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Kevin C Kain

Publications and source records attributed to Kevin C Kain.

At least 19 recordsLinked to original sources
PubMed2006

Simultaneous host and parasite expression profiling identifies tissue-specific transcriptional programs associated with susceptibility or resistance to experimental cerebral malaria.

BACKGROUND: The development and outcome of cerebral malaria (CM) reflects a complex interplay between parasite-expressed virulence factors and host response to infection. The murine CM model, Plasmodium berghei ANKA (PbA), which simulates many of the features of human CM, provides an excellent system to study this host/parasite interface. We designed "combination" microarrays that concurrently detect genome-wide transcripts of both PbA and mouse, and examined parasite and host transcriptional programs during infection of CM-susceptible (C57BL/6) and CM-resistant (BALB/c) mice. RESULTS: Analysis of expression data from brain, lung, liver, and spleen of PbA infected mice showed that both host and parasite gene expression can be examined using a single microarray, and parasite transcripts can be detected within whole organs at a time when peripheral blood parasitemia is low. Parasites display a unique transcriptional signature in each tissue, and lung appears to be a large reservoir for metabolically active parasites. In comparisons of susceptible versus resistant animals, both host and parasite display distinct, organ-specific transcriptional profiles. Differentially expressed mouse genes were related to humoral immune response, complement activation, or cell-cell interactions. PbA displayed differential expression of genes related to biosynthetic activities. CONCLUSION: These data show that host and parasite gene expression profiles can be simultaneously analysed using a single "combination" microarray, and that both the mouse and malaria parasite display distinct tissue- and strain-specific responses during infection. This technology facilitates the dissection of host-pathogen interactions in experimental cerebral malaria and could be extended to other disease models.

Animals↗
PubMed2006

Disruption of JNK2 decreases the cytokine response to Plasmodium falciparum glycosylphosphatidylinositol in vitro and confers protection in a cerebral malaria model.

Host inflammatory responses to Plasmodium falciparum GPI (pfGPI) anchors are believed to play an important role in the pathophysiology of severe malaria. However, relatively little is known about the signal transduction pathways involved in pfGPI-stimulated inflammatory response and its potential contribution to severe malaria syndromes. In this study, we investigated the role of MAPK activation in pfGPI-induced cytokine secretion and examined the role of selected MAPKs in a model of cerebral malaria in vivo. We demonstrate that ERK1/2, JNK, p38, c-Jun, and activating transcription factor-2 became phosphorylated in pfGPI-stimulated macrophages. A JNK inhibitor (1,9-pyrazoloanthrone) inhibited pfGPI-induced phosphorylation of JNK, c-Jun, and activating transcription factor-2 and significantly decreased pfGPI-induced TNF-alpha secretion. pfGPI-stimulated JNK and c-Jun phosphorylation was absent in Jnk2(-/-) macrophages but unchanged in Jnk1(-/-) and Jnk3(-/-) macrophages compared with wild-type macrophages. Jnk2(-/-) macrophages secreted significantly less TNF-alpha in response to pfGPI than macrophages from Jnk1(-/-), Jnk3(-/-), and wild-type counterparts. Furthermore, we demonstrate a role for JNK2 in mediating inflammatory responses and severe malaria in vivo. In contrast to wild-type or Jnk1(-/-) mice, Jnk2(-/-) mice had lower levels of TNF-alpha in vivo and exhibited significantly higher survival rates when challenged with Plasmodium berghei ANKA. These results provide direct evidence that pfGPI induces TNF-alpha secretion through activation of MAPK pathways, including JNK2. These results suggest that JNK2 is a potential target for therapeutic interventions in severe malaria.

Animals↗
PubMed2006

HIV immunosuppression and antimalarial efficacy: sulfadoxine-pyrimethamine for the treatment of uncomplicated malaria in HIV-infected adults in Siaya, Kenya.

BACKGROUND: The altered immune response of persons with human immunodeficiency virus (HIV) infection could result in increased rates of antimalarial treatment failure. We investigated the influence of HIV infection on the response to sulfadoxine-pyrimethamine treatment. METHODS: Febrile adults with Plasmodium falciparum parasitemia were treated with sulfadoxine-pyrimethamine and were monitored for 28 days. HIV status and CD4 cell count were determined at study enrollment. RESULTS: Of the adults enrolled in the study, 508 attended all follow-up visits, including 130 HIV-uninfected adults, 256 HIV-infected adults with a high CD4 cell count (> or =200 cells/ micro L), and 122 HIV-infected adults with a low CD4 cell count (<200 cells/ micro L). The hazard of treatment failure at day 28 of follow-up was significantly higher for HIV-infected adults with a low CD4 cell count (20.5%) than for HIV-uninfected adults (7.7%). Anemia (hemoglobin level, <110 g/L) modified the effect of HIV status on treatment failure. When we controlled for fever and parasite density, the hazard of treatment failure for HIV-infected adults with a low CD4 cell count and anemia was 3.4 times higher than that for HIV-uninfected adults (adjusted hazard ratio, 3.38; 95% confidence interval, 1.56-7.34). CONCLUSIONS: HIV-infected persons with a low CD4 cell count and anemia have an increased risk of antimalarial treatment failure. The response to malaria treatment in HIV-infected persons must be carefully monitored. Proven measures for the control and prevention of malaria must be incorporated into the basic package of services provided by HIV/acquired immunodeficiency syndrome care and treatment programs in malarious areas.

Adult↗
PubMed2006

Illness in travelers visiting friends and relatives: a review of the GeoSentinel Surveillance Network.

Travelers returning to their country of origin to visit friends and relatives (VFRs) have increased risk of travel-related health problems. We examined GeoSentinel data to compare travel characteristics and illnesses acquired by 3 groups of travelers to low-income countries: VFRs who had originally been immigrants (immigrant VFRs), VFRs who had not originally been immigrants (traveler VFRs), and tourist travelers. Immigrant VFRs were predominantly male, had a higher mean age, and disproportionately required treatment as inpatients. Only 16% of immigrant VFRs sought pretravel medical advice. Proportionately more immigrant VFRs visited sub-Saharan Africa and traveled for >30 days, whereas tourist travelers more often traveled to Asia. Systemic febrile illnesses (including malaria), nondiarrheal intestinal parasitic infections, respiratory syndromes, tuberculosis, and sexually transmitted diseases were more commonly diagnosed among immigrant VFRs, whereas acute diarrhea was comparatively less frequent. Immigrant VFRs and traveler VFRs had different demographic characteristics and types of travel-related illnesses. A greater proportion of immigrant VFRs presented with serious, potentially preventable travel-related illnesses than did tourist travelers.

Adolescent↗
PubMed2006

Placental chondroitin sulfate A-binding malarial isolates evade innate phagocytic clearance.

Pregnancy-associated malaria is characterized by the accumulation of parasitized erythrocytes (PEs) and monocytes in the placenta, and they are believed to directly contribute to adverse birth outcomes. Although most parasite isolates adhere to CD36, placental isolates express novel variant surface antigens (VSAs) and bind to chondroitin sulfate A (CSA). CSA-binding PEs are rarely observed outside of pregnancy, and most primigravid women lack immunity and must rely on innate immune mechanisms to clear these placental parasite variants. We hypothesized that differences in VSA expression and adhesive phenotype between pregnancy-associated (CSA-binding) and non-pregnancy-associated (CD36-binding) isolates may have direct implications for the failure of primigravid women to control the placental parasite burden through innate phagocytic pathways. We demonstrate here, both in vitro and in vivo, that there is a nonopsonic phagocytic defect for CSA-binding PEs. The ability of CSA-binding PEs to evade innate clearance pathways may contribute to the parasite accumulation and recruitment of monocytes that characterize placental malaria.

Animals↗
PubMed2006

Real-time polymerase chain reaction assay for the rapid detection and characterization of chloroquine-resistant Plasmodium falciparum malaria in returned travelers.

BACKGROUND: Imported drug-resistant malaria is a growing problem in industrialized countries. Rapid and accurate diagnosis is essential to prevent malaria-associated mortality in returned travelers. However, outside of a limited number of specialized centers, the microscopic diagnosis of malaria is slow, unreliable, and provides little information about drug resistance. Molecular diagnostics have the potential to overcome these limitations. OBJECTIVE: We developed and evaluated a rapid, real-time polymerase chain reaction (PCR) assay to detect Plasmodium falciparum malaria and chloroquine (CQ)-resistance determinants in returned travelers who are febrile. METHODS: A real-time PCR assay based on detection of the K76T mutation in PfCRT (K76T) of P. falciparum was developed on a LightCycler platform (Roche). The performance characteristics of the real-time assay were compared with those of the nested PCR-restriction fragment-length polymorphism (RFLP) and the sequence analyses of samples obtained from 200 febrile returned travelers, who included 125 infected with P. falciparum (48 of whom were infected CQ-susceptible [K76] and 77 of whom were CQ-resistant [T76] P. falciparum), 22 infected with Plasmodium vivax, 10 infected with Plasmodium ovale, 3 infected with Plasmodium malariae malaria, and 40 infected with other febrile syndromes. All patient samples were coded, and all analyses were performed blindly. RESULTS: The real-time PCR assay detected multiple pfcrt haplotypes associated with CQ resistance in geographically diverse malaria isolates acquired by travelers. Compared with nested-PCR RFLP (the reference standard), the real-time assay was 100% sensitive and 96.2% specific for detection of the P. falciparum K76T mutation. CONCLUSION: This assay is rapid, sensitive, and specific for the detection and characterization of CQ-resistant P. falciparum malaria in returned travelers. This assay is automated, standardized, and suitable for routine use in clinical diagnostic laboratories.

Animals↗
PubMed2005

Travel patterns and risk behaviour of HIV-positive people travelling internationally.

BACKGROUND: International travel is associated with an increased risk of enteric, vector-borne, sexually transmitted and blood-borne infections. These risks are even higher among immunocompromised people, such as those with HIV infection. We conducted a study to determine HIV-positive people's travel patterns and risk behaviours while abroad. METHODS: We conducted an anonymous survey of HIV-positive people attending an HIV clinic in a tertiary care hospital in Toronto about their travel activities and pretravel precautions as well as their burden of illness and risk exposure during travel. We compared the characteristics of respondents who had travelled outside Canada and the United States (international travellers) with those of respondents who had not travelled internationally. RESULTS: Of 290 HIV-positive people who participated in the study, 133 (45.9%) indicated that they had travelled internationally in the 5 years before the survey. These people were predominantly men (93.2%) and well educated (60.0% had a university level education), and they had travelled mostly for personal reasons (89.5%) on trips that lasted 3.6 weeks on average. Only 58 (43.6%) sought health advice before travelling, and only 17 (12.8%) sought advice from a travel clinic. Five (3.8%) had received live vaccines before travel, and 9 (6.8%) had taken malaria chemoprophylaxis. Of the 119 international travellers who were taking antiretroviral therapy; 35 (29.4%) reported either discontinuing their medications or being poorly compliant with the therapy while travelling. Thirty-one (23.3%) of the 133 international travellers reported having had casual sexual activity with new partners while travelling, and only 18 (58.1%) of them reported always using a condom. Twenty-one (15.8%) of the 133 reported having had risky exposure to sharps. Twenty-four (18.0%) said they had become ill enough while travelling to require medical attention. INTERPRETATION: Only one-fifth of HIV-positive people surveyed who travelled internationally sought advice from a health professional before their trip. Their travel was associated with poor adherence to antiretroviral therapy, risky sexual practices and risky exposure to sharps.

Adult↗
PubMed2005

Entamoeba histolytica: identification of a distinct beta2 integrin-like molecule with a potential role in cellular adherence.

Entamoeba histolytica infection causes dysentery, intestinal colitis, and hepatic abscess in an estimated 50 million people worldwide. Attachment of E. histolytica trophozoites to intestinal epithelium and vascular endothelium during liver metastasis results in an inflammatory process. We report the identification of a distinct amebic beta2 integrin (CD18)-like molecule which affords adherence to TNF-alpha-activated endothelial cells. Data from flow cytometry and indirect immunofluorescence assays suggest the amebic beta2 integrin was localized to focal adhesion plates and was present in both E. histolytica and Entamoeba dispar. The amebic beta2 integrin appeared to be distinct from the amebic Gal/GalNAc lectin based on recombinant expression, amebic colocalization, and ELISA studies. Trophozoite adherence to endothelial cells expressing ICAM-1 (CD54) following activation with TNF-alpha or ICAM-1-transfected CHO cells was specifically inhibited with anti-CD18 or anti-CD54 MAbs. In summary, evidence in support of a distinct beta2 integrin-like molecule participating in amebic adherence to TNF-alpha-activated endothelial cells expressing ICAM-1 is presented. The presence of integrin-dependent binding may allow trophozoites to opportunistically adhere to activated intestinal epithelium or vascular endothelium expressing ICAM-1 during amebic colitis or hepatic abscess.

Animals↗
PubMed2005

Peroxisome proliferator-activated receptor gamma and retinoid X receptor agonists have minimal effects on the interaction of endothelial cells with Plasmodium falciparum-infected erythrocytes.

Peroxisome proliferator-activated receptor gamma-retinoid X receptor (PPARgamma-RXR) agonists had minimal effects on the surface levels of CD36, intercellular cell adhesion molecule-1, or platelet-endothelial cell adhesion molecule-1 and had no effect on the cytoadherence of infected erythrocytes to either human umbilical vein endothelial cells or human microvascular endothelial cells or on malaria-induced interleukin-6 secretion from these cells. PPARgamma-RXR agonists do not significantly modify malaria-infected erythrocyte-endothelial cell interactions in vitro.

Animals↗
PubMed2005

Nonopsonic phagocytosis of erythrocytes infected with ring-stage Plasmodium falciparum.

Ring-stage parasitized erythrocytes (RPEs) were demonstrated to interact with effector cells of the innate immune system. With receptor blockade studies and CD36-null macrophages, human and murine macrophages were shown to phagocytose RPEs through the pattern recognition receptor CD36. These in vitro data implicate scavenger receptors in the clearance of RPEs.

Animals↗
PubMed2005

Atovaquone/proguanil for the prophylaxis and treatment of malaria.

Increases in international travel and escalating drug resistance have resulted in a growing number of travelers at risk of contracting malaria. Drug resistance and intolerance to standard agents such as chloroquine, sulfadoxine/pyrimethamine and mefloquine has highlighted the need for new antimalarials. The recently licensed fixed combination of atovaquone and proguanil hydrochloride (Malarone) is a promising new agent to prevent and treat Plasmodium falciparum malaria. Randomized controlled trials have shown that atovaquone/proguanil is well tolerated and efficacious for the prevention and treatment of drug-resistant P. falciparum malaria. Atovaquone/proguanil is active against the liver stage of P. falciparum malaria parasites and when used as a prophylactic agent it can be discontinued shortly after leaving malaria-endemic areas, offering a clear advantage for drug adherence.

Animals↗
PubMed2005

Emergence of atovaquone-proguanil resistance during treatment of Plasmodium falciparum malaria acquired by a non-immune north American traveller to west Africa.

The importation of drug-resistant malaria is a growing public health problem in non-endemic countries. The combination of atovaquone and proguanil (Malarone) has become established as an agent of choice to prevent and treat chloroquine-resistant Plasmodium falciparum malaria in travelers. We describe the first reported case in North America of genetically confirmed atovaquone/proguanil-resistant P. falciparum malaria. Polymerase chain reaction and sequence analysis of the primary and recrudescent isolates confirmed the acquisition of a point mutation (Tyr268Ser) in the cytochrome b gene of the recrudescent isolate known to confer high-level resistance to atovaquone. Suboptimal therapy may have played a contributory role in the emergence of resistance.

Adult↗
PubMed2005

Dynamic changes in clinical features and cytokine/chemokine responses in SARS patients treated with interferon alfacon-1 plus corticosteroids.

Severe acute respiratory syndrome (SARS), caused by a novel coronavirus, emerged in early 2003 as a major international health crisis. We report on serum cytokine levels, viral load and clinical parameters over the course of the disease in a cohort of nine adult SARS patients treated with steroids and interferon alfacon-1 at North York General Hospital in Toronto, Ontario. Considerable variation among SARS patients with respect to circulating viral load and patterns of SARS-CoV-evoked cytokine responses was recorded. No single cytokine profile was observed in all patients, yet serum concentrations of interferon (IFN)-gamma, interleukin (IL)-10, CXCL10, CCL5 and CXCL8 were found to be elevated above normal levels during the course of the disease in all patients. Expression levels for IL-10, IFN-gamma and CXCL10 consistently peaked within 4 days of peak viral load. IL-12p70, IL-4 and tumour necrosis factor-alpha concentrations were consistently highest within 5 days of peak viral load. These results suggest that elevated levels of inflammatory cytokines are sensitive correlates of disease severity, including lung abnormalities and viral load in serum, and may provide a tool for monitoring disease progression in affected individuals.

Administration, Oral↗
PubMed2004

Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus.

Severe acute respiratory syndrome (SARS) is characterized by pulmonary compromise; however, patients often have evidence of other organ dysfunction that may reflect extrapulmonary dissemination of SARS coronavirus (SARS-CoV). We report on the distribution and viral load of SARS-CoV in multiple organ samples from patients who died of SARS during the Toronto outbreak. SARS-CoV was detected in lung (100%), bowel (73%), liver (41%), and kidney (38%) in 19 patients who died of SARS, with the highest viral loads observed in lung (1.0 x 10(10) copies/g) and bowel (2.7 x 10(9) copies/g). Fatal SARS was associated with multiorgan viral dissemination in a distribution that has implications for disease manifestation, viral shedding, and transmission.

Coronavirus↗
PubMed2004

Tropical pulmonary eosinophilia: a case series in a setting of nonendemicity.

BACKGROUND: Tropical pulmonary eosinophilia (TPE) is a rare but serious manifestation of infection with the lymphatic filarial parasites Wuchereria bancrofti and Brugia malayi. Although endemicity is limited to the tropical and subtropical regions of Africa, South America, and Asia, immigration and travel practices have led to the diagnosis of TPE in areas of nonendemicity. METHODS: We herein present a case series of all patients with TPE who presented to the Toronto General Hospital during 1990-2003. RESULTS: Seventeen individuals presented with TPE during the study period, and all were of South Asian ancestry. All 17 received an incorrect diagnosis at presentation (median number of consultations before diagnosis, 2), the most frequent of which was asthma (76%). Eosinophil count, serum immunoglobulin E levels, and anti-filarial antibody titers were elevated in all patients. Ten of 14 patients had an abnormal chest radiograph finding, and 11 of 12 patients had abnormal results of pulmonary function tests. CONCLUSIONS: TPE is an important diagnostic consideration in patients with eosinophilia, respiratory symptoms, and history of exposure to this disease. In the untreated individual, TPE can lead to chronic and progressive respiratory compromise and death. Prompt recognition and treatment with diethylcarbamazine is therefore key to minimizing morbidity and mortality.

Adolescent↗
PubMed2004

Malaria in travelers: a review of the GeoSentinel surveillance network.

BACKGROUND: Malaria is a common and important infection in travelers. METHODS: We have examined data reported to the GeoSentinel surveillance network to highlight characteristics of malaria in travelers. RESULTS: A total of 1140 malaria cases were reported (60% of cases were due to Plasmodium falciparum, 24% were due to Plasmodium vivax). Male subjects constituted 69% of the study population. The median duration of travel was 34 days; however, 37% of subjects had a travel duration of < or =4 weeks. The majority of travellers did not have a pretravel encounter with a health care provider. Most cases occurred in travelers (39%) or immigrants/refugees (38%). The most common reasons for travel were to visit friends/relatives (35%) or for tourism (26%). Three-quarters of infections were acquired in sub-Saharan Africa. Severe and/or complicated malaria occurred in 33 cases, with 3 deaths. Compared with others in the GeoSentinel database, patients with malaria had traveled to sub-Saharan Africa more often, were more commonly visiting friends/relatives, had traveled for longer periods, presented sooner after return, were more likely to have a fever at presentation, and were less likely to have had a pretravel encounter. In contrast to immigrants and visitors of friends or relatives, a higher proportion (73%) of the missionary/volunteer group who developed malaria had a pretravel encounter with a health care provider. Travel to sub-Saharan Africa and Oceania was associated with the greatest relative risk of acquiring malaria. CONCLUSIONS: We have used a global database to identify patient and travel characteristics associated with malaria acquisition and characterized differences in patient type, destinations visited, travel duration, and malaria species acquired.

Africa↗
PubMed2004

Complicated and fatal Strongyloides infection in Canadians: risk factors, diagnosis and management.

Strongyloidiasis, which is caused by the nematode Strongyloides stercoralis, is a common and persistent infection, particularly in developing countries. In the setting of compromised cellular immunity, it can result in fulminant dissemination with case-fatality rates of over 70%. The majority of new Canadian immigrants come from countries where Strongyloides is highly endemic; therefore, the burden of Strongyloides may be underappreciated in Canada. Because early diagnosis and therapy can have a marked impact on disease outcome, screening for this infection should be considered mandatory for patients who have a history of travel or residence in a disease-endemic area and risk factors for disseminated disease (e.g., corticosteroid use and human T-lymphotropic virus type I infection).

Animals↗