Biomedical subjects

K C Kain

Publications and source records attributed to K C Kain.

At least 19 recordsLinked to original sources

PubMed2001

Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study.

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

Adolescent↗

PubMed2001

Malaria chemoprophylaxis in the age of drug resistance. II. Drugs that may be available in the future.

All current regimens of malaria chemoprophylaxis have serious drawbacks as a result of either suboptimal efficacy, difficulty with medication compliance, or adverse events. Two 8-aminoquinolines may be approaching registration, with primaquine having completed its prophylactic field testing and tafenoquine having begun advanced field testing at the end of 2000. Primaquine has long been used for management of relapses of malaria, but in the past decade, it has been reexamined for use in malaria prevention in order to stop infection in the liver. In field trials performed in Indonesia and Colombia, the efficacy of primaquine for malaria prevention was approximately 90%, compared with that of placebo. Because of its short half-life, primaquine requires daily administration. For adults, the prevention regimen is 30 mg base daily (0.5 mg base/kg/day), and it can probably be discontinued soon after departure from an area where malaria is endemic. To kill parasites that already exist in the liver, terminal prophylaxis is given after exposure to relapses of malaria infection; for adults, such prophylaxis usually consists of 15 mg base (0.3 mg base/kg/day) given daily for 2 weeks. Primaquine-induced gastrointestinal disturbances can be minimized if the drug is taken with food. Neither primaquine nor tafenoquine should be given to persons with glucose-6-phosphate dehydrogenase deficiency, to avoid the development of potentially severe drug-induced hemolysis. Tafenoquine is an analogue of primaquine that is more potent than the parent drug. Field trials in Kenya, Ghana, Gabon, and Southeast Asia have demonstrated an efficacy rate of approximately 90% for tafenoquine. Its long half-life allows for infrequent dosing (currently tested at 200 mg base/week), and its effect on parasites at the liver stage may allow for drug discontinuation at the time of departure from the area of endemicity.

Aminoquinolines↗

PubMed2001

Malaria chemoprophylaxis in the age of drug resistance. I. Currently recommended drug regimens.

As international travel becomes increasingly common and resistance to antimalarial drugs escalates, a growing number of travelers are at risk for contracting malaria. Parasite resistance to chloroquine and proguanil and real or perceived intolerance among patients to standard prophylactic agents such as mefloquine have highlighted the need for new antimalarial drugs. Promising new regimens include atovaquone and proguanil, in combination; primaquine; and a related 8-aminoquinoline, tafenoquine. These agents are active against the liver stage of the malaria parasite and therefore can be discontinued shortly after the traveler leaves an area where malaria is endemic, which encourages adherence to the treatment regimen. Part 1 of this series reviews currently recommended chemoprophylactic drug regimens, and part 2 will focus on 8-aminoquinoline drugs.

Animals↗

PubMed2001

Transfusion-transmitted babesiosis in Ontario: first reported case in Canada.

Babesiosis has only recently been reported in Canada, but a number of transfusion-transmitted cases of this infection have been reported from the United States. We present a case of transfusion-transmitted babesiosis that occurred in Canada. Canadian physicians must consider babesiosis in the differential diagnosis of patients who experience fever or a hemolytic reaction after blood transfusion. Prompt recognition and treatment are important, because Babesia infections can be severe or fatal in certain risk groups. Better strategies to prevent transfusion-transmitted babesiosis are required.

Adult↗

PubMed2001

Peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF-alpha secretion by monocytes/macrophages.

Severe and fatal malaria is associated with the failure of host defenses to control parasite replication, excessive secretion of proinflammatory cytokines such as TNF-alpha, and sequestration of parasitized erythrocytes (PEs) in vital organs. The identification of CD36 as a major sequestration receptor has led to the assumption that it contributes to the pathophysiology of severe malaria and has prompted the development of antiadherence therapies to disrupt the CD36-PE interaction. This concept has been challenged by unexpected evidence that individuals deficient in CD36 are more susceptible to severe and cerebral malaria. In this study, we demonstrate that CD36 is the major receptor mediating nonopsonic phagocytosis of PEs by macrophages, a clearance mechanism of potential importance in nonimmune hosts at the greatest risk of severe malaria. CD36-mediated uptake of PEs occurs via a novel pathway that does not involve thrombospondin, the vitronectin receptor, or phosphatidylserine recognition. Furthermore, we show that proliferator-activated receptor gamma-retinoid X receptor agonists induce an increase in CD36-mediated phagocytosis and a decrease in parasite-induced TNF-alpha secretion. Specific up-regulation of monocyte/macrophage CD36 may represent a novel therapeutic strategy to prevent or treat severe malaria.

Alitretinoin↗

PubMed2001

Malaria deaths in visitors to Canada and in Canadian travellers: a case series.

Over the last decade there has been a marked increase in case of drug-resistant and severe malaria in Canadian travellers. We report 7 deaths due to falciparum malaria that occurred in Canada or in Canadian travellers. Risks for malaria infection include inappropriate recommendations for malaria prevention by health care providers and lack of knowledge about or adherence to appropriate recommendations by the travelling public. Risks for death include delays in seeking medical attention, delays in diagnosis and inadequate care by Canadian physicians and hospitals, and lack of access to parenteral therapy for severe malaria. Malaria infections and deaths are preventable. Better education of health care providers and travellers about the risks of malaria and appropriate prevention and treatment measures may decrease this unnecessary burden on the Canadian health care system.

Adult↗

PubMed2001

Transfusion-transmitted malaria in Canada.

Three cases of transfusion-transmitted malaria in Canada are described. Although very rare, this diagnosis should be considered in transfusion recipients who have undiagnosed symptoms consistent with malaria. Thick and thin blood smears should be urgently examined to exclude this possibility.

Adult↗

PubMed2001

Plasmodium falciparum malaria in Laos: chloroquine treatment outcome and predictive value of molecular markers.

A 28-day treatment trial was undertaken, to determine the efficacy of chloroquine in Laos and to assess the predictive value of molecular markers (cg2, pfmdr1, and pfcrt) that were previously linked to chloroquine resistance. In total, 522 febrile patients were screened for falciparum malaria by rapid diagnostic assays. Of 81 patients (15.5% prevalence) who were positive by the assays and microscopy, 48 were eligible to participate in the 28-day trial. Nine patients defaulted. Chloroquine cured 54% (95% confidence interval, 45.8-61.8) of falciparum-infected patients. Of 18 (46%) patients with treatment failure, 13 (72%) experienced high-grade resistance. Polymorphisms in cg2 and the N86Y mutation in PfMDR1 were not predictive of treatment outcome. A mutation in PfCRT (K76T) was perfectly associated with in vivo chloroquine resistance. However, K76T was also present in in vivo-sensitive isolates, which suggests that the presence of this mutation was necessary, but not sufficient, to predict in vivo outcome in this cohort.

Adolescent↗

PubMed2001

Plasmodium vivax: ookinete destruction and oocyst development arrest are responsible for Anopheles albimanus resistance to circumsporozoite phenotype VK247 parasites.

Anopheles albimanus and An. pseudopunctipennis differ in their susceptibilities to Plasmodium vivax circumsporozoite phenotypes. An. pseudopunctipennis is susceptible to phenotype VK247 but almost refractory to VK210. In contrast, An. albimanus is almost refractory to VK247 but susceptible to VK210. To investigate the site in the mosquito and the parasite stage at which resistance mechanisms affect VK247 development in An. albimanus, parasite development was followed in a series of experiments in which both mosquitoes species were simultaneously infected with blood from patients. Parasite phenotype was determined in mature oocysts and salivary gland sporozoites by use of immunofluorescence and Western blot assays and/or gene identification. Ookinete maturation and their densities within the bloodmeal bolus were similar in both mosquito species. Ookinete densities on the internal midgut surface of An. albimanus were 4.7 times higher than those in An. pseudopunctipennis; however, the densities of developing oocysts on the external midgut surface were 6.12 times higher in the latter species. Electron microscopy observation of ookinetes in An. albimanus midgut epithelium indicated severe parasite damage. These results indicate that P. vivax VK247 parasites are destroyed at different parasite stages during migration in An. albimanus midguts. A portion, accumulated on the internal midgut surface, is probably destroyed by the mosquito's digestive enzymes and another portion is most likely destroyed by mosquito defense molecules within the midgut epithelium. A third group, reaching the external midgut surface, initiates oocyst development, but over 90% of them interrupt their development and die. The identification of mechanisms that participate in parasite destruction could provide new elements to construct transgenic mosquitoes resistant to malaria parasites.

Animals↗

PubMed2001

Entamoeba dispar: molecular characterization of the galactose/N-acetyl-d-galactosamine lectin.

Amebiasis contributes to approximately 50 million cases of life-threatening dysentery worldwide. Comparison of the lectins from Entamoeba histolytica (pathogenic) and Entamoeba dispar (nonpathogenic) was undertaken to elucidate the differential roles of this molecule in invasion versus colonization. Surface lectin was less abundant on axenic E. dispar than on axenic E. histolytica, commensurate with differences in lectin (heavy and light subunits) RNA when assessed by semiquantitative RT-PCR. The 1G7 epitope, which falls within the immunodominant and immunoprotective cysteine-rich region (480-900), was absent on axenic E. dispar. Indirect immunofluorescence, transient transection of COS7, and immunoprecipitation demonstrated that the 1G7 epitope was conserved in the nonpathogenic lectin homologue but not exposed on live E. dispar trophozoites. Hgl2 (E. histolytica) and Dhgl2 (E. dispar) lectin homologues demonstrated comparable high-affinity binding to multivalent GalNAc(19) BSA. These data provide evidence for relative gene and conformational regulation of the E.dispar lectin.

Animals↗

PubMed2001

Characterization of peroxynitrite-oxidized low density lipoprotein binding to human CD36.

Peroxynitrite-mediated oxidation may be an important physiological mechanism for oxidation of low density lipoprotein (LDL), however, the molecular basis for the interaction of peroxynitrite oxidized LDL (OxLDL) with scavenger receptors such as CD36, has not been characterized. In this study, we compared the biochemical characteristics and receptor binding of LDL that was oxidized using: (1) Cu2+, a standard method of oxidizing LDL in vitro; and (2) 3-morpholinosydnonimine (SIN-1), a source of peroxynitrite. Both methods of oxidation caused an increase in electrophoretic migration of LDL, but greater mobility was observed with Cu2+-OxLDL. In addition, greater fragmentation of apolipoprotein B was observed following Cu2+ oxidation than after SIN-1 oxidation. The levels of lipid peroxides and thiobarbituric acid reactive substances were similar after 20 h of oxidation by both methods, although the time-course was distinct. Cu2+ and SIN-1-OxLDL bound specifically to the macrophage scavenger receptor CD36 with high affinity. Binding of the 20 h SIN-1 treated LDL to CD36 was comparable to a 4 h Cu2+ modified LDL. The binding of Cu2+ and SIN-1-OxLDL to CD36 was similar under different biochemical conditions and modifications of the receptor, suggesting that OxLDL particles, generated by either method, bind to the same domain of CD36. The results demonstrate that SIN-1 produced an oxidized LDL particle that binds specifically to CD36 and suggests that peroxynitrite OxLDL may represent a more physiologically relevant model than Cu2+-OxLDL for studying the interactions of OxLDL with cells and lipoprotein receptors in vitro.

Animals↗

PubMed2001

PCR-based ELISA technique for malaria diagnosis of specimens from Thailand.

We performed a field evaluation of polymerase chain reaction (PCR)-based enzyme-linked immuno-sorbent assays (ELISA) for the diagnosis of malaria. A commercially available PCR-ELISA microplate hybridization (MPH) assay was used. Blood specimens were collected from 300 volunteers seeking care at malaria clinics in Thailand. Examination of 200 high power fields by Giemsa-stained thick and thin smear (GTTS) revealed 51 P. falciparum (Pf), 45 P. vivax (Pv), seven mixed Pf-Pv infections. These plus a random sample of 48 GTTS-negative specimens were selected for this study. All 151 specimens were processed for parasite DNA extraction and assayed by PCR-MPH. The target DNA sequence of the 18S small subunit ribosomal RNA (SSUrRNA) gene was amplified by PCR and hybridized with species-specific probes for Pf, Pv, P. malariae (Pm) and P. ovale (Po) immobilized in the wells of the microtiter plate and detected by colorimetric assay. Colour development was assessed at an optical density (OD) of 405 nm. An absorbance reading of > or = 0.1 was used as a positive cut-off. In comparison with GTTS results, PCR-MPH sensitivity was 91.4% (53/58, 95% CI 84.2-98.6) for Pf, 94.2% (49/52, 87.9-100) for Pv and specificity was 95.8% (46/48, 95% CI 90.2-100). There was statistically significant positive correlation between parasite densities < or = 7000/microl blood and absorbance reading, suggestive of PCR-MPH being semiquantitative. PCR-MPH also detected additional Pf and Pv cases as well as Pm and Po.

Adolescent↗

PubMed2001

The performance and utility of rapid diagnostic assays for Plasmodium falciparum malaria in a field setting in the Lao People's Democratic Republic.

Rapid diagnostic assays for malaria have the potential to improve the management and control of the disease in developing countries. The objectives of the present study were to evaluate, in a field setting, the performance of several such assays for Plasmodium falciparum infection and to examine the usefulness of these assays in identifying subjects for treatment trials in rural field sites. Residents of 12 villages in Laos who presented with fever were eligible for inclusion. Blood was collected by fingerprick for a dipstick assay, developed by the Program for Appropriate Technology in Health (PATH), performed and interpreted in the field by local healthcare workers. Compared with 'blinded' reference microscopy (N =196), the sensitivity and specificity of the PATH assay were 96.2% and 93.0%, respectively. Two rapid diagnostic assays (PATH and OptiMAL) were also performed on the subset of subjects eligible to participate in an in-vivo treatment trial (N = 97), and the results again compared with those of 'blinded' reference microscopy. In this subset, a subject was considered a 'true positive' if found positive by microscopy or the alternate rapid assay. Using this modified reference standard, the sensitivity and specificity of the PATH assay were 96.7% and 94.4%, and those of the OptiMAL assay were 91.8% and 100%, respectively. Both of the rapid assays tested therefore appear suitable for use in rural field settings by local healthcare providers and can accurately identify participants for treatment trials.

Developing Countries↗

PubMed2001

Molecular markers for chloroquine-resistant Plasmodium falciparum malaria in Thailand and Laos.

Chloroquine-resistant Plasmodium falciparum is well documented in Thailand. Laos, however, continues to use chloroquine (CQ) as the first-line therapy for the treatment of P. falciparum malaria. The objective of the present study was to determine the prevalence, in these two areas, of the cg2, pfmdr1 and pfcrt allelic types that have previously been associated with CQ resistance. Isolates of P. falciparum were collected from participants in ongoing treatment studies conducted in Thailand (near the Thai-Cambodian border) and in Laos (Vang Vieng district). The pfmdr1 and pfcrt alleles were characterized by PCR-RFLP and mutations in cg2 were characterized by PCR and single-stranded-conformation-polymorphism (SSCP) electrophoresis. Eight (32%) of the 25 Laotian isolates but only one (4%) of the 25 Thai isolates were found to contain the pfmdr1 mutation N86Y (P = 0.02). In contrast, the cg2 polymorphisms previously associated with CQ resistance were present in only 10 of the isolates from Laos but 24 of those from Thailand (40% v. 96%; P < 0.001). All the samples from both countries contained the pfcrt K76T mutant allele reported to confer resistance to CQ. The results may indicate that drug pressure for the maintenance of the pfmdr1 and cg2 alleles varies in intensity in the Thai and Laotian study areas, probably reflecting differences in the national malaria-treatment policies of Thailand and Laos.

ATP-Binding Cassette Transporters↗

PubMed2001

Development of monoclonal antibodies which specifically recognize Entamoeba histolytica in preserved stool samples.

We report the generation of monoclonal antibodies against a recombinant 170-kDa subunit of the Gal or GalNAc lectin of Entamoeba histolytica that specifically recognize E. histolytica but not Entamoeba dispar in preserved stool samples. These antibodies do not cross-react with other bowel protozoa, including Entamoeba coli, Giardia lamblia, and Dientamoeba fragilis.

Animals↗

PubMed2001

Comparison of IsoCode STIX and FTA Gene Guard collection matrices as whole-blood storage and processing devices for diagnosis of malaria by PCR.

We compared two collection devices, IsoCode and FTA, with whole blood for the diagnosis of malaria by PCR (n = 100). Using whole blood as the reference standard, both devices were sensitive for the detection of single-species malaria infections by PCR (> or =96%). However, the detection of mixed infections was suboptimal (IsoCode was 42% sensitive, and FTA was 63% sensitive).

Animals↗

PubMed2001

Malaria rapid diagnostic devices: performance characteristics of the ParaSight F device determined in a multisite field study.

Microscopic detection of parasites has been the reference standard for malaria diagnosis for decades. However, difficulty in maintaining required technical skills and infrastructure has spurred the development of several nonmicroscopic malaria rapid diagnostic devices based on the detection of malaria parasite antigen in whole blood. The ParaSight F test is one such device. It detects the presence of Plasmodium falciparum-specific histidine-rich protein 2 by using an antigen-capture immunochromatographic strip format. The present study was conducted at outpatient malaria clinics in Iquitos, Peru, and Maesod, Thailand. Duplicate, blinded, expert microscopy was employed as the reference standard for evaluating device performance. Of 2,988 eligible patients, microscopy showed that 547 (18%) had P. falciparum, 658 (22%) had P. vivax, 2 (0.07%) had P. malariae, and 1,750 (59%) were negative for Plasmodium. Mixed infections (P. falciparum and P. vivax) were identified in 31 patients (1%). The overall sensitivity of ParaSight F for P. falciparum was 95%. When stratified by magnitude of parasitemia (no. of asexual parasites per microliter of whole blood), sensitivities were 83% (>0 to 500 parasites/microl), 87% (501 to 1,000/microl), 98% (1,001 to 5,000/microl), and 98% (>5,000/microl). Device specificity was 86%.

Animals↗

PubMed2000

Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study. Malarone International Study Team.

BACKGROUND: Chloroquine plus proguanil is widely used for malaria chemoprophylaxis despite low effectiveness in areas where multidrug-resistant malaria occurs. Studies have shown that atovaquone and proguanil hydrochloride is safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but little is known about non-immune travellers. METHODS: In a double-blind equivalence trial, 1083 participants travelling to a malaria-endemic area were randomly assigned to two treatment groups: atovaquone-proguanil plus placebos for chloroquine and proguanil, or chloroquine, proguanil, and placebo for atovaquone-proguanil. Follow-up was by telephone 7 and 60 days after travel and at a clinic at 28 days. Serum samples were tested for antibodies to a malaria circumsporozoite protein. Blood and serum samples of participants with a potential malaria diagnosis were tested in a reference laboratory. FINDINGS: 7 days after travel, at least one adverse event was reported by 311 (61%) of 511 participants who received atovaquone-proguanil and 329 (64%) of 511 who received chloroquine-proguanil. People receiving atovaquone-proguanil had a lower frequency of treatment-related gastrointestinal adverse events (59 [12%] vs 100 [20%], p=0.001), and of treatment-related adverse events of moderate or severe intensity (37 [7%] vs 56 [11%], p=0.05). There were fewer treatment-related adverse events that caused prophylaxis to be discontinued in the atovaquone-proguanil group than in the chloroquine-proguanil group (one [0.2%] vs ten [2%], p=0.015). INTERPRETATION: Overall the two preparations were similarly tolerated. However, significantly fewer adverse gastrointestinal events were observed in the atovaquone-proguanil group in than in the chloroquine-proguanil group.

Adolescent↗