Abstract

The enteric pathogen Toxoplasma gondii is controlled by a vigorous innate T helper 1 (Th1) cell response in the murine model. We demonstrated that after oral infection, the parasite rapidly recruited inflammatory monocytes [Gr1(+) (Ly6C(+), Ly6G(-)) F4/80(+)CD11b(+)CD11c(-)], which established a vital defensive perimeter within the villi of the ileum in the small intestine. Mice deficient of the chemokine receptor CCR2 or the ligand CCL2 failed to recruit Gr1(+) inflammatory monocytes, whereas dendritic cells and resident tissue macrophages remained unaltered. The selective ...

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Dunay, Ildiko R Damatta, Renato A Fux, Blima Presti, Rachel Greco, Suellen Colonna, Marco Sibley, L David AI036629/AI/NIAID NIH HHS/ AI071299/AI/NIAID NIH HHS/ R01 AI036629-15/AI/NIAID NIH HHS/ R21 AI071299-01/AI/NIAID NIH HHS/ R21 AI071299-02/AI/NIAID NIH HHS/ Immunity. 2008 Aug 15;29(2):306-17.

Abstract

Previous studies have implicated T cell production of IL-17 in resistance to Toxoplasma gondii as well as the development of immune-mediated pathology during this infection. Analysis of C57BL/6 and C57BL/6 RAG(-/-) mice challenged with T. gondii-identified NK cells as a major innate source of IL-17. The ability of soluble Toxoplasma Ag to stimulate NK cells to produce IL-17 was dependent on the presence of accessory cells and the production of IL-6, IL-23, and TGF-beta. In contrast, these events were inhibited by ...

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Passos, Sara T Silver, Jonathan S O'Hara, Aisling C Sehy, David Stumhofer, Jason S Hunter, Christopher A AI 07532/AI/NIAID NIH HHS/ AI 42334/AI/NIAID NIH HHS/ D43 TW007127/TW/FIC NIH HHS/ P01 AI043620-115813/AI/NIAID NIH HHS/ R01 AI042334-12/AI/NIAID NIH HHS/ Baltimore, Md. : 1950 J Immunol. 2010 Feb 15;184(4):1776-83. Epub 2010 Jan 18.

Abstract

In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained after biomarker assays of archived maternal sera and by obstetric records was related to an increased risk of schizophrenia. Thus far, it has been ...

Abstract

During acute infection in human and animal hosts, the obligate intracellular protozoan Toxoplasma gondii infects a variety of cell types, including leukocytes. Poised to respond to invading pathogens, dendritic cells (DC) may also be exploited by T. gondii for spread in the infected host. Here, we report that human and mouse myeloid DC possess functional γ-aminobutyric acid (GABA) receptors and the machinery for GABA biosynthesis and secretion. Shortly after T. gondii infection (genotypes I, II and III), DC responded with enhanced ...

Abstract

Detection of Toxoplasma gondii in blood by means of the polymerase chain reaction (PCR) may facilitate early diagnosis of toxoplasmosis in different groups of patients. We evaluated this approach in 42 patients presenting with ocular or psychotic diseases by comparing the sensitivity and specificity of PCR after heat treatment using a microwave oven with a standard genomic DNA extraction method for paired serum and whole blood samples. The presence of serum IgM and IgG antibodies against T. gondii was detected using ...

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Meganathan, Puviarasi Singh, Sujaya Ling, Lau Yee Singh, Jesjeet Subrayan, Visvaraja Nissapatorn, Veeranoot eng Thailand 2010/06/29 06:00 Southeast Asian J Trop Med Public Health. 2010 Mar;41(2):265-73.

Abstract

A total of 1,885 blood and stool samples of four main protozoan parasitic infections were retrospectively reviewed from January, 2000 to April, 2004. Eleven of the 1,350 stool samples were shown positive for Cryptosporidium and Giardia infections; one of the 5 cases was clinically diagnosed as gastrointestinal cryptosporidiosis, while 6 cases were giardiasis. In patients with giardiasis, children were among the high-risk groups, making up 66.7% of these patients. The common presenting signs and symptoms were: diarrhea (83.3%), loss of appetite ...

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Cited By (since 1996): 7 Export Date: 15 October 2012 Source: Scopus PubMed ID: 16438180 Language of Original Document: English Correspondence Address: Nissapatorn, V.email: nissapat@hotmail.com

Abstract

Cerebral toxoplasmosis remains one of the most common focal brain lesions in patients with acquired immune deficiency syndrome (AIDS). Diagnosis is a challenge because on cranial imaging it closely mimics central nervous system lymphoma, primary and metastatic central nervous system (CNS) tumors, or other intracranial infections like tuberculoma or abscesses. A magnetic resonance imaging (MRI) feature on postcontrast T1-weighted sequences considered pathognomonic of toxoplasmosis is ...

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Novikova, T V Gracheva, L I Goncharov, D B Nikolaeva, T N Comparative Study Russia (Federation) Meditsinskaia parazitologiia i parazitarnye bolezni Med Parazitol (Mosk). 2005 Jul-Sep;(3):26-8.

Abstract

Chronic infection with Toxoplasma gondii is one of the most common parasitic infections in humans. Formation of tissue cysts is the basis of persistence of the parasite in infected hosts, and this cyst stage has generally been regarded as untouchable. Here we provide the first evidence that the immune system can eliminate T. gondii cysts from the brains of infected hosts when immune T cells are transferred into infected immunodeficient animals that have already developed large numbers of cysts. This T ...

Abstract

A patient with AIDS, treated with highly active antiretroviral therapy and trimethoprim-sulfamethoxazole, presented with confusion, a hemifield defect, and a mass lesion in the right occipital lobe. A brain biopsy confirmed granulomatous amebic encephalitis (GAE) due to Acanthamoeba castellanii. The patient was treated with fluconazole and sulfadiazine, and the lesion was surgically excised. This is the first case of AIDS-associated GAE responding favorably to therapy. The existence of a solitary brain lesion, absence of other sites of infection, and intense cellular ...

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References: Arias Fernandez, C., Paniagua Crespo, E., (1992), pp. 143-162. , Avances en parasitologia: Protozoologia. Universidad Santiago de Compostela, La Coruna, SpainBottone, E.J., Free-living amebas of the genera Acanthamoeba and Naegleria: An overview and basic microbiological correlates (1993) Mt. Sinai J. Med., 60, pp. 260-270; Calore, E.E., Cavaliere, M.J., Calore, N.M.P., Cerebral amebiasis in the acquired immunodeficiency syndrome (1997) Acta Neurol. Belg., 97, pp. 248-250; Carr, A., Marriott, D., Field, A., Vasak, E., Cooper, D.A., Treatment of HIV-1 associated microsporidiosis and

Abstract

Background. The combination of didanosine, lamivudine, and efavirenz (ddI/3TC/EFV) for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection has been insufficiently analyzed in clinical trials. Methods. We conducted an open-label, randomized study to compare the noninferiority of ddI/3TC/EFV with the lamivudine-zidovudine tablet and EFV (COM/EFV), both administered with food to improve tolerability and convenience. Patients were stratified by HIV-1 RNA level of <5.0 log10 or ≥5.0 log 10 copies/mL. The primary end point was the percentage of patients ...

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References: Hammer, S.M., Saag, M.S., Schechter, M., Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel (2006) JAMA, 296, pp. 827-843; Recommendations of GESIDA/Spanish AIDS Plan on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2007) (2007) Enferm Infecc Microbiol Clin, 25, pp. 32-53. , Expert Committee of GESIDA and the National AIDS Plan; Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, , http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf, Panel on Antiretroviral

Abstract

Importance of the field: Malaria still remains one of the deadliest infectious diseases having a tremendous morbidity and mortality impact in the developing world. Computational tools such as quantitative structureactivity relationship (QSAR) studies help medicinal chemists to understand the consistent relationship between antimalarial activity and molecular properties, and design new potent and selective ligands that may act on different classes of antimalarial drug targets so that these compounds may eventually be synthesized and assayed. Area covered in this review: In the ...

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Correspondence Address: Roy, K.; Department of Pharmaceutical Technology, Drug Theoretics and Cheminformatics Laboratory, Jadavpur University, Kolkata 700 032, India; email: kunalroy_in@yahoo.com

Abstract

Summary.  We present a Bayesian evidence synthesis model combining data on seroprevalence, seroconversion and tests of recent infection, to produce estimates of current incidence of toxoplasmosis in the UK. The motivation for the study was the need for an estimate of current average incidence in the UK, with a realistic assessment of its uncertainty, to inform a decision model for a national screening programme to prevent congenital toxoplasmosis. The model has a hierarchical structure over geographic region, a random-walk model for ...

Abstract

INTRODUCTION: Female immigration from less developed countries into Spain has grown in number over the years, and could contribute to changing the prevalence of routine serological markers in pregnant women. MATERIAL AND METHODS: From April 2007 until May 2008 we studied the prevalence of serum antibodies against Treponema pallidum, Toxoplasma gondii, rubella virus, human immunodeficiency virus (HIV 1/2), and hepatitis B virus (HBV) in samples from 4,171 immigrant and Spanish pregnant women in Granada. RESULTS: The seroprevalence of toxoplasmosis in pregnant ...

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DA - 20101129 IS - 1578-1852 (Electronic) IS - 0213-005X (Linking) LA - spa PT - English Abstract PT - Journal Article SB - IM

Abstract

OBJECTIVE: Executive dysfunction is one of the most prominent and functionally important cognitive deficits in schizophrenia. Although strong associations have been identified between executive impairments and structural and functional prefrontal cortical deficits, the etiological factors that contribute to disruption of this important cognitive domain remain unclear. Increasing evidence suggests that schizophrenia has a neurodevelopmental etiology, and several prenatal infections have been associated with risk of this disorder. The authors examined whether prenatal infection is associated with executive dysfunction in patients with ...

Abstract

BACKGROUND:The parasite Toxoplasma gondii infects 30-60% of humans worldwide. Latent toxoplasmosis, i.e., the life-long presence of Toxoplasma cysts in neural and muscular tissues, leads to prolongation of reaction times in infected subjects. It is not known, however, whether the changes observed in the laboratory influence the performance of subjects in real-life situations.METHODS:The seroprevalence of latent toxoplasmosis in subjects involved in traffic accidents (N = 146) and in the general population living in the same area (N = 446) was compared by ...

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This article was found by searching the Pubmed database, using the keywords, 'toxoplasmosis' and 'incidence'. I feel it is paticularly relevant to C500, microbiology, especially parisitology.

The authors of the article set out to investigate whether latent toxoplasmosis was a factor in traffic accidents. The methods used were to test hospital outpatients involved in traffic accidents for the disease. Only patients who had caused trafic accidents were tested, and those involved in alcohol related accidents were discounted. A control group was also

Abstract

This paper considers nonparametric estimation of age- and time-specific trends in disease incidence using serial prevalence data collected from multiple cross-sectional samples of a population over time. The methodology accounts for differential selection of diseased and undiseased individuals resulting, for example, from differences in mortality. It is shown that when a log-linear incidence odds model is adopted, an EM algorithm provides a convenient method for carrying out maximum likelihood estimation, primarily using existing generalized linear models software. The procedure is quite ...

Abstract

We discuss the assessment of age- and time-specific disease incidence using prevalence data. A method is described for conveniently fitting a discrete-time multiplicative model, subject to positivity constraints, using the EM-algorithm. Together with smoothing, it allows essentially nonparametric assessment of incidence trends. The method is illustrated using previously analyzed data on toxoplasmosis. ...

Abstract

Toxoplasma (Tp) membrane antigens separated by discontinuous SDS-polyacrylamide gel electrophoresis were electrophoretically transferred to nitrocellulose and detected with avidin-biotin (AB), peroxidase anti-peroxidase complex (PAP) or indirect immunoperoxidase (IIP) methods. In the AB method, the nitrocellulose was treated with biotinylated monoclonal antibodies and avidin-labeled peroxidase. In the PAP method, it was treated with monoclonal antibody, rabbit anti-mouse IgG antibody, goat anti-rabbit IgG antibody and PAP. Of the two, the AB method was the more sensitive and specific for Tp membrane antigen. The ...

Abstract

BACKGROUND:The association between toxoplasmosis and psychiatric disorders has been reported in a few anecdotal reports.CASE PRESENTATION:A case of depression with toxoplasma seropositivity is presented. The patient with depression showed poor response to antidepressants, for which he was investigated and was found positive on the serological test for the toxoplasma. The response to antidepressant treatment improved only after adequate treatment for toxoplasma.CONCLUSIONS:The case suggests a probable association between toxoplasmosis and depression. ...

Abstract

The generation of an adaptive immune response against intracellular pathogens requires the recruitment of effector T cells to sites of infection. Here we show that the chemokine IP-10, a specific chemoattractant for activated T cells, controls this process in mice naturally infected with Toxoplasma gondii. Neutralization of IP-10 in infected mice inhibited the massive influx of T cells into tissues and impaired antigen-specific T cell effector functions. This resulted in >1000-fold increase in tissue parasite burden and a marked increase in ...

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May

Abstract

Toxoplasma gondii was found in endemic Hawaiian birds, including 2 nene geese (Nesochen sandvicensis), 1 red-footed booby (Sula sula), and an introduced bird, the Erckels francolin (Francolinus erckelii). All 4 birds died of disseminated toxoplasmosis; the parasite was found in sections of many organs, and the diagnosis was confirmed by immunohistochemical staining with anti-T. gondii-specific polyclonal antibodies. This is the first report of toxoplasmosis in these species of birds. ...

Abstract

New forms of catalytic epidemic models were developed to estimate the incidence of primary toxoplasmosis infection from age- and time-specific seroprevalence data collected from persons aged 0-100 years in South Yorkshire, England, 1969-1990. Piecewise constant and exponential polynomial functions were used to assess the way in which incidence depended on age and time, and to guide the choice of parametric models suitable for prediction. Incidence estimates were biased unless both age- and time-dependence were allowed for. New findings on the epidemiology ...

Abstract

Calcium controls a number of critical events, including motility, secretion, cell invasion and egress by apicomplexan parasites. Compared to animal and plant cells, the molecular mechanisms that govern calcium signalling in parasites are poorly understood. Here we show that the production of the phytohormone abscisic acid (ABA) controls calcium signalling within the apicomplexan parasite Toxoplasma gondii, an opportunistic human pathogen. In plants, ABA controls a number of important events, including environmental stress responses, embryo development and seed dormancy. ABA induces production ...

Abstract

Toxoplasmosis is one of the more common parasitic zoonoses world-wide. Its causative agent, Toxoplasma gondii, is a facultatively heteroxenous, polyxenous protozoon that has developed several potential routes of transmission within and between different host species. If first contracted during pregnancy, T. gondii may be transmitted vertically by tachyzoites that are passed to the foetus via the placenta. Horizontal transmission of T. gondii may involve three life-cycle stages, i.e. ingesting infectious oocysts from the environment or ingesting tissue cysts or tachyzoites which ...

Abstract

PURPOSE OF REVIEW: The purpose of this review is to update the latest information on a long-recognized infectious disease, ocular toxoplasmosis. RECENT FINDINGS: Topics include how the disease is acquired, how to make a clinical diagnosis, and what laboratory tests to order when the diagnosis is not clear. New insights into the genetic make-up of the parasite and new treatment alternatives are discussed. SUMMARY: Recent findings are updated on the epidemiologic status of the disease, methods for correct diagnosis of unusual ...

Abstract

AIM: To assess functional impairment in terms of visual acuity reduction and visual field defects in inactive ocular toxoplasmosis. METHODS: 61 patients with known ocular toxoplasmosis in a quiescent state were included in this prospective, cross-sectional study. A complete ophthalmic examination, retinal photodocumentation and standard automated perimetry (Octopus perimeter, program G2) were performed. Visual acuity was classified on the basis of the World Health Organization definition of visual impairment and blindness: normal (> or =20/25), mild (20/25 to 20/60), moderate (20/60 ...

Abstract

OBJECTIVES: To present the data supporting the possible relationship of ocular toxoplasmosis to antitumor necrosis factor-alpha (TNF-alpha) therapy in patients with rheumatoid arthritis (RA). METHODS: A Medline search was performed using the words "toxoplasmosis, anti-TNF-alpha antagonists, chorioretinitis." We report 2 RA patients who developed ocular toxoplasmosis while receiving anti-TNF-alpha therapy. RESULTS: In addition to our patients with toxoplasmic chorioretinitis, there are 2 published cases of cerebral toxoplasmosis during treatment with anti-TNF-alpha agents. CONCLUSION: The risk of serious toxoplasmic infection during anti-TNF-alpha ...

Abstract

PURPOSE: To document fluorescein and indocyanine green angiographic findings in patients with ocular toxoplasmosis. METHODS: Charts of patients with ocular toxoplasmosis who were evaluated with fluorescein and indocyanine green angiograpy were reviewed. RESULTS: In this study, eight (38%) females and 13 (62%) males with a mean age of 20.3 years were included. Of the 21 patients, five (24%) had bilateral involvement with active or inactive toxoplasmic lesion. There were active lesions in 12 (46%) eyes and inactive lesions in 14 (54%) ...

Abstract

PURPOSE: To review recent observations regarding the sources of Toxoplasma gondii infection and rates of ocular involvement in cases of infection acquired after birth, and to reconcile them with older observations and widely held beliefs about the pathogenesis of ocular toxoplasmosis. METHOD: A review of pertinent reports from the medical literature. RESULTS: There are several potential sources and routes of infection, including inhalation of spores and ingestion of contaminated drinking water, that were previously unrecognized. Ocular involvement in cases of acquired ...

Abstract

PURPOSE: To determine the effectiveness of systemic antibiotic treatment for toxoplasmic retinochoroiditis. CLINICAL RELEVANCE: Toxoplasma retinochoroiditis is a significant cause of visual morbidity. Multiple different antibiotic regimens are used, but controversy about treatment effectiveness remains. LITERATURE REVIEWED: Searches were conducted of Cochrane Controlled Trials Register, Medline (1966 onward), Embase (1980 onward), Dissertation Abstracts (1861 onward), Lilacs (1982 onward), and Pascal (1984 onward). Pharmaceutical companies were contacted for unpublished data. Any randomized controlled trials that compared antibiotics versus placebo in immunocompetent patients ...

Abstract

We tested the hypothesis that the parasite Toxoplasma gondii manipulates the behaviour of its intermediate rat host in order to increase its chance of being predated by cats, its feline definitive host, thereby ensuring the completion of its life cycle. Here we report that, although rats have evolved anti–predator avoidance of areas with signs of cat presence, T. gondii's manipulation appears to alter the rat's perception of cat predation risk, in some cases turning their innate aversion into an imprudent attraction. ...

Abstract

The boy-to-girl ratio at birth (secondary sex ratio) is around 0.51 in most populations. The sex ratio varies between societies and may be influenced by many factors, such as stress and immunosuppression, age, primiparity, the sex of the preceding siblings and the socioeconomic status of the parents. As parasite infection affects many immunological and physiological parameters of the host, we analyzed the effect of latent toxoplasmosis on sex ratios in humans. Clinical records of 1,803 infants born from 1996 to 2004 ...

Abstract

Toxoplasma gondii, a parasitic protozoan, infects about 30-60% of people worldwide. The latent toxoplasmosis, i.e. life-long presence of cysts in the brain and muscular tissues, has no effect on human health. However, infected subjects score worse in psychomotor performance tests and have different personality profiles than Toxoplasma-negative subjects. The mechanism of this effect is unknown; however, it is supposed that presence of parasites' cysts in the brain induces an increase of the concentration of dopamine. Here we search for the existence ...

Abstract

Toxoplasma gondii, the coccidian parasite, is known to induce changes in the behaviour of its intermediate hosts. The high prevalence of this parasite in the human population (20-80%) offers the opportunity of studying the influence of the parasite on human behaviour by screening of a normal population. A total of 224 men and 170 women were tested for toxoplasmosis and their personality profiles were measured by Cattell's questionnaire. Highly significant differences between Toxoplasma-infected and uninfected subjects were observed (P < 0.01). ...

Abstract

Infection with Toxoplasma gondii can lead to congenital and acquired disease, resulting in loss of vision and neurologic illness. We tested sera collected in the National Health and Examination Survey (NHANES) from 1999-2000 for T. gondii-specific immunoglobulin G antibodies and compared these results with results from sera obtained in the NHANES III survey (1988-1994). NHANES collects data on a nationally representative sample of the U.S. civilian population. Of 4,234 persons 12-49 years of age in NHANES 1999-2000, 15.8= (age-adjusted, 95% confidence ...

Abstract

Infection with Toxoplasma gondii can cause severe illness when the organism is contracted congenitally or when it is reactivated in immune-suppressed persons. To determine the prevalence of T. gondii infection in a representative sample of the US population, the authors tested sera from participants in the Third National Health and Nutrition Examination Survey (1988–1994) for immunoglobulin G antibodies to T. gondii. Of 27,145 persons aged ≥12 years, 17,658 (65%) had sera tested. The overall age-adjusted seroprevalence was 22.5% (95% confidence interval ...

Abstract

Recent epidemiologic studies indicate that infectious agents may contribute to some cases of schizophrenia. In animals, infections with Toxoplasma gondii can alter behavior and neurotransmitter function. In humans, acute infection with T. gondii can produce psychotic symptoms similar to those displayed by persons with schizophrenia. Since 1953, a total of 19 studies of T. gondii antibodies in persons with schizophrenia and other severe psychiatric disorders and in controls have been reported; 18 reported a higher percentage of antibodies in the affected ...

Abstract

Infections by the protozoan parasite Toxoplasma gondii are widely prevalent world-wide in animals and humans. This paper reviews the life cycle; the structure of tachyzoites, bradyzoites, oocysts, sporocysts, sporozoites and enteroepithelial stages of T. gondii; and the mode of penetration of T. gondii. The review provides a detailed account of the biology of tissue cysts and bradyzoites including in vivo and in vitro development, methods of separation from host tissue, tissue cyst rupture, and relapse. The mechanism of in vivo and ...

Abstract

In Turkey, traffic accidents are the major causes of mortality and morbidity. According to the statistics made by Turkish Security Headquarters in the year 2000, 7500 people are killed in the traffic accidents every year. Drivers are mostly blamed for the traffic accidents. Tired, weary, sleepy and absentminded driving are common reasons for traffic accidents due to many reasons. Among these reasons mental and reflex conditions of drivers are significant. Toxoplasmosis is one of the most common zoonoses throughout the world. ...

Abstract

The efficacy of atovaquone (ATO) combined with clindamycin (CLI) against Toxoplasma gondii was examined in murine models of infection with a mouse-non-virulent (Me49) strain. Swiss-Webster mice inoculated by mouth with 10 or 20 cysts were treated with ATO and CLI alone or combined at dosages of ATO 5-100 and CLI 25-400 mg/kg/day for 2-4 weeks. Drug treatment was initiated (i) day 4 post-infection (acute infection), (ii) 3 months post-infection (chronic infection) and (iii) following a 2-3 week course of treatment with ...

Abstract

BACKGROUND:Recently, a negative association between Toxoplasma-infection and novelty seeking was reported. The authors suggested that changes of personality trait were caused by manipulation activity of the parasite, aimed at increasing the probability of transmission of the parasite from an intermediate to a definitive host. They also suggested that low novelty seeking indicated an increased level of the neurotransmitter dopamine in the brain of infected subjects, a phenomenon already observed in experimentally infected rodents. However, the changes in personality can also be ...

Abstract

Objective: To compare the prevalence of Toxoplasma infection between the first-episode schizophrenia and the controls and to compare the clinical features between the Toxoplasma-seronegative and Toxoplasma-seropositive patients with schizophrenia. Method: The rate of serum reactivity to Toxoplasma in 600 schizophrenia, 600 affective disorders, and 400 controls was investigated. The clinical symptoms of the schizophrenia patients were scored and compared. Results: The rate of IgG antibody, not IgM in the schizophrenia patients, was higher than the control groups, and the odds ratio of schizophrenia ...

Abstract

The apical complex of Toxoplasma gondii is widely believed to serve essential functions in both invasion of its host cells (including human cells), and in replication of the parasite. The understanding of apical complex function, the basis for its novel structure, and the mechanism for its motility are greatly impeded by lack of knowledge of its molecular composition. We have partially purified the conoid/apical complex, identified ~200 proteins that represent 70% of its cytoskeletal protein components, characterized seven novel proteins, and ...