; Ewig, Santiago; Fey, Paul D; File, Thomas M; Restrepo, Marcos I; Roberts, Jason A; Waterer, Grant W; Cruse, Peggy; Knight, Shandra L; Brozek, Jan L

    2016-09-01

    It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.These guidelines are intended for use by healthcare professionals who care for patients at risk for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), including specialists in infectious diseases, pulmonary diseases, critical care, and surgeons, anesthesiologists, hospitalists, and any clinicians and healthcare providers caring for hospitalized patients with nosocomial pneumonia. The panel's recommendations for the diagnosis and treatment of HAP and VAP are based upon evidence derived from topic-specific systematic literature reviews. PMID:27418577

  17. Clinical, Paraclinical, and Antimicrobial Resistance Features of Community-Acquired Acute Bacterial Meningitis at a Large Infectious Diseases Ward in Tehran, Iran.

    PubMed

    Heydari, Behrooz; Khalili, Hossein; Karimzadeh, Iman; Emadi-Kochak, Hamid

    2016-01-01

    In this study demographic, clinical, paraclinical, microbiological, and therapeutic features of patients with community-acquired acute bacterial meningitis admitted to a referral center for infectious diseases in Iran, have been evaluated. Medical records of adult (> 18 years) individuals with confirmed diagnosis of community-acquired bacterial meningitis during a 4-year period were retrospectively reviewed. All required data were obtained from patients' medical charts. Available findings about antimicrobial susceptibility of isolated bacteria from CSF and/or blood were also collected. Kirby-Bauer disc diffusion method was used to determine their antimicrobial susceptibility profile. Details of medical management including antibiotic regimen, duration, patients' outcome, and possible sequelae of meningitis were recorded. The most commonly isolated microorganism from CSF or blood of patients was Streptococcus pneumonia (33.33%) followed by Neisseria meningitidis (27.78%) and Haemophilus influenza (16.67%). The most common antimicrobial regimen was ceftriaxone plus vancomycin (69.44%) followed by ceftriaxone plus vancomycin plus ampicillin (11.11%). Neurological sequelae of meningitis including cranial nerve palsy, deafness, and hemiparesis were identified in 4 (11.11%), 2 (5.56%), and 1 (2.78%) subjects, respectively. Regarding mortality, only 3 (8.33%) patients died from bacterial meningitis and the remaining 33 individuals discharged from the hospital. In conclusion, findings of the current study demonstrated that the mean incidence of acute bacterial meningitis in a referral infectious diseases ward in Iran was 9 episodes per year. The majority cases of community-acquired acute bacterial meningitis admitted to our center had negative CSF culture and classic triad of meningitis was absent in them. PMID:27610176

  18. Clinical, Paraclinical, and Antimicrobial Resistance Features of Community-Acquired Acute Bacterial Meningitis at a Large Infectious Diseases Ward in Tehran, Iran

    PubMed Central

    Heydari, Behrooz; Khalili, Hossein; Karimzadeh, Iman; Emadi-Kochak, Hamid

    2016-01-01

    In this study demographic, clinical, paraclinical, microbiological, and therapeutic features of patients with community-acquired acute bacterial meningitis admitted to a referral center for infectious diseases in Iran, have been evaluated. Medical records of adult (> 18 years) individuals with confirmed diagnosis of community-acquired bacterial meningitis during a 4-year period were retrospectively reviewed. All required data were obtained from patients’ medical charts. Available findings about antimicrobial susceptibility of isolated bacteria from CSF and/or blood were also collected. Kirby-Bauer disc diffusion method was used to determine their antimicrobial susceptibility profile. Details of medical management including antibiotic regimen, duration, patients’ outcome, and possible sequelae of meningitis were recorded. The most commonly isolated microorganism from CSF or blood of patients was Streptococcus pneumonia (33.33%) followed by Neisseria meningitidis (27.78%) and Haemophilus influenza (16.67%). The most common antimicrobial regimen was ceftriaxone plus vancomycin (69.44%) followed by ceftriaxone plus vancomycin plus ampicillin (11.11%). Neurological sequelae of meningitis including cranial nerve palsy, deafness, and hemiparesis were identified in 4 (11.11%), 2 (5.56%), and 1 (2.78%) subjects, respectively. Regarding mortality, only 3 (8.33%) patients died from bacterial meningitis and the remaining 33 individuals discharged from the hospital. In conclusion, findings of the current study demonstrated that the mean incidence of acute bacterial meningitis in a referral infectious diseases ward in Iran was 9 episodes per year. The majority cases of community-acquired acute bacterial meningitis admitted to our center had negative CSF culture and classic triad of meningitis was absent in them. PMID:27610176

  19. Sexually Transmitted Diseases as a Risk for Acquiring HIV Infection among the Population of Men Who Have Sex with Men--A Case-Control Study.

    PubMed

    Lakoseljac, Danijela; Gjenero-Margan, Ira; Kolarić, Branko; Rukavina, Tomislav; Blazić, Tatjana Nemeth

    2015-09-01

    At the beginning of the 1980-ies, HIV infection and AIDS were described for the first time, this among the population of men who have sex with other men. Nearly thirty years later, the MSM population is still a population under heightened risk for acquiring HIV infection and other sexually transmitted diseases. This study investigates sexually transmitted diseases as a risk for HIV infection. A total of 296 men who have sex with men (MSM) were included in this case control study. Differences among the frequencies of sexually transmitted diseases among the MSM of HIV positive and HIV negative status were tested. The history of HIV positive more often states falling ill with sexually transmitted diseases than this was the case before they became HIV positive, unlike those MSM who are not HIV infected (45.9%:11.1% that is OR 6.79, 95% CI 3.49-13.19). Hepatitis B infection is more frequent in HIV positive MSM (11.5%:1.9%; OR 6.58, 95% CI 1.86-23.3). The frequency of gonorrhea in case history of HIV positive MSM is significantly higher than in the HIV negative group (11.5%:3.8%, OR 3.24, 95% CI 1.13-9.34). In the group of HIV positive MSM, unlike the HIV negative group, syphilis (14.8:1.0%, OR 1774, 95% CI 3.43-122.87) and genital herpes (8.2%:0.5%, OR 18.39, 95% CI 2.03-424.7) are more frequent. The results of this study will be used in future preventive activities focused on the population of MSM, as a population under particular risk for acquiring sexually transmitted infections. PMID:26898074

  20. Clinical Outcomes of Thirteen Patients with Acute Chagas Disease Acquired through Oral Transmission from Two Urban Outbreaks in Northeastern Brazil

    PubMed Central

    Bastos, Claudilson J. C.; Aras, Roque; Mota, Gildo; Reis, Francisco; Dias, Juarez Pereira; de Jesus, Robson Silva; Freire, Miralba Silva; de Araújo, Eline G.; Prazeres, Juliana; Grassi, Maria Fernanda Rios

    2010-01-01

    Background Outbreaks of orally transmitted Trypanosoma cruzi continue to be reported in Brazil and are associated with a high mortality rate, mainly due to myocarditis. Methods This study is a detailed report on the disease progression of acute Chagas disease in 13 patients who were infected during two micro-outbreaks in two northeastern Brazilian towns. Clinical outcomes as well as EKG and ECHO results are described, both before and after benznidazole treatment. Results Fever and dyspnea were the most frequent symptoms observed. Other clinical findings included myalgia, periorbital edema, headache and systolic murmur. Two patients died of cardiac failure before receiving benznidazole treatment. EKG and ECHO findings frequently showed a disturbance in ventricular repolarization and pericardial effusion. Ventricular dysfunction (ejection fraction <55%) was present in 27.3% of patients. After treatment, EKG readings normalized in 91.7% of patients. Ventricular repolarization abnormalities persisted in 50% of the patients, while sinus bradycardia was observed in 18%. The systolic ejection fraction normalized in two out of three patients with initially depressed ventricular function, while pericardial effusion disappeared. Conclusions Myocarditis is frequently found and potentially severe in patients with acute Chagas disease. Benznidazole treatment may improve clinical symptoms, as well as EKG and ECHO findings. PMID:20559542

  1. The oral microbiome diversity and its relation to human diseases.

    PubMed

    He, Jinzhi; Li, Yan; Cao, Yangpei; Xue, Jin; Zhou, Xuedong

    2015-01-01

    As one of the most clinically relevant human habitats, the human mouth is colonized by a set of microorganisms, including bacteria, archaea, fungi, and viruses. Increasing evidence has supported that these microbiota contribute to the two commonest oral diseases of man (dental caries and periodontal diseases), presenting significant risk factors to human health conditions, such as tumor, diabetes mellitus, cardiovascular diseases, bacteremia, preterm birth, and low birth weight in infants. It is widely accepted that oral microorganisms cause diseases mainly by a synergistic or cooperative way, and the interspecies interactions within the oral community play a crucial role in determining whether oral microbiota elicit diseases or not. Since a comprehensive understanding of the complex interspecies interactions within a community needs the knowledge of its endogenous residents, a plenty of research have been carried out to explore the oral microbial diversity. In this review, we focus on the recent progress in this field, including the oral microbiome composition and its association with human diseases.

  2. Human Pluripotent Stem Cells: Applications and Challenges in Neurological Diseases

    PubMed Central

    Hibaoui, Youssef; Feki, Anis

    2012-01-01

    The ability to generate human pluripotent stem cells (hPSCs) holds great promise for the understanding and the treatment of human neurological diseases in modern medicine. The hPSCs are considered for their in vitro use as research tools to provide relevant cellular model for human diseases, drug discovery, and toxicity assays and for their in vivo use in regenerative medicine applications. In this review, we highlight recent progress, promises, and challenges of hPSC applications in human neurological disease modeling and therapies. PMID:22934023

  3. Geographic Distribution and Expansion of Human Lyme Disease, United States.

    PubMed

    Kugeler, Kiersten J; Farley, Grace M; Forrester, Joseph D; Mead, Paul S

    2015-08-01

    Lyme disease occurs in specific geographic regions of the United States. We present a method for defining high-risk counties based on observed versus expected number of reported human Lyme disease cases. Applying this method to successive periods shows substantial geographic expansion of counties at high risk for Lyme disease.

  4. Induced pluripotent stem cells for modelling human diseases

    PubMed Central

    Unternaehrer, Juli J.; Daley, George Q.

    2011-01-01

    Research into the pathophysiological mechanisms of human disease and the development of targeted therapies have been hindered by a lack of predictive disease models that can be experimentally manipulated in vitro. This review describes the current state of modelling human diseases with the use of human induced pluripotent stem (iPS) cell lines. To date, a variety of neurodegenerative diseases, haematopoietic disorders, metabolic conditions and cardiovascular pathologies have been captured in a Petri dish through reprogramming of patient cells into iPS cells followed by directed differentiation of disease-relevant cells and tissues. However, realizing the true promise of iPS cells for advancing our basic understanding of disease and ultimately providing novel cell-based therapies will require more refined protocols for generating the highly specialized cells affected by disease, coupled with strategies for drug discovery and cell transplantation. PMID:21727133

  5. The human RBPome: from genes and proteins to human disease.

    PubMed

    Neelamraju, Yaseswini; Hashemikhabir, Seyedsasan; Janga, Sarath Chandra

    2015-09-01

    RNA binding proteins (RBPs) play a central role in mediating post transcriptional regulation of genes. However less is understood about them and their regulatory mechanisms. In this study, we construct a catalogue of 1344 experimentally confirmed RBPs. The domain architecture of RBPs enabled us to classify them into three groups - Classical (29%), Non-classical (19%) and unclassified (52%). A higher percentage of proteins with unclassified domains reveals the presence of various uncharacterised motifs that can potentially bind RNA. RBPs were found to be highly disordered compared to Non-RBPs (p<2.2e-16, Fisher's exact test), suggestive of a dynamic regulatory role of RBPs in cellular signalling and homeostasis. Evolutionary analysis in 62 different species showed that RBPs are highly conserved compared to Non-RBPs (p<2.2e-16, Wilcox-test), reflecting the conservation of various biological processes like mRNA splicing and ribosome biogenesis. The expression patterns of RBPs from human proteome map revealed that ~40% of them are ubiquitously expressed and ~60% are tissue-specific. RBPs were also seen to be highly associated with several neurological disorders, cancer and inflammatory diseases. Anatomical contexts like B cells, T-cells, foetal liver and foetal brain were found to be strongly enriched for RBPs, implying a prominent role of RBPs in immune responses and different developmental stages. The catalogue and meta-analysis presented here should form a foundation for furthering our understanding of RBPs and the cellular networks they control, in years to come. This article is part of a Special Issue entitled: Proteomics in India. PMID:25982388

  6. Acquired immunodeficiency syndrome/human immunodeficiency virus knowledge, attitudes, and practices, and use of healthcare services among rural migrants: a cross-sectional study in China

    PubMed Central

    2014-01-01

    Background Today’s rapid growth of migrant populations has been a major contributor to the human immunodeficiency virus (HIV) epidemic. However, relatively few studies have focused on HIV/acquired immunodeficiency syndrome (AIDS)-related knowledge, attitudes, and practice among rural-to-urban migrants in China. This cross-sectional study was to assess HIV/AIDS-related knowledge and perceptions, including knowledge about reducing high-risk sex. Methods Two-phase stratified cluster sampling was applied and 2,753 rural migrants participated in this study. An anonymous self-administered questionnaire was conducted in Guangdong and Sichuan provinces in 2007. Descriptive analysis was used to present the essential characteristics of the respondents. Chi-square test and multiple logistic regression models were performed to examine the associations between identified demographic factors and high-risk sex, sexually transmitted disease (STD) symptoms, and access to HIV screening services among the seven types of workers. Results 58.6% of participants were knowledgeable about HIV/AIDS transmission, but approximately 90% had a negative attitude towards the AIDS patients, and that 6.2% had engaged in high-risk sex in the past 12 months. Logistic regression analysis revealed sex, marital status, income, migration and work experience to be associated with high-risk sex. Among the 13.9% of workers who reported having STD symptoms, risk factors that were identified included female gender, high monthly income, being married, daily laborer or entertainment worker, frequent migration, and length of work experience. Only 3% of migrant workers received voluntary free HIV screening, which was positively associated with monthly income and workplace. Conclusions HIV/AIDS knowledge, attitudes, and practices among rural migrants in China remain a thorny health issue, and use of healthcare services needs to be improved. Low levels of education and knowledge regarding HIV/AIDS among

  7. Extracellular RNAs: development as biomarkers of human disease

    PubMed Central

    Quinn, Joseph F.; Patel, Tushar; Wong, David; Das, Saumya; Freedman, Jane E.; Laurent, Louise C.; Carter, Bob S.; Hochberg, Fred; Keuren-Jensen, Kendall Van; Huentelman, Matt; Spetzler, Robert; Kalani, M. Yashar S.; Arango, Jorge; Adelson, P. David; Weiner, Howard L.; Gandhi, Roopali; Goilav, Beatrice; Putterman, Chaim; Saugstad, Julie A.

    2015-01-01

    Ten ongoing studies designed to test the possibility that extracellular RNAs may serve as biomarkers in human disease are described. These studies, funded by the NIH Common Fund Extracellular RNA Communication Program, examine diverse extracellular body fluids, including plasma, serum, urine and cerebrospinal fluid. The disorders studied include hepatic and gastric cancer, cardiovascular disease, chronic kidney disease, neurodegenerative disease, brain tumours, intracranial haemorrhage, multiple sclerosis and placental disorders. Progress to date and the plans for future studies are outlined. PMID:26320940

  8. Generation of improved humanized mouse models for human infectious diseases

    PubMed Central

    Brehm, Michael A.; Wiles, Michael V.; Greiner, Dale L.; Shultz, Leonard D.

    2014-01-01

    The study of human-specific infectious agents has been hindered by the lack of optimal small animal models. More recently development of novel strains of immunodeficient mice has begun to provide the opportunity to utilize small animal models for the study of many human-specific infectious agents. The introduction of a targeted mutation in the IL2 receptor common gamma chain gene (IL2rgnull) in mice already deficient in T and B cells led to a breakthrough in the ability to engraft hematopoietic stem cells, as well as functional human lymphoid cells and tissues, effectively creating human immune systems in immunodeficient mice. These humanized mice are becoming increasingly important as pre-clinical models for the study of human immunodeficiency virus-1 (HIV-1) and other human-specific infectious agents. However, there remain a number of opportunities to further improve humanized mouse models for the study of human-specific infectious agents. This is being done by the implementation of innovative technologies, which collectively will accelerate the development of new models of genetically modified mice, including; i) modifications of the host to reduce innate immunity, which impedes human cell engraftment; ii) genetic modification to provide human-specific growth factors and cytokines required for optimal human cell growth and function; iii) and new cell and tissue engraftment protocols. The development of “next generation” humanized mouse models continues to provide exciting opportunities for the establishment of robust small animal models to study the pathogenesis of human-specific infectious agents, as well as for testing the efficacy of therapeutic agents and experimental vaccines. PMID:24607601

  9. Using Human Induced Pluripotent Stem Cells to Model Skeletal Diseases.

    PubMed

    Barruet, Emilie; Hsiao, Edward C

    2016-01-01

    Musculoskeletal disorders affecting the bones and joints are major health problems among children and adults. Major challenges such as the genetic origins or poor diagnostics of severe skeletal disease hinder our understanding of human skeletal diseases. The recent advent of human induced pluripotent stem cells (human iPS cells) provides an unparalleled opportunity to create human-specific models of human skeletal diseases. iPS cells have the ability to self-renew, allowing us to obtain large amounts of starting material, and have the potential to differentiate into any cell types in the body. In addition, they can carry one or more mutations responsible for the disease of interest or be genetically corrected to create isogenic controls. Our work has focused on modeling rare musculoskeletal disorders including fibrodysplasia ossificans progressive (FOP), a congenital disease of increased heterotopic ossification. In this review, we will discuss our experiences and protocols differentiating human iPS cells toward the osteogenic lineage and their application to model skeletal diseases. A number of critical challenges and exciting new approaches are also discussed, which will allow the skeletal biology field to harness the potential of human iPS cells as a critical model system for understanding diseases of abnormal skeletal formation and bone regeneration.

  10. De novo mutations in human genetic disease.

    PubMed

    Veltman, Joris A; Brunner, Han G

    2012-08-01

    New mutations have long been known to cause genetic disease, but their true contribution to the disease burden can only now be determined using family-based whole-genome or whole-exome sequencing approaches. In this Review we discuss recent findings suggesting that de novo mutations play a prominent part in rare and common forms of neurodevelopmental diseases, including intellectual disability, autism and schizophrenia. De novo mutations provide a mechanism by which early-onset reproductively lethal diseases remain frequent in the population. These mutations, although individually rare, may capture a significant part of the heritability for complex genetic diseases that is not detectable by genome-wide association studies. PMID:22805709

  11. Targeting xenobiotic receptors PXR and CAR in human diseases

    PubMed Central

    Banerjee, Monimoy; Robbins, Delira; Chen, Taosheng

    2014-01-01

    Nuclear receptors such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenobiotic receptors regulating not only drug metabolism and disposition but also various human diseases such as cancer, diabetes, inflammatory disease, metabolic disease and liver diseases, suggesting that PXR and CAR are promising targets for drug discovery. Consequently, there is an urgent need to discover and develop small molecules that target these PXR- and/or CAR-mediated human-disease-related pathways for relevant therapeutic applications. This review proposes approaches to target PXR and CAR, either individually or simultaneously, in the context of various human diseases, taking into consideration the structural differences between PXR and CAR. PMID:25463033

  12. Spontaneous retroperitoneal hemorrhage presenting as hemoperitoneum secondary to renal cyst rupture in a peritoneal dialysis patient with acquired cystic kidney disease.

    PubMed

    Biyik, Z; Solak, Y; Gaipov, A; Ozbek, O; Esen, H; Turk, S

    2015-01-01

    Spontaneous retroperitoneal hemorrhage (SRH) is a rare and potentially fatal condition. Acquired cystic kidney disease (ACKD) may cause SRH in hemodialysis patients. However, presentation of retroperitoneal hematoma as hemoperitoneum in peritoneal dialysis (PD) patients is exceedingly rare. We report a 44-year-old male PD patient who presented with hemoperitoneum secondary to retroperitoneal hematoma. The reason of SRH was rupture of the cysts of ACKD. The patient underwent unilateral nephrectomy with subsequent disappearance of hemoperitoneum. The importance of this case lies in the fact that the patients who have been receiving dialysis for a long time should be under surveillance in terms of ACKD development and potential associated complications such as cyst hemorrhage and malignancy.

  13. Exploiting the unique regenerative capacity of the liver to underpin cell and gene therapy strategies for genetic and acquired liver disease.

    PubMed

    Logan, Grant J; de Alencastro, Gustavo; Alexander, Ian E; Yeoh, George C

    2014-11-01

    The number of genetic or acquired diseases of the liver treatable by organ transplantation is ever-increasing as transplantation techniques improve placing additional demands on an already limited organ supply. While cell and gene therapies are distinctly different modalities, they offer a synergistic alternative to organ transplant due to distinct architectural and physiological properties of the liver. The hepatic blood supply and fenestrated endothelial system affords relatively facile accessibility for cell and/or gene delivery. More importantly, however, the remarkable capacity of hepatocytes to proliferate and repopulate the liver creates opportunities for new treatments based on emerging technologies. This review will summarise current understanding of liver regeneration, describe clinical and experimental cell and gene therapeutic modalities and discuss critical challenges to translate these new technologies to wider clinical utility. This article is part of a Directed Issue entitled: "Regenerative Medicine: the challenge of translation".

  14. Spontaneous retroperitoneal hemorrhage presenting as hemoperitoneum secondary to renal cyst rupture in a peritoneal dialysis patient with acquired cystic kidney disease

    PubMed Central

    Biyik, Z.; Solak, Y.; Gaipov, A.; Ozbek, O.; Esen, H.; Turk, S.

    2015-01-01

    Spontaneous retroperitoneal hemorrhage (SRH) is a rare and potentially fatal condition. Acquired cystic kidney disease (ACKD) may cause SRH in hemodialysis patients. However, presentation of retroperitoneal hematoma as hemoperitoneum in peritoneal dialysis (PD) patients is exceedingly rare. We report a 44-year-old male PD patient who presented with hemoperitoneum secondary to retroperitoneal hematoma. The reason of SRH was rupture of the cysts of ACKD. The patient underwent unilateral nephrectomy with subsequent disappearance of hemoperitoneum. The importance of this case lies in the fact that the patients who have been receiving dialysis for a long time should be under surveillance in terms of ACKD development and potential associated complications such as cyst hemorrhage and malignancy. PMID:26199480

  15. Generation of Transgenic Monkeys with Human Inherited Genetic Disease

    PubMed Central

    Chan, Anthony W.S; Yang, Shang-Hsun

    2009-01-01

    Modeling human diseases using nonhuman primates including chimpanzee, rhesus, cynomolgus, marmoset and squirrel monkeys has been reported in the past decades. Due to the high similarity between nonhuman primates and humans, including genome constitution, cognitive behavioral functions, anatomical structure, metabolic, reproductive, and brain functions; nonhuman primates have played an important role in understanding physiological functions of the human body, clarifying the underlying mechanism of human diseases, and the development of novel treatments for human diseases. However, nonhuman primate research has been restricted to cognitive, behavioral, biochemical and pharmacological approaches of human diseases due to the limitation of gene transfer technology in nonhuman primates. The recent advancement in transgenic technology that has led to the generation of the first transgenic monkey in 2001 and a transgenic monkey model of Huntington's disease (HD) in 2008 has changed that focus. The creation of transgenic HD monkeys that replicate key pathological features of human HD patients further suggests the crucial role of nonhuman primates in the future development of biomedicine. These successes have opened the door to genetic manipulation in nonhuman primates and a new era in modeling human inherited genetic disorders. We focused on the procedures in creating transgenic Huntington's disease monkeys, but our work can be applied to transgenesis in other nonhuman primate species. PMID:19467335

  16. [Acquired haemophilia (acquired factor VIII inhibitor)].

    PubMed

    Ceresetto, José M; Duboscq, Cristina; Fondevila, Carlos; Tezanos Pinto, Miguel

    2015-01-01

    Acquired haemophilia is a rare disorder. The clinical picture ranges from mild ecchymosis and anaemia to life threatening bleeding in up to 20% of patients. The disease is produced by an antibody against Factor VIII and it usually occurs in the elderly, with no previous history of a bleeding disorder. It can be associated to an underlying condition such as cancer, autoimmune disorders, drugs or pregnancy. It has a typical laboratory pattern with isolated prolonged activated partial thromboplastin time (aPTT) that fails to correct upon mixing tests with normal plasma and low levels of factor VIII. Treatment recommendations are based on controlling the acute bleeding episodes with either bypassing agent, recombinant activated factor VII or activated prothrombin complex concentrate, and eradication of the antibody with immunosuppressive therapy.

  17. Metatranscriptomics of the human oral microbiome during health and disease.

    PubMed

    Jorth, Peter; Turner, Keith H; Gumus, Pinar; Nizam, Nejat; Buduneli, Nurcan; Whiteley, Marvin

    2014-04-01

    The human microbiome plays important roles in health, but when disrupted, these same indigenous microbes can cause disease. The composition of the microbiome changes during the transition from health to disease; however, these changes are often not conserved among patients. Since microbiome-associated diseases like periodontitis cause similar patient symptoms despite interpatient variability in microbial community composition, we hypothesized that human-associated microbial communities undergo conserved changes in metabolism during disease. Here, we used patient-matched healthy and diseased samples to compare gene expression of 160,000 genes in healthy and diseased periodontal communities. We show that health- and disease-associated communities exhibit defined differences in metabolism that are conserved between patients. In contrast, the metabolic gene expression of individual species was highly variable between patients. These results demonstrate that despite high interpatient variability in microbial composition, disease-associated communities display conserved metabolic profiles that are generally accomplished by a patient-specific cohort of microbes. IMPORTANCE The human microbiome project has shown that shifts in our microbiota are associated with many diseases, including obesity, Crohn's disease, diabetes, and periodontitis. While changes in microbial populations are apparent during these diseases, the species associated with each disease can vary from patient to patient. Taking into account this interpatient variability, we hypothesized that specific microbiota-associated diseases would be marked by conserved microbial community behaviors. Here, we use gene expression analyses of patient-matched healthy and diseased human periodontal plaque to show that microbial communities have highly conserved metabolic gene expression profiles, whereas individual species within the community do not. Furthermore, disease-associated communities exhibit conserved changes

  18. Statistical insights into major human muscular diseases.

    PubMed

    Gupta, Shakti; Kim, Sung-Min; Wang, Yu; Dinasarapu, Ashok Reddy; Subramaniam, Shankar

    2014-07-15

    Muscular diseases lead to muscle fiber degeneration, impairment of mobility, and in some cases premature death. Many of these muscular diseases are largely idiopathic. The goal of this study was to identify biomarkers based on their functional role and possible mechanisms of pathogenesis, specific to individual muscular disease. We analyzed the muscle transcriptome from five major muscular diseases: acute quadriplegic myopathy (AQM), amyotrophic lateral sclerosis (ALS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), dermatomyositis (DM) and polymyositis (PM) using pairwise statistical comparison to identify uniquely regulated genes in each muscular disease. The genome-wide information encoded in the transcriptome provided biomarkers and functional insights into dysregulation in each muscular disease. The analysis showed that the dysregulation of genes in forward membrane pathway, responsible for transmitting action potential from neural excitation, is unique to AQM, while the dysregulation of myofibril genes, determinant of the mechanical properties of muscle, is unique to ALS, dysregulation of ER protein processing, responsible for correct protein folding, is unique to DM, and upregulation of immune response genes is unique to PM. We have identified biomarkers specific to each muscular disease which can be used for diagnostic purposes.

  19. Functional Analysis of the Human Genome:. Study of Genetic Disease

    NASA Astrophysics Data System (ADS)

    Tsui, Lap-Chee

    2003-04-01

    I will divide my remarks into 3 parts. First, I will give a brief summary of the Human Genome Project. Second, I will describe our work on human chromosome 7 to illustrate how we could contribute to the Project and disease research. Third, I would like to bring across the argument that study of genetic disease is an integral component of the Human Genome Project. In particular, I will use cystic fibrosis as an example to elaborate why I consider disease study is a part of functional genomics.

  20. Influence of the greenhouse effect on human health through stratospheric cooling: Possible increase in acquired immunodeficient syndrome

    SciTech Connect

    Okamoto, Kazuto; Tsushima, Hiroshi; Tanimoto, Shin

    1996-09-01

    The greenhouse effect cools the stratosphere and increases formation of PSC (polar stratospheric cloud) in polar regions and enhances ozone depletion. If the enhanced ozone depletion diffused to lower latitudes, it could increase ultraviolet radiation (UV), which might increase acquired immunodeficiency syndrome (AIDS). Epidemiological studies are made to test this hypothesis. The relation between AIDS prevalence R and latitude {theta}. Comparison of analyses shows that R of Caucasians would be higher than Non-Caucasians at the same {theta}. These trends are similar to those of skin cancers known to be caused by UV. In developing countries poverty, malnutrition, etc., could cause high R, and since most developing countries are located at low {theta}, the low {theta} increase may be due to these factors. However if so in Africa they are about the same and the low {theta} increase would disappear, but data on African countries also show the low {theta} increase and the significant correlation. Some countries at low {theta} have low R, probably because HIV is not prevalent for them. Then the upper envelope of the distribution of R would be cases when HIV is prevalent and UV is most effective. Therefore analyses are repeated using maxima of R within intervals of {theta} of 1, 3 and 5{degree}. In all cases the low {theta} increase and the correlation becomes more significant. These results support the hypothesis that AIDS is promoted by UV.

  1. Systemic Acquired Resistance

    PubMed Central

    2006-01-01

    Upon infection with necrotizing pathogens many plants develop an enhanced resistance to further pathogen attack also in the uninoculated organs. This type of enhanced resistance is referred to as systemic acquired resistance (SAR). In the SAR state, plants are primed (sensitized) to more quickly and more effectively activate defense responses the second time they encounter pathogen attack. Since SAR depends on the ability to access past experience, acquired disease resistance is a paradigm for the existence of a form of “plant memory”. Although the phenomenon has been known since the beginning of the 20th century, major progress in the understanding of SAR was made over the past sixteen years. This review covers the current knowledge of molecular, biochemical and physiological mechanisms that are associated with SAR. PMID:19521483

  2. Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases

    PubMed Central

    Lintner, Katherine E.; Wu, Yee Ling; Yang, Yan; Spencer, Charles H.; Hauptmann, Georges; Hebert, Lee A.; Atkinson, John P.; Yu, C. Yung

    2016-01-01

    The complement system consists of effector proteins, regulators, and receptors that participate in host defense against pathogens. Activation of the complement system, via the classical pathway (CP), has long been recognized in immune complex-mediated tissue injury, most notably systemic lupus erythematosus (SLE). Paradoxically, a complete deficiency of an early component of the CP, as evidenced by homozygous genetic deficiencies reported in human, are strongly associated with the risk of developing SLE or a lupus-like disease. Similarly, isotype deficiency attributable to a gene copy-number (GCN) variation and/or the presence of autoantibodies directed against a CP component or a regulatory protein that result in an acquired deficiency are relatively common in SLE patients. Applying accurate assay methodologies with rigorous data validations, low GCNs of total C4, and heterozygous and homozygous deficiencies of C4A have been shown as medium to large effect size risk factors, while high copy numbers of total C4 or C4A as prevalent protective factors, of European and East-Asian SLE. Here, we summarize the current knowledge related to genetic deficiency and insufficiency, and acquired protein deficiencies for C1q, C1r, C1s, C4A/C4B, and C2 in disease pathogenesis and prognosis of SLE, and, briefly, for other systemic autoimmune diseases. As the complement system is increasingly found to be associated with autoimmune diseases and immune-mediated diseases, it has become an attractive therapeutic target. We highlight the recent developments and offer a balanced perspective concerning future investigations and therapeutic applications with a focus on early components of the CP in human systemic autoimmune diseases. PMID:26913032

  3. "Miniguts" from plucked human hair meet Crohn's disease.

    PubMed

    Hohwieler, M; Renz, S; Liebau, S; Lin, Q; Lechel, A; Klaus, J; Perkhofer, L; Zenke, M; Seufferlein, T; Illing, A; Müller, M; Kleger, A

    2016-08-01

    Human pluripotent stem cells represent a powerful tool to study human embryonic development and disease but also open up novel strategies for cell replacement therapies. Their capacity to give rise to every cell type of the human body, meanwhile, enables researchers to generate high yields of mesodermal, ectodermal, but also endodermal-derived tissues such as hepatic, pancreatic, or intestinal cells. Another progress in the field came with the advent of 3-dimensional culture conditions, so-called organoids, which facilitate maturation of stem cells and in turn more faithfully recapitulate human tissue architecture. While several studies reported the derivation of organoid cultures from adult intestinal tissue, the derivation of intestinal organoids derived from plucked human hair of Crohn's disease patients has not been reported. The current research project reports such successful generation and characterization of induced pluripotent stem cells (iPSCs) derived from hair sheet keratinocyte cultures of a patient with Crohn's disease. Stepwise differentiation along the intestinal lineage showed no differences in intermediate stages such as definitive endoderm formation. We also directed the patterned primitive gut tube toward intestinal organoids resembling the cellular architecture of human "miniguts". As expected from current pathophysiological knowledge on Crohn's disease, there were no obvious morphological differences in the "miniguts" derived from healthy control and diseased patient-induced pluripotent stem cells. Taken together, our platform will enable for detailed and complementary phenotyping of the pathophysiology of Crohn's disease in a novel disease-in-a-dish format.

  4. Modelling human disease with pluripotent stem cells

    PubMed Central

    Park, In-Hyun; Sullivan, Gareth J.

    2013-01-01

    Recent progress in the field of cellular reprogramming has opened up the doors to a new era of disease modelling, as pluripotent stem cells representing a myriad of genetic diseases can now be produced from patient tissue. These cells can be expanded and differentiated to produce a potentially limitless supply of the affected cell type, which can then be used as a tool to improve understanding of disease mechanisms and test therapeutic interventions. This process requires high levels of scrutiny and validation at every stage, but international standards for the characterisation of pluripotent cells and their progeny have yet to be established. Here we discuss the current state of the art with regard to modelling diseases affecting the ectodermal, mesodermal and endodermal lineages, focussing on studies which have demonstrated a disease phenotype in the tissue of interest. We also discuss the utility of pluripotent cell technology for the modelling of cancer and infectious disease. Finally, we spell out the technical and scientific challenges which must be addressed if the field is to deliver on its potential and produce improved patient outcomes in the clinic. PMID:23444871

  5. A disease model descriptive of progression between chronic obstructive pulmonary disease exacerbations and community-acquired pneumonia: roles for underlying lung disease and the pharmacokinetics/pharmacodynamics of the antibiotic.

    PubMed

    File, Thomas M; Monte, Scott V; Schentag, Jerome J; Paladino, Joseph A; Klugman, Keith P; Lavin, Bruce; Yu, Victor L; Singer, Mendel E; Adelman, Martin H

    2009-01-01

    Patients with chronic obstructive pulmonary disease (COPD) may progress to community-acquired pneumonia (CAP), but there has been no formal study of the factors responsible. We studied the influence of severity of underlying lung disease, pathogen characteristics and the ratio of the area under the concentration-time curve from 0-24h to minimum inhibitory concentration (AUC24/MIC), i.e. the area under the inhibitory curve (AUIC), during the progression from acute exacerbation of chronic bronchitis (AECB) in COPD to CAP. The model parameters were derived from a multinational database of 3885 patients with AECB or CAP (April 1996 to July 2006). Patients with underlying COPD were evaluated in two separate analyses: infection progression between COPD and CAP within Global Initiative for Chronic Obstructive Lung Disease (GOLD)-like grouping (GLG); and distribution of pathogen by GLG, CAP and AECB. Secondary analyses examined the impact of target AUIC attainment on progression to CAP for Streptococcus pneumoniae. The relative impact of GLG and AUIC were modelled in multivariate logistic regression for S. pneumoniae. Progression to CAP linked directly with GLG I/II, III and IV (18.3%, 31.7% and 48.9%, respectively; P < 0.001). Progression to CAP was strongly associated with S. pneumoniae (57.3%), whilst other pathogens were predominant in AECB that did not progress to CAP (61.7%) (P = 0.002). AUIC > or = 100 was associated with AECB (65.1%) and AUIC < 100 with CAP (91.7%) (P < 0.001). In conclusion, the frequency of progression to CAP increases directly with GLG. For S. pneumoniae, achieving an AUIC > or =100 can attenuate progression, regardless of GLG. Thus, AUIC > or = 100 appears to be a viable antibiotic selection strategy to protect patients with S. pneumoniae from developing CAP.

  6. The WOMED model of benign thyroid disease: Acquired magnesium deficiency due to physical and psychological stressors relates to dysfunction of oxidative phosphorylation

    PubMed Central

    Moncayo, Roy; Moncayo, Helga

    2014-01-01

    Background The aim of this study was to discern whether a relation between biochemical parameters, sonography and musculoskeletal data exists in cases of hyperthyroidism and whether they are modifiable through supplementation with selenomethionine and magnesium citrate as well as by acupuncture and manual medicine methods. Results A direct correlation between whole blood selenium and serum magnesium was found in subjects without thyroid disease and in menopausal women while it was reversed in cases of thyroid diseases as well as in patients with depression, infection, and in infertile women. Vascularization indices were elevated in cases of newly diagnosed benign thyroid diseases. Musculoskeletal changes i.e. lateral tension and idiopathic moving toes, as well as situations of physical and psychological stress and minor trauma and infection led to an increase of vascularization. Magnesium levels correlated negatively with these two conditions. The supplementation brought a reduction of the vascularization indices and reduced the incidence of idiopathic moving toes. Treatment of lateral tension required manual medicine methods and acupuncture (gastrocnemius). A small subgroup of patients showed a further reduction of hyper-vascularization after receiving coenzyme Q10. Conclusions We interpret the elevated thyroid vascularization and low magnesium levels as signs of an inflammatory process related to the musculoskeletal changes. Improvement of thyroid function and morphology can be achieved after correcting the influence of stressors together with the supplementation regime. We hypothesize that the central biochemical event in thyroid disease is that of an acquired, altered mitochondrial function due to deficiency of magnesium, selenium, and coenzyme Q10. PMID:26675817

  7. Global Burden of Human Brucellosis: A Systematic Review of Disease Frequency

    PubMed Central

    Dean, Anna S.; Crump, Lisa; Greter, Helena; Schelling, Esther; Zinsstag, Jakob

    2012-01-01

    Background This report presents a systematic review of scientific literature published between 1990–2010 relating to the frequency of human brucellosis, commissioned by WHO. The objectives were to identify high quality disease incidence data to complement existing knowledge of the global disease burden and, ultimately, to contribute towards the calculation of a Disability-Adjusted Life Years (DALY) estimate for brucellosis. Methods/Principal Findings Thirty three databases were searched, identifying 2,385 articles relating to human brucellosis. Based on strict screening criteria, 60 studies were selected for quality assessment, of which only 29 were of sufficient quality for data analysis. Data were only available from 15 countries in the regions of Northern Africa and Middle East, Western Europe, Central and South America, Sub-Saharan Africa, and Central Asia. Half of the studies presented incidence data, six of which were longitudinal prospective studies, and half presented seroprevalence data which were converted to incidence rates. Brucellosis incidence varied widely between, and within, countries. Although study biases cannot be ruled out, demographic, occupational, and socioeconomic factors likely play a role. Aggregated data at national or regional levels do not capture these complexities of disease dynamics and, consequently, at-risk populations or areas may be overlooked. In many brucellosis-endemic countries, health systems are weak and passively-acquired official data underestimate the true disease burden. Conclusions High quality research is essential for an accurate assessment of disease burden, particularly in Eastern Europe, the Asia-Pacific, Central and South America and Africa where data are lacking. Providing formal epidemiological and statistical training to researchers is essential for improving study quality. An integrated approach to disease surveillance involving both human health and veterinary services would allow a better understanding

  8. Genomic responses in mouse models poorly mimic human inflammatory diseases

    PubMed Central

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  9. Engineering Large Animal Species to Model Human Diseases.

    PubMed

    Rogers, Christopher S

    2016-07-01

    Animal models are an important resource for studying human diseases. Genetically engineered mice are the most commonly used species and have made significant contributions to our understanding of basic biology, disease mechanisms, and drug development. However, they often fail to recreate important aspects of human diseases and thus can have limited utility as translational research tools. Developing disease models in species more similar to humans may provide a better setting in which to study disease pathogenesis and test new treatments. This unit provides an overview of the history of genetically engineered large animals and the techniques that have made their development possible. Factors to consider when planning a large animal model, including choice of species, type of modification and methodology, characterization, production methods, and regulatory compliance, are also covered. © 2016 by John Wiley & Sons, Inc.

  10. The human microbiome in rheumatic autoimmune diseases: A comprehensive review.

    PubMed

    Coit, Patrick; Sawalha, Amr H

    2016-09-01

    The human microbiome consists of the total diversity of microbiota and their genes. High-throughput sequencing has allowed for inexpensive and rapid evaluation of taxonomic representation and functional capability of the microbiomes of human body sites. Autoimmune and inflammatory rheumatic diseases are characterized by dysbiosis of the microbiome. Microbiome dysbiosis can be influenced by host genetics and environmental factors. Dysbiosis is also associated with shifts in certain functional pathways. The goal of this article is to provide a current and comprehensive review of the unique characteristics of the microbiome of patients with autoimmune and inflammatory rheumatic diseases, measured using high-throughput sequencing. We also highlight the need for broader studies utilizing a longitudinal approach to better understand how the human microbiome contributes to disease susceptibility, and to characterize the role of the interaction between host genetics and microbial diversity in the pathogenesis of autoimmune diseases, disease manifestations, and progression. PMID:27493014

  11. Role of Epigenetics in Biology and Human Diseases.

    PubMed

    Moosavi, Azam; Motevalizadeh Ardekani, Ali

    2016-11-01

    For a long time, scientists have tried to describe disorders just by genetic or environmental factors. However, the role of epigenetics in human diseases has been considered from a half of century ago. In the last decade, this subject has attracted many interests, especially in complicated disorders such as behavior plasticity, memory, cancer, autoimmune disease, and addiction as well as neurodegenerative and psychological disorders. This review first explains the history and classification of epigenetic modifications, and then the role of epigenetic in biology and connection between the epigenetics and environment are explained. Furthermore, the role of epigenetics in human diseases is considered by focusing on some diseases with some complicated features, and at the end, we have given the future perspective of this field. The present review article provides concepts with some examples to reveal a broad view of different aspects of epigenetics in biology and human diseases.

  12. Engineering Large Animal Species to Model Human Diseases.

    PubMed

    Rogers, Christopher S

    2016-01-01

    Animal models are an important resource for studying human diseases. Genetically engineered mice are the most commonly used species and have made significant contributions to our understanding of basic biology, disease mechanisms, and drug development. However, they often fail to recreate important aspects of human diseases and thus can have limited utility as translational research tools. Developing disease models in species more similar to humans may provide a better setting in which to study disease pathogenesis and test new treatments. This unit provides an overview of the history of genetically engineered large animals and the techniques that have made their development possible. Factors to consider when planning a large animal model, including choice of species, type of modification and methodology, characterization, production methods, and regulatory compliance, are also covered. © 2016 by John Wiley & Sons, Inc. PMID:27367161

  13. Role of Epigenetics in Biology and Human Diseases

    PubMed Central

    Moosavi, Azam; Ardekani, Ali Motevalizadeh

    2016-01-01

    For a long time, scientists have tried to describe disorders just by genetic or environmental factors. However, the role of epigenetics in human diseases has been considered from a half of century ago. In the last decade, this subject has attracted many interests, especially in complicated disorders such as behavior plasticity, memory, cancer, autoimmune disease, and addiction as well as neurodegenerative and psychological disorders. This review first explains the history and classification of epigenetic modifications, and then the role of epigenetic in biology and connection between the epigenetics and environment are explained. Furthermore, the role of epigenetics in human diseases is considered by focusing on some diseases with some complicated features, and at the end, we have given the future perspective of this field. The present review article provides concepts with some examples to reveal a broad view of different aspects of epigenetics in biology and human diseases. PMID:27377127

  14. Role of Epigenetics in Biology and Human Diseases.

    PubMed

    Moosavi, Azam; Motevalizadeh Ardekani, Ali

    2016-11-01

    For a long time, scientists have tried to describe disorders just by genetic or environmental factors. However, the role of epigenetics in human diseases has been considered from a half of century ago. In the last decade, this subject has attracted many interests, especially in complicated disorders such as behavior plasticity, memory, cancer, autoimmune disease, and addiction as well as neurodegenerative and psychological disorders. This review first explains the history and classification of epigenetic modifications, and then the role of epigenetic in biology and connection between the epigenetics and environment are explained. Furthermore, the role of epigenetics in human diseases is considered by focusing on some diseases with some complicated features, and at the end, we have given the future perspective of this field. The present review article provides concepts with some examples to reveal a broad view of different aspects of epigenetics in biology and human diseases. PMID:27377127

  15. Rapidly progressive dementias and the treatment of human prion diseases

    PubMed Central

    Lyketsos, Constantine G

    2012-01-01

    Importance of the field Rapidly progressive dementia (RPD) has many possible etiologies and definitive treatment is reliant upon an accurate diagnosis from an appropriate diagnostic work-up. A large portion of the neurodegenerative causes of RPD are due to prion diseases (e.g., Creutzfeldt–Jakob disease). The study of prion diseases, for which there is no currently available treatment, has public health implications and is becoming increasingly more relevant to our understanding of other protein misfolding disorders including Alzheimer’s disease, frontotemporal degeneration, and Parkinson’s disease. Areas covered in this review This article begins with an overview of the etiologies and diagnostic work-up of RPD followed by a detailed review of the literature concerning the treatment of human prion diseases (1971 to present). What the reader will gain The reader will understand the differential diagnosis and work-up of RPD as it pertains to its treatment, as well as an in-depth understanding of treatments of human prion diseases. Take home message An accurate diagnosis of the cause of RPD is of paramount importance when determining appropriate treatment. Most studies of the treatment for human prion diseases are case reports or case series, and results from only one randomized, placebo-controlled study have been reported in the literature (flupirtine). Studies have been hindered by disease heterogeneity and lack of standardized outcome measures. Although no effective prion disease treatment has been revealed through these studies, they provide important considerations for future studies. PMID:21091283

  16. Computational approaches for human disease gene prediction and ranking.

    PubMed

    Zhu, Cheng; Wu, Chao; Aronow, Bruce J; Jegga, Anil G

    2014-01-01

    While candidate gene association studies continue to be the most practical and frequently employed approach in disease gene investigation for complex disorders, selecting suitable genes to test is a challenge. There are several computational approaches available for selecting and prioritizing disease candidate genes. A majority of these tools are based on guilt-by-association principle where novel disease candidate genes are identified and prioritized based on either functional or topological similarity to known disease genes. In this chapter we review the prioritization criteria and the algorithms along with some use cases that demonstrate how these tools can be used for identifying and ranking human disease candidate genes.

  17. Salicylic Acid and Systemic Acquired Resistance Play a Role in Attenuating Crown Gall Disease Caused by Agrobacterium tumefaciens1[W][OA

    PubMed Central

    Anand, Ajith; Uppalapati, Srinivasa Rao; Ryu, Choong-Min; Allen, Stacy N.; Kang, Li; Tang, Yuhong; Mysore, Kirankumar S.

    2008-01-01

    We investigated the effects of salicylic acid (SA) and systemic acquired resistance (SAR) on crown gall disease caused by Agrobacterium tumefaciens. Nicotiana benthamiana plants treated with SA showed decreased susceptibility to Agrobacterium infection. Exogenous application of SA to Agrobacterium cultures decreased its growth, virulence, and attachment to plant cells. Using Agrobacterium whole-genome microarrays, we characterized the direct effects of SA on bacterial gene expression and showed that SA inhibits induction of virulence (vir) genes and the repABC operon, and differentially regulates the expression of many other sets of genes. Using virus-induced gene silencing, we further demonstrate that plant genes involved in SA biosynthesis and signaling are important determinants for Agrobacterium infectivity on plants. Silencing of ICS (isochorismate synthase), NPR1 (nonexpresser of pathogenesis-related gene 1), and SABP2 (SA-binding protein 2) in N. benthamiana enhanced Agrobacterium infection. Moreover, plants treated with benzo-(1,2,3)-thiadiazole-7-carbothioic acid, a potent inducer of SAR, showed reduced disease symptoms. Our data suggest that SA and SAR both play a major role in retarding Agrobacterium infectivity. PMID:18156296

  18. Skin Diseases: Cross-section of human skin

    MedlinePlus

    Skip Navigation Bar Home Current Issue Past Issues Skin Diseases Cross-section of human skin Past Issues / Fall 2008 Table of Contents For ... Logical Images, Inc. I n the areas of skin health and skin diseases, the NIH's National Institute ...

  19. Immunoregulatory networks in human Chagas disease

    PubMed Central

    Dutra, Walderez O.; Menezes, Cristiane A.S.; Magalhães, Luisa M. D.; Gollob, Kenneth J.

    2014-01-01

    Summary Chagas disease, caused by the infection with Trypanosoma cruzi, is endemic in all Latin America. Due to the increase in population migration, Chagas disease has spread worldwide and is now considered a health issue not only in endemic countries. While most chronically infected individuals remain asymptomatic, approximately 30% of the patients develop a potentially deadly cardiomyopathy. The exact mechanisms that underlie the establishment and maintenance of the cardiac pathology are not clear. However, there is consistent evidence that immunoregulatory cytokines are critical for orchestrating the immune response and, thus, influence disease development or control. While the asymptomatic (indeterminate) form represents a state of balance between the host and the parasite, the establishment of the cardiac form represents the loss of this balance. Analysis of data obtained from several studies have led to the hypothesis that the indeterminate form is associated with an anti-inflammatory cytokine profile, represented by high expression of IL-10, while cardiac form is associated with a high production of IFN-gamma and TNF-alpha in relation to IL-10, leading to an inflammatory profile. Here, we discuss the immunoregulatory events that might influence disease outcome, as well as the mechanisms that influence the establishment of these complex immunoregulatory networks. PMID:24611805

  20. Characteristics and Clinical Management of a Cluster of 3 Patients With Ebola Virus Disease, Including the First Domestically Acquired Cases in the United States

    PubMed Central

    Liddell, Allison M.; Davey, Richard T.; Mehta, Aneesh K.; Varkey, Jay B.; Kraft, Colleen S.; Tseggay, Gebre K.; Badidi, Oghenetega; Faust, Andrew C.; Brown, Katia V.; Suffredini, Anthony F.; Barrett, Kevin; Wolcott, Mark J.; Marconi, Vincent C.; Lyon, G. Marshall; Weinstein, Gary L.; Weinmeister, Kenney; Sutton, Shelby; Hazbun, Munir; Albariño, César G.; Reed, Zachary; Cannon, Debi; Ströher, Ute; Feldman, Mark; Ribner, Bruce S.; Lane, H. Clifford; Fauci, Anthony S.; Uyeki, Timothy M.

    2015-01-01

    Background More than 26 000 cases of Ebola virus disease (EVD) have been reported in western Africa, with high mortality. Several patients have been medically evacuated to hospitals in the United States and Europe. Detailed clinical data are limited on the clinical course and management of patients with EVD outside western Africa. Objective To describe the clinical characteristics and management of a cluster of patients with EVD, including the first cases of Ebola virus (EBOV) infection acquired in the United States. Design Retrospective clinical case series. Setting Three U.S. hospitals in September and October 2014. Patients First imported EVD case identified in the United States and 2 secondary EVD cases acquired in the United States in critical care nurses who cared for the index case patient. Measurements Clinical recovery, EBOV RNA level, resolution of Ebola viremia, survival with discharge from hospital, or death. Results The index patient had high EBOV RNA levels, developed respiratory and renal failure requiring critical care support, and died. Both patients with secondary EBOV infection had nonspecific signs and symptoms and developed moderate illness; EBOV RNA levels were moderate, and both patients recovered. Limitation Both surviving patients received uncontrolled treatment with multiple investigational agents, including convalescent plasma, which limits generalizability of the results. Conclusion Early diagnosis, prompt initiation of supportive medical care, and moderate clinical illness likely contributed to successful outcomes in both survivors. The inability to determine the potential benefit of investigational therapies and the effect of patient-specific factors that may have contributed to less severe illness highlight the need for controlled clinical studies of these interventions, especially in the setting of a high level of supportive medical care. Primary Funding Source None. PMID:25961438

  1. Multifractal detrended fluctuation analysis of human gait diseases

    PubMed Central

    Dutta, Srimonti; Ghosh, Dipak; Chatterjee, Sucharita

    2013-01-01

    In this paper multifractal detrended fluctuation analysis (MFDFA) is used to study the human gait time series for normal and diseased sets. It is observed that long range correlation is primarily responsible for the origin of multifractality. The study reveals that the degree of multifractality is more for normal set compared to diseased set. However, the method fails to distinguish between the two diseased sets. PMID:24109454

  2. Interference between the agents of Lyme disease and human granulocytic ehrlichiosis in a natural reservoir host.

    PubMed

    Levin, M L; Fish, D

    2001-01-01

    Agents of Lyme disease (Borrelia burgdorferi) and human granulocytic ehrlichiosis (Ehrlichia phagocytophila) are perpetuated in a natural cycle involving the black-legged tick (Ixodes scapularis) and its vertebrate hosts. Using I. scapularis nymphs as the mode of infectious challenge, we studied how infection with one pathogen in white-footed mice (Peromyscus leucopus) affects their ability to acquire the other agent and subsequently to infect larvae, which these agents would do in nature. Two groups of mice were infected with either B. burgdorferi or E. phagocytophila. One week later, B. burgdorferi-infected mice were challenged with E. phagocytophila, and E. phagocytophila-infected mice were challenged with B. burgdorferi. Simultaneously, two control groups of uninfected mice were infected with each agent from the same tick cohorts used on the first groups of mice. Uninfected I. scapularis larvae were fed on all mice for xenodiagnosis at weekly intervals lasting 2 months. For the B. burgdorferi challenge, all control and E. phagocytophila-infected mice acquired B. burgdorferi. However, fewer xenodiagnostic larvae acquired B. burgdorferi from mice with mixed infections compared with mice infected with B. burgdorferi only. For the E. phagocytophila challenge, all five control mice acquired E. phagocytophila, but only two of five mice infected with B. burgdorferi subsequently acquired E. phagocytophila. Consequently, mice with both infections produced fewer xenodiagnostic ticks infected with E. phagocytophila than mice infected with E. phagocytophila only. Thus, a primary infection with either B. burgdorferi or E. phagocytophila in mice inhibited transmission of a second agent, suggesting interference between these two agents.

  3. A pathway-based view of human diseases and disease relationships.

    PubMed

    Li, Yong; Agarwal, Pankaj

    2009-01-01

    It is increasingly evident that human diseases are not isolated from each other. Understanding how different diseases are related to each other based on the underlying biology could provide new insights into disease etiology, classification, and shared biological mechanisms. We have taken a computational approach to studying disease relationships through 1) systematic identification of disease associated genes by literature mining, 2) associating diseases to biological pathways where disease genes are enriched, and 3) linking diseases together based on shared pathways. We identified 4,195 candidate disease associated genes for 1028 diseases. On average, about 50% of disease associated genes of a disease are statistically mapped to pathways. We generated a disease network which consists of 591 diseases and 6,931 disease relationships. We examined properties of this network and provided examples of novel disease relationships which cannot be readily captured through simple literature search or gene overlap analysis. Our results could potentially provide insights into the design of novel, pathway-guided therapeutic interventions for diseases.

  4. Guidelines for investigating causality of sequence variants in human disease.

    PubMed

    MacArthur, D G; Manolio, T A; Dimmock, D P; Rehm, H L; Shendure, J; Abecasis, G R; Adams, D R; Altman, R B; Antonarakis, S E; Ashley, E A; Barrett, J C; Biesecker, L G; Conrad, D F; Cooper, G M; Cox, N J; Daly, M J; Gerstein, M B; Goldstein, D B; Hirschhorn, J N; Leal, S M; Pennacchio, L A; Stamatoyannopoulos, J A; Sunyaev, S R; Valle, D; Voight, B F; Winckler, W; Gunter, C

    2014-04-24

    The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

  5. Integrated Genomic and Network-Based Analyses of Complex Diseases and Human Disease Network.

    PubMed

    Al-Harazi, Olfat; Al Insaif, Sadiq; Al-Ajlan, Monirah A; Kaya, Namik; Dzimiri, Nduna; Colak, Dilek

    2016-06-20

    A disease phenotype generally reflects various pathobiological processes that interact in a complex network. The highly interconnected nature of the human protein interaction network (interactome) indicates that, at the molecular level, it is difficult to consider diseases as being independent of one another. Recently, genome-wide molecular measurements, data mining and bioinformatics approaches have provided the means to explore human diseases from a molecular basis. The exploration of diseases and a system of disease relationships based on the integration of genome-wide molecular data with the human interactome could offer a powerful perspective for understanding the molecular architecture of diseases. Recently, subnetwork markers have proven to be more robust and reliable than individual biomarker genes selected based on gene expression profiles alone, and achieve higher accuracy in disease classification. We have applied one of these methodologies to idiopathic dilated cardiomyopathy (IDCM) data that we have generated using a microarray and identified significant subnetworks associated with the disease. In this paper, we review the recent endeavours in this direction, and summarize the existing methodologies and computational tools for network-based analysis of complex diseases and molecular relationships among apparently different disorders and human disease network. We also discuss the future research trends and topics of this promising field. PMID:27318646

  6. Integrated Genomic and Network-Based Analyses of Complex Diseases and Human Disease Network.

    PubMed

    Al-Harazi, Olfat; Al Insaif, Sadiq; Al-Ajlan, Monirah A; Kaya, Namik; Dzimiri, Nduna; Colak, Dilek

    2016-06-20

    A disease phenotype generally reflects various pathobiological processes that interact in a complex network. The highly interconnected nature of the human protein interaction network (interactome) indicates that, at the molecular level, it is difficult to consider diseases as being independent of one another. Recently, genome-wide molecular measurements, data mining and bioinformatics approaches have provided the means to explore human diseases from a molecular basis. The exploration of diseases and a system of disease relationships based on the integration of genome-wide molecular data with the human interactome could offer a powerful perspective for understanding the molecular architecture of diseases. Recently, subnetwork markers have proven to be more robust and reliable than individual biomarker genes selected based on gene expression profiles alone, and achieve higher accuracy in disease classification. We have applied one of these methodologies to idiopathic dilated cardiomyopathy (IDCM) data that we have generated using a microarray and identified significant subnetworks associated with the disease. In this paper, we review the recent endeavours in this direction, and summarize the existing methodologies and computational tools for network-based analysis of complex diseases and molecular relationships among apparently different disorders and human disease network. We also discuss the future research trends and topics of this promising field.

  7. Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells.

    PubMed

    Jones, H E; Goddard, L; Gee, J M W; Hiscox, S; Rubini, M; Barrow, D; Knowlden, J M; Williams, S; Wakeling, A E; Nicholson, R I

    2004-12-01

    De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 microM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinib-resistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)delta, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 microM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinib-resistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.

  8. Polymicrobial Interactions: Impact on Pathogenesis and Human Disease

    PubMed Central

    Peters, Brian M.; Jabra-Rizk, Mary Ann; O'May, Graeme A.; Costerton, J. William

    2012-01-01

    Summary: Microorganisms coexist in a complex milieu of bacteria, fungi, archaea, and viruses on or within the human body, often as multifaceted polymicrobial biofilm communities at mucosal sites and on abiotic surfaces. Only recently have we begun to appreciate the complicated biofilm phenotype during infection; moreover, even less is known about the interactions that occur between microorganisms during polymicrobial growth and their implications in human disease. Therefore, this review focuses on polymicrobial biofilm-mediated infections and examines the contribution of bacterial-bacterial, bacterial-fungal, and bacterial-viral interactions during human infection and potential strategies for protection against such diseases. PMID:22232376

  9. Iron–sulfur cluster biogenesis and human disease

    PubMed Central

    Rouault, Tracey A.; Tong, Wing Hang

    2008-01-01

    Iron–sulfur (Fe–S) clusters are essential for numerous biological processes, including mitochondrial respiratory chain activity and various other enzymatic and regulatory functions. Human Fe–S cluster assembly proteins are frequently encoded by single genes, and inherited defects in some of these genes cause disease. Recently, the spectrum of diseases attributable to abnormal Fe–S cluster biogenesis has extended beyond Friedreich ataxia to include a sideroblastic anemia with deficiency of glutaredoxin 5 and a myopathy associated with a deficiency of a Fe–S cluster assembly scaffold protein, ISCU. Mutations within other mammalian Fe–S cluster assembly genes could be causative for human diseases that manifest distinctive combinations of tissue-specific impairments. Thus, defects in the iron–sulfur cluster biogenesis pathway could underlie many human diseases. PMID:18606475

  10. MicroRNA in human cancer and chronic inflammatory diseases.

    PubMed

    Kanwar, Jagat R; Mahidhara, Ganesh; Kanwar, Rupinder K

    2010-06-01

    MicroRNAs (miRNAs) are the non-coding RNAs that act as post-translational regulators to their complimentary messenger RNAs (mRNA). Due to their specific gene silencing property, miRNAs have been implicated in a number of cellular and developmental processes. Also, it has been proposed that a particular set of miRNA spectrum is expressed only in a particular type of tissue. Many interesting findings related to the differential expression of miRNAs in various human diseases including several types of cancers, neurodegenerative diseases and metabolic diseases have been reported. Deregulation of miRNA expression in different types of human diseases and the roles various miRNAs play as tumour suppressors as well as oncogenes, suggest their contribution to cancer and/or in other disease development. These findings have possible implications in the development of diagnostics and/or therapeutics in human malignancies. In this review, we discuss various miRNAs that are differentially expressed in human chronic inflammatory diseases, neurodegenerative diseases, cancer and the further prospective development of miRNA based diagnostics and therapeutics.

  11. Natural selection on genes that underlie human disease susceptibility

    PubMed Central

    Blekhman, Ran; Man, Orna; Herrmann, Leslie; Boyko, Adam R.; Indap, Amit; Kosiol, Carolin; Bustamante, Carlos D.; Teshima, Kosuke M.; Przeworski, Molly

    2008-01-01

    What evolutionary forces shape genes that contribute to the risk of human disease? Do similar selective pressures act on alleles that underlie simple vs. complex disorders? [1-3]. Answers to these questions will shed light on the origin of human disorders (e.g., [4]), and help to predict the population frequencies of alleles that contribute to disease risk, with important implications for the efficient design of mapping studies [5-7]. As a first step towards addressing them, we created a hand-curated version of the Mendelian Inheritance in Man database (OMIM). We then examined selective pressures on Mendelian disease genes, genes that contribute to complex disease risk and genes known to be essential in mouse, by analyzing patterns of human polymorphism and of divergence between human and rhesus macaque. We find that Mendelian disease genes appear to be under widespread purifying selection, especially when the disease mutations are dominant (rather than recessive). In contrast, the class of genes that influence complex disease risk shows little signs of evolutionary conservation, possibly because this category includes both targets of purifying and positive selection. PMID:18571414

  12. Wildlife disease prevalence in human-modified landscapes.

    PubMed

    Brearley, Grant; Rhodes, Jonathan; Bradley, Adrian; Baxter, Greg; Seabrook, Leonie; Lunney, Daniel; Liu, Yan; McAlpine, Clive

    2013-05-01

    Human-induced landscape change associated with habitat loss and fragmentation places wildlife populations at risk. One issue in these landscapes is a change in the prevalence of disease which may result in increased mortality and reduced fecundity. Our understanding of the influence of habitat loss and fragmentation on the prevalence of wildlife diseases is still in its infancy. What is evident is that changes in disease prevalence as a result of human-induced landscape modification are highly variable. The importance of infectious diseases for the conservation of wildlife will increase as the amount and quality of suitable habitat decreases due to human land-use pressures. We review the experimental and observational literature of the influence of human-induced landscape change on wildlife disease prevalence, and discuss disease transmission types and host responses as mechanisms that are likely to determine the extent of change in disease prevalence. It is likely that transmission dynamics will be the key process in determining a pathogen's impact on a host population, while the host response may ultimately determine the extent of disease prevalence. Finally, we conceptualize mechanisms and identify future research directions to increase our understanding of the relationship between human-modified landscapes and wildlife disease prevalence. This review highlights that there are rarely consistent relationships between wildlife diseases and human-modified landscapes. In addition, variation is evident between transmission types and landscape types, with the greatest positive influence on disease prevalence being in urban landscapes and directly transmitted disease systems. While we have a limited understanding of the potential influence of habitat loss and fragmentation on wildlife disease, there are a number of important areas to address in future research, particularly to account for the variability in increased and decreased disease prevalence. Previous studies

  13. Golgi glycosylation and human inherited diseases.

    PubMed

    Freeze, Hudson H; Ng, Bobby G

    2011-09-01

    The Golgi factory receives custom glycosylates and dispatches its cargo to the correct cellular locations. The process requires importing donor substrates, moving the cargo, and recycling machinery. Correctly glycosylated cargo reflects the Golgi's quality and efficiency. Genetic disorders in the specific equipment (enzymes), donors (nucleotide sugar transporters), or equipment recycling/reorganization components (COG, SEC, golgins) can all affect glycosylation. Dozens of human glycosylation disorders fit these categories. Many other genes, with or without familiar names, well-annotated pedigrees, or likely homologies will join the ranks of glycosylation disorders. Their broad and unpredictable case-by-case phenotypes cross the traditional medical specialty boundaries. The gene functions in patients may be elusive, but their common feature may include altered glycosylation that provide clues to Golgi function. This article focuses on a group of human disorders that affect protein or lipid glycosylation. Readers may find it useful to generalize some of these patient-based, translational observations to their own research. PMID:21709180

  14. Golgi Glycosylation and Human Inherited Diseases

    PubMed Central

    Freeze, Hudson H.; Ng, Bobby G.

    2011-01-01

    The Golgi factory receives custom glycosylates and dispatches its cargo to the correct cellular locations. The process requires importing donor substrates, moving the cargo, and recycling machinery. Correctly glycosylated cargo reflects the Golgi's quality and efficiency. Genetic disorders in the specific equipment (enzymes), donors (nucleotide sugar transporters), or equipment recycling/reorganization components (COG, SEC, golgins) can all affect glycosylation. Dozens of human glycosylation disorders fit these categories. Many other genes, with or without familiar names, well-annotated pedigrees, or likely homologies will join the ranks of glycosylation disorders. Their broad and unpredictable case-by-case phenotypes cross the traditional medical specialty boundaries. The gene functions in patients may be elusive, but their common feature may include altered glycosylation that provide clues to Golgi function. This article focuses on a group of human disorders that affect protein or lipid glycosylation. Readers may find it useful to generalize some of these patient-based, translational observations to their own research. PMID:21709180

  15. Impacts of Gut Bacteria on Human Health and Diseases

    PubMed Central

    Zhang, Yu-Jie; Li, Sha; Gan, Ren-You; Zhou, Tong; Xu, Dong-Ping; Li, Hua-Bin

    2015-01-01

    Gut bacteria are an important component of the microbiota ecosystem in the human gut, which is colonized by 1014 microbes, ten times more than the human cells. Gut bacteria play an important role in human health, such as supplying essential nutrients, synthesizing vitamin K, aiding in the digestion of cellulose, and promoting angiogenesis and enteric nerve function. However, they can also be potentially harmful due to the change of their composition when the gut ecosystem undergoes abnormal changes in the light of the use of antibiotics, illness, stress, aging, bad dietary habits, and lifestyle. Dysbiosis of the gut bacteria communities can cause many chronic diseases, such as inflammatory bowel disease, obesity, cancer, and autism. This review summarizes and discusses the roles and potential mechanisms of gut bacteria in human health and diseases. PMID:25849657

  16. Human Microbiome and its Association With Health and Diseases.

    PubMed

    Althani, Asmaa A; Marei, Hany E; Hamdi, Wedad S; Nasrallah, Gheyath K; El Zowalaty, Mohamed E; Al Khodor, Souhaila; Al-Asmakh, Maha; Abdel-Aziz, Hassan; Cenciarelli, Carlo

    2016-08-01

    Human microbiota are distinct communities of microorganisms that resides at different body niches. Exploration of the human microbiome has become a reality due to the availability of powerful metagenomics and metatranscriptomic analysis technologies. Recent advances in sequencing and bioinformatics over the past decade help provide a deep insight into the nature of the host-microbial interactions and identification of potential deriver genes and pathways associated with human health, well-being, and predisposition to different diseases. In the present review, we outline recent studies devoted to elucidate the possible link between the microbiota and various type of diseases. The present review also highlights the potential utilization of microbiota as a potential therapeutic option to treat a wide array of human diseases. J. Cell. Physiol. 231: 1688-1694, 2016. © 2015 Wiley Periodicals, Inc.

  17. Human-induced pluripotent stem cells: potential for neurodegenerative diseases.

    PubMed

    Ross, Christopher A; Akimov, Sergey S

    2014-09-15

    The cell biology of human neurodegenerative diseases has been difficult to study till recently. The development of human induced pluripotent stem cell (iPSC) models has greatly enhanced our ability to model disease in human cells. Methods have recently been improved, including increasing reprogramming efficiency, introducing non-viral and non-integrating methods of cell reprogramming, and using novel gene editing techniques for generating genetically corrected lines from patient-derived iPSCs, or for generating mutations in control cell lines. In this review, we highlight accomplishments made using iPSC models to study neurodegenerative disorders such as Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Fronto-Temporal Dementia, Alzheimer's disease, Spinomuscular Atrophy and other polyglutamine diseases. We review disease-related phenotypes shown in patient-derived iPSCs differentiated to relevant neural subtypes, often with stressors or cell "aging", to enhance disease-specific phenotypes. We also discuss prospects for the future of using of iPSC models of neurodegenerative disorders, including screening and testing of therapeutic compounds, and possibly of cell transplantation in regenerative medicine. The new iPSC models have the potential to greatly enhance our understanding of pathogenesis and to facilitate the development of novel therapeutics.

  18. Sex-specific genetic architecture of human disease.

    PubMed

    Ober, Carole; Loisel, Dagan A; Gilad, Yoav

    2008-12-01

    Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases. PMID:19002143

  19. Current and Emerging Biomarkers of Cell Death in Human Disease

    PubMed Central

    Li, Kongning; Wu, Deng; Chen, Xi; Zhang, Ting; Zhang, Lu; Yi, Ying; Miao, Zhengqiang; Jin, Nana; Bi, Xiaoman; Wang, Hongwei; Wang, Dong

    2014-01-01

    Cell death is a critical biological process, serving many important functions within multicellular organisms. Aberrations in cell death can contribute to the pathology of human diseases. Significant progress made in the research area enormously speeds up our understanding of the biochemical and molecular mechanisms of cell death. According to the distinct morphological and biochemical characteristics, cell death can be triggered by extrinsic or intrinsic apoptosis, regulated necrosis, autophagic cell death, and mitotic catastrophe. Nevertheless, the realization that all of these efforts seek to pursue an effective treatment and cure for the disease has spurred a significant interest in the development of promising biomarkers of cell death to early diagnose disease and accurately predict disease progression and outcome. In this review, we summarize recent knowledge about cell death, survey current and emerging biomarkers of cell death, and discuss the relationship with human diseases. PMID:24949464

  20. Sex-Specific Genetic Architecture of Human Disease

    PubMed Central

    Ober, Carole; Loisel, Dagan A.; Gilad, Yoav

    2009-01-01

    Sexual dimorphism in anatomical, physiological, and behavioural traits characterize many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course, and severity of many common diseases, including cardiovascular diseases, autoimmune diseases, and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological, and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases. PMID:19002143

  1. Effects of Environmental Pollutants on Cellular Iron Homeostasis and Ultimate Links to Human Disease

    PubMed Central

    Schreinemachers, Dina M.; Ghio, Andrew J.

    2016-01-01

    Chronic disease has increased in the past several decades, and environmental pollutants have been implicated. The magnitude and variety of diseases may indicate the malfunctioning of some basic mechanisms underlying human health. Environmental pollutants demonstrate a capability to complex iron through electronegative functional groups containing oxygen, nitrogen, or sulfur. Cellular exposure to the chemical or its metabolite may cause a loss of requisite functional iron from intracellular sites. The cell is compelled to acquire further iron critical to its survival by activation of iron-responsive proteins and increasing iron import. Iron homeostasis in the exposed cells is altered due to a new equilibrium being established between iron-requiring cells and the inappropriate chelator (the pollutant or its catabolite). Following exposure to environmental pollutants, the perturbation of functional iron homeostasis may be the mechanism leading to adverse biological effects. Understanding the mechanism may lead to intervention methods for this major public health concern. PMID:26966372

  2. Effects of Environmental Pollutants on Cellular Iron Homeostasis and Ultimate Links to Human Disease.

    PubMed

    Schreinemachers, Dina M; Ghio, Andrew J

    2016-01-01

    Chronic disease has increased in the past several decades, and environmental pollutants have been implicated. The magnitude and variety of diseases may indicate the malfunctioning of some basic mechanisms underlying human health. Environmental pollutants demonstrate a capability to complex iron through electronegative functional groups containing oxygen, nitrogen, or sulfur. Cellular exposure to the chemical or its metabolite may cause a loss of requisite functional iron from intracellular sites. The cell is compelled to acquire further iron critical to its survival by activation of iron-responsive proteins and increasing iron import. Iron homeostasis in the exposed cells is altered due to a new equilibrium being established between iron-requiring cells and the inappropriate chelator (the pollutant or its catabolite). Following exposure to environmental pollutants, the perturbation of functional iron homeostasis may be the mechanism leading to adverse biological effects. Understanding the mechanism may lead to intervention methods for this major public health concern.

  3. Interneurons in the human olfactory system in Alzheimer's disease.

    PubMed

    Saiz-Sanchez, Daniel; Flores-Cuadrado, Alicia; Ubeda-Bañon, Isabel; de la Rosa-Prieto, Carlos; Martinez-Marcos, Alino

    2016-02-01

    The principal olfactory structures display Alzheimer's disease (AD) related pathology at early stages of the disease. Consequently, olfactory deficits are among the earliest symptoms. Reliable olfactory tests for accurate clinical diagnosis are rarely made. In addition, neuropathological analysis postmortem of olfactory structures is often not made. Therefore, the relationship between the clinical features and the underlying pathology is poorly defined. Traditionally, research into Alzheimer's disease has focused on the degeneration of cortical temporal projection neurons and cholinergic neurons. Recent evidence has demonstrated the neurodegeneration of interneuron populations in AD. This review provides an updated overview of the pathological involvement of interneuron populations in the human olfactory system in Alzheimer's disease.

  4. Disguising the taste of antiretrovirals for pediatric patients infected with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome: creative flavor compounding and techniques, part 2.

    PubMed

    Horace, Alexis E; Akbarian-Tefagh, Jessica

    2013-01-01

    Adherence to antiretrovirals for pediatric patients is challenging for a variety of reasons, many of which are quite obvious. The medication's taste and texture may contribute to a child's resistance to following their regimen. To make the problem of compliance even more complex, there are fewer pediatric-friendly formulations available and fewer alternative options for antiretrovirals when compared to formulations and alternatives available to adults. For the sake of compliance, it is vital that parents and/or caregivers be offered innovative ways to disguise the taste of antiretrovirals for pediatric patients infected with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome. Compounding pharmacists can play an important role in finding answers to this situation. This article provides an in-depth discussion on some of the specific flavoring and taste-masking options that are available in the effort to increase adherence in the pediatric patient population.

  5. Rare structural genetic variation in human prion diseases.

    PubMed

    Lukic, Ana; Uphill, James; Brown, Craig A; Beck, John; Poulter, Mark; Campbell, Tracy; Adamson, Gary; Hummerich, Holger; Whitfield, Jerome; Ponto, Claudia; Zerr, Inga; Lloyd, Sarah E; Collinge, John; Mead, Simon

    2015-05-01

    Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.

  6. Animal models of human granulocyte diseases.

    PubMed

    Schäffer, Alejandro A; Klein, Christoph

    2013-02-01

    In vivo animal models have proven very useful to the understanding of basic biologic pathways of the immune system, a prerequisite for the development of innovate therapies. This article addresses currently available models for defined human monogenetic defects of neutrophil granulocytes, including murine, zebrafish, and larger mammalian species. Strengths and weaknesses of each system are summarized, and clinical investigators may thus be inspired to develop further lines of research to improve diagnosis and therapy by use of the appropriate animal model system. PMID:23351993

  7. DUF1220 domains, cognitive disease, and human brain evolution.

    PubMed

    Dumas, L; Sikela, J M

    2009-01-01

    We have established that human genome sequences encoding a novel protein domain, DUF1220, show a dramatically elevated copy number in the human lineage (>200 copies in humans vs. 1 in mouse/rat) and may be important to human evolutionary adaptation. Copy-number variations (CNVs) in the 1q21.1 region, where most DUF1220 sequences map, have now been implicated in numerous diseases associated with cognitive dysfunction, including autism, autism spectrum disorder, mental retardation, schizophrenia, microcephaly, and macrocephaly. We report here that these disease-related 1q21.1 CNVs either encompass or are directly flanked by DUF1220 sequences and exhibit a dosage-related correlation with human brain size. Microcephaly-producing 1q21.1 CNVs are deletions, whereas macrocephaly-producing 1q21.1 CNVs are duplications. Similarly, 1q21.1 deletions and smaller brain size are linked with schizophrenia, whereas 1q21.1 duplications and larger brain size are associated with autism. Interestingly, these two diseases are thought to be phenotypic opposites. These data suggest a model which proposes that (1) DUF1220 domain copy number may be involved in influencing human brain size and (2) the evolutionary advantage of rapidly increasing DUF1220 copy number in the human lineage has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders. PMID:19850849

  8. Glycoconjugates in human milk: protecting infants from disease.

    PubMed

    Peterson, Robyn; Cheah, Wai Yuen; Grinyer, Jasmine; Packer, Nicolle

    2013-12-01

    Breastfeeding is known to have many health benefits for a newborn. Not only does human milk provide an excellent source of nutrition, it also contains components that protect against infection from a wide range of pathogens. Some of the protective properties of human milk can be attributed to the immunoglobulins. Yet, there is another level of defense provided by the "sweet" protective agents that human milk contains, including free oligosaccharides, glycoproteins and glycolipids. Sugar epitopes in human milk are similar to the glycan receptors that serve as pathogen adhesion sites in the human gastrointestinal tract and other epithelial cell surfaces; hence, the milk glycans can competitively bind to and remove the disease-causing microorganisms before they cause infection. The protective value of free oligosaccharides in human milk has been well researched and documented. Human milk glycoconjugates have received less attention but appear to play an equally important role. Here, we bring together the breadth of research that has focused on the protective mechanisms of human milk glycoconjugates, with a particular focus on the glycan moieties that may play a role in disease prevention. In addition, human milk glycoconjugates are compared with bovine milk glycoconjugates in terms of their health benefits for the human infant.

  9. Acquired cystic disease-associated renal cell carcinoma with gain of chromosomes 3, 7, and 16, gain of chromosome X, and loss of chromosome Y.

    PubMed

    Kuroda, Naoto; Shiotsu, Tomoyuki; Hes, Ondrej; Michal, Michal; Shuin, Taro; Lee, Gang-Hong

    2010-12-01

    Acquired cystic disease (ACD)-associated renal cell carcinoma (RCC) has been recently described. To date, there are no reports on genetic findings of G-band karyotype of ACD-associated RCC. In this article, we report the first report of G-band karyotype of ACD-associated RCC. A 66-year-old Japanese man was found to have a left renal tumor during the follow-up of hemodialysis consequent to chronic renal failure. Left nephrectomy was performed. Histological examination of three tumors in the left kidney showed the cribriform or microcystic growth pattern of neoplastic cells with eosinophilic cytoplasm, and many oxalate crystals were observed. The G-band karyotype of ACD-associated RCC showed 49, X, +X, -Y, +3, +7, +16. These chromosomal abnormalities resemble those of sporadic papillary RCC that has been previously reported. Finally, we suggest that this tumor may show a close relationship between ACD-associated RCC and papillary RCC, but a large-scale study will be needed to clarify the relationship between ACD-associated RCC and papillary RCC.

  10. Candida albicans Biofilms and Human Disease.

    PubMed

    Nobile, Clarissa J; Johnson, Alexander D

    2015-01-01

    In humans, microbial cells (including bacteria, archaea, and fungi) greatly outnumber host cells. Candida albicans is the most prevalent fungal species of the human microbiota; this species asymptomatically colonizes many areas of the body, particularly the gastrointestinal and genitourinary tracts of healthy individuals. Alterations in host immunity, stress, resident microbiota, and other factors can lead to C. albicans overgrowth, causing a wide range of infections, from superficial mucosal to hematogenously disseminated candidiasis. To date, most studies of C. albicans have been carried out in suspension cultures; however, the medical impact of C. albicans (like that of many other microorganisms) depends on its ability to thrive as a biofilm, a closely packed community of cells. Biofilms are notorious for forming on implanted medical devices, including catheters, pacemakers, dentures, and prosthetic joints, which provide a surface and sanctuary for biofilm growth. C. albicans biofilms are intrinsically resistant to conventional antifungal therapeutics, the host immune system, and other environmental perturbations, making biofilm-based infections a significant clinical challenge. Here, we review our current knowledge of biofilms formed by C. albicans and closely related fungal species. PMID:26488273

  11. Women and the Acquired Immunodeficiency Syndrome

    PubMed Central

    Wofsy, Constance B.

    1988-01-01

    SPECIAL EDITOR'S NOTE: Constance B. Wofsy, MD, is Co-Director of AIDS Activities at San Francisco General Hospital and Medical Center, as well as Associate Clinical Professor of Medicine at the University of California, San Francisco; Assistant Chief, Infectious Diseases, San Francisco General Hospital; and Principal Investigator, Project AWARE (Association for Women's AIDS Research and Education). Although she was not able to contribute an article for WOMEN AND MEDICINE on this very important subject, she kindly agreed to an interview. Both physicians and nonphysicians were asked what questions they had about the acquired immunodeficiency syndrome (AIDS) and the human immunodeficiency virus (HIV) in women. Images PMID:3250110

  12. Human genomic disease variants: A neutral evolutionary explanation

    PubMed Central

    Dudley, Joel T.; Kim, Yuseob; Liu, Li; Markov, Glenn J.; Gerold, Kristyn; Chen, Rong; Butte, Atul J.; Kumar, Sudhir

    2012-01-01

    Many perspectives on the role of evolution in human health include nonempirical assumptions concerning the adaptive evolutionary origins of human diseases. Evolutionary analyses of the increasing wealth of clinical and population genomic data have begun to challenge these presumptions. In order to systematically evaluate such claims, the time has come to build a common framework for an empirical and intellectual unification of evolution and modern medicine. We review the emerging evidence and provide a supporting conceptual framework that establishes the classical neutral theory of molecular evolution (NTME) as the basis for evaluating disease- associated genomic variations in health and medicine. For over a decade, the NTME has already explained the origins and distribution of variants implicated in diseases and has illuminated the power of evolutionary thinking in genomic medicine. We suggest that a majority of disease variants in modern populations will have neutral evolutionary origins (previously neutral), with a relatively smaller fraction exhibiting adaptive evolutionary origins (previously adaptive). This pattern is expected to hold true for common as well as rare disease variants. Ultimately, a neutral evolutionary perspective will provide medicine with an informative and actionable framework that enables objective clinical assessment beyond convenient tendencies to invoke past adaptive events in human history as a root cause of human disease. PMID:22665443

  13. FISH CONSUMPTION, METHYLMERCURY, AND HUMAN HEART DISEASE.

    SciTech Connect

    LIPFERT, F.W.; SULLIVAN, T.M.

    2005-09-21

    Environmental mercury continues to be of concern to public health advocates, both in the U.S. and abroad, and new research continues to be published. A recent analysis of potential health benefits of reduced mercury emissions has opened a new area of public health concern: adverse effects on the cardiovascular system, which could account for the bulk of the potential economic benefits. The authors were careful to include caveats about the uncertainties of such impacts, but they cited only a fraction of the applicable health effects literature. That literature includes studies of the potentially harmful ingredient (methylmercury, MeHg) in fish, as well as of a beneficial ingredient, omega-3 fatty acids or ''fish oils''. The U.S. Food and Drug Administration (FDA) recently certified that some of these fat compounds that are primarily found in fish ''may be beneficial in reducing coronary heart disease''. This paper briefly summarizes and categorizes the extensive literature on both adverse and beneficial links between fish consumption and cardiovascular health, which are typically based on studies of selected groups of individuals (cohorts). Such studies tend to comprise the ''gold standard'' of epidemiology, but cohorts tend to exhibit a great deal of variability, in part because of the limited numbers of individuals involved and in part because of interactions with other dietary and lifestyle considerations. Note that eating fish will involve exposure to both the beneficial effects of fatty acids and the potentially harmful effects of contaminants like Hg or PCBs, all of which depend on the type of fish but tend to be correlated within a population. As a group, the cohort studies show that eating fish tends to reduce mortality, especially due to heart disease, for consumption rates up to about twice weekly, above which the benefits tend to level off. A Finnish cohort study showed increased mortality risks in the highest fish-consuming group ({approx}3 times

  14. "Miniguts" from plucked human hair meet Crohn's disease.

    PubMed

    Hohwieler, M; Renz, S; Liebau, S; Lin, Q; Lechel, A; Klaus, J; Perkhofer, L; Zenke, M; Seufferlein, T; Illing, A; Müller, M; Kleger, A

    2016-08-01

    Human pluripotent stem cells represent a powerful tool to study human embryonic development and disease but also open up novel strategies for cell replacement therapies. Their capacity to give rise to every cell type of the human body, meanwhile, enables researchers to generate high yields of mesodermal, ectodermal, but also endodermal-derived tissues such as hepatic, pancreatic, or intestinal cells. Another progress in the field came with the advent of 3-dimensional culture conditions, so-called organoids, which facilitate maturation of stem cells and in turn more faithfully recapitulate human tissue architecture. While several studies reported the derivation of organoid cultures from adult intestinal tissue, the derivation of intestinal organoids derived from plucked human hair of Crohn's disease patients has not been reported. The current research project reports such successful generation and characterization of induced pluripotent stem cells (iPSCs) derived from hair sheet keratinocyte cultures of a patient with Crohn's disease. Stepwise differentiation along the intestinal lineage showed no differences in intermediate stages such as definitive endoderm formation. We also directed the patterned primitive gut tube toward intestinal organoids resembling the cellular architecture of human "miniguts". As expected from current pathophysiological knowledge on Crohn's disease, there were no obvious morphological differences in the "miniguts" derived from healthy control and diseased patient-induced pluripotent stem cells. Taken together, our platform will enable for detailed and complementary phenotyping of the pathophysiology of Crohn's disease in a novel disease-in-a-dish format. PMID:27415403

  15. Insights into the evolutionary features of human neurodegenerative diseases.

    PubMed

    Panda, Arup; Begum, Tina; Ghosh, Tapash Chandra

    2012-01-01

    Comparative analyses between human disease and non-disease genes are of great interest in understanding human disease gene evolution. However, the progression of neurodegenerative diseases (NDD) involving amyloid formation in specific brain regions is still unknown. Therefore, in this study, we mainly focused our analysis on the evolutionary features of human NDD genes with respect to non-disease genes. Here, we observed that human NDD genes are evolutionarily conserved relative to non-disease genes. To elucidate the conserved nature of NDD genes, we incorporated the evolutionary attributes like gene expression level, number of regulatory miRNAs, protein connectivity, intrinsic disorder content and relative aggregation propensity in our analysis. Our studies demonstrate that NDD genes have higher gene expression levels in favor of their lower evolutionary rates. Additionally, we observed that NDD genes have higher number of different regulatory miRNAs target sites and also have higher interaction partners than the non-disease genes. Moreover, miRNA targeted genes are known to have higher disorder content. In contrast, our analysis exclusively established that NDD genes have lower disorder content. In favor of our analysis, we found that NDD gene encoded proteins are enriched with multi interface hubs (party hubs) with lower disorder contents. Since, proteins with higher disorder content need to adapt special structure to reduce their aggregation propensity, NDD proteins found to have elevated relative aggregation propensity (RAP) in support of their lower disorder content. Finally, our categorical regression analysis confirmed the underlined relative dominance of protein connectivity, 3'UTR length, RAP, nature of hubs (singlish/multi interface) and disorder content for such evolutionary rates variation between human NDD genes and non-disease genes.

  16. Significance of murine retroviral mutagenesis for identification of disease genes in human acute myeloid leukemia.

    PubMed

    Erkeland, Stefan J; Verhaak, Roel G W; Valk, Peter J M; Delwel, Ruud; Löwenberg, Bob; Touw, Ivo P

    2006-01-15

    Retroviral insertion mutagenesis is considered a powerful tool to identify cancer genes in mice, but its significance for human cancer has remained elusive. Moreover, it has recently been debated whether common virus integrations are always a hallmark of tumor cells and contribute to the oncogenic process. Acute myeloid leukemia (AML) is a heterogeneous disease with a variable response to treatment. Recurrent cytogenetic defects and acquired mutations in regulatory genes are associated with AML subtypes and prognosis. Recently, gene expression profiling (GEP) has been applied to further risk stratify AML. Here, we show that mouse leukemia genes identified by retroviral insertion mutagenesis are more frequently differentially expressed in distinct subclasses of adult and pediatric AML than randomly selected genes or genes located more distantly from a virus integration site. The candidate proto-oncogenes showing discriminative expression in primary AML could be placed in regulatory networks mainly involved in signal transduction and transcriptional control. Our data support the validity of retroviral insertion mutagenesis in mice for human disease and indicate that combining these murine screens for potential proto-oncogenes with GEP in human AML may help to identify critical disease genes and novel pathogenetic networks in leukemia.

  17. Drosophila tools and assays for the study of human diseases

    PubMed Central

    Ugur, Berrak; Chen, Kuchuan; Bellen, Hugo J.

    2016-01-01

    ABSTRACT Many of the internal organ systems of Drosophila melanogaster are functionally analogous to those in vertebrates, including humans. Although humans and flies differ greatly in terms of their gross morphological and cellular features, many of the molecular mechanisms that govern development and drive cellular and physiological processes are conserved between both organisms. The morphological differences are deceiving and have led researchers to undervalue the study of invertebrate organs in unraveling pathogenic mechanisms of diseases. In this review and accompanying poster, we highlight the physiological and molecular parallels between fly and human organs that validate the use of Drosophila to study the molecular pathogenesis underlying human diseases. We discuss assays that have been developed in flies to study the function of specific genes in the central nervous system, heart, liver and kidney, and provide examples of the use of these assays to address questions related to human diseases. These assays provide us with simple yet powerful tools to study the pathogenic mechanisms associated with human disease-causing genes. PMID:26935102

  18. Non-coding genetic variants in human disease

    PubMed Central

    Zhang, Feng; Lupski, James R.

    2015-01-01

    Genetic variants, including single-nucleotide variants (SNVs) and copy number variants (CNVs), in the non-coding regions of the human genome can play an important role in human traits and complex diseases. Most of the genome-wide association study (GWAS) signals map to non-coding regions and potentially point to non-coding variants, whereas their functional interpretation is challenging. In this review, we discuss the human non-coding variants and their contributions to human diseases in the following four parts. (i) Functional annotations of non-coding SNPs mapped by GWAS: we discuss recent progress revealing some of the molecular mechanisms for GWAS signals affecting gene function. (ii) Technical progress in interpretation of non-coding variants: we briefly describe some of the technologies for functional annotations of non-coding variants, including the methods for genome-wide mapping of chromatin interaction, computational tools for functional predictions and the new genome editing technologies useful for dissecting potential functional consequences of non-coding variants. (iii) Non-coding CNVs in human diseases: we review our emerging understanding the role of non-coding CNVs in human disease. (iv) Compound inheritance of large genomic deletions and non-coding variants: compound inheritance at a locus consisting of coding variants plus non-coding ones is described. PMID:26152199

  19. Human bulbar conjunctival hemodynamics in hemoglobin SS and SC disease.

    PubMed

    Wanek, Justin; Gaynes, Bruce; Lim, Jennifer I; Molokie, Robert; Shahidi, Mahnaz

    2013-08-01

    The known biophysical variations of hemoglobin (Hb) S and Hb C may result in hemodynamic differences between subjects with SS and SC disease. The purpose of this study was to measure and compare conjunctival hemodynamics between subjects with Hb SS and SC hemoglobinopathies. Image sequences of the conjunctival microcirculation were acquired in 9 healthy control subjects (Hb AA), 24 subjects with SC disease, and 18 subjects with SS disease, using a prototype imaging system. Diameter (D) and blood velocity (V) measurements were obtained in multiple venules of each subject. Data were categorized according to venule caliber by averaging V and D for venules with diameters less than (vessel size 1) or greater than (vessel size 2) 15 µm. V in vessel size 2 was significantly greater than V in vessel size 1 in the AA and SS groups (P ≥ 0.009), but not in the SC group (P = 0.1). V was significantly lower in the SC group as compared to the SS group (P = 0.03). In AA and SS groups, V correlated with D (P ≤ 0.005), but the correlation was not statistically significant in the SC group (P = 0.08). V was inversely correlated with hematocrit in the SS group for large vessels (P = 0.03); however, no significant correlation was found in the SC group (P ≥ 0.2). Quantitative assessment of conjunctival microvascular hemodynamics in SS and SC disease may advance understanding of sickle cell disease pathophysiology and thereby improve therapeutic interventions.

  20. Human Disease Insight: An integrated knowledge-based platform for disease-gene-drug information.

    PubMed

    Tasleem, Munazzah; Ishrat, Romana; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-01-01

    The scope of the Human Disease Insight (HDI) database is not limited to researchers or physicians as it also provides basic information to non-professionals and creates disease awareness, thereby reducing the chances of patient suffering due to ignorance. HDI is a knowledge-based resource providing information on human diseases to both scientists and the general public. Here, our mission is to provide a comprehensive human disease database containing most of the available useful information, with extensive cross-referencing. HDI is a knowledge management system that acts as a central hub to access information about human diseases and associated drugs and genes. In addition, HDI contains well-classified bioinformatics tools with helpful descriptions. These integrated bioinformatics tools enable researchers to annotate disease-specific genes and perform protein analysis, search for biomarkers and identify potential vaccine candidates. Eventually, these tools will facilitate the analysis of disease-associated data. The HDI provides two types of search capabilities and includes provisions for downloading, uploading and searching disease/gene/drug-related information. The logistical design of the HDI allows for regular updating. The database is designed to work best with Mozilla Firefox and Google Chrome and is freely accessible at http://humandiseaseinsight.com.

  1. Human Disease Insight: An integrated knowledge-based platform for disease-gene-drug information.

    PubMed

    Tasleem, Munazzah; Ishrat, Romana; Islam, Asimul; Ahmad, Faizan; Hassan, Md Imtaiyaz

    2016-01-01

    The scope of the Human Disease Insight (HDI) database is not limited to researchers or physicians as it also provides basic information to non-professionals and creates disease awareness, thereby reducing the chances of patient suffering due to ignorance. HDI is a knowledge-based resource providing information on human diseases to both scientists and the general public. Here, our mission is to provide a comprehensive human disease database containing most of the available useful information, with extensive cross-referencing. HDI is a knowledge management system that acts as a central hub to access information about human diseases and associated drugs and genes. In addition, HDI contains well-classified bioinformatics tools with helpful descriptions. These integrated bioinformatics tools enable researchers to annotate disease-specific genes and perform protein analysis, search for biomarkers and identify potential vaccine candidates. Eventually, these tools will facilitate the analysis of disease-associated data. The HDI provides two types of search capabilities and includes provisions for downloading, uploading and searching disease/gene/drug-related information. The logistical design of the HDI allows for regular updating. The database is designed to work best with Mozilla Firefox and Google Chrome and is freely accessible at http://humandiseaseinsight.com. PMID:26631432

  2. Spectroscopy techniques for human disease diagnosis

    NASA Astrophysics Data System (ADS)

    Navas-Moreno, Maria

    2011-12-01

    Modern medicine would benefit from the pursuit of new, more specific and easier to implement diagnosis tools. In recent years, Raman scattering, surface-enhanced Raman scattering and fluorescence spectroscopy have proven to be successful diagnostic techniques for a wide range of diseases including atherosclerosis, kidney stones, bone diseases, diabetes, and a wide collection of neoplasms. Optical spectroscopy has several advantages over more traditional diagnostic methods (i.e., histopathology, quantitative PCR, etc.) such as faster data analysis, nonspecific sample preparation, nonspecific labels/reagents/antibodies usage requirements, and immediate on-site implementation. In the present work, label-free in vitro fluorescence and surface enhanced Raman scattering (SERS) spectroscopy have been used to differentiate between blood cells of patients affected with myeloproliferative neoplasms (MPN) and those of healthy subjects. The SERS technique has also been applied to hemoglobin variants as well as to serum obtained from patients affected with chronic heart failure who positively or negatively responded to the seasonal influenza vaccine. We found that spectral ratios of the background fluorescence intensity that accompanies the SERS spectra of granulocytes serve as excellent markers for the presence of MPNs. In addition, we also found expression dysregulation of two hypoxia induced factor regulated genes, which correlates with our results obtained by SERS spectroscopy assay in MPN patients and supports the presence of the Warburg effect in MPNs. We hypothesize that SERS measures metabolic change in granulocytes through two possible mechanisms: (i) Changes in dielectric properties of the environment surrounding the silver-cell interface; and (ii) changes in flavin adenine dinucleotide concentrations, which in turn changes the relative contribution of the autofluorescence to the emission spectrum. These hypotheses are supported by SERS measurement of 2-deoxy

  3. Molecular and genetic inflammation networks in major human diseases.

    PubMed

    Zhao, Yongzhong; Forst, Christian V; Sayegh, Camil E; Wang, I-Ming; Yang, Xia; Zhang, Bin

    2016-07-19

    It has been well-recognized that inflammation alongside tissue repair and damage maintaining tissue homeostasis determines the initiation and progression of complex diseases. Albeit with the accomplishment of having captured the most critical inflammation-involved molecules, genetic susceptibilities, epigenetic factors, and environmental factors, our schemata on the role of inflammation in complex diseases remain largely patchy, in part due to the success of reductionism in terms of research methodology per se. Omics data alongside the advances in data integration technologies have enabled reconstruction of molecular and genetic inflammation networks which shed light on the underlying pathophysiology of complex diseases or clinical conditions. Given the proven beneficial role of anti-inflammation in coronary heart disease as well as other complex diseases and immunotherapy as a revolutionary transition in oncology, it becomes timely to review our current understanding of the molecular and genetic inflammation networks underlying major human diseases. In this review, we first briefly discuss the complexity of infectious diseases and then highlight recently uncovered molecular and genetic inflammation networks in other major human diseases including obesity, type II diabetes, coronary heart disease, late onset Alzheimer's disease, Parkinson's disease, and sporadic cancer. The commonality and specificity of these molecular networks are addressed in the context of genetics based on genome-wide association study (GWAS). The double-sword role of inflammation, such as how the aberrant type 1 and/or type 2 immunity leads to chronic and severe clinical conditions, remains open in terms of the inflammasome and the core inflammatome network features. Increasingly available large Omics and clinical data in tandem with systems biology approaches have offered an exciting yet challenging opportunity toward reconstruction of more comprehensive and dynamic molecular and genetic

  4. Gene-environment interactions in human disease: nuisance or opportunity?

    PubMed

    Ober, Carole; Vercelli, Donata

    2011-03-01

    Many environmental risk factors for common, complex human diseases have been revealed by epidemiologic studies, but how genotypes at specific loci modulate individual responses to environmental risk factors is largely unknown. Gene-environment interactions will be missed in genome-wide association studies and could account for some of the 'missing heritability' for these diseases. In this review, we focus on asthma as a model disease for studying gene-environment interactions because of relatively large numbers of candidate gene-environment interactions with asthma risk in the literature. Identifying these interactions using genome-wide approaches poses formidable methodological problems, and elucidating molecular mechanisms for these interactions has been challenging. We suggest that studying gene-environment interactions in animal models, although more tractable, might not be sufficient to shed light on the genetic architecture of human diseases. Lastly, we propose avenues for future studies to find gene-environment interactions.

  5. Modeling cognition and disease using human glial chimeric mice.

    PubMed

    Goldman, Steven A; Nedergaard, Maiken; Windrem, Martha S

    2015-08-01

    As new methods for producing and isolating human glial progenitor cells (hGPCs) have been developed, the disorders of myelin have become especially compelling targets for cell-based therapy. Yet as animal modeling of glial progenitor cell-based therapies has progressed, it has become clear that transplanted hGPCs not only engraft and expand within murine hosts, but dynamically outcompete the resident progenitors so as to ultimately dominate the host brain. The engrafted human progenitor cells proceed to generate parenchymal astrocytes, and when faced with a hypomyelinated environment, oligodendrocytes as well. As a result, the recipient brains may become inexorably humanized with regards to their resident glial populations, yielding human glial chimeric mouse brains. These brains provide us a fundamentally new tool by which to assess the species-specific attributes of glia in modulating human cognition and information processing. In addition, the cellular humanization of these brains permits their use in studying glial infectious and inflammatory disorders unique to humans, and the effects of those disorders on the glial contributions to cognition. Perhaps most intriguingly, by pairing our ability to construct human glial chimeras with the production of patient-specific hGPCs derived from pluripotential stem cells, we may now establish mice in which a substantial proportion of resident glia are both human and disease-derived. These mice in particular may provide us new opportunities for studying the human-specific contributions of glia to psychopathology, as well as to higher cognition. As such, the assessment of human glial chimeric mice may provide us new insight into the species-specific contributions of glia to human cognitive evolution, as well as to the pathogenesis of human neurological and neuropsychiatric disease.

  6. Exploring human disease using the Rat Genome Database

    PubMed Central

    Laulederkind, Stanley J. F.; De Pons, Jeff; Nigam, Rajni; Smith, Jennifer R.; Tutaj, Marek; Petri, Victoria; Hayman, G. Thomas; Wang, Shur-Jen; Ghiasvand, Omid; Thota, Jyothi; Dwinell, Melinda R.

    2016-01-01

    ABSTRACT Rattus norvegicus, the laboratory rat, has been a crucial model for studies of the environmental and genetic factors associated with human diseases for over 150 years. It is the primary model organism for toxicology and pharmacology studies, and has features that make it the model of choice in many complex-disease studies. Since 1999, the Rat Genome Database (RGD; http://rgd.mcw.edu) has been the premier resource for genomic, genetic, phenotype and strain data for the laboratory rat. The primary role of RGD is to curate rat data and validate orthologous relationships with human and mouse genes, and make these data available for incorporation into other major databases such as NCBI, Ensembl and UniProt. RGD also provides official nomenclature for rat genes, quantitative trait loci, strains and genetic markers, as well as unique identifiers. The RGD team adds enormous value to these basic data elements through functional and disease annotations, the analysis and visual presentation of pathways, and the integration of phenotype measurement data for strains used as disease models. Because much of the rat research community focuses on understanding human diseases, RGD provides a number of datasets and software tools that allow users to easily explore and make disease-related connections among these datasets. RGD also provides comprehensive human and mouse data for comparative purposes, illustrating the value of the rat in translational research. This article introduces RGD and its suite of tools and datasets to researchers – within and beyond the rat community – who are particularly interested in leveraging rat-based insights to understand human diseases. PMID:27736745

  7. Myiasis as a risk factor for prion diseases in humans.

    PubMed

    Lupi, O

    2006-10-01

    Prion diseases are transmissible spongiform encephalopathies of humans and animals. The oral route is clearly associated with some prion diseases, according to the dissemination of bovine spongiform encephalopathy (BSE or mad cow disease) in cattle and kuru in humans. However, other prion diseases such as scrapie (in sheep) and chronic wasting disease (CWD) (in cervids) cannot be explained in this way and are probably more associated with a pattern of horizontal transmission in both domestic and wild animals. The skin and mucous membranes are a potential target for prion infections because keratinocytes and lymphocytes are susceptible to the abnormal infective isoform of the prion protein. Iatrogenic transmission of Creutzfeldt-Jakob disease (CJD) was also recognized after corneal transplants in humans and scrapie was successfully transmitted to mice after ocular instillation of infected brain tissue, confirming that these new routes could also be important in prion infections. Some ectoparasites have been proven to harbour prion rods in laboratory experiments. Prion rods were identified in both fly larvae and pupae; adult flies are also able to express prion proteins. The most common causes of myiasis in cattle and sheep, closely related animals with previous prion infections, are Hypoderma bovis and Oestrus ovis, respectively. Both species of flies present a life cycle very different from human myiasis, as they have a long contact with neurological structures, such as spinal canal and epidural fat, which are potentially rich in prion rods. Ophthalmomyiases in humans is commonly caused by both species of fly larvae worldwide, providing almost direct contact with the central nervous system (CNS). The high expression of the prion protein on the skin and mucosa and the severity of the inflammatory response to the larvae could readily increase the efficiency of transmission of prions in both animals and humans. PMID:16987255

  8. Human immunodeficiency virus type 1 expression in the central nervous system correlates directly with extent of disease

    SciTech Connect

    Weiser, B.; La Neve, D.; Eilbott, D.J.; Burger, H.; Seidman, R. ); Peress, N. Veterans Administration Medical Center, Northport, NY )

    1990-05-01

    To investigate human immunodeficiency virus type 1 (HIV-1) pathogenesis in infected individuals and examine the correlation of HIV-1 expression with extent of clinical and pathologic disease, the authors studied spinal cords from acquired immunodeficiency syndrome patients with a wide range of spinal cord pathology. By performing in situ hybridization with HIV-1-specific riboprobes, they detected HIV-1 RNA in all 10 cords from acquired immunodeficiency syndrome patients with a common, characteristic pathologic entity called vacuolar myelopathy but not in 10 control cords from HIV-1-infected and uninfected patients. In the cords from individuals with vacuolar myelopathy, the level of HIV-1 RNA expression correlated directly with extent of spinal cord pathology and clinical findings. These data support a role for HIV-1 int he pathogenesis of tissue damage and related clinical disease in infected individuals.

  9. Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

    PubMed Central

    Boudoulas, Konstantinos Dean; Mohler, Peter J

    2011-01-01

    Over the past fifteen years, our understanding of the molecular mechanisms underlying human disease has flourished in large part due to the discovery of gene mutations linked with membrane ion channels and transporters. In fact, ion channel defects (“channelopathies” — the focus of this review series) have been associated with a spectrum of serious human disease phenotypes including cystic fibrosis, cardiac arrhythmia, diabetes, skeletal muscle defects, and neurological disorders. However, we now know that human disease, particularly excitable cell disease, may be caused by defects in non-ion channel polypeptides including in cellular components residing well beneath the plasma membrane. For example, over the past few years, a new class of potentially fatal cardiac arrhythmias has been linked with cytoplasmic proteins that include sub-membrane adapters such as ankyrin-B (ANK2), ankyrin-G (ANK3), and alpha-1 syntrophin, membrane coat proteins including caveolin-3 (CAV3), signaling platforms including yotiao (AKAP9), and cardiac enzymes (GPD1L). The focus of this review is to detail the exciting role of lamins, yet another class of gene products that have provided elegant new insight into human disease. PMID:21642948

  10. [Human adjuvant disease which developed after silicone augumentation mammoplasty].

    PubMed

    Muramatsu, Yoko; Sugino, Keishi; Kikuchi, Naoshi; Sano, Go; Isobe, Kazutoshi; Takai, Yujiro; Takagi, Keigo; Shibuya, Kazutoshi; Homma, Sakae

    2009-03-01

    A 73-year-old woman was admitted to our hospital to evaluate mediastinal lymphadenopathy found on a chest CT scan. She had undergone mammoplasty with silicone augmentation 50 years previously and had the implants removed 5 years previously. Biopsied specimens of a mediastinal lymph node under video-assisted thoracic surgery (VATS) revealed multiple hyalinized non-caseating epithelioid cell granulomas and multinucleated giant cells and foamy macrophages containing some vacuoles. According to these clinicopathological findings, we diagnosed human adjuvant disease which developed after mammoplasty with silicone augmentation. In cases of mammoplasty, we should pay attention to the complication of chronic thoracic disorder as a human adjuvant disease.

  11. Natural selection and infectious disease in human populations

    PubMed Central

    Karlsson, Elinor K.; Kwiatkowski, Dominic P.; Sabeti, Pardis C.

    2015-01-01

    The ancient biological 'arms race' between microbial pathogens and humans has shaped genetic variation in modern populations, and this has important implications for the growing field of medical genomics. As humans migrated throughout the world, populations encountered distinct pathogens, and natural selection increased the prevalence of alleles that are advantageous in the new ecosystems in both host and pathogens. This ancient history now influences human infectious disease susceptibility and microbiome homeostasis, and contributes to common diseases that show geographical disparities, such as autoimmune and metabolic disorders. Using new high-throughput technologies, analytical methods and expanding public data resources, the investigation of natural selection is leading to new insights into the function and dysfunction of human biology. PMID:24776769

  12. Linking Microbiota to Human Diseases: A Systems Biology Perspective.

    PubMed

    Wu, Hao; Tremaroli, Valentina; Bäckhed, Fredrik

    2015-12-01

    The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2 diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction.

  13. Human Polyomavirus Reactivation: Disease Pathogenesis and Treatment Approaches

    PubMed Central

    De Gascun, Cillian F.; Carr, Michael J.

    2013-01-01

    JC and BK polyomaviruses were discovered over 40 years ago and have become increasingly prevalent causes of morbidity and mortality in a variety of distinct, immunocompromised patient cohorts. The recent discoveries of eight new members of the Polyomaviridae family that are capable of infecting humans suggest that there are more to be discovered and raise the possibility that they may play a more significant role in human disease than previously understood. In spite of this, there remains a dearth of specific therapeutic options for human polyomavirus infections and an incomplete understanding of the relationship between the virus and the host immune system. This review summarises the human polyomaviruses with particular emphasis on pathogenesis in those directly implicated in disease aetiology and the therapeutic options available for treatment in the immunocompromised host. PMID:23737811

  14. Human prion diseases: surgical lessons learned from iatrogenic prion transmission.

    PubMed

    Bonda, David J; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L; Schonberger, Lawrence B; Cali, Ignazio

    2016-07-01

    The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood "infectious protein" has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission

  15. [The Biological Function of SHP2 in Human Disease].

    PubMed

    Li, S M

    2016-01-01

    Tyrosyl phosphorylation participates in various pathological and physiological processes, which are regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). The Src homology-2 domain containing phosphatase SHP2 (encoded by PTPN11) is an important phosphatase, which was found to be implicated in the regulation of genetic disease, development, metabolic, neurological, muscle, skeletal disease and cancer. Germline mutations in PTPN11 cause the Noonan Syndrome, LEOPARD syndrome and metachondromatosis. Somatic PTPN11 mutations occur in hematologic malignancies and in solid tumors. SHP2 is also an important component in oncogenic signaling pathways. It may play different roles in different stages and positions of human cancers. Whether SHP2 is an oncogene or cancer suppressor gene remains to be elucidated. Elucidation of the regulatory mechanisms of SHP2 in human disease will provide new insights into disease and new targets for therapy. Here, we summarized the structural basis and recent research progression on SHP2 in various human disease, including genetic and cancer diseases. PMID:27028808

  16. Therapy of Human Papillomavirus-Related Disease

    PubMed Central

    Stern, Peter L.; van der Burg, Sjoerd H.; Hampson, Ian N.; Broker, Thomas; Fiander, Alison; Lacey, Charles J.; Kitchener, Henry C.; Einstein, Mark H.

    2014-01-01

    This chapter reviews the current treatment of chronic and neoplastic HPV-associated conditions and the development of novel therapeutic approaches. Surgical excision of HPV-associated lower genital tract neoplasia is very successful but largely depends on secondary prevention programmes for identification of disease. Only high-risk HPV-driven chronic, preneoplastic lesions and some very early cancers cannot be successfully treated by surgical procedures alone. Chemoradiation therapy of cervical cancer contributes to the 66–79% cervical cancer survival at 5 years. Outlook for those patients with persistent or recurrent cervical cancer following treatment is very poor. Topical agents such as imiquimod (immune response modifier), cidofovir (inhibition of viral replication; induction apoptosis) or photodynamic therapy (direct damage of tumour and augmentation of anti-tumour immunity) have all shown some useful efficacy (~50–60%) in treatment of high grade vulvar intraepithelial neoplasia. Provider administered treatments of genital warts include cryotherapy, trichloracetic acid, or surgical removal which has the highest primary clearance rate. Patient applied therapies include podophyllotoxin and imiquimod. Recurrence after “successful” treatment is 30–40%. Further improvements could derive from a rational combination of current therapy with new drugs targeting molecular pathways mediated by HPV in cancer. Small molecule inhibitors targeting the DNA binding activities of HPV E1/E2 or the anti-apoptotic consequences of E6/E7 oncogenes are in preclinical development. Proteasome and histone deacetylase inhibitors, which can enhance apoptosis in HPV positive tumour cells, are being tested in early clinical trials. Chronic high-risk HPV infection/neoplasia is characterised by systemic and/or local immune suppressive regulatory or escape factors. Recently two E6/E7 vaccines have shown some clinical efficacy in high grade VIN patients and this correlated with strong

  17. Epstein-Barr virus and human diseases: recent advances in diagnosis.

    PubMed Central

    Okano, M; Thiele, G M; Davis, J R; Grierson, H L; Purtilo, D T

    1988-01-01

    Since the discovery of Epstein-Barr virus (EBV) from a cultured Burkitt's lymphoma cell line in 1964, the virus has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma, and infectious mononucleosis. During the recent decade, EBV has been etiologically implicated in a broad spectrum of human diseases. The precise role of this virus in these diseases is not well understood, but clearly, defective immunosurveillance against the virus may permit an uncontrolled proliferation of EBV-infected cells. As a result, a growing number of cases of EBV-associated B-cell proliferative diseases or lymphoma have been noted in patients with primary and acquired immunodeficiencies. These lymphoproliferative diseases and others, such as chronic mononucleosis syndrome, are leading to new areas of investigation which are providing information regarding the pathogenetic mechanisms of EBV-induced diseases. The early accurate diagnosis of EBV infection can be achieved by performing EBV-specific serology, detecting for EBV-determined nuclear antigen in tissues, establishing spontaneous lymphoid cell lines, and using molecular hybridization techniques for demonstrating the presence of viral genome in affected lesions. Images PMID:2848624

  18. Of fish and men: using zebrafish to fight human diseases.

    PubMed

    Ablain, Julien; Zon, Leonard I

    2013-12-01

    Long restricted to the field of developmental biology, the use of the zebrafish (Danio rerio) has extended to the study of human pathogenesis. Fostered by the rapid adaptation of new technologies, the design and analysis of fish models of human diseases have contributed important findings that are now making their way from aquariums to clinics. Here we outline the clinical relevance of the zebrafish as a model organism. PMID:24275383

  19. Human prion disease and relative risk associated with chronic wasting disease.

    PubMed

    Mawhinney, Samantha; Pape, W John; Forster, Jeri E; Anderson, C Alan; Bosque, Patrick; Miller, Michael W

    2006-10-01

    The transmission of the prion disease bovine spongiform encephalopathy (BSE) to humans raises concern about chronic wasting disease (CWD), a prion disease of deer and elk. In 7 Colorado counties with high CWD prevalence, 75% of state hunting licenses are issued locally, which suggests that residents consume most regionally harvested game. We used Colorado death certificate data from 1979 through 2001 to evaluate rates of death from the human prion disease Creutzfeldt-Jakob disease (CJD). The relative risk (RR) of CJD for CWD-endemic county residents was not significantly increased (RR 0.81, 95% confidence interval [CI] 0.40-1.63), and the rate of CJD did not increase over time (5-year RR 0.92, 95% CI 0.73-1.16). In Colorado, human prion disease resulting from CWD exposure is rare or nonexistent. However, given uncertainties about the incubation period, exposure, and clinical presentation, the possibility that the CWD agent might cause human disease cannot be eliminated. PMID:17176567

  20. Molecular identification of the causative agent of human strongyloidiasis acquired in Tanzania: dispersal and diversity of Strongyloides spp. and their hosts.

    PubMed

    Hasegawa, Hideo; Sato, Hiroshi; Fujita, Shiho; Nguema, Pierre Philippe Mbehang; Nobusue, Kenichi; Miyagi, Kei; Kooriyama, Takanori; Takenoshita, Yuji; Noda, Shohei; Sato, Akiko; Morimoto, Azusa; Ikeda, Yatsukaho; Nishida, Toshisada

    2010-09-01

    In order to identify the causative agent of imported strongyloidiasis found in a Japanese mammalogist, who participated in a field survey in Tanzania, the hyper-variable region IV (HVR-IV) of 18S ribosomal DNA and partial mitochondrial cytochrome c-oxidase subunit 1 gene (cox1) were analyzed and compared with Strongyloides fuelleborni collected from apes and monkeys of Africa and Japan, and S. stercoralis from humans, apes and dogs. The HVR-IV and cox1 of the patient's worms were identical to or only slightly differed from those of worms parasitic in Tanzanian chimpanzees and yellow baboons, demonstrating that the patient acquired the infection during her field survey in Tanzania. Phylogenetic analysis with the maximum-likelihood method largely divided isolates of S. fuelleborni into three groups, which corresponded to geographical localities but not to host species. Meanwhile, isolates of S. stercoralis were grouped by the phylogenetic analysis into dog-parasitic and primate-parasitic clades, and not to geographical regions. It is surmised that subspeciation has occurred in S. fuelleborni during the dispersal of primates in Africa and Asia, while worldwide dispersal of S. stercoralis seems to have occurred more recently by migration and the activities of modern humans. PMID:20621633

  1. Human embryonic stem cells are pre-mitotically committed to self-renewal and acquire a lengthened G1 phase upon lineage programming

    PubMed Central

    Becker, Klaus A.; Stein, Janet L.; Lian, Jane B.; van Wijnen, Andre J.; Stein, Gary S.

    2009-01-01

    Self-renewal of human embryonic stem (ES) cells proceeds by a unique abbreviated cell cycle with a shortened G1 phase and distinctions in molecular cell cycle regulatory parameters. In this study, we show that early lineage-commitment of pluripotent hES cells modifies cell cycle kinetics. Human ES cells acquire a lengthened G1 within 72 h after lineage-programming is initiated, as reflected by loss of the pluripotency factor Oct4 and alterations in nuclear morphology. In hES cells that maintain the pristine pluripotent state, we find that autocrine mechanisms contribute to sustaining the abbreviated cell cycle. Our data show that naive and mitotically synchronized pluripotent hES cells are competent to initiate two consecutive S phases in the absence of external growth factors. We conclude that short term self-renewal of pluripotent hES cells occurs autonomously, in part due to secreted factors, and that pluripotency is functionally linked to the abbreviated hES cell cycle. PMID:19774559

  2. Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

    PubMed

    Liu, Ying; Deng, Wenbin

    2016-05-01

    With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control

  3. Molecular approaches to human polygenic disease - Symposium 130

    SciTech Connect

    Not Available

    1987-01-01

    This volume deals with the application of recombinant DNA techniques to the identification of diseases that have more than one inherited component. Focus is on the polygenic factors responsible for coronary atherosclerosis. Several other disorders having a polygenic orgin are also discussed, including hypertension, diabetes mellitus, psychiatric diseases, and autoimmune (HLA-related) disorders. Problems raised by the study of different families or different populations are covered, as well as the possibility of applying molecular techniques to disease prevention-for example, through gene therapy. Also explored are some of the ethical issues that relate to human gene mapping.

  4. Mapping Gene Associations in Human Mitochondria using Clinical Disease Phenotypes

    PubMed Central

    Scharfe, Curt; Lu, Henry Horng-Shing; Neuenburg, Jutta K.; Allen, Edward A.; Li, Guan-Cheng; Klopstock, Thomas; Cowan, Tina M.; Enns, Gregory M.; Davis, Ronald W.

    2009-01-01

    Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the

  5. Microbial contact during pregnancy, intestinal colonization and human disease.

    PubMed

    Rautava, Samuli; Luoto, Raakel; Salminen, Seppo; Isolauri, Erika

    2012-10-01

    Interaction with colonizing intestinal bacteria is essential for healthy intestinal and immunological development in infancy. Advances in understanding early host-microbe interactions indicate that this early microbial programming begins in utero and is substantially modulated by mode of birth, perinatal antibiotics and breastfeeding. Furthermore, it has become evident that this stepwise microbial colonization process, as well as immune and metabolic programming by the microbiota, might have a long-lasting influence on the risk of not only gastrointestinal disease, but also allergic, autoimmune and metabolic disease, in later life. Modulating early host-microbe interaction by maternal probiotic intervention during pregnancy and breastfeeding offers a promising novel tool to reduce the risk of disease. In this Review, we describe the current body of knowledge regarding perinatal microbial contact, initial intestinal colonization and its association with human disease, as well as means of modulating early host-microbe interaction to reduce the risk of disease in the child.

  6. Effects of antibiotics on human microbiota and subsequent disease.

    PubMed

    Keeney, Kristie M; Yurist-Doutsch, Sophie; Arrieta, Marie-Claire; Finlay, B Brett

    2014-01-01

    Although antibiotics have significantly improved human health and life expectancy, their disruption of the existing microbiota has been linked to significant side effects such as antibiotic-associated diarrhea, pseudomembranous colitis, and increased susceptibility to subsequent disease. By using antibiotics to break colonization resistance against Clostridium, Salmonella, and Citrobacter species, researchers are now exploring mechanisms for microbiota-mediated modulation against pathogenic infection, revealing potential roles for different phyla and family members as well as microbiota-liberated sugars, hormones, and short-chain fatty acids in regulating pathogenicity. Furthermore, connections are now being made between microbiota dysbiosis and a variety of different diseases such as rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, atopy, and obesity. Future advances in the rapidly developing field of microbial bioinformatics will enable researchers to further characterize the mechanisms of microbiota modulation of disease and potentially identify novel therapeutics against disease.

  7. Contrasting Roles of the Apoplastic Aspartyl Protease APOPLASTIC, ENHANCED DISEASE SUSCEPTIBILITY1-DEPENDENT1 and LEGUME LECTIN-LIKE PROTEIN1 in Arabidopsis Systemic Acquired Resistance.

    PubMed

    Breitenbach, Heiko H; Wenig, Marion; Wittek, Finni; Jordá, Lucia; Maldonado-Alconada, Ana M; Sarioglu, Hakan; Colby, Thomas; Knappe, Claudia; Bichlmeier, Marlies; Pabst, Elisabeth; Mackey, David; Parker, Jane E; Vlot, A Corina

    2014-04-22

    Systemic acquired resistance (SAR) is an inducible immune response that depends on ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1). Here, we show that Arabidopsis (Arabidopsis thaliana) EDS1 is required for both SAR signal generation in primary infected leaves and SAR signal perception in systemic uninfected tissues. In contrast to SAR signal generation, local resistance remains intact in eds1 mutant plants in response to Pseudomonas syringae delivering the effector protein AvrRpm1. We utilized the SAR-specific phenotype of the eds1 mutant to identify new SAR regulatory proteins in plants conditionally expressing AvrRpm1. Comparative proteomic analysis of apoplast-enriched extracts from AvrRpm1-expressing wild-type and eds1 mutant plants led to the identification of 12 APOPLASTIC, EDS1-DEPENDENT (AED) proteins. The genes encoding AED1, a predicted aspartyl protease, and another AED, LEGUME LECTIN-LIKE PROTEIN1 (LLP1), were induced locally and systemically during SAR signaling and locally by salicylic acid (SA) or its functional analog, benzo 1,2,3-thiadiazole-7-carbothioic acid S-methyl ester. Because conditional overaccumulation of AED1-hemagglutinin inhibited SA-induced resistance and SAR but not local resistance, the data suggest that AED1 is part of a homeostatic feedback mechanism regulating systemic immunity. In llp1 mutant plants, SAR was compromised, whereas the local resistance that is normally associated with EDS1 and SA as well as responses to exogenous SA appeared largely unaffected. Together, these data indicate that LLP1 promotes systemic rather than local immunity, possibly in parallel with SA. Our analysis reveals new positive and negative components of SAR and reinforces the notion that SAR represents a distinct phase of plant immunity beyond local resistance.

  8. Prioritizing protein complexes implicated in human diseases by network optimization

    PubMed Central

    2014-01-01

    Background The detection of associations between protein complexes and human inherited diseases is of great importance in understanding mechanisms of diseases. Dysfunctions of a protein complex are usually defined by its member disturbance and consequently result in certain diseases. Although individual disease proteins have been widely predicted, computational methods are still absent for systematically investigating disease-related protein complexes. Results We propose a method, MAXCOM, for the prioritization of candidate protein complexes. MAXCOM performs a maximum information flow algorithm to optimize relationships between a query disease and candidate protein complexes through a heterogeneous network that is constructed by combining protein-protein interactions and disease phenotypic similarities. Cross-validation experiments on 539 protein complexes show that MAXCOM can rank 382 (70.87%) protein complexes at the top against protein complexes constructed at random. Permutation experiments further confirm that MAXCOM is robust to the network structure and parameters involved. We further analyze protein complexes ranked among top ten for breast cancer and demonstrate that the SWI/SNF complex is potentially associated with breast cancer. Conclusions MAXCOM is an effective method for the discovery of disease-related protein complexes based on network optimization. The high performance and robustness of this approach can facilitate not only pathologic studies of diseases, but also the design of drugs targeting on multiple proteins. PMID:24565064

  9. 75 FR 6675 - Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): Human...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-10

    ..., National Center for HIV, Hepatitis and Sexually Transmitted Diseases Prevention, 1600 Clifton Road, NE... HUMAN SERVICES Centers for Disease Control and Prevention Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): Human Immunodeficiency Virus (HIV) Prevention Projects for...

  10. 75 FR 52356 - Disease, Disability, and Injury Prevention and Control Special Emphasis Panel: National Human...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-25

    ... HUMAN SERVICES Centers for Disease Control and Prevention Disease, Disability, and Injury Prevention and Control Special Emphasis Panel: National Human Immunodeficiency Virus (HIV) Behavioral Surveillance... Disease Registry. Dated: August 18, 2010. Elaine L. Baker, Director, Management Analysis and...

  11. Lyme disease: a unique human model for an infectious etiology of rheumatic disease.

    PubMed Central

    Malawista, S. E.; Steere, A. C.; Hardin, J. A.

    1984-01-01

    Lyme disease is a complex immune-mediated multi-system disorder that is infectious in origin and inflammatory or "rheumatic" in expression. Through its epidemiologic characteristics, large numbers of a seasonally synchronized patient population are readily available for prospective study. Lyme disease has a known clinical onset ("zero time"), marked by the characteristic expanding skin lesion, erythema chronicum migrans, and a clearly defined pre-articular phase. At least some manifestations of the disorder are responsive to antibiotics, and the causative agent--a spirochete--is now known. These advantages make Lyme disease unique as a human model for an infectious etiology of rheumatic disease. PMID:6516449

  12. Part 1: The Human Gut Microbiome in Health and Disease

    PubMed Central

    Bull, Matthew J.; Plummer, Nigel T.

    2014-01-01

    The bacterial cells harbored within the human gastrointestinal tract (GIT) outnumber the host’s cells by a factor of 10 and the genes encoded by the bacteria resident within the GIT outnumber their host’s genes by more than 100 times. These human digestive-tract associated microbes are referred to as the gut microbiome. The human gut microbiome and its role in both health and disease has been the subject of extensive research, establishing its involvement in human metabolism, nutrition, physiology, and immune function. Imbalance of the normal gut microbiota have been linked with gastrointestinal conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), and wider systemic manifestations of disease such as obesity, type 2 diabetes, and atopy. In the first part of this review, we evaluate our evolving knowledge of the development, complexity, and functionality of the healthy gut microbiota, and the ways in which the microbial community is perturbed in dysbiotic disease states; the second part of this review covers the role of interventions that have been shown to modulate and stabilize the gut microbiota and also to restore it to its healthy composition from the dysbiotic states seen in IBS, IBD, obesity, type 2 diabetes, and atopy. PMID:26770121

  13. Part 1: The Human Gut Microbiome in Health and Disease.

    PubMed

    Bull, Matthew J; Plummer, Nigel T

    2014-12-01

    The bacterial cells harbored within the human gastrointestinal tract (GIT) outnumber the host's cells by a factor of 10 and the genes encoded by the bacteria resident within the GIT outnumber their host's genes by more than 100 times. These human digestive-tract associated microbes are referred to as the gut microbiome. The human gut microbiome and its role in both health and disease has been the subject of extensive research, establishing its involvement in human metabolism, nutrition, physiology, and immune function. Imbalance of the normal gut microbiota have been linked with gastrointestinal conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), and wider systemic manifestations of disease such as obesity, type 2 diabetes, and atopy. In the first part of this review, we evaluate our evolving knowledge of the development, complexity, and functionality of the healthy gut microbiota, and the ways in which the microbial community is perturbed in dysbiotic disease states; the second part of this review covers the role of interventions that have been shown to modulate and stabilize the gut microbiota and also to restore it to its healthy composition from the dysbiotic states seen in IBS, IBD, obesity, type 2 diabetes, and atopy. PMID:26770121

  14. Molecular Genetic Approaches to Human Diseases Involving Mental Retardation.

    ERIC Educational Resources Information Center

    Latt, Samuel A.; And Others

    1984-01-01

    Recombinant DNA techniques provide new approaches to the diagnosis and analysis of inherited human diseases associated with mental retardation, such as Lesch-Nyhan syndrome, phenylketonauria, the Fragile X syndrome, Down syndrome, and those associated with deletions or duplications of subchromosomal regions. (Author/CL)

  15. PXR- and CAR-mediated herbal effect on human diseases.

    PubMed

    Xu, Chenshu; Huang, Min; Bi, Huichang

    2016-09-01

    The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that regulate a broad range of genes involved in drug metabolism and transport. A variety of naturally occurring compounds present in herbal medicines were identified as ligands of PXR and CAR. Recently, accumulative evidences have revealed the PXR- and CAR-mediated herbal effect against multiple human diseases, including inflammatory bowel disease (IBD), cholestatic liver disease, and jaundice. The current review summarized the recent progress in identifying the expanding libraries of herbal medicine as ligands for PXR and CAR. Moreover, the potential for herbal medicines as promising therapeutic agents which were mainly regulated through PXR/CAR signaling pathways was also discussed. The discovery of herbal medicines as modulators of PXR and CAR, and their PXR- and CAR-mediated effect on human diseases will provide a basis for rational drug design, and eventually be explored as a novel therapeutic approach against human diseases. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

  16. A chemo-centric view of human health and disease

    PubMed Central

    Duran-Frigola, Miquel; Rossell, David; Aloy, Patrick

    2014-01-01

    Efforts to compile the phenotypic effects of drugs and environmental chemicals offer the opportunity to adopt a chemo-centric view of human health that does not require detailed mechanistic information. Here, we consider thousands of chemicals and analyze the relationship of their structures with adverse and therapeutic responses. Our study includes molecules related to the etiology of 934 health threatening conditions and used to treat 835 diseases. We first identify chemical moieties that could be independently associated with each phenotypic effect. Using these fragments, we build accurate predictors for approximately 400 clinical phenotypes, finding many privileged and liable structures. Finally, we connect two diseases if they relate to similar chemical structures. The resulting networks of human conditions are able to predict disease comorbidities, as well as identifying potential drug side effects and opportunities for drug repositioning, and show a remarkable coincidence with clinical observations. PMID:25435099

  17. Leveraging human-centered design in chronic disease prevention.

    PubMed

    Matheson, Gordon O; Pacione, Chris; Shultz, Rebecca K; Klügl, Martin

    2015-04-01

    Bridging the knowing-doing gap in the prevention of chronic disease requires deep appreciation and understanding of the complexities inherent in behavioral change. Strategies that have relied exclusively on the implementation of evidence-based data have not yielded the desired progress. The tools of human-centered design, used in conjunction with evidence-based data, hold much promise in providing an optimal approach for advancing disease prevention efforts. Directing the focus toward wide-scale education and application of human-centered design techniques among healthcare professionals will rapidly multiply their effective ability to bring the kind of substantial results in disease prevention that have eluded the healthcare industry for decades. This, in turn, would increase the likelihood of prevention by design.

  18. Receptor Coactivators: Master Regulators of Human Health and Disease

    PubMed Central

    Dasgupta, Subhamoy; Lonard, David M.; O’Malley, Bert W.

    2015-01-01

    Transcriptional coregulators (coactivators and corepressors) have emerged as the principal modulators of the functions of nuclear receptors and other transcription factors. During the decade since the discovery of steroid receptor coactivator-1 (SRC-1), the first authentic coregulator, more than 400 coregulators have been identified and characterized, and deciphering their function has contributed significantly to our understanding of their role in human physiology. Deregulated expression of coregulators has been implicated in diverse disease states and related pathologies. The advancement of molecular technologies has enabled us to better characterize the molecular associations of the SRC family of coactivators with other protein complexes in the context of gene regulation. These continuing discoveries not only expand our knowledge of the roles of coactivators in various human diseases but allow us to discover novel coactivator-targeting strategies for therapeutic intervention in these diseases. PMID:24111892

  19. Leveraging human-centered design in chronic disease prevention.

    PubMed

    Matheson, Gordon O; Pacione, Chris; Shultz, Rebecca K; Klügl, Martin

    2015-04-01

    Bridging the knowing-doing gap in the prevention of chronic disease requires deep appreciation and understanding of the complexities inherent in behavioral change. Strategies that have relied exclusively on the implementation of evidence-based data have not yielded the desired progress. The tools of human-centered design, used in conjunction with evidence-based data, hold much promise in providing an optimal approach for advancing disease prevention efforts. Directing the focus toward wide-scale education and application of human-centered design techniques among healthcare professionals will rapidly multiply their effective ability to bring the kind of substantial results in disease prevention that have eluded the healthcare industry for decades. This, in turn, would increase the likelihood of prevention by design. PMID:25700655

  20. DUF1220 Domains, Cognitive Disease, and Human Brain Evolution

    PubMed Central

    Dumas, L.; Sikela, J.M.

    2010-01-01

    We have established that human genome sequences encoding a novel protein domain, DUF1220, show a dramatically elevated copy number in the human lineage (>200 copies in humans vs. 1 in mouse/rat) and may be important to human evolutionary adaptation. Copy-number variations (CNVs) in the 1q21.1 region, where most DUF1220 sequences map, have now been implicated in numerous diseases associated with cognitive dysfunction, including autism, autism spectrum disorder, mental retardation, schizophrenia, microcephaly, and macrocephaly. Although the data are only correlative at this point, we report here that these disease-related 1q21.1 CNVs either encompass or are directly flanked by DUF1220 sequences and exhibit a dosage-related correlation with human brain size. Microcephaly-producing 1q21.1 CNVs are deletions, whereas macrocephaly-producing 1q21.1 CNVs are duplications. Similarly, 1q21.1 deletions and smaller brain size are linked with schizophrenia, whereas 1q21.1 duplications and larger brain size are associated with autism. Interestingly, these two diseases are thought to be phenotypic opposites. These data suggest a model which proposes that (1) DUF1220 domain copy number may be involved in influencing human brain size and (2) the evolutionary advantage of rapidly increasing DUF1220 copy number in the human lineage has resulted in favoring retention of the high genomic instability of the 1q21.1 region, which, in turn, has precipitated a spectrum of recurrent human brain and developmental disorders. PMID:19850849

  1. AFRICAN GENETIC DIVERSITY: Implications for Human Demographic History, Modern Human Origins, and Complex Disease Mapping

    PubMed Central

    Campbell, Michael C.; Tishkoff, Sarah A.

    2010-01-01

    Comparative studies of ethnically diverse human populations, particularly in Africa, are important for reconstructing human evolutionary history and for understanding the genetic basis of phenotypic adaptation and complex disease. African populations are characterized by greater levels of genetic diversity, extensive population substructure, and less linkage disequilibrium (LD) among loci compared to non-African populations. Africans also possess a number of genetic adaptations that have evolved in response to diverse climates and diets, as well as exposure to infectious disease. This review summarizes patterns and the evolutionary origins of genetic diversity present in African populations, as well as their implications for the mapping of complex traits, including disease susceptibility. PMID:18593304

  2. The impact of the human genome project on complex disease.

    PubMed

    Bailey, Jessica N Cooke; Pericak-Vance, Margaret A; Haines, Jonathan L

    2014-07-16

    In the decade that has passed since the initial release of the Human Genome, numerous advancements in science and technology within and beyond genetics and genomics have been encouraged and enhanced by the availability of this vast and remarkable data resource. Progress in understanding three common, complex diseases: age-related macular degeneration (AMD), Alzheimer's disease (AD), and multiple sclerosis (MS), are three exemplars of the incredible impact on the elucidation of the genetic architecture of disease. The approaches used in these diseases have been successfully applied to numerous other complex diseases. For example, the heritability of AMD was confirmed upon the release of the first genome-wide association study (GWAS) along with confirmatory reports that supported the findings of that state-of-the art method, thus setting the foundation for future GWAS in other heritable diseases. Following this seminal discovery and applying it to other diseases including AD and MS, the genetic knowledge of AD expanded far beyond the well-known APOE locus and now includes more than 20 loci. MS genetics saw a similar increase beyond the HLA loci and now has more than 100 known risk loci. Ongoing and future efforts will seek to define the remaining heritability of these diseases; the next decade could very well hold the key to attaining this goal.

  3. [Parasitic zoonotic disease agents in human and animal drinking water].

    PubMed

    Karanis, P

    2000-08-01

    Human- and veterinary important parasites of the subkingdom of protozoans and helminths infect humans and animals by ingestion of parasites in contaminated water. The parasites are excreted from the body of infected humans, livestock, zoo animals, companion animals or wild animals in the feces. Recreational waters, agricultural practices and wild animals serve as vehicles of transmission of the parasites in the water supplies. The following topics are addressed: a) the life cycles of parasitic diseases-causing agents with proven or potential transmission via water b) the development and the current research status of the analytical techniques for the detection of parasitic diseases-causing agents from water c) the occurrence of Cryptosporidium and Giardia in surface water supplies and in treated water d) the possible water sources and transmission ways of the parasites into the water supplies e) the behaviour and the possibilities for the removal or elimination of the parasites by water treatment.

  4. Humane killing of animals for disease control purposes.

    PubMed

    Thornber, P M; Rubira, R J; Styles, D K

    2014-04-01

    Killing for disease control purposes is an emotional issue for everyone concerned. Large-scale euthanasia or depopulation of animals may be necessary for the emergency control or eradication of animal diseases, to remove animals from a compromised situation (e.g. following flood, storm, fire, drought or a feed contamination event), to effect welfare depopulation when there is an oversupply due to a dysfunctional or closed marketing channel, or to depopulate and dispose of animals with minimal handling to decrease the risk of a zoonotic disease infecting humans. The World Organisation for Animal Health (OIE) developed international standards to provide advice on humane killing for various species and situations. Some fundamental issues are defined, such as competency of animal handling and implementation of humane killing techniques. Some of these methods have been used for many years, but novel approaches for the mass killing of particular species are being explored. Novel vaccines and new diagnostic techniques that differentiate between vaccinated and infected animals will save many animals from being killed as part of biosecurity response measures. Unfortunately, the destruction of affected livestock will still be required to control diseases whilst vaccination programmes are activated or where effective vaccines are not available. This paper reviews the principles of humane destruction and depopulation and explores available techniques with their associated advantages and disadvantages. It also identifies some current issues that merit consideration, such as legislative conflicts (emergency disease legislation versus animal welfare legislation, occupational health and safety), media issues, opinions on the future approaches to killing for disease control, and animal welfare.

  5. Humane killing of animals for disease control purposes.

    PubMed

    Thornber, P M; Rubira, R J; Styles, D K

    2014-04-01

    Killing for disease control purposes is an emotional issue for everyone concerned. Large-scale euthanasia or depopulation of animals may be necessary for the emergency control or eradication of animal diseases, to remove animals from a compromised situation (e.g. following flood, storm, fire, drought or a feed contamination event), to effect welfare depopulation when there is an oversupply due to a dysfunctional or closed marketing channel, or to depopulate and dispose of animals with minimal handling to decrease the risk of a zoonotic disease infecting humans. The World Organisation for Animal Health (OIE) developed international standards to provide advice on humane killing for various species and situations. Some fundamental issues are defined, such as competency of animal handling and implementation of humane killing techniques. Some of these methods have been used for many years, but novel approaches for the mass killing of particular species are being explored. Novel vaccines and new diagnostic techniques that differentiate between vaccinated and infected animals will save many animals from being killed as part of biosecurity response measures. Unfortunately, the destruction of affected livestock will still be required to control diseases whilst vaccination programmes are activated or where effective vaccines are not available. This paper reviews the principles of humane destruction and depopulation and explores available techniques with their associated advantages and disadvantages. It also identifies some current issues that merit consideration, such as legislative conflicts (emergency disease legislation versus animal welfare legislation, occupational health and safety), media issues, opinions on the future approaches to killing for disease control, and animal welfare. PMID:25000803

  6. Use of model organism and disease databases to support matchmaking for human disease gene discovery.

    PubMed

    Mungall, Christopher J; Washington, Nicole L; Nguyen-Xuan, Jeremy; Condit, Christopher; Smedley, Damian; Köhler, Sebastian; Groza, Tudor; Shefchek, Kent; Hochheiser, Harry; Robinson, Peter N; Lewis, Suzanna E; Haendel, Melissa A

    2015-10-01

    The Matchmaker Exchange application programming interface (API) allows searching a patient's genotypic or phenotypic profiles across clinical sites, for the purposes of cohort discovery and variant disease causal validation. This API can be used not only to search for matching patients, but also to match against public disease and model organism data. This public disease data enable matching known diseases and variant-phenotype associations using phenotype semantic similarity algorithms developed by the Monarch Initiative. The model data can provide additional evidence to aid diagnosis, suggest relevant models for disease mechanism and treatment exploration, and identify collaborators across the translational divide. The Monarch Initiative provides an implementation of this API for searching multiple integrated sources of data that contextualize the knowledge about any given patient or patient family into the greater biomedical knowledge landscape. While this corpus of data can aid diagnosis, it is also the beginning of research to improve understanding of rare human diseases.

  7. Impact of climate change on human infectious diseases: Empirical evidence and human adaptation.

    PubMed

    Wu, Xiaoxu; Lu, Yongmei; Zhou, Sen; Chen, Lifan; Xu, Bing

    2016-01-01

    Climate change refers to long-term shifts in weather conditions and patterns of extreme weather events. It may lead to changes in health threat to human beings, multiplying existing health problems. This review examines the scientific evidences on the impact of climate change on human infectious diseases. It identifies research progress and gaps on how human society may respond to, adapt to, and prepare for the related changes. Based on a survey of related publications between 1990 and 2015, the terms used for literature selection reflect three aspects--the components of infectious diseases, climate variables, and selected infectious diseases. Humans' vulnerability to the potential health impacts by climate change is evident in literature. As an active agent, human beings may control the related health effects that may be effectively controlled through adopting proactive measures, including better understanding of the climate change patterns and of the compound disease-specific health effects, and effective allocation of technologies and resources to promote healthy lifestyles and public awareness. The following adaptation measures are recommended: 1) to go beyond empirical observations of the association between climate change and infectious diseases and develop more scientific explanations, 2) to improve the prediction of spatial-temporal process of climate change and the associated shifts in infectious diseases at various spatial and temporal scales, and 3) to establish locally effective early warning systems for the health effects of predicated climate change.

  8. Impact of climate change on human infectious diseases: Empirical evidence and human adaptation.

    PubMed

    Wu, Xiaoxu; Lu, Yongmei; Zhou, Sen; Chen, Lifan; Xu, Bing

    2016-01-01

    Climate change refers to long-term shifts in weather conditions and patterns of extreme weather events. It may lead to changes in health threat to human beings, multiplying existing health problems. This review examines the scientific evidences on the impact of climate change on human infectious diseases. It identifies research progress and gaps on how human society may respond to, adapt to, and prepare for the related changes. Based on a survey of related publications between 1990 and 2015, the terms used for literature selection reflect three aspects--the components of infectious diseases, climate variables, and selected infectious diseases. Humans' vulnerability to the potential health impacts by climate change is evident in literature. As an active agent, human beings may control the related health effects that may be effectively controlled through adopting proactive measures, including better understanding of the climate change patterns and of the compound disease-specific health effects, and effective allocation of technologies and resources to promote healthy lifestyles and public awareness. The following adaptation measures are recommended: 1) to go beyond empirical observations of the association between climate change and infectious diseases and develop more scientific explanations, 2) to improve the prediction of spatial-temporal process of climate change and the associated shifts in infectious diseases at various spatial and temporal scales, and 3) to establish locally effective early warning systems for the health effects of predicated climate change. PMID:26479830

  9. Human Disease-Drug Network Based on Genomic Expression Profiles

    PubMed Central

    Hu, Guanghui; Agarwal, Pankaj

    2009-01-01

    Background Drug repositioning offers the possibility of faster development times and reduced risks in drug discovery. With the rapid development of high-throughput technologies and ever-increasing accumulation of whole genome-level datasets, an increasing number of diseases and drugs can be comprehensively characterized by the changes they induce in gene expression, protein, metabolites and phenotypes. Methodology/Principal Findings We performed a systematic, large-scale analysis of genomic expression profiles of human diseases and drugs to create a disease-drug network. A network of 170,027 significant interactions was extracted from the ∼24.5 million comparisons between ∼7,000 publicly available transcriptomic profiles. The network includes 645 disease-disease, 5,008 disease-drug, and 164,374 drug-drug relationships. At least 60% of the disease-disease pairs were in the same disease area as determined by the Medical Subject Headings (MeSH) disease classification tree. The remaining can drive a molecular level nosology by discovering relationships between seemingly unrelated diseases, such as a connection between bipolar disorder and hereditary spastic paraplegia, and a connection between actinic keratosis and cancer. Among the 5,008 disease-drug links, connections with negative scores suggest new indications for existing drugs, such as the use of some antimalaria drugs for Crohn's disease, and a variety of existing drugs for Huntington's disease; while the positive scoring connections can aid in drug side effect identification, such as tamoxifen's undesired carcinogenic property. From the ∼37K drug-drug relationships, we discover relationships that aid in target and pathway deconvolution, such as 1) KCNMA1 as a potential molecular target of lobeline, and 2) both apoptotic DNA fragmentation and G2/M DNA damage checkpoint regulation as potential pathway targets of daunorubicin. Conclusions/Significance We have automatically generated thousands of disease and

  10. Impact of highly active antiretroviral therapy on oral manifestations of patients with human immunodeficiency virus/acquired immuno deficiency syndrome in South India

    PubMed Central

    Rao, K. V. S. Eswara; Chitturi, Ravi Teja; Kattappagari, Kiran Kumar; Kantheti, Lalith Prakash Chandra; Poosarla, Chandrasekhar; Baddam, Venkat Ramana Reddy

    2015-01-01

    Background: Human immunodeficiency virus (HIV) infection remains a global health problem, although the development of highly active antiretroviral therapy (HAART) has significantly modified the course of HIV disease into a manageable disease with improved quality-of-life mainly in the developed countries. Very few studies are available regarding effect of HAART on oral lesions in developing countries like India. Aims and Objectives: The aim was to document and compare oral lesions in HIV-seropositive patients before and after HAART. Materials and Methods: Oral manifestations were recorded in 320 HIV seropositive patients attending to the Voluntary Counseling and Confidential Testing Centre at the Government General Hospital, Guntur, before and after treating with HAART and the results were statistically analyzed using Student's t-test and Chi-square test. Results: Oral Candidiasis was significantly reduced in patients under HAART after 3 months. Furthermore, there was decreased incidence of periodontal diseases, but increased hyperpigmentation in patients undergoing HAART. Conclusion: The oral manifestations of HIV infection have changed due to the advent of HAART. Many opportunistic infections have resolved as a result of an improved immune system. Though the risk of hyperpigmentation in those with HAART has increased the prevalence of oral candidiasis and periodontal diseases were less in patients who had access to HAART. PMID:26392652

  11. Human bulbar conjunctival hemodynamics in hemoglobin SS and SC disease

    PubMed Central

    Wanek, Justin; Gaynes, Bruce; Lim, Jennifer I.; Molokie, Robert; Shahidi, Mahnaz

    2014-01-01

    The known biophysical variations of hemoglobin (Hb) S and Hb C may result in hemodynamic differences between subjects with SS and SC disease. The purpose of this study was to measure and compare conjunctival hemodynamics between subjects with Hb SS and SC hemoglobinopathies. Image sequences of the conjunctival microcirculation were acquired in 9 healthy control subjects (Hb AA), 24 subjects with SC disease, and 18 subjects with SS disease, using a prototype imaging system. Diameter (D) and blood velocity (V) measurements were obtained in multiple venules of each subject. Data were categorized according to venule caliber by averaging V and D for venules with diameters less than (vessel size 1) or greater than (vessel size 2) 15 µm. V in vessel size 2 was significantly greater than V in vessel size 1 in the AA and SS groups (P ≥ 0.009), but not in the SC group (P = 0.1). V was significantly lower in the SC group as compared to the SS group (P = 0.03). In AA and SS groups, V correlated with D (P ≥ 0.005), but the correlation was not statistically significant in the SC group (P = 0.08). V was inversely correlated with hematocrit in the SS group for large vessels (P = 0.03); however, no significant correlation was found in the SC group (P ≥ 0.2). Quantitative assessment of conjunctival microvascular hemodynamics in SS and SC disease may advance understanding of sickle cell disease pathophysiology and thereby improve therapeutic interventions. PMID:23657867

  12. Molecular Mechanisms of Acrolein Toxicity: Relevance to Human Disease

    PubMed Central

    Moghe, Akshata; Ghare, Smita; Lamoreau, Bryan; Mohammad, Mohammad; Barve, Shirish; McClain, Craig; Joshi-Barve, Swati

    2015-01-01

    Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and its potential as a serious environmental health threat is beginning to be recognized. Humans are exposed to acrolein per oral (food and water), respiratory (cigarette smoke, automobile exhaust, and biocide use) and dermal routes, in addition to endogenous generation (metabolism and lipid peroxidation). Acrolein has been suggested to play a role in several disease states including spinal cord injury, multiple sclerosis, Alzheimer’s disease, cardiovascular disease, diabetes mellitus, and neuro-, hepato-, and nephro-toxicity. On the cellular level, acrolein exposure has diverse toxic effects, including DNA and protein adduction, oxidative stress, mitochondrial disruption, membrane damage, endoplasmic reticulum stress, and immune dysfunction. This review addresses our current understanding of each pathogenic mechanism of acrolein toxicity, with emphasis on the known and anticipated contribution to clinical disease, and potential therapies. PMID:25628402

  13. Molecular mechanisms of acrolein toxicity: relevance to human disease.

    PubMed

    Moghe, Akshata; Ghare, Smita; Lamoreau, Bryan; Mohammad, Mohammad; Barve, Shirish; McClain, Craig; Joshi-Barve, Swati

    2015-02-01

    Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and its potential as a serious environmental health threat is beginning to be recognized. Humans are exposed to acrolein per oral (food and water), respiratory (cigarette smoke, automobile exhaust, and biocide use) and dermal routes, in addition to endogenous generation (metabolism and lipid peroxidation). Acrolein has been suggested to play a role in several disease states including spinal cord injury, multiple sclerosis, Alzheimer's disease, cardiovascular disease, diabetes mellitus, and neuro-, hepato-, and nephro-toxicity. On the cellular level, acrolein exposure has diverse toxic effects, including DNA and protein adduction, oxidative stress, mitochondrial disruption, membrane damage, endoplasmic reticulum stress, and immune dysfunction. This review addresses our current understanding of each pathogenic mechanism of acrolein toxicity, with emphasis on the known and anticipated contribution to clinical disease, and potential therapies.

  14. Attitudes of Turkish midwives and nurses working at hospitals towards people living with human immunodeficiency virus/acquired immune deficiency syndrome.

    PubMed

    Akgun Kostak, Melahat; Unsar, Serap; Kurt, Seda; Erol, Ozgul

    2012-10-01

    Health professionals caring for people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) show poor or negative attitudes because of fear of contagion. Therefore, it is important to know the attitudes of midwives' and nurses' towards people living with HIV/AIDS. The aim of this descriptive and cross-sectional study is to assess the attitudes of Turkish midwives and nurses working at hospitals to people living with HIV/AIDS and to identify factors that affect these attitudes. A group of 46 midwives and 192 nurses working in hospitals were included in the study. Data were collected through AIDS Attitude Scale. Age, professional experience, number of children and marital status influenced the attitudes of the participants towards people living with HIV/AIDS. We concluded that higher level of education appear to positively influence the attitudes of the participants. Education programmes including evidence-based nursing implications might be planned to improve positive attitudes and to prevent stigmatization of people living with HIV/AIDS.

  15. Intersection of Smoking, Human immunodeficiency virus/acquired immunodeficiency syndrome and Cancer: Proceedings of the 8th Annual Texas Conference on Health Disparities

    PubMed Central

    Rajendiran, Smrithi; Kashyap, Meghana V.; Vishwanatha, Jamboor K.

    2013-01-01

    The Texas Center for Health Disparities, a National Institute on Minority Health and Health Disparities Center of Excellence, presents an annual conference to discuss prevention, awareness education and ongoing research about health disparities both in Texas and among the national population. The 2013 Texas Conference on Health Disparities brought together experts, in research, patient care and community outreach, on the “Intersection of Smoking, Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and Cancer”. Smoking, HIV/AIDS and cancer are three individual areas of public health concern, each with its own set of disparities and risk factors based on race, ethnicity, gender, geography and socio-economic status. Disparities among patient populations, in which these issues are found to be comorbid, provide valuable information on goals for patient care. The conference consisted of three sessions addressing “Comorbidities and Treatment”, “Public Health Perspectives”, and “Best Practices”. This article summarizes the basic science, clinical correlates and public health data presented by the speakers. PMID:24227993

  16. [A case of non-acquired immunodeficiency syndrome-defining lung adenocarcinoma in a multidrug-resistant human immunodeficiency virus-positive patient].

    PubMed

    Mori, Naoyoshi; Maeda, Hikaru; Fujiwara, Kentarou; Taniguchi, Haruki

    2013-10-01

    We report a case of non-acquired immunodeficiency syndrome-defining lung adenocarcinoma in a multidrug-resistant human immunodeficiency virus (HIV)-positive patient. The patient was a 47-year-old Japanese woman who received salvage combination anti-retroviral therapy with darunavir plus ritonavir plus raltegravir plus tenofovir/emtricitabine in May 2009. She was diagnosed with lung adenocarcinoma (T3N3M1, stage IV) in November 2010 and was not found to possess any activating mutations in the epidermal growth factor receptor gene. Therefore, 6 courses of carboplatin plus pemetrexed and 3 courses of gemcitabine followed by erlotinib were administrated, and therapy was changed to home medical care. The only drug-related adverse event was grade 1 neutropenia, and drug interaction between the simultaneously administered anti-retroviral and chemotherapeutic agents was not confirmed. The patient battled lung adenocarcinoma for 1 year after the diagnosis and died of cancer progression in October 2011. Her performance status was stable and the CD4 (+) lymphocyte count and HIV load were well controlled throughout the course of treatment. In conclusion, the agents used for this patient show high tolerability and can be used as an effective treatment strategy for lung cancer occurring in HIV-positive patients.

  17. Escitalopram treatment of depression in human immunodeficiency virus/acquired immunodeficiency syndrome: a randomized, double-blind, placebo-controlled study.

    PubMed

    Hoare, Jacqueline; Carey, Paul; Joska, John A; Carrara, Henri; Sorsdahl, Katherine; Stein, Dan J

    2014-02-01

    Depression can be a chronic and impairing illness in people with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. Large randomized studies of newer selective serotonin reuptake inhibitors such as escitalopram in the treatment of depression in HIV, examining comparative treatment efficacy and safety, have yet to be done in HIV-positive patients. This was a fixed-dose, placebo-controlled, randomized, double-blind study to investigate the efficacy of escitalopram in HIV-seropositive subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder. One hundred two participants were randomly assigned to either 10 mg of escitalopram or placebo for 6 weeks. An analysis of covariance of the completers found that there was no advantage for escitalopram over placebo on the Montgomery-Asberg Depression Rating Scale (p = 0.93). Sixty-two percent responded to escitalopram and 59% responded to placebo on the Clinical Global Impression Scale. Given the relatively high placebo response, future trials in this area need to be selective in participant recruitment and to be adequately powered.

  18. Effect of traditional Chinese medicine for treating human immunodeficiency virus infections and acquired immune deficiency syndrome: Boosting immune and alleviating symptoms.

    PubMed

    Zou, Wen; Wang, Jian; Liu, Ying

    2016-01-01

    To respond to the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic in China, the integration of antiretroviral therapy (ART) and traditional Chinese medicine (TCM) has important implications in health outcomes, especially in China where the use of TCM is widespread. The National Free TCM Pilot Program for HIV Infected People began in 5 provinces (Henan, Hebei, Anhui, Hubei, and Guangdong) in 2004, and quickly scaled up to 19 provinces, autonomous regions, and municipalities in China including some places with high prevalence, 26,276 adults have been treated thus far. Usually, people with HIV infection seek TCM for four main reasons: to enhance immune function, to treat symptoms, to improve quality of life, and to reduce side effects related to medications. Evidences from randomized controlled clinical trials suggested some beneficial effects of use of traditional Chinese herbal medicine for HIV infections and AIDS. More proofs from large, well-designed, rigorous trials is needed to give firm support. Challenges include interaction between herbs and antiretroviral drugs, stigma and discrimination. The Free TCM Program has made considerable progress in providing the necessary alternative care and treatment for HIV-infected people in China, and has strong government support for continued improvement and expansion, establishing and improving a work mechanism integrating Chinese and Western medicines.

  19. Effect of traditional Chinese medicine for treating human immunodeficiency virus infections and acquired immune deficiency syndrome: Boosting immune and alleviating symptoms.

    PubMed

    Zou, Wen; Wang, Jian; Liu, Ying

    2016-01-01

    To respond to the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic in China, the integration of antiretroviral therapy (ART) and traditional Chinese medicine (TCM) has important implications in health outcomes, especially in China where the use of TCM is widespread. The National Free TCM Pilot Program for HIV Infected People began in 5 provinces (Henan, Hebei, Anhui, Hubei, and Guangdong) in 2004, and quickly scaled up to 19 provinces, autonomous regions, and municipalities in China including some places with high prevalence, 26,276 adults have been treated thus far. Usually, people with HIV infection seek TCM for four main reasons: to enhance immune function, to treat symptoms, to improve quality of life, and to reduce side effects related to medications. Evidences from randomized controlled clinical trials suggested some beneficial effects of use of traditional Chinese herbal medicine for HIV infections and AIDS. More proofs from large, well-designed, rigorous trials is needed to give firm support. Challenges include interaction between herbs and antiretroviral drugs, stigma and discrimination. The Free TCM Program has made considerable progress in providing the necessary alternative care and treatment for HIV-infected people in China, and has strong government support for continued improvement and expansion, establishing and improving a work mechanism integrating Chinese and Western medicines. PMID:26577109

  20. Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease

    PubMed Central

    Voisset, Cécile; Weiss, Robin A.; Griffiths, David J.

    2008-01-01

    Summary: Retroviruses are an important group of pathogens that cause a variety of diseases in humans and animals. Four human retroviruses are currently known, including human immunodeficiency virus type 1, which causes AIDS, and human T-lymphotropic virus type 1, which causes cancer and inflammatory disease. For many years, there have been sporadic reports of additional human retroviral infections, particularly in cancer and other chronic diseases. Unfortunately, many of these putative viruses remain unproven and controversial, and some retrovirologists have dismissed them as merely “human rumor viruses.” Work in this field was last reviewed in depth in 1984, and since then, the molecular techniques available for identifying and characterizing retroviruses have improved enormously in sensitivity. The advent of PCR in particular has dramatically enhanced our ability to detect novel viral sequences in human tissues. However, DNA amplification techniques have also increased the potential for false-positive detection due to contamination. In addition, the presence of many families of human endogenous retroviruses (HERVs) within our DNA can obstruct attempts to identify and validate novel human retroviruses. Here, we aim to bring together the data on “novel” retroviral infections in humans by critically examining the evidence for those putative viruses that have been linked with disease and the likelihood that they represent genuine human infections. We provide a background to the field and a discussion of potential confounding factors along with some technical guidelines. In addition, some of the difficulties associated with obtaining formal proof of causation for common or ubiquitous agents such as HERVs are discussed. PMID:18322038

  1. Mobile technologies for disease surveillance in humans and animals.

    PubMed

    Mwabukusi, Mpoki; Karimuribo, Esron D; Rweyemamu, Mark M; Beda, Eric

    2014-01-01

    A paper-based disease reporting system has been associated with a number of challenges. These include difficulties to submit hard copies of the disease surveillance forms because of poor road infrastructure, weather conditions or challenging terrain, particularly in the developing countries. The system demands re-entry of the data at data processing and analysis points, thus making it prone to introduction of errors during this process. All these challenges contribute to delayed acquisition, processing and response to disease events occurring in remote hard to reach areas. Our study piloted the use of mobile phones in order to transmit near to real-time data from remote districts in Tanzania (Ngorongoro and Ngara), Burundi (Muyinga) and Zambia (Kazungula and Sesheke). Two technologies namely, digital and short messaging services were used to capture and transmit disease event data in the animal and human health sectors in the study areas based on a server-client model. Smart phones running the Android operating system (minimum required version: Android 1.6), and which supported open source application, Epicollect, as well as the Open Data Kit application, were used in the study. These phones allowed collection of geo-tagged data, with the opportunity of including static and moving images related to disease events. The project supported routine disease surveillance systems in the ministries responsible for animal and human health in Burundi, Tanzania and Zambia, as well as data collection for researchers at the Sokoine University of Agriculture, Tanzania. During the project implementation period between 2011 and 2013, a total number of 1651 diseases event-related forms were submitted, which allowed reporters to include GPS coordinates and photographs related to the events captured. It was concluded that the new technology-based surveillance system is useful in providing near to real-time data, with potential for enhancing timely response in rural remote areas of

  2. Proteomics in farm animals models of human diseases.

    PubMed

    Ceciliani, Fabrizio; Restelli, Laura; Lecchi, Cristina

    2014-10-01

    The need to provide in vivo complex environments to understand human diseases strongly relies on the use of animal models, which traditionally include small rodents and rabbits. It is becoming increasingly evident that the few species utilised to date cannot be regarded as universal. There is a great need for new animal species that are naturally endowed with specific features relevant to human diseases. Farm animals, including pigs, cows, sheep and horses, represent a valid alternative to commonly utilised rodent models. There is an ample scope for the application of proteomic techniques in farm animals, and the establishment of several proteomic maps of plasma and tissue has clearly demonstrated that farm animals provide a disease environment that closely resembles that of human diseases. The present review offers a snapshot of how proteomic techniques have been applied to farm animals to improve their use as biomedical models. Focus will be on specific topics of biomedical research in which farm animal models have been characterised through the application of proteomic techniques.

  3. Human anthrax as a re-emerging disease.

    PubMed

    Doganay, Mehmet; Demiraslan, Hayati

    2015-01-01

    Anthrax is primarily a disease of herbivores and the etiological agent is B. anthracis which is a gram-positive, aerobic, spore-forming, and rod shaped bacterium. Bacillus anthracis spores are highly resistant to heat, pressure, ultraviolet and ionizing radiation, chemical agents and disinfectants. For these reasons, B. anthracis spores are an attractive choice as biological agents for the use of bioweapon and/or bioterrorism. Soil is the main reservoir for the infectious agent. The disease most commonly affects wild and domestic mammals. Human are secondarily infected by contact with infected animals and contaminated animal products or directly expose to B. anthracis spores. Anthrax occurs worldwide. This infection is still endemic or hyperendemic in both animals and humans in some part of areas of the world; particularly in Middle East, West Africa, Central Asia, some part of India, South America. However, some countries are claiming free of anthrax, and anthrax has become a re-emerging disease in western countries with the intentional outbreak. Currently, anthrax is classified according to its setting as (1) naturally occurring anthrax, (2) bioterrorism-related anthrax. Vast majority of human anthrax are occurring as naturally occurring anthrax in the world. It is also a threaten disease for western countries. The aim of this paper is to review the relevant patents, short historical perspective, microbiological and epidemiological features, clinical presentations and treatment.

  4. Autoantibodies with Enzymatic Properties in Human Autoimmune Diseases

    PubMed Central

    Wootla, Bharath; Lacroix-Desmazes, Sébastien; Warrington, Arthur E.; Bieber, Allan J.; Kaveri, Srini V.; Rodriguez, Moses

    2011-01-01

    Immunoglobulins (Ig) or antibodies are heavy plasma proteins, with sugar chains added to amino acid residues by N-linked glycosylation and occasionally by O-linked glycosylation. The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation with activation of complement and activation of effector cells. In addition to this plethora of functions, some antibodies express enzymatic activity. Antibodies endowed with enzymatic properties have been described in human autoimmune manifestations for more than a decade in a variety of disorders such as autoimmune thyroiditis, systemic erythematosus (SLE), scleroderma, rheumatoid arthritis (RA), multiple sclerosis (MS) and acquired hemophilia (AH). Antibodies isolated from these conditions were able to specifically hydrolyze thyroglobulin, DNA, RNA, myelin basic protein (MBP), and factor VIII (FVIII) or factor IX (FIX), respectively. The therapeutic relevance of these findings is discussed. PMID:21624820

  5. Markers predicting progression of human immunodeficiency virus-related disease.

    PubMed Central

    Tsoukas, C M; Bernard, N F

    1994-01-01

    Human immunodeficiency virus (HIV) interacts with the immune system throughout the course of infection. For most of the disease process, HIV activates the immune system, and the degree of activation can be assessed by measuring serum levels of molecules such as beta 2-microglobulin and neopterin, as well as other serum and cell surface phenotype markers. The levels of some of these markers correlate with clinical progression of HIV disease, and these markers may be useful as surrogate markers for development of clinical AIDS. Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management. Surrogate markers of HIV infection are, by definition, measurable traits that correlate with disease progression. An ideal marker should identify patients at highest risk of disease progression, provide information on how long an individual has been infected, help in staging HIV disease, predict development of opportunistic infections associated with AIDS, monitor the therapeutic efficacy of immunomodulating or antiviral treatments, and the easily quantifiable, reliable, clinically available, and affordable. This review examines the current state of knowledge and the role of surrogate markers in the natural history and treatment of HIV infection. The clinical usefulness of each marker is assessed with respect to the criteria outlined for the ideal surrogate marker for HIV disease progression. PMID:8118788

  6. Acquired aplastic anemia.

    PubMed

    Keohane, Elaine M

    2004-01-01

    Acquired aplastic anemia (AA) is a disorder characterized by a profound deficit of hematopoietic stem and progenitor cells, bone marrow hypocellularity, and peripheral blood pancytopenia. It primarily affects children, young adults, and those over 60 years of age. The majority of cases are idiopathic; however, idiosyncratic reactions to some drugs, chemicals, and viruses have been implicated in its etiology. An autoimmune T-cell reaction likely causes the stem cell depletion, but the precise mechanism, as well as the eliciting and target antigens, is unknown. Symptoms vary from severe life-threatening cytopenias to moderate or non-severe disease that does not require transfusion support. The peripheral blood typically exhibits pancytopenia, reticulocytopenia, and normocytic or macrocytic erythrocytes. The bone marrow is hypocellular and may exhibit dysplasia of the erythrocyte precursors. First line treatment for severe AA consists of hematopoietic stem cell transplantation in young patients with HLA identical siblings, while immunosuppression therapy is used for older patients and for those of any age who lack a HLA matched donor. Patients with AA have an increased risk of developing paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), or acute leukemia. Further elucidation of the pathophysiology of this disease will result in a better understanding of the interrelationship among AA, PNH, and MDS, and may lead to novel targeted therapies.

  7. Functional roles of alternative splicing factors in human disease

    PubMed Central

    Cieply, Benjamin; Carstens, Russ P

    2015-01-01

    Alternative splicing (AS) is an important mechanism used to generate greater transcriptomic and proteomic diversity from a finite genome. Nearly all human gene transcripts are alternatively spliced and can produce protein isoforms with divergent and even antagonistic properties that impact cell functions. Many AS events are tightly regulated in a cell-type or tissue-specific manner, and at different developmental stages. AS is regulated by RNA-binding proteins, including cell- or tissue-specific splicing factors. In the past few years, technological advances have defined genome-wide programs of AS regulated by increasing numbers of splicing factors. These splicing regulatory networks (SRNs) consist of transcripts that encode proteins that function in coordinated and related processes that impact the development and phenotypes of different cell types. As such, it is increasingly recognized that disruption of normal programs of splicing regulated by different splicing factors can lead to human diseases. We will summarize examples of diseases in which altered expression or function of splicing regulatory proteins has been implicated in human disease pathophysiology. As the role of AS continues to be unveiled in human disease and disease risk, it is hoped that further investigations into the functions of numerous splicing factors and their regulated targets will enable the development of novel therapies that are directed at specific AS events as well as the biological pathways they impact. WIREs RNA 2015, 6:311–326. doi: 10.1002/wrna.1276 For further resources related to this article, please visit the http://wires.wiley.com/remdoi.cgi?doi=10.1002/wrna.1276WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article. PMID:25630614

  8. The Burden of Human Papillomavirus Infections and Related Diseases in Sub-Saharan Africa

    PubMed Central

    De Vuyst, Hugo; Alemany, Laia; Lacey, Charles; Chibwesha, Carla J.; Sahasrabuddhe, Vikrant; Banura, Cecily; Denny, Lynette; Parham, Groesbeck P.

    2014-01-01

    Despite the scarcity of high quality cancer registries and lack of reliable mortality data, it is clear that human papillomavirus (HPV)-associated diseases, particularly cervical cancer, are major causes of morbidity and mortality in sub-Saharan Africa (SSA). Cervical cancer incidence rates in SSA are the highest in the world and the disease is the most common cause of cancer death among women in the region. The high incidence of cervical cancer is a consequence of the inability of most countries to either initiate or sustain cervical cancer prevention services. In addition, it appears that the prevalence of HPV in women with normal cytology is higher than in more developed areas of the world, at an average of 24%. There is, however, significant regional variation in SSA, with the highest incidence of HPV infection and cervical cancer found in Eastern and Western Africa. It is expected that, due to aging and growth of the population, but also to lack of access to appropriate prevention services and the concomitant human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic, cervical cancer incidence and mortality rates in SSA will rise over the next 20 years. HPV16 and 18 are the most common genotypes in cervical cancer in SSA, although other carcinogenic HPV types, such as HPV45 and 35, are also relatively more frequent compared with other world regions. Data on other HPV-related anogenital cancers including those of the vulva, vagina, anus, and penis, are limited. Genital warts are common and associated with HPV types 6 and 11. HIV infection increases incidence and prevalence of all HPV-associated diseases. Sociocultural determinants of HPV-related disease, as well as the impact of forces that result in social destabilization, demand further study. Strategies to reduce the excessive burden of HPV-related diseases in SSA include age-appropriate prophylactic HPV vaccination, cervical cancer prevention services for women of the reproductive

  9. Credit scores, cardiovascular disease risk, and human capital

    PubMed Central

    Israel, Salomon; Caspi, Avshalom; Belsky, Daniel W.; Harrington, HonaLee; Hogan, Sean; Houts, Renate; Ramrakha, Sandhya; Sanders, Seth; Poulton, Richie; Moffitt, Terrie E.

    2014-01-01

    Credit scores are the most widely used instruments to assess whether or not a person is a financial risk. Credit scoring has been so successful that it has expanded beyond lending and into our everyday lives, even to inform how insurers evaluate our health. The pervasive application of credit scoring has outpaced knowledge about why credit scores are such useful indicators of individual behavior. Here we test if the same factors that lead to poor credit scores also lead to poor health. Following the Dunedin (New Zealand) Longitudinal Study cohort of 1,037 study members, we examined the association between credit scores and cardiovascular disease risk and the underlying factors that account for this association. We find that credit scores are negatively correlated with cardiovascular disease risk. Variation in household income was not sufficient to account for this association. Rather, individual differences in human capital factors—educational attainment, cognitive ability, and self-control—predicted both credit scores and cardiovascular disease risk and accounted for ∼45% of the correlation between credit scores and cardiovascular disease risk. Tracing human capital factors back to their childhood antecedents revealed that the characteristic attitudes, behaviors, and competencies children develop in their first decade of life account for a significant portion (∼22%) of the link between credit scores and cardiovascular disease risk at midlife. We discuss the implications of these findings for policy debates about data privacy, financial literacy, and early childhood interventions. PMID:25404329

  10. Credit scores, cardiovascular disease risk, and human capital.

    PubMed

    Israel, Salomon; Caspi, Avshalom; Belsky, Daniel W; Harrington, HonaLee; Hogan, Sean; Houts, Renate; Ramrakha, Sandhya; Sanders, Seth; Poulton, Richie; Moffitt, Terrie E

    2014-12-01

    Credit scores are the most widely used instruments to assess whether or not a person is a financial risk. Credit scoring has been so successful that it has expanded beyond lending and into our everyday lives, even to inform how insurers evaluate our health. The pervasive application of credit scoring has outpaced knowledge about why credit scores are such useful indicators of individual behavior. Here we test if the same factors that lead to poor credit scores also lead to poor health. Following the Dunedin (New Zealand) Longitudinal Study cohort of 1,037 study members, we examined the association between credit scores and cardiovascular disease risk and the underlying factors that account for this association. We find that credit scores are negatively correlated with cardiovascular disease risk. Variation in household income was not sufficient to account for this association. Rather, individual differences in human capital factors—educational attainment, cognitive ability, and self-control—predicted both credit scores and cardiovascular disease risk and accounted for ∼45% of the correlation between credit scores and cardiovascular disease risk. Tracing human capital factors back to their childhood antecedents revealed that the characteristic attitudes, behaviors, and competencies children develop in their first decade of life account for a significant portion (∼22%) of the link between credit scores and cardiovascular disease risk at midlife. We discuss the implications of these findings for policy debates about data privacy, financial literacy, and early childhood interventions.

  11. Credit scores, cardiovascular disease risk, and human capital.

    PubMed

    Israel, Salomon; Caspi, Avshalom; Belsky, Daniel W; Harrington, HonaLee; Hogan, Sean; Houts, Renate; Ramrakha, Sandhya; Sanders, Seth; Poulton, Richie; Moffitt, Terrie E

    2014-12-01

    Credit scores are the most widely used instruments to assess whether or not a person is a financial risk. Credit scoring has been so successful that it has expanded beyond lending and into our everyday lives, even to inform how insurers evaluate our health. The pervasive application of credit scoring has outpaced knowledge about why credit scores are such useful indicators of individual behavior. Here we test if the same factors that lead to poor credit scores also lead to poor health. Following the Dunedin (New Zealand) Longitudinal Study cohort of 1,037 study members, we examined the association between credit scores and cardiovascular disease risk and the underlying factors that account for this association. We find that credit scores are negatively correlated with cardiovascular disease risk. Variation in household income was not sufficient to account for this association. Rather, individual differences in human capital factors—educational attainment, cognitive ability, and self-control—predicted both credit scores and cardiovascular disease risk and accounted for ∼45% of the correlation between credit scores and cardiovascular disease risk. Tracing human capital factors back to their childhood antecedents revealed that the characteristic attitudes, behaviors, and competencies children develop in their first decade of life account for a significant portion (∼22%) of the link between credit scores and cardiovascular disease risk at midlife. We discuss the implications of these findings for policy debates about data privacy, financial literacy, and early childhood interventions. PMID:25404329

  12. Characterization of Disease-Associated Mutations in Human Transmembrane Proteins

    PubMed Central

    Molnár, János; Szakács, Gergely; Tusnády, Gábor E.

    2016-01-01

    Transmembrane protein coding genes are commonly associated with human diseases. We characterized disease causing mutations and natural polymorphisms in transmembrane proteins by mapping missense genetic variations from the UniProt database on the transmembrane protein topology listed in the Human Transmembrane Proteome database. We found characteristic differences in the spectrum of amino acid changes within transmembrane regions: in the case of disease associated mutations the non-polar to non-polar and non-polar to charged amino acid changes are equally frequent. In contrast, in the case of natural polymorphisms non-polar to charged amino acid changes are rare while non-polar to non-polar changes are common. The majority of disease associated mutations result in glycine to arginine and leucine to proline substitutions. Mutations to positively charged amino acids are more common in the center of the lipid bilayer, where they cause more severe structural and functional anomalies. Our analysis contributes to the better understanding of the effect of disease associated mutations in transmembrane proteins, which can help prioritize genetic variations in personal genomic investigations. PMID:26986070

  13. Noncommunicable diseases and human rights: a promising synergy.

    PubMed

    Gruskin, Sofia; Ferguson, Laura; Tarantola, Daniel; Beaglehole, Robert

    2014-05-01

    Noncommunicable diseases (NCDs) have finally emerged onto the global health and development agenda. Despite the increasingly important role human rights play in other areas of global health, their contribution to NCD prevention and control remains nascent. The recently adopted Global Action Plan for the Prevention and Control of NCDs 2013-2020 is an important step forward, but the lack of concrete attention to human rights is a missed opportunity. With practical implications for policy development, priority setting, and strategic design, human rights offer a logical, robust set of norms and standards; define the legal obligations of governments; and provide accountability mechanisms that can be used to enhance current approaches to NCD prevention and control. Harnessing the power of human rights can strengthen action for NCDs at the local, national, and global levels.

  14. Model systems of human papillomavirus-associated disease.

    PubMed

    Doorbar, John

    2016-01-01

    Human papillomaviruses (HPVs) cause a range of serious diseases, including the vast majority of cervical cancers, most anal cancers and around half of head and neck cancers. They are also responsible for troublesome benign epithelial lesions, including genital warts and laryngeal papillomas, and in some individuals HPVs lead to recurrent respiratory papillomatosis and other difficult-to-manage diseases. As a result, there is a great need for model systems that accurately mimic papillomavirus infections in humans. This is complicated by the diverse variety of HPVs, which now number over 200 types, and the different strategies they have evolved to persist in the population. The most well-developed models involve the culture of HPV-containing keratinocytes in organotypic raft culture, an approach which appears to accurately mimic the life cycle of several of the high-risk cancer-associated HPV types. Included amongst these are HPV16 and 18, which cause the majority of cervical cancers. The low-risk HPV types persist less well in tissue-culture models, and our ability to study the productive life cycle of these viruses is more limited. Although ongoing research is likely to improve this situation, animal models of papillomavirus disease can provide considerable basic information as to how lesions form, regress and can be controlled by the immune system. The best studied are cottontail rabbit papillomavirus, rabbit oral papillomavirus and, more recently, mouse papillomavirus (MmuPV), the last of which is providing exciting new insights into viral tropisms and immune control. In addition, transgenic models of disease have helped us to understand the consequences of persistent viral gene expression and the importance of co-factors such as hormones and UV irradiation in the development of neoplasia and cancer. It is hoped that such disease models will eventually lead us to better understanding and better treatments for human disease. PMID:26456009

  15. Model systems of human papillomavirus-associated disease.

    PubMed

    Doorbar, John

    2016-01-01

    Human papillomaviruses (HPVs) cause a range of serious diseases, including the vast majority of cervical cancers, most anal cancers and around half of head and neck cancers. They are also responsible for troublesome benign epithelial lesions, including genital warts and laryngeal papillomas, and in some individuals HPVs lead to recurrent respiratory papillomatosis and other difficult-to-manage diseases. As a result, there is a great need for model systems that accurately mimic papillomavirus infections in humans. This is complicated by the diverse variety of HPVs, which now number over 200 types, and the different strategies they have evolved to persist in the population. The most well-developed models involve the culture of HPV-containing keratinocytes in organotypic raft culture, an approach which appears to accurately mimic the life cycle of several of the high-risk cancer-associated HPV types. Included amongst these are HPV16 and 18, which cause the majority of cervical cancers. The low-risk HPV types persist less well in tissue-culture models, and our ability to study the productive life cycle of these viruses is more limited. Although ongoing research is likely to improve this situation, animal models of papillomavirus disease can provide considerable basic information as to how lesions form, regress and can be controlled by the immune system. The best studied are cottontail rabbit papillomavirus, rabbit oral papillomavirus and, more recently, mouse papillomavirus (MmuPV), the last of which is providing exciting new insights into viral tropisms and immune control. In addition, transgenic models of disease have helped us to understand the consequences of persistent viral gene expression and the importance of co-factors such as hormones and UV irradiation in the development of neoplasia and cancer. It is hoped that such disease models will eventually lead us to better understanding and better treatments for human disease.

  16. The DNA-damage response in human biology and disease

    PubMed Central

    Jackson, Stephen P.; Bartek, Jiri

    2010-01-01

    The prime objective for every life-form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which impact a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management. PMID:19847258

  17. Plant polyphenols as dietary antioxidants in human health and disease.

    PubMed

    Pandey, Kanti Bhooshan; Rizvi, Syed Ibrahim

    2009-01-01

    Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. In the last decade, there has been much interest in the potential health benefits of dietary plant polyphenols as antioxidant. Epidemiological studies and associated meta-analyses strongly suggest that long term consumption of diets rich in plant polyphenols offer protection against development of cancers, cardiovascular diseases, diabetes, osteoporosis and neurodegenerative diseases. Here we present knowledge about the biological effects of plant polyphenols in the context of relevance to human health.

  18. Plant polyphenols as dietary antioxidants in human health and disease

    PubMed Central

    Pandey, Kanti Bhooshan

    2009-01-01

    Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. In the last decade, there has been much interest in the potential health benefits of dietary plant polyphenols as antioxidant. Epidemiological studies and associated meta-analyses strongly suggest that long term consumption of diets rich in plant polyphenols offer protection against development of cancers, cardiovascular diseases, diabetes, osteoporosis and neurodegenerative diseases. Here we present knowledge about the biological effects of plant polyphenols in the context of relevance to human health. PMID:20716914

  19. Therapeutic modulators of STAT signalling for human diseases.

    PubMed

    Miklossy, Gabriella; Hilliard, Tyvette S; Turkson, James

    2013-08-01

    The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials. PMID:23903221

  20. Therapeutic modulators of STAT signalling for human diseases

    PubMed Central

    Miklossy, Gabriella; Hilliard, Tyvette S.; Turkson, James

    2014-01-01

    The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials. PMID:23903221

  1. Disease Ontology 2015 update: an expanded and updated database of human diseases for linking biomedical knowledge through disease data

    PubMed Central

    Kibbe, Warren A.; Arze, Cesar; Felix, Victor; Mitraka, Elvira; Bolton, Evan; Fu, Gang; Mungall, Christopher J.; Binder, Janos X.; Malone, James; Vasant, Drashtti; Parkinson, Helen; Schriml, Lynn M.

    2015-01-01

    The current version of the Human Disease Ontology (DO) (http://www.disease-ontology.org) database expands the utility of the ontology for the examination and comparison of genetic variation, phenotype, protein, drug and epitope data through the lens of human disease. DO is a biomedical resource of standardized common and rare disease concepts with stable identifiers organized by disease etiology. The content of DO has had 192 revisions since 2012, including the addition of 760 terms. Thirty-two percent of all terms now include definitions. DO has expanded the number and diversity of research communities and community members by 50+ during the past two years. These community members actively submit term requests, coordinate biomedical resource disease representation and provide expert curation guidance. Since the DO 2012 NAR paper, there have been hundreds of term requests and a steady increase in the number of DO listserv members, twitter followers and DO website usage. DO is moving to a multi-editor model utilizing Protégé to curate DO in web ontology language. This will enable closer collaboration with the Human Phenotype Ontology, EBI's Ontology Working Group, Mouse Genome Informatics and the Monarch Initiative among others, and enhance DO's current asserted view and multiple inferred views through reasoning. PMID:25348409

  2. Disease Ontology 2015 update: An expanded and updated database of human diseases for linking biomedical knowledge through disease data

    SciTech Connect

    Kibbe, Warren A.; Arze, Cesar; Felix, Victor; Mitraka, Elvira; Bolton, Evan; Fu, Gang; Mungall, Christopher J.; Binder, Janos X.; Malone, James; Vasant, Drashtti; Parkinson, Helen; Schriml, Lynn M.

    2014-10-27

    The current version of the Human Disease Ontology (DO) (http://www.disease-ontology.org) database expands the utility of the ontology for the examination and comparison of genetic variation, phenotype, protein, drug and epitope data through the lens of human disease. DO is a biomedical resource of standardized common and rare disease concepts with stable identifiers organized by disease etiology. The content of DO has had 192 revisions since 2012, including the addition of 760 terms. Thirty-two percent of all terms now include definitions. DO has expanded the number and diversity of research communities and community members by 50+ during the past two years. These community members actively submit term requests, coordinate biomedical resource disease representation and provide expert curation guidance. Since the DO 2012 NAR paper, there have been hundreds of term requests and a steady increase in the number of DO listserv members, twitter followers and DO website usage. DO is moving to a multi-editor model utilizing Protégé to curate DO in web ontology language. In conclusion, this will enable closer collaboration with the Human Phenotype Ontology, EBI's Ontology Working Group, Mouse Genome Informatics and the Monarch Initiative among others, and enhance DO's current asserted view and multiple inferred views through reasoning.

  3. Disease Ontology 2015 update: An expanded and updated database of human diseases for linking biomedical knowledge through disease data

    DOE PAGES

    Kibbe, Warren A.; Arze, Cesar; Felix, Victor; Mitraka, Elvira; Bolton, Evan; Fu, Gang; Mungall, Christopher J.; Binder, Janos X.; Malone, James; Vasant, Drashtti; et al

    2014-10-27

    The current version of the Human Disease Ontology (DO) (http://www.disease-ontology.org) database expands the utility of the ontology for the examination and comparison of genetic variation, phenotype, protein, drug and epitope data through the lens of human disease. DO is a biomedical resource of standardized common and rare disease concepts with stable identifiers organized by disease etiology. The content of DO has had 192 revisions since 2012, including the addition of 760 terms. Thirty-two percent of all terms now include definitions. DO has expanded the number and diversity of research communities and community members by 50+ during the past two years.more » These community members actively submit term requests, coordinate biomedical resource disease representation and provide expert curation guidance. Since the DO 2012 NAR paper, there have been hundreds of term requests and a steady increase in the number of DO listserv members, twitter followers and DO website usage. DO is moving to a multi-editor model utilizing Protégé to curate DO in web ontology language. In conclusion, this will enable closer collaboration with the Human Phenotype Ontology, EBI's Ontology Working Group, Mouse Genome Informatics and the Monarch Initiative among others, and enhance DO's current asserted view and multiple inferred views through reasoning.« less

  4. Disease Ontology 2015 update: an expanded and updated database of human diseases for linking biomedical knowledge through disease data.

    PubMed

    Kibbe, Warren A; Arze, Cesar; Felix, Victor; Mitraka, Elvira; Bolton, Evan; Fu, Gang; Mungall, Christopher J; Binder, Janos X; Malone, James; Vasant, Drashtti; Parkinson, Helen; Schriml, Lynn M

    2015-01-01

    The current version of the Human Disease Ontology (DO) (http://www.disease-ontology.org) database expands the utility of the ontology for the examination and comparison of genetic variation, phenotype, protein, drug and epitope data through the lens of human disease. DO is a biomedical resource of standardized common and rare disease concepts with stable identifiers organized by disease etiology. The content of DO has had 192 revisions since 2012, including the addition of 760 terms. Thirty-two percent of all terms now include definitions. DO has expanded the number and diversity of research communities and community members by 50+ during the past two years. These community members actively submit term requests, coordinate biomedical resource disease representation and provide expert curation guidance. Since the DO 2012 NAR paper, there have been hundreds of term requests and a steady increase in the number of DO listserv members, twitter followers and DO website usage. DO is moving to a multi-editor model utilizing Protégé to curate DO in web ontology language. This will enable closer collaboration with the Human Phenotype Ontology, EBI's Ontology Working Group, Mouse Genome Informatics and the Monarch Initiative among others, and enhance DO's current asserted view and multiple inferred views through reasoning.

  5. Lipidomics of human brain aging and Alzheimer's disease pathology.

    PubMed

    Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

    2015-01-01

    Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context.

  6. Cellular reprogramming for understanding and treating human disease.

    PubMed

    Kanherkar, Riya R; Bhatia-Dey, Naina; Makarev, Evgeny; Csoka, Antonei B

    2014-01-01

    In the last two decades we have witnessed a paradigm shift in our understanding of cells so radical that it has rewritten the rules of biology. The study of cellular reprogramming has gone from little more than a hypothesis, to applied bioengineering, with the creation of a variety of important cell types. By way of metaphor, we can compare the discovery of reprogramming with the archeological discovery of the Rosetta stone. This stone slab made possible the initial decipherment of Egyptian hieroglyphics because it allowed us to see this language in a way that was previously impossible. We propose that cellular reprogramming will have an equally profound impact on understanding and curing human disease, because it allows us to perceive and study molecular biological processes such as differentiation, epigenetics, and chromatin in ways that were likewise previously impossible. Stem cells could be called "cellular Rosetta stones" because they allow also us to perceive the connections between development, disease, cancer, aging, and regeneration in novel ways. Here we present a comprehensive historical review of stem cells and cellular reprogramming, and illustrate the developing synergy between many previously unconnected fields. We show how stem cells can be used to create in vitro models of human disease and provide examples of how reprogramming is being used to study and treat such diverse diseases as cancer, aging, and accelerated aging syndromes, infectious diseases such as AIDS, and epigenetic diseases such as polycystic ovary syndrome. While the technology of reprogramming is being developed and refined there have also been significant ongoing developments in other complementary technologies such as gene editing, progenitor cell production, and tissue engineering. These technologies are the foundations of what is becoming a fully-functional field of regenerative medicine and are converging to a point that will allow us to treat almost any disease. PMID

  7. Cellular reprogramming for understanding and treating human disease

    PubMed Central

    Kanherkar, Riya R.; Bhatia-Dey, Naina; Makarev, Evgeny; Csoka, Antonei B.

    2014-01-01

    In the last two decades we have witnessed a paradigm shift in our understanding of cells so radical that it has rewritten the rules of biology. The study of cellular reprogramming has gone from little more than a hypothesis, to applied bioengineering, with the creation of a variety of important cell types. By way of metaphor, we can compare the discovery of reprogramming with the archeological discovery of the Rosetta stone. This stone slab made possible the initial decipherment of Egyptian hieroglyphics because it allowed us to see this language in a way that was previously impossible. We propose that cellular reprogramming will have an equally profound impact on understanding and curing human disease, because it allows us to perceive and study molecular biological processes such as differentiation, epigenetics, and chromatin in ways that were likewise previously impossible. Stem cells could be called “cellular Rosetta stones” because they allow also us to perceive the connections between development, disease, cancer, aging, and regeneration in novel ways. Here we present a comprehensive historical review of stem cells and cellular reprogramming, and illustrate the developing synergy between many previously unconnected fields. We show how stem cells can be used to create in vitro models of human disease and provide examples of how reprogramming is being used to study and treat such diverse diseases as cancer, aging, and accelerated aging syndromes, infectious diseases such as AIDS, and epigenetic diseases such as polycystic ovary syndrome. While the technology of reprogramming is being developed and refined there have also been significant ongoing developments in other complementary technologies such as gene editing, progenitor cell production, and tissue engineering. These technologies are the foundations of what is becoming a fully-functional field of regenerative medicine and are converging to a point that will allow us to treat almost any disease. PMID

  8. Adult human metapneumonovirus (hMPV) pneumonia mimicking Legionnaire's disease.

    PubMed

    Cunha, Burke A; Irshad, Nadia; Connolly, James J

    2016-01-01

    In adults hospitalized with viral pneumonias the main differential diagnostic consideration is influenza pneumonia. The respiratory viruses causing viral influenza like illnesses (ILIs), e.g., RSV may closely resemble influenza. Rarely, extrapulmonary findings of some ILIs may resemble Legionnaire's disease (LD), e.g., adenovirus, human parainfluenza virus (HPIV-3). We present a most unusual case of human metapneumonovirus pneumonia (hMPV) with some characteristic extrapulmonary findings characteristic of LD, e.g., relative bradycardia, as well as mildly elevated serum transaminases and hyphosphatemia. We believe this is the first reported case of hMPV pneumonia in a hospitalized adult that had some features of LD.

  9. Adult human metapneumonovirus (hMPV) pneumonia mimicking Legionnaire's disease.

    PubMed

    Cunha, Burke A; Irshad, Nadia; Connolly, James J

    2016-01-01

    In adults hospitalized with viral pneumonias the main differential diagnostic consideration is influenza pneumonia. The respiratory viruses causing viral influenza like illnesses (ILIs), e.g., RSV may closely resemble influenza. Rarely, extrapulmonary findings of some ILIs may resemble Legionnaire's disease (LD), e.g., adenovirus, human parainfluenza virus (HPIV-3). We present a most unusual case of human metapneumonovirus pneumonia (hMPV) with some characteristic extrapulmonary findings characteristic of LD, e.g., relative bradycardia, as well as mildly elevated serum transaminases and hyphosphatemia. We believe this is the first reported case of hMPV pneumonia in a hospitalized adult that had some features of LD. PMID:26988110

  10. Human rabies: a reemerging disease in Costa Rica?

    PubMed

    Badilla, Xiomara; Pérez-Herra, Victor; Quirós, Ligia; Morice, Ana; Jiménez, Edwin; Sáenz, Elizabeth; Salazar, Fernando; Fernández, Rodrigo; Orciari, Lillian; Yager, Pamela; Whitfield, Sylvia; Rupprecht, Charles E

    2003-06-01

    Two human rabies cases caused by a bat-associated virus variant were identified in September 2001 in Costa Rica, after a 31-year absence of the disease in humans. Both patients lived in a rural area where cattle had a high risk for bat bites, but neither person had a definitive history of being bitten by a rabid animal. Characterization of the rabies viruses from the patients showed that the reservoir was the hematophagous Vampire Bat, Desmodus rotundus, and that a sick cat was the vector. PMID:12781014

  11. HIV Disease: Current Concepts.

    ERIC Educational Resources Information Center

    Keeling, Richard P.

    1993-01-01

    Describes human immunodeficiency virus (HIV), newly characterized human retrovirus which causes chronic, progressive, immune deficiency disease, the most severe phase of which is Acquired Immune Deficiency Syndrome (AIDS). Reviews most important current epidemiologic, clinical, and virologic information about HIV and HIV disease and provides…

  12. RNAi and small interfering RNAs in human disease therapeutic applications

    PubMed Central

    Lares, Monica R.; Rossi, John J.; Ouellet, Dominique L.

    2010-01-01

    Small interfering RNAs (siRNAs) have shown to effectively down-regulate gene expression in human cells, giving them potential to eradicate disease. Prospects for clinical applications are discussed in this review, along with an overview of recent history and our current understanding of siRNAs used for therapeutic application in human diseases, such as cancer and viral infections. Over recent years, progress has been made in lipids, ligands, nanoparticles, polymers and viral vectors as delivery agents and for gene-based expression of siRNA to enhance the efficacy and specificity of these methods while at the same time reducing toxicity. It has become apparent that given the recent advances in chemistry and delivery, RNAi will soon prove to be an important and widely used therapeutic modality. PMID:20833440

  13. Mitochondrial DNA heteroplasmy in human health and disease

    PubMed Central

    STEFANO, GEORGE B.; KREAM, RICHARD M.

    2016-01-01

    The biomedical literature has extensively documented the functional roles of genetic polymorphisms in concert with well-characterized somatic mutations in the etiology and progression of major metastatic diseases afflicting human populations. Mitochondrial heteroplasmy exists as a dynamically determined co-expression of inherited polymorphisms and somatic mutations in varying ratios within individual mitochondrial DNA genomes with repetitive patterns of tissue specificity. Mechanistically, carcinogenic cellular processes include profound alterations of normative mitochondrial function, notably dependence on aerobic and anaerobic glycolysis, and aberrant production and release of lactate, according to a classic theory. Within the translational context of human health and disease, the present review discusses the necessity of establishing critical foci designed to probe multiple biological roles of mitochondrial heteroplasmy in cancer biology. PMID:26998260

  14. Probing Mechanisms That Underlie Human Neurodegenerative Diseases in Drosophila

    PubMed Central

    Jaiswal, M.; Sandoval, H.; Zhang, K.; Bayat, V.; Bellen, H.J.

    2013-01-01

    The fruit fly, Drosophila melanogaster, is an excellent organism for the study of the genetic and molecular basis of metazoan development. Drosophila provides numerous tools and reagents to unravel the molecular and cellular functions of genes that cause human disease, and the past decade has witnessed a significant expansion of the study of neurodegenerative disease mechanisms in flies. Here we review the interplay between oxidative stress and neuronal toxicity. We cover some of the studies that show how proteasome degradation of protein aggregates, autophagy, mitophagy, and lysosomal function affect the quality control mechanisms required for neuronal survival. We discuss how forward genetic screens in flies have led to the isolation of a few loci that cause neurodegeneration, paving the way for large-scale systematic screens to identify such loci in flies as well as promoting gene discovery in humans. PMID:22974305

  15. Mitochondrial Protein Import and Human Health and Disease

    PubMed Central

    MacKenzie, James A.; Mark Payne, R.

    2009-01-01

    The targeting and assembly of nuclear-encoded mitochondrial proteins are essential processes because the energy supply of humans is dependent upon the proper functioning of mitochondria. Defective import of mitochondrial proteins can arise from mutations in the targeting signals within precursor proteins, from mutations that disrupt the proper functioning of the import machinery, or from deficiencies in the chaperones involved in the proper folding and assembly of proteins once they are imported. Defects in these steps of import have been shown to lead to oxidative stress, neurodegenerative diseases, and metabolic disorders. In addition, protein import into mitochondria has been found to be a dynamically regulated process that varies in response to conditions such as oxidative stress, aging, drug treatment, and exercise. This review focuses on how mitochondrial protein import affects human health and disease. PMID:17300922

  16. Resident memory T cells in human health and disease

    PubMed Central

    Clark, Rachael A.

    2015-01-01

    Resident memory T cells are non-recirculating memory T cells that persist long term in epithelial barrier tissues, including the gastrointestinal tract, lung, skin and reproductive tract. Resident memory T cells persist in the absence of antigens, have impressive effector functions and provide rapid on-site immune protection against known pathogens in peripheral tissues. A fundamentally distinct gene expression program differentiates resident memory T cells from circulating T cells. Although these cells likely evolved to provide rapid immune protection against pathogens, autoreactive, aberrantly activated and malignant resident memory cells contribute to numerous human inflammatory diseases including mycosis fungoides and psoriasis. This review will discuss both the science and medicine of resident memory T cells, exploring how these cells contribute to healthy immune function and discussing what is known about how these cells contribute to human inflammatory and autoimmune diseases. PMID:25568072

  17. Transposable elements in cancer and other human diseases.

    PubMed

    Chenais, Benoit

    2015-01-01

    Transposable elements (TEs) are mobile DNA sequences representing a substantial fraction of most genomes. Through the creation of new genes and functions, TEs are important elements of genome plasticity and evolution. However TE insertion in human genomes may be the cause of genetic dysfunction and alteration of gene expression contributing to cancer and other human diseases. Besides the chromosome rearrangements induced by TE repeats, this mini-review shows how gene expression may be altered following TE insertion, for example by the creation of new polyadenylation sites, by the creation of new exons (exonization), by exon skipping and by other modification of alternative splicing, and also by the alteration of regulatory sequences. Through the correlation between TE mobility and the methylation status of DNA, the importance of chromatin regulation is evident in several diseases. Finally this overview ends with a brief presentation of the use of TEs as biotechnology tools for insertional mutagenesis screening and gene therapy with DNA transposons.

  18. A Novel Human Body Area Network for Brain Diseases Analysis.

    PubMed

    Lin, Kai; Xu, Tianlang

    2016-10-01

    Development of wireless sensor and mobile communication technology provide an unprecedented opportunity for realizing smart and interactive healthcare systems. Designing such systems aims to remotely monitor the health and diagnose the diseases for users. In this paper, we design a novel human body area network for brain diseases analysis, which is named BABDA. Considering the brain is one of the most complex organs in the human body, the BABDA system provides four function modules to ensure the high quality of the analysis result, which includes initial data collection, data correction, data transmission and comprehensive data analysis. The performance evaluation conducted in a realistic environment with several criteria shows the availability and practicability of the BABDA system. PMID:27526187

  19. Assessing the human gut microbiota in metabolic diseases.

    PubMed

    Karlsson, Fredrik; Tremaroli, Valentina; Nielsen, Jens; Bäckhed, Fredrik

    2013-10-01

    Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens-derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology.

  20. A Novel Human Body Area Network for Brain Diseases Analysis.

    PubMed

    Lin, Kai; Xu, Tianlang

    2016-10-01

    Development of wireless sensor and mobile communication technology provide an unprecedented opportunity for realizing smart and interactive healthcare systems. Designing such systems aims to remotely monitor the health and diagnose the diseases for users. In this paper, we design a novel human body area network for brain diseases analysis, which is named BABDA. Considering the brain is one of the most complex organs in the human body, the BABDA system provides four function modules to ensure the high quality of the analysis result, which includes initial data collection, data correction, data transmission and comprehensive data analysis. The performance evaluation conducted in a realistic environment with several criteria shows the availability and practicability of the BABDA system.

  1. Assessing the Human Gut Microbiota in Metabolic Diseases

    PubMed Central

    Karlsson, Fredrik; Tremaroli, Valentina; Nielsen, Jens; Bäckhed, Fredrik

    2013-01-01

    Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens–derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology. PMID:24065795

  2. Beyond the zebrafish: diverse fish species for modeling human disease

    PubMed Central

    Schartl, Manfred

    2014-01-01

    ABSTRACT In recent years, zebrafish, and to a lesser extent medaka, have become widely used small animal models for human diseases. These organisms have convincingly demonstrated the usefulness of fish for improving our understanding of the molecular and cellular mechanisms leading to pathological conditions, and for the development of new diagnostic and therapeutic tools. Despite the usefulness of zebrafish and medaka in the investigation of a wide spectrum of traits, there is evidence to suggest that other fish species could be better suited for more targeted questions. With the emergence of new, improved sequencing technologies that enable genomic resources to be generated with increasing efficiency and speed, the potential of non-mainstream fish species as disease models can now be explored. A key feature of these fish species is that the pathological condition that they model is often related to specific evolutionary adaptations. By exploring these adaptations, new disease-causing and disease-modifier genes might be identified; thus, diverse fish species could be exploited to better understand the complexity of disease processes. In addition, non-mainstream fish models could allow us to study the impact of environmental factors, as well as genetic variation, on complex disease phenotypes. This Review will discuss the opportunities that such fish models offer for current and future biomedical research. PMID:24271780

  3. Interconversion of the Specificities of Human Lysosomal Enzymes Associated with Fabry and Schindler Diseases

    SciTech Connect

    Tomasic, Ivan B.; Metcalf, Matthew C.; Guce, Abigail I.; Clark, Nathaniel E.; Garman, Scott C.

    2010-09-03

    The human lysosomal enzymes {alpha}-galactosidase ({alpha}-GAL, EC 3.2.1.22) and {alpha}-N-acetylgalactosaminidase ({alpha}-NAGAL, EC 3.2.1.49) share 46% amino acid sequence identity and have similar folds. The active sites of the two enzymes share 11 of 13 amino acids, differing only where they interact with the 2-position of the substrates. Using a rational protein engineering approach, we interconverted the enzymatic specificity of {alpha}-GAL and {alpha}-NAGAL. The engineered {alpha}-GAL (which we call {alpha}-GALSA) retains the antigenicity of {alpha}-GAL but has acquired the enzymatic specificity of {alpha}-NAGAL. Conversely, the engineered {alpha}-NAGAL (which we call {alpha}-NAGAL{sup EL}) retains the antigenicity of {alpha}-NAGAL but has acquired the enzymatic specificity of the {alpha}-GAL enzyme. Comparison of the crystal structures of the designed enzyme {alpha}-GAL{sup SA} to the wild-type enzymes shows that active sites of {alpha}-GAL{sup SA} and {alpha}-NAGAL superimpose well, indicating success of the rational design. The designed enzymes might be useful as non-immunogenic alternatives in enzyme replacement therapy for treatment of lysosomal storage disorders such as Fabry disease.

  4. Are human endogenous retroviruses triggers of autoimmune diseases? Unveiling associations of three diseases and viral loci.

    PubMed

    Nexø, Bjørn A; Villesen, Palle; Nissen, Kari K; Lindegaard, Hanne M; Rossing, Peter; Petersen, Thor; Tarnow, Lise; Hansen, Bettina; Lorenzen, Tove; Hørslev-Petersen, Kim; Jensen, Sara B; Bahrami, Shervin; Lajer, Maria; Schmidt, Kathrine L M; Parving, Hans-Henrik; Junker, Peter; Laska, Magdalena J

    2016-02-01

    Autoimmune diseases encompass a plethora of conditions in which the immune system attacks its own tissue, identifying them as foreign. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus was associated with each of the three diseases. Although there was a significant overlap, most loci only occurred in one of the studied disease. Remarkably, within each disease, there was a statistical interaction (synergy) between two loci. Additional synergy between retroviral loci and human lymphocyte antigens is reported for multiple sclerosis. We speculate the possibility that recombinants or mixed viral particles are formed and that the resulting viruses stimulate the innate immune system, thereby initiating the autoimmune response. PMID:26091722

  5. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

    PubMed Central

    Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie; Li, Xiaojie; Chandler-Militello, Devin; Mauceri, Joseph; Burm, Hayley B.; Toner, Michael; Osipovitch, Mikhail; Jim Xu, Qiwu; Ding, Fengfei; Wang, Fushun; Kang, Ning; Kang, Jian; Curtin, Paul C.; Brunner, Daniela; Windrem, Martha S.; Munoz-Sanjuan, Ignacio; Nedergaard, Maiken; Goldman, Steven A.

    2016-01-01

    The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder. PMID:27273432

  6. Mitochondrial DNA variation in human radiation and disease.

    PubMed

    Wallace, Douglas C

    2015-09-24

    Environmental adaptation, predisposition to common diseases, and, potentially, speciation may all be linked through the adaptive potential of mitochondrial DNA (mtDNA) alterations of bioenergetics. This Perspective synthesizes evidence that human mtDNA variants may be adaptive or deleterious depending on environmental context and proposes that the accrual of mtDNA variation could contribute to animal speciation via adaptation to marginal environments.

  7. Does biodiversity protect humans against infectious disease? Reply

    USGS Publications Warehouse

    Wood, Chelsea L.; Lafferty, Kevin D.; DeLeo, Giulio; Young, Hillary S.; Hudson, Peter J.; Kuris, Armand M.

    2016-01-01

    The dilution effect is the sort of idea that everyone wants to be true. If nature protects humans against infectious disease, imagine the implications: nature's value could be tallied in terms of human suffering avoided. This makes a potent argument for conservation, convincing even to those who would otherwise be disinclined to support conservation initiatives. The appeal of the dilution effect has been recognized by others: “the desire to make the case for conservation has led to broad claims regarding the benefits of nature conservation for human health” (Bauch et al. 2015). Randolph and Dobson (2012) were among the first to critique these claims, making the case that promotion of conservation to reduce Lyme disease risk, although well intentioned, was flawed. Along with Randolph and Dobson's critique, there have been several calls for a more nuanced scientific assessment of the relationship between biodiversity and disease transmission (Dunn 2010, Salkeld et al. 2013, Wood and Lafferty 2013, Young et al. 2013). In response, supporters of the dilution effect have instead increased the scope of their generalizations with review papers, press releases, and, like Levi et al. (2015), letters. These responses have been successful; it is not uncommon to read papers that repeat the assertion that biodiversity generally interferes with disease transmission and that conservation will therefore generally benefit human health. Here, we explain how Levi et al. (2015) and other, similar commentaries use selective interpretation and shifting definitions to argue for the generality of the dilution effect hypothesis.

  8. Molecular basis of telomere dysfunction in human genetic diseases.

    PubMed

    Sarek, Grzegorz; Marzec, Paulina; Margalef, Pol; Boulton, Simon J

    2015-11-01

    Mutations in genes encoding proteins required for telomere structure, replication, repair and length maintenance are associated with several debilitating human genetic disorders. These complex telomere biology disorders (TBDs) give rise to critically short telomeres that affect the homeostasis of multiple organs. Furthermore, genome instability is often a hallmark of telomere syndromes, which are associated with increased cancer risk. Here, we summarize the molecular causes and cellular consequences of disease-causing mutations associated with telomere dysfunction.

  9. Mitochondrial DNA Variation in Human Radiation and Disease

    PubMed Central

    Wallace, Douglas C.

    2016-01-01

    Environmental adaptation, predisposition to common diseases, and, potentially, speciation may all be linked through the adaptive potential of mitochondrial DNA (mtDNA) alterations of bioenergetics. This Perspective synthesizes evidence that human mtDNA variants may be adaptive or deleterious depending on environmental context and proposes that the accrual of mtDNA variation could contribute to animal speciation via adaptation to marginal environments. PMID:26406369

  10. Using Genomics to Study Human Biology and Disease

    SciTech Connect

    Myers, Ricard M.

    2005-04-06

    The Human Genome Project culminated in April 2003 with the finished DNA sequence of all of the human chromosomes. This book of information, particularly in conjunction with the genome sequences of many other organisms, has already begun to revolutionize the way that biomedical scientists study our species. The identification of essentially all of our genes has provided a template upon which researchers can discover basic processes that govern cells, organs, and the whole organism, and to understand the fundamental causes of the diseases that occur when something goes wrong with a gene or a set of genes. The Genome Project has already made it possible to identify the genes that are defective in more than 1,000 rare inherited diseases, and these discoveries have helped to understand the mechanisms of the more common forms of these disorders. This understanding of primary defects in diseases - which is translated as mutations in genes that encode proteins that serve specific functions - is transforming the way that biotechnology and pharmaceutical companies identify drug targets, and a few notable cases have already had a striking impact on specific diseases. In addition, it has become clear that the differential response to drugs in human populations is heavily influenced by genes, and a whole field called pharmacogenetics has begun to identify these genetic factors. Such knowledge will allow physicians to prescribe drugs targeted to each individual, with the potential to increase efficacy and decrease side-effects. Determining the DNA sequence of the human genome and identifying the genes has been an exciting endeavor, but we are only just beginning to understand the treasures present in all of our DNA. My presentation will briefly describe the road we took to get the sequence, as well as the tools that we are developing to unlock its secrets.

  11. Identification of susceptibility genes and genetic modifiers of human diseases

    NASA Astrophysics Data System (ADS)

    Abel, Kenneth; Kammerer, Stefan; Hoyal, Carolyn; Reneland, Rikard; Marnellos, George; Nelson, Matthew R.; Braun, Andreas

    2005-03-01

    The completion of the human genome sequence enables the discovery of genes involved in common human disorders. The successful identification of these genes is dependent on the availability of informative sample sets, validated marker panels, a high-throughput scoring technology, and a strategy for combining these resources. We have developed a universal platform technology based on mass spectrometry (MassARRAY) for analyzing nucleic acids with high precision and accuracy. To fuel this technology, we generated more than 100,000 validated assays for single nucleotide polymorphisms (SNPs) covering virtually all known and predicted human genes. We also established a large DNA sample bank comprised of more than 50,000 consented healthy and diseased individuals. This combination of reagents and technology allows the execution of large-scale genome-wide association studies. Taking advantage of MassARRAY"s capability for quantitative analysis of nucleic acids, allele frequencies are estimated in sample pools containing large numbers of individual DNAs. To compare pools as a first-pass "filtering" step is a tremendous advantage in throughput and cost over individual genotyping. We employed this approach in numerous genome-wide, hypothesis-free searches to identify genes associated with common complex diseases, such as breast cancer, osteoporosis, and osteoarthritis, and genes involved in quantitative traits like high density lipoproteins cholesterol (HDL-c) levels and central fat. Access to additional well-characterized patient samples through collaborations allows us to conduct replication studies that validate true disease genes. These discoveries will expand our understanding of genetic disease predisposition, and our ability for early diagnosis and determination of specific disease subtype or progression stage.

  12. G-quadruplex nucleic acids and human disease

    PubMed Central

    Wu, Yuliang; Brosh, Robert M.

    2010-01-01

    Alternate DNA structures that deviate from B-form double-stranded DNA such as G-quadruplex (G4) DNA can be formed by sequences that are widely distributed throughout the human genome. G-quadruplex secondary structures, formed by the stacking of planar quartets composed of four guanines that interact by Hoogsteen hydrogen bonding, can affect cellular DNA replication and transcription, and influence genomic stability. The unique metabolism of G-rich chromosomal regions that potentially form quadruplexes may influence a number of biological processes including immunoglobulin gene rearrangements, promoter activation and telomere maintenance. A number of human diseases are characterized by telomere defects, and it is proposed that G-quadruplex structures which form at telomere ends play an important role in telomere stability. Evidence from cellular studies and model organisms suggests that diseases with known defects in G4 DNA helicases are likely to be perturbed in telomere maintenance and cellular DNA replication. In this minireview, we discuss the connections of G-quadruplex nucleic acids to human genetic diseases and cancer based on the recent literature. PMID:20670277

  13. Human nephron number: implications for health and disease.

    PubMed

    Bertram, John F; Douglas-Denton, Rebecca N; Diouf, Boucar; Hughson, Michael D; Hoy, Wendy E

    2011-09-01

    Several studies have shown that total nephron (glomerular) number varies widely in normal human kidneys. Whereas the studies agree that average nephron number is approximately 900,000 to 1 million per kidney, numbers for individual kidneys range from approximately 200,000 to >2.5 million. Several studies have shown loss of glomeruli due to age-related glomerulosclerosis. The rates of loss vary among individuals depending upon blood pressure, diseases affecting the kidney, and other attributes of health, but most of the variation in nephron number is present at birth and is therefore developmentally determined. For example, in a relatively small study of nephron number in 15 children <3 months of age, we found that nephron number ranged from approximately 250,000 to 1.1 million. Given that no new nephrons are formed in human kidneys after approximately 36 weeks' gestation, much interest has focused on renal function and health in individuals born with relatively low nephron endowment. Several studies have reported a direct correlation between birth weight and nephron number and an indirect association between nephron number and blood pressure. Associations between low birth weight and cardiovascular disease, including hypertension, have also been widely reported. This report provides an update on our current knowledge of human nephron number and the associations with adult health and disease.

  14. Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease.

    PubMed

    Burdge, Graham C; Lillycrop, Karen A

    2010-08-21

    There is considerable evidence for induction of differential risk of noncommunicable diseases in humans by variation in the quality of the early life environment. Studies in animal models show that induction and stability of induced changes in the phenotype of the offspring involve altered epigenetic regulation by DNA methylation and covalent modifications of histones. These findings indicate that such epigenetic changes are highly gene specific and function at the level of individual CpG dinucleotides. Interventions using supplementation with folic acid or methyl donors during pregnancy, or folic acid after weaning, alter the phenotype and epigenotype induced by maternal dietary constraint during gestation. This suggests a possible means for reducing risk of induced noncommunicable disease, although the design and conduct of such interventions may require caution. The purpose of this review is to discuss recent advances in understanding the mechanism that underlies the early life origins of disease and to place these studies in a broader life-course context.

  15. The human gut microbiome impacts health and disease.

    PubMed

    Ehrlich, Stanislav Dusko

    2016-01-01

    The human gut microbiome can now be characterized in unprecedented detail by an approach based on high-throughput sequencing of total stool DNA, that we name quantitative metagenomics. Central to the approach is a catalog that lists all the genes of intestinal microbes that are known - 9.9 millions, identified by the analysis of 1267 stool samples. Beyond the gene list, genetic units that carry them begun to be known; many of these correspond to bacterial species that were never isolated and cultured yet. Quantitative metagenomics allows developing powerful algorithms to diagnose a disease, monitor patients and identify individuals at risk to progress towards a disease. This lays ground for developing new approaches to better restore and even preserve the health by modulation of the altered microbiome, which contributes to promote or aggravate a disease.