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Biomedical subjects

Kevin C Kain

Publications and source records attributed to Kevin C Kain.

At least 37 records · Page 2Linked to original sources
PubMed2004

Inactivation of Plasmodium falciparum by photodynamic excitation of heme-cycle intermediates derived from delta-aminolevulinic acid.

Transfusion-transmitted malaria (TTM), especially that caused by Plasmodium falciparum, is of great concern in malaria-endemic areas. As a result of increased international travel, migration, and the spread of drug-resistant parasites, TTM is also a growing problem in industrialized nations. An effective and inexpensive means of inactivating malaria parasites in blood products would represent an important advance. In this report, we demonstrate that photoactivation of plasmodial heme-cycle intermediates, derived from supplemental delta -aminolevulinic acid (ALA), by exposure to simple white light in the presence of ALA, reduces P. falciparum in culture to levels that are undetectable by light microscopy or lactate dehydrogenase assay. Photodynamic excitation of presumed heme-cycle intermediates, which was revealed by fluorescence microscopy, did not appear to adversely affect the viability of erythrocytes. These data suggest that this pathogen-inactivation strategy, which uses inexpensive reagents and white light, may represent an appropriate means of inactivating malaria parasites in blood products in resource-poor settings.

Aminolevulinic Acid↗
PubMed2004

Malaria.

Malaria is a parasitic infection of global importance. Although relatively uncommon in developed countries, where the disease occurs mainly in travellers who have returned from endemic regions, it remains one of the most prevalent infections of humans worldwide. In endemic regions, malaria is a significant cause of morbidity and mortality and creates enormous social and economic burdens. Current efforts to control malaria focus on reducing attributable morbidity and mortality. Targeted chemoprophylaxis and use of insecticide-treated bed nets have been successful in some endemic areas. For travellers to malaria-endemic regions, personal protective measures and appropriate chemoprophylaxis can significantly reduce the risk of infection. Prompt evaluation of the febrile traveller, a high degree of suspicion of malaria, rapid and accurate diagnosis, and appropriate antimalarial therapy are essential in order to optimize clinical outcomes of infected patients. Additional approaches to malaria control, including genetic manipulation of mosquitoes and malaria vaccines, are areas of ongoing research.

Anemia↗
PubMed2004

CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages.

Phagocytic cells represent an important line of innate defense against malaria; however, little is known of the mechanism by which macrophages recognize Plasmodium falciparum-parasitized erythrocytes (PEs). Using macrophages from CD36 wild-type (WT), CD36-null, and CD36 transgenically-rescued rodents, we demonstrate a major role for CD36 in the phagocytosis of PEs. WT macrophages display enhanced phagocytic capacity for nonopsonized PEs, compared with that for CD36-null mouse and rat macrophages. Transgenic rescue of CD36-deficient rats restored macrophage phagocytic capacity for PEs. CD36 receptor blockade with monoclonal antibodies and proteolytic cleavage of CD36 ligands from the surface of PEs inhibited the uptake of PEs. Up-regulation of rodent CD36 by use of peroxisome proliferator-activated receptor (PPARgamma) agonists increased the phagocytosis of PEs. CD36-mediated uptake of PEs did not result in increased tumor necrosis factor-alpha secretion, of which high levels are associated with adverse outcomes in malaria. These studies support the use of these rodent models to examine PE-CD36 interactions.

Animals↗
PubMed2004

Leprosy in Toronto: an analysis of 184 imported cases.

BACKGROUND: Leprosy is a rare but serious mycobacterial infection. Immigration from areas where the disease is endemic has resulted in the importation of leprosy into countries where it is not endemic and where physicians and health care workers have little or no experience in diagnosis and therapy. In this study we characterized leprosy patients seen in a tropical disease unit that manages most of the reported leprosy cases in Canada. METHODS: We reviewed the clinical records of all 184 leprosy patients who were referred to the Tropical Disease Unit at Toronto General Hospital between 1979 and 2002 and abstracted demographic and clinical information. RESULTS: Patients were more likely to be male (122 or 66.3%) and of Indian (44 or 23.9%), Filipino (49 or 26.6%) or Vietnamese (37 or 20.1%) origin. Patients experienced symptoms for a mean of 4.8 years before referral to the Tropical Disease Unit. Most had no family history of leprosy (152/172 or 88.4%). Most patients presented with either borderline tuberculoid (80 or 43.5%) or borderline lepromatous (37 or 20.1%) disease. On average, patients presented with 5.8 skin lesions. Upper- and lower-extremity nerve dysfunction was common at presentation, with up to one-third of patients demonstrating either sensory or motor loss. A significantly greater lag time to presentation was observed in patients who emigrated from low-prevalence regions (p < 0.001). INTERPRETATION: Leprosy is a chronic infectious disease that is associated with serious morbidity if left untreated. Leprosy is uncommon in developed countries, but it is important for physicians to have a high index of suspicion when a foreign-born patient presents with chronic dermatitis and peripheral nerve involvement.

Adult↗
PubMed2004

Leprosy: a primer for Canadian physicians.

Leprosy is a rare but serious infectious disease caused by Mycobacterium leprae. While global prevalence of the disease is decreasing, increasing rates of immigration from countries where leprosy is endemic have led to the recognition of this illness in North America. Classically, leprosy presents as hypopigmented cutaneous macules along with sensory and motor peripheral neuropathies, although the clinical manifestations vary along a disease spectrum. In addition to primary infection, patients may undergo a "reaction," an acute inflammatory response to the mycobacterium, which leads to pain and erythema of skin lesions and dangerous neuritis. Reactions can occur at any time during the course of leprosy, but they tend to be precipitated by treatment. They are a significant cause of impaired quality of life due to marked nerve damage and thus warrant prompt intervention. Although leprosy may have a protracted onset and be difficult to recognize, cure is achievable with appropriate multidrug therapy. Because untreated leprosy can result in permanent, irreversible nerve damage and secondary transmission, early diagnosis and treatment are essential to minimize morbidity.

Diagnosis, Differential↗
PubMed2004

Serial nosocomial transmission of Plasmodium falciparum malaria from patient to nurse to patient.

BACKGROUND: Nosocomial transmission of malaria is a rare phenomenon in the United States. OBJECTIVE: To describe the probable transmission of Plasmodium falciparum malaria from a patient to a healthcare worker and then from the healthcare worker to another patient. DESIGN: Case series. SETTING: Two community hospitals in Massachusetts. INTERVENTION: Routine medical and supportive care. MEASUREMENTS: Clinical and laboratory evaluation. RESULTS: A nurse developed falciparum malaria after a needlestick injury from a patient with documented falciparum malaria. Three days prior to her diagnosis, she cared for another patient, who subsequently developed falciparum malaria. That patient's parasite isolate genetically matched the nurse's isolate by two independent DNA fingerprinting techniques. CONCLUSION: After extensive evaluation, we believe that a nurse who had acquired falciparum malaria via needlestick subsequently transmitted malaria to another patient via a break in standard precautions. The implications of this mechanism of transmission are discussed.

Adult↗
PubMed2004

Evaluation of the RealArt Malaria LC real-time PCR assay for malaria diagnosis.

PCR-based methods have advantages over traditional microscopic methods for the diagnosis of malaria, especially in cases of low parasitemia and mixed infections. However, current PCR-based assays are often labor-intensive and not readily quantifiable and have the potential for contamination due to a requirement for postamplification sample handling. Real-time PCR can address these limitations. This study evaluated the performance characteristics of a commercial malaria real-time PCR assay (RealArt Malaria LC Assay; Artus GmbH, Hamburg, Germany) on the LightCycler platform for the detection of malaria parasites in 259 febrile returned travelers. Compared to nested PCR as the reference standard, the real-time assay had a sensitivity of 99.5%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.6% for the detection of malaria. Our results indicate that the RealArt assay is a rapid (<45 min), sensitive, and specific method for the detection of malaria in returned travelers.

Animals↗
PubMed2004

Severe acute respiratory syndrome-associated coronavirus in lung tissue.

Efforts to contain severe acute respiratory syndrome (SARS) have been limited by the lack of a standardized, sensitive, and specific test for SARS-associated coronavirus (CoV). We used a standardized reverse transcription-polymerase chain reaction assay to detect SARS-CoV in lung samples obtained from well-characterized patients who died of SARS and from those who died of other reasons. SARS-CoV was detected in all 22 postmortem lung tissues (to 10(9) viral copies/g) from 11 patients with probable SARS but was not detected in any of the 23 lung control samples (sample analysis was blinded). The sensitivity and specificity (95% confidence interval) were 100% (84.6% to 100%) and 100% (85.1% to 100%), respectively. Viral loads were significantly associated with a shorter course of illness but not with the use of ribavirin or steroids. CoV was consistently identified in the lungs of all patients who died of SARS but not in control patients, supporting a primary role for CoV in deaths.

Adult↗
PubMed2003

Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study.

CONTEXT: Severe acute respiratory syndrome (SARS) is a new clinical entity for which no effective therapeutic strategy has been developed. OBJECTIVE: To provide preliminary results on the potential therapeutic benefit and tolerability of interferon alfacon-1 plus corticosteroids for SARS. DESIGN, SETTING, AND PATIENTS: Open-label study of 22 patients diagnosed as having probable SARS at North York General Hospital, Toronto, Ontario, between April 11 and May 30, 2003. INTERVENTIONS: Thirteen patients were treated with corticosteroids alone and 9 patients were treated with corticosteroids plus subcutaneous interferon alfacon-1. MAIN OUTCOME MEASURES: Clinical parameters, including oxygen saturation and requirement, laboratory measures, and serial chest radiography results. RESULTS: Resolution of fever and lymphopenia were similar between the 2 treatment groups. Of the 13 patients treated with corticosteroids alone, 5 (38.5%) were transferred to the intensive care unit, 3 (23.1%) required intubation and mechanical ventilation, and 1 (7.7%) died. Of the 9 patients in the interferon alfacon-1 treatment group, 3 (33.3%) were transferred to the intensive care unit, 1 (11.1%) required intubation and mechanical ventilation, and none died. The interferon alfacon-1 treatment group had a shorter time to 50% resolution of lung radiographic abnormalities (median time, 4 days vs 9 days; P =.001), had better oxygen saturation (P =.02), resolved their need for supplemental oxygen more rapidly (median, 10 days vs 16 days; P =.02), had less of an increase in creatine kinase levels (P =.03), and showed a trend toward more rapid resolution of lactate dehydrogenase levels compared with the group receiving corticosteroids alone. CONCLUSIONS: In this preliminary, uncontrolled study of patients with SARS, use of interferon alfacon-1 plus corticosteroids was associated with reduced disease-associated impaired oxygen saturation, more rapid resolution of radiographic lung abnormalities, and lower levels of creatine kinase. These findings suggest that further investigation may be warranted to determine the role of interferon alfacon-1 as a therapeutic agent for the treatment of SARS.

Adult↗
PubMed2003

Effect of HIV-1 antiretroviral drugs on cytoadherence and phagocytic clearance of Plasmodium falciparum-parasitised erythrocytes.

In response to the HIV/AIDS pandemic, antiretroviral treatment is currently being implemented in sub-Saharan Africa, where malaria and HIV-1 co-infections are highly prevalent. The effectiveness and tolerability of antiretrovirals in patients with malaria and HIV-1 co-infection have not been investigated. Antiretrovirals decrease CD36 surface concentrations in vivo, which might impair receptor function and affect parasite-host interactions. Thus, we investigated the effects of these drugs on CD36-mediated cytoadherence and non-opsonic phagocytosis of Plasmodium falciparum parasitised erythrocytes in vitro. The protease-inhibitor class of antiretrovirals particularly impairs CD36-mediated cytoadherence and non-opsonic phagocytosis of parasitised erythrocytes by human macrophages. Such treatment might therefore contribute to altered malaria disease outcomes in co-infected patients.

Africa South of the Sahara↗
PubMed2003

Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa.

We report a case of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to Kenya. Recurrent parasitemia occurred 30 days after directly observed therapy with a combination of atovaquone and proguanil. Treatment failure was confirmed by genetic fingerprinting and sequencing. The primary isolate had wild-type sequence of cytochrome b; however, the recrudescent isolate had a single mutation at position 268 (Tyr268Ser).

Adult↗
PubMed2003

Reversal of mefloquine and quinine resistance in Plasmodium falciparum with NP30.

Quinoline resistance in malaria is frequently compared with P-glycoprotein-mediated multidrug resistance (mdr) in mammalian cells. We have previously reported that nonylphenolethoxylates, such as NP30, are potential Plasmodium falciparum P-glycoprotein substrates and drug efflux inhibitors. We used in vitro assays to compare the ability of verapamil and NP30 to sensitize two parasite isolates to four quinolines: chloroquine (CQ), mefloquine (MF), quinine (QN), and quinidine (QD). NP30 was able to sensitize (reversal, >80%) P. falciparum to MF, QN, QD, and, to a lesser extent, CQ. The presence of 2 micro M verapamil had no effect on mefloquine resistance; however, the presence of verapamil modulated the activities of QN and QD in a manner parallel to that observed for CQ. Genetic analysis of putative quinoline resistance genes did not suggest an association between known point mutations in pfcrt and pfmdr1 and NP30 sensitization activity. We conclude that the sensitization action of NP30 is distinct both phenotypically and genotypically from that of verapamil.

Animals↗
PubMed2003

CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum.

Gametocytes, the sexual stages of malaria parasites (Plasmodium spp.) that are transmissible to mosquitoes, have been the focus of much recent research as potential targets for novel drug and vaccine therapies. However, little is known about the host clearance of gametocyte-infected erythrocytes (GEs). Using a number of experimental strategies, we found that the scavenger receptor CD36 mediates the uptake of nonopsonized erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum by monocytes and culture-derived macrophages (Mphis). Light microscopy and immunofluorescence assays revealed that stage I and IIA gametocytes were readily internalized by monocytes and Mphis. Pretreating monocytes and Mphis with a monoclonal antibody that blocked CD36 resulted in a significant reduction in phagocytosis, as did treating GEs with low concentrations of trypsin to remove P. falciparum erythrocyte membrane protein 1 (PfEMP-1), a parasite ligand for CD36. Pretreating monocytes and Mphis with peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists, which specifically upregulate CD36, resulted in a significant increase in the phagocytosis of GEs. Murine CD36 on mouse Mphis also mediated the phagocytosis of P. falciparum stage I and IIA gametocytes, as determined by receptor blockade with anti-murine CD36 monoclonal antibodies and the lack of uptake by CD36-null Mphis. These results indicate that phagocytosis of stage I and IIA gametocytes by monocytes and Mphis appears to be mediated to a large extent by the interaction of PfEMP-1 and CD36, suggesting that CD36 may play a role in innate clearance of these early sexual stages.

Animals↗
PubMed2003

Devices for rapid diagnosis of Malaria: evaluation of prototype assays that detect Plasmodium falciparum histidine-rich protein 2 and a Plasmodium vivax-specific antigen.

The ParaSight F test was developed as a pioneer industry effort in the large-scale, process-controlled production of a device for the rapid diagnosis of malaria. This device performed well in field settings but was limited to the detection of a single malaria species, Plasmodium falciparum. The ParaSight F+V assay advanced upon the ParaSight F test format by incorporating a monoclonal antibody directed against a proprietary Plasmodium vivax-specific antigen, in addition to the antibody directed against P. falciparum histidine-rich protein 2, which was used in the ParaSight F assay. The modified assay was developed to add the capability to detect P. falciparum and P. vivax in a single-test-strip format. The present study evaluated three distinct ParaSight F+V prototypes with samples from symptomatic patients in regions of Thailand and Peru where malaria is endemic. Over a 2-year enrollment period (1998 and 1999), a total of 4,894 patients consented to participation in the study. Compared with the results for duplicate microscopic examinations of Giemsa-stained blood smears as the reference diagnostic standard, each successive prototype showed substantial improvement in performance. The final ParaSight F+V prototype, evaluated in 1999, had an overall sensitivity for detection of asexual P. falciparum parasites of 98%. The sensitivity of the device was 100% for P. falciparum densities of >500 parasites/ micro l, with a sensitivity of 83% for parasite densities of </=500/ micro l. The specificity for the exclusion of P. falciparum was 93%. For P. vivax, the overall sensitivity was 87% for the final 1999 prototype. The sensitivities calculated for different levels of P. vivax parasitemia were 99% for parasite densities of >5,000/ micro l, 92% for parasite densities of 1,001 to 5,000/ micro l, 94% for parasite densities of 501 to 1,000/ micro l, and 55% for parasite densities of 1 to 500/ micro l. The specificity for the exclusion of P. vivax was 87%. The areas under the receiver operating characteristic curves for the diagnostic performance of the assay for the detection of P. falciparum and P. vivax were 0.8907 and 0.8522, respectively. These findings indicate that assays for rapid diagnosis have the potential to enhance diagnostic capabilities in those instances in which skilled microscopy is not readily available.

Animals↗
PubMed2003

Current status and replies to frequently posed questions on atovaquone plus proguanil (Malarone) for the prevention of malaria.

Each year at least 30 000 Western travellers acquire malaria and approximately 1-4% of those who acquire Plasmodium falciparum malaria will die as a result of infection. Almost all cases and fatalities are preventable with the use of measures to reduce mosquito bites and appropriate chemoprophylaxis for those at high risk of infection. There are currently a limited number of licensed drugs available to prevent malaria in travellers. New effective and well tolerated agents are urgently needed because of increasing resistance to antimalarials such as chloroquine and proguanil, and real and perceived intolerance to standard drugs such as mefloquine. A newly licensed antimalarial (atovaquone plus proguanil; Malarone) compares favourably with other drug options, although some prescribers may be unfamiliar with the specific advantages and disadvantages of this antimalarial. This article reviews recent clinical experience and randomised controlled trial data in order to address frequently asked questions about this new combination drug.

Antimalarials↗
PubMed2003

Atovaquone/proguanil: the need for family protection.

An increasing number of families, including children and the elderly, are seeking more adventurous travel in exotic parts of the world. Holiday destinations now include once-remote regions such as subSaharan Africa and New Guinea. This increase in visits to tropical and subtropical regions, combined with widespread chloroquine-resistant malaria, now places millions of Western travelers at risk of infection annually. At least 30,000 travelers from industrialized countries are reported to contract malaria each year and approximately 1 in 100 travelers who acquire Plasmodium falciparum malaria will die.

Adult↗