Diagnosis, Diagnostics, Immunodiagnosis & Immunodiagnostics:


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3363.   Akpede GO.  Akenzua GI.  Management of children with prolonged fever of unknown origin and difficulties in the management of fever of unknown origin in children in developing countries. [Review] [90 refs] Paediatric Drugs.  3(4):247-62, 2001.


  This is Part II of a 2-part paper on fever of unknown origin (FUO) in children. It examines the aetiology and management of prolonged FUO in children and the difficulties in the management of FUO in children in developing countries. Part I of this paper discussed acute FUO in children and was published in the March 2001 issue of Paediatric Drugs. Prolonged FUO is documented fever of more than 7 to 10 days which has no apparent source and no apparent diagnosis after 1 week of clinical investigations. About 34% of cases of prolonged FUO are caused by infections, with bacterial meningitis and urinary tract infection accounting for about 6.5 and 11.4%, respectively, of cases attributable to infections. Chronic infections, particularly tuberculosis and 'old' disorders such as Kawasaki disease, cat-scratch disease and Epstein-Barr virus infection presenting with 'new' manifestations, collagen-vascular diseases and neoplastic disorders are the other issues of major concern in prolonged FUO. Overall, however, there is a trend towards an increased number of undiagnosed cases. This is due to advancements in diagnostic techniques, such that illnesses which were previously common among the causes of prolonged FUO are now diagnosed earlier, before the presentation becomes that of prolonged FUO. Clinical examination supplemented with laboratory tests to screen for serious bacterial infections should be the mainstay of initial evaluation of children with prolonged FUO. Use of scanning techniques (such as computerised tomography and ultrasound) as additional supplements to this clinical examination may allow for the earlier diagnosis of causes of prolonged FUO in children such as 'occult' abdominal tumours. A common error in management of children with prolonged FUO is the failure to perform a complete history and physical examination; repeated clinical examination and continued observation are of paramount importance in the diagnosis of difficult cases. Major difficulties in the management of FUO in children in developing countries include constraints in the availability and reliability of laboratory tests, cost, misuse of antibiotics and difficulties encountered in the diagnosis of malaria and typhoid fever. Malaria and typhoid fever are major aetiological considerations in both acute and prolonged FUO in children in developing countries. The newer quinolones may hold great promise for the treatment of serious bacterial infections, including meningitis, which are associated with prolonged FUO in developing countries. [References: 90]


3364.    Ansah EK.  Gyapong JO.  Agyepong IA.  Evans DB.  Improving adherence to malaria treatment for children: the use of pre-packed chloroquine tablets vs. chloroquine syrup.  Tropical Medicine & International Health.  6(7):496-504, 2001 Jul.


  Malaria is a major cause of morbidity and mortality among children under five in sub-Saharan Africa. Prompt diagnosis and adequate treatment of acute clinical episodes are essential to reduce morbidity and prevent complications and mortality. In many countries, chloroquine syrup is the mainstay of malaria treatment for children under five. Not only is syrup more expensive than tablets, adherence to the prescribed dose at home is a problem because mothers use wrongly sized measuring devices or have difficulty with the instructions. We investigated the impact of introducing pre-packed tablets for children on adherence to treatment and compared the total cost of the tablets with that of syrup. Children aged 0--5 years diagnosed with malaria at the clinic over a 6-week period received either pre-packed tablets or syrup by random assignment. The principal caregivers were interviewed at home on day 4 after attending the clinic. Of the 155 caregivers given pre-packed tablets, 91% (n=141) adhered to the recommended dosage, while only 42% (n=61) of 144 who were provided syrup did. Only 20% of caregivers who received syrup used an accurate 5 ml measure. The cost of treatment with tablets was about one-quarter that of syrup and 62% (n=96) of caregivers preferred tablets. Pre-packed chloroquine tablets are a viable alternative to syrup.


3365.    Beeson JG.  Reeder JC.  Rogerson SJ.  Brown GV. Parasite adhesion and immune evasion in placental malaria. [Review] [65 refs] Trends in Parasitology.  17(7):331-7, 2001 Jul.


  Parasite sequestration in the placenta is a key feature of infection by Plasmodium falciparum during pregnancy and is associated with severe adverse outcomes for both mother and baby. Here, James Beeson and colleagues draw together the findings of recent studies on parasite mechanisms that mediate this process. They review evidence for novel parasite variants that appear able to evade pre-existing immunity, for the adhesion of P. falciparum-infected erythrocytes to placental glycosaminoglycans (and the molecular basis of these parasite properties) and for the expression of var genes encoding the variant antigen and adhesive ligand P. falciparum-erythrocyte membrane protein 1 (PfEMP1). [References: 65]

3366.    Borruat FX.  Nater B.  Robyn L.  Genton B. Prolonged visual illusions induced by mefloquine (Lariam): a case report.  Journal of Travel Medicine.  8(3):148-9, 2001 May-Jun.


3367.   Carrasquilla G. An ecosystem approach to malaria control in an urban setting. Cadernos de Saude Publica.  17 Suppl:171-9, 2001.


  We conducted a research project aimed at strengthening local government and the community for a sustainable malaria control strategy. The project began with a baseline diagnosis of malaria prevalence, a KAP survey, entomology, and health services delivery, after which an epidemiological study was performed to identify risk factors associated with malaria, thereafter used to plan intervention measures. A program evaluation was conducted five years later. By using an ecosystem approach to reanalyze data, this paper discusses how malaria arises from a complex interaction of cultural, economic, ecological, social, and individual factors. Intervention measures require an intersectorial and transdisciplinary approach that does not exist at the moment. Health sector leadership is limited, and there is no true community participation. Implications for research, including the use of qualitative and quantitative methods, study design, and complexity of data analysis are discussed. Finally, implications for malaria control are discussed, stressing the differences between the ecosystem and integrated disease control approaches.

3368.    Carter R.  Transmission blocking malaria vaccines. Vaccine.  19(17-19):2309-14, 2001 Mar 21.


  Transmission blocking vaccines (TBVs) against malaria are intended to induce immunity against the stages of the parasites which infect mosquitoes so that TBV-immunised individuals cannot transmit malaria. As malarial infections are transmitted mainly within a few hundreds of meters from an infectious human source, TBVs used within in a community would protect the immediate neighbourhood of the vaccinated individuals. TBVs against the two major species of human malaria, Plasmodium falciparum and P. vivax, are under development. Candidate TBV constructs for both Plasmodium species have been successfully tested in animal systems and testing is in progress with clinical grade material in humans.

3369.    Carucci DJ. Genomic tools for gene and protein discovery in malaria: toward new vaccines. Vaccine.  19(17-19):2315-8, 2001 Mar 21.


  Advances in malaria vaccine and drug development have been hindered in part by the complex multistage life cycle of the parasite, much of which is inaccessible to study, and by a large genome encoding over 5000 genes. Two human models of immunity to malaria, however, suggest that the development of an effective vaccine is within reach. We have outlined a strategy to identify the expression of hundreds to thousands of potential vaccine targets employing recently developed technologies for gene and protein expression. Combined with the exciting developments of malaria DNA vaccine technologies, these approaches form the basis for malaria subunit vaccines that may mimic the protective efficacy of our human model systems and provide the foundation for novel approaches to vaccine development for a range of pathogens.

3370.    Chandramohan D.  Carneiro I.  Kavishwar A.  Brugha R.  Desai V.  Greenwood B. A clinical algorithm for the diagnosis of malaria: results of an evaluation in an area of low endemicity. Tropical Medicine & International Health.  6(7):505-10, 2001 Jul.


  We conducted a study of 1945 children and 2885 adults who presented with fever to a hospital outpatients clinic in an urban area of India order to develop and evaluate a clinical algorithm for the diagnosis of malaria. Only 139 (7%) children and 349 (12%) adults had microscopically confirmed malaria. None of the symptoms or signs elicited from the respondents were good predictors of clinical malaria. Simple scores were derived through combining clinical features which were associated with slide positivity or were judged by clinicians to be important. The best-performing algorithms were a score of 4 clinical features in children (sensitivity 60.0% and specificity 61.2%) and a score of 5 in adults (sensitivity 54.6% and specificity 57.5%). The clinical features differed and algorithm performances were poorer than in previous studies in highly endemic areas. The conclusion is that malaria diagnosis in areas of low endemicity requires microscopy to be accurate.


3371.   Congpuong K.  Bualombai P.  Jitchamroen S.  Konchom S.  Comparison of the OptiMAL rapid test with routine microscopic examination of Giemsa-Stained Thick Blood Film for diagnosis of malaria. Journal of the Medical Association of Thailand.  84(3):357-63, 2001 Mar.


  The OptiMAL is a rapid immunodiagnostic test developed by Flow Inc., Portland, Oreg. for diagnosis and differentiation of P. falciparum and non P. falciparum malaria infection. It has been based on detection of circulating parasite lactate dehydrogenase enzyme (pLDH), produced by live Plasmodium parasites. The purpose of this study was to compare the efficacy of the OptiMAL test with routine microscopic examination of Giemsa-Stained Thick Blood Film (routine GS-TBF) for the diagnosis of malaria at a local malaria clinic in a hyperendemic area of Thailand by using a standard GS-TBF (standard GS-TBF) as reference. One hundred and seventy five patients attending the clinic were recruited; 50, 42 and 83 were falciparum malaria, vivax malaria and non-malaria patients, respectively. Compared with the reference, the OptiMAL test had sensitivities of 92 per cent and 97.6 per cent, whereas, the routine GS-TBF had sensitivities of 81.3 per cent and 81 per cent for the detection of P. falciparum and P. vivax, respectively. Both tests showed no false positive resulting in 100 per cent specificities. However, the OptiMAL test was able to detect only 20 per cent of infection with less than 200 parasitaemia/microlitre. It was also shown in our study that the OptiMAL test was advantageous in follow-up of the treatment outcome. No false positive occurred among 40 follow-up cases. The OptiMAL test detected malaria infection more accurately than the routine GS-TBF (p < 0.05) and was simple, easy to perform and rapid. It is an alternative tool for the diagnosis of malaria in a hyperendemic area where experienced microscopists are not available.

3372.   Cowman AF.  Functional analysis of drug resistance in Plasmodium falciparum in the post-genomic era. [Review] [72 refs] International Journal for Parasitology.  31(9):871-8, 2001 Jul.


  Malaria has plagued humans throughout recorded history and results in the death of over 2 million people per year. The protozoan parasite Plasmodium falciparum causes the most severe form of malaria in humans. Chemotherapy has become one of the major control strategies for this parasite; however, the development of drug resistance to virtually all of the currently available drugs is causing a crisis in the use and deployment of these compounds for prophylaxis and treatment of this disease. The genome sequence of P. falciparum is providing the informational base for the use of whole-genome strategies such as bioinformatics, microarrays and genetic mapping. These approaches, together with the availability of a high-resolution genome linkage map consisting of hundreds of microsatellite markers and the advanced technologies of transfection and proteomics, will facilitate an integrated approach to address important biological questions. In this review we will discuss strategies to identify novel genes involved in the molecular mechanisms used by the parasite to circumvent the lethal effect of current chemotherapeutic agents. [References: 72]

3373.   Cunha BA. The diagnosis of imported malaria.  Archives of Internal Medicine.  161(15):1926-8, 2001 Aug 13-27.

3374.   Ghoshal UC.  Somani S.  Chetri K.  Akhtar P.  Aggarwal R.  Naik SR. Plasmodium falciparum and hepatitis E virus co-infection in fulminant hepatic failure. Indian Journal of Gastroenterology.  20(3):111, 2001 May-Jun.


  Acute hepatitis E and falciparum malaria can each present with fulminant hepatic failure and are common in tropical countries. However, co-existence of these two conditions has not been reported. We report a 20-year-old girl who presented with fever and altered sensorium. Peripheral smear was positive for Plasmodium falciparum, and IgM anti-HEV was positive. She died despite antimalarial drugs and supportive management. Postmortem liver tissue showed changes suggestive of acute viral hepatitis.


3375.   Goodman CA.  Coleman PG.  Mills AJ. The cost-effectiveness of antenatal malaria prevention in sub-Saharan Africa. American Journal of Tropical Medicine & Hygiene.  64(1-2 Suppl):45-56, 2001 Jan-Feb.


  Antimalarial chemoprophylaxis during pregnancy significantly increases the birth weight of babies born to primigravidae, but coverage in sub-Saharan Africa is very limited. This analysis assessed whether increasing coverage is justified on cost-effectiveness grounds. A standardized modeling framework was used to estimate ranges for the cost per discounted year of life lost averted by weekly chloroquine chemoprophylaxis and intermittent sulfadoxine-pyrimethamine (SP) treatment for primigravidae in an operational setting with moderate to high malaria transmission. The SP regimen was found to be more cost-effective than the chloroquine regimen, because of both lower costs and higher compliance. Both regimens appear to be a good value for money in comparison with other methods of malaria control and based on rough cost-effectiveness guidelines for low-income countries, even with high levels of drug resistance. However, extending the SP regimen to all gravidae and increasing the number of doses per pregnancy could make the intervention significantly less cost-effective.


3376.    Iqbal J.  Hira PR.  Sher A.  Al-Enezi AA. Diagnosis of imported malaria by Plasmodium lactate dehydrogenase (pLDH) and histidine-rich protein 2 (PfHRP-2)-based immunocapture assays. American Journal of Tropical Medicine & Hygiene.  64(1-2):20-3, 2001 Jan-Feb.


  This study was conducted to evaluate the performance of two rapid non-microscopic assays: Plasmodium lactate dehydrogenase (pLDH) assay (OptiMAL) and Plasmodium falciparum histidine-rich protein 2 (PfHRP-2) assay (ICT Malaria). The assays were used to detect malaria infection in 515 immigrants living in Kuwait. The performance of both assays was compared to that of microscopy of Giemsa-stained thick blood films and to each other. Of the 515 patients tested, 163 were positive for malaria parasites by microscopy of thick blood film. Of these, 87 were infected with Plasmodium vivax parasites, 63 with P. falciparum, 1 with Plasmodium malariae, and 12 had mixed infections of P. falciparum and P. vivax. The PfHRP-2 assay detected 53 P. falciparum infections and, as expected, failed to detect all but one case of P. vivax. Three cases of mixed infections were also not detected by this assay. The pLDH assay detected 56 P. falciparum cases and 77 P. vivax infections but failed to detect 4 cases of mixed infections. Compared to microscopy, the performance of both the assays to diagnose P. falciparum infection was comparable. The sensitivity for the PfHRP-2 assay was 82% with a specificity of 99.0% and for the pLDH assay the sensitivity was 89% with a specificity of 99.5%. The PfHRP-2 assay detected 4 false positive cases, 2 of which were also detected by the pLDH assay. These patients reported treatment with chloroquine in the last 2-5 weeks. Though the immunocapture diagnostic assays may be helpful in certain situations, microscopy of thick blood film is still the method of choice in diagnosing imported malaria.

3377.    Josefson D. Drugs for malaria and psychosis may offer hope to people with CJD. BMJ.  323(7310):416, 2001 Aug 25.

3378.    Kain KC.  Shanks GD.  Keystone JS. Malaria chemoprophylaxis in the age of drug resistance. I. Currently recommended drug regimens. [Review] [33 refs] Clinical Infectious Diseases.  33(2):226-34, 2001 Jul 15.


  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. [References: 33]

3379.    Klement E.  Chauveheid MP.  Thellier M.  Bricaire F.  Danis M.  Caumes E.  Subacute clinical forms of Plasmodium falciparum malaria in travelers receiving chloroquine-proguanil prophylaxis.  Clinical Infectious Diseases.  33(1):e1-2, 2001 Jul 1.


  We have observed 4 French travelers, returning from African countries, who were not immune to malaria and were receiving chloroquine-proguanil prophylaxis, in whom the diagnosis of malaria could easily have been missed because the clinical signs were uncommon. These cases suggest that chloroquine-proguanil prophylaxis is not always effective and that travelers with unexplained symptoms should be monitored closely for malaria.

3380.    Miller RS.  McDaniel P.  Wongsrichanalai C. Following the course of malaria treatment by detecting parasite lactate dehydrogenase enzyme. British Journal of Haematology.  113(2):558-9, 2001 May.


3381.   Murphy SC.  Breman JG. Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy. [Review] [94 refs] American Journal of Tropical Medicine & Hygiene.  64(1-2 Suppl):57-67, 2001 Jan-Feb.


  Evaluations of the African childhood malaria burden do not fully quantify the contributions of cerebral malaria (CM), CM-associated neurological sequelae, malarial anemia, respiratory distress, hypoglycemia, and pregnancy-related complications. We estimated the impact of these malaria manifestations on members of the African population < 5 years old. Calculations were based on an extensive literature review that used National Library of Medicine search engines, other bibliographic sources, and demographic data. In sub-Saharan Africa, CM annually affects 575,000 children < 5 years of age and 110,000 (approximately 19% case fatality rate [CFR]) die. Childhood survivor, of CM experience developmental and behavioral impairments: each year, 9,000-19,000 children (> 2% of survivors of CM) < 5 years of age in Africa experience neurological complications lasting > 6 months. Severe malarial anemia heavily burdens hospitals with rising admission and CFRs and with treatments that are complicated by limited and sometimes contaminated blood supplies. Severe malarial anemia occurs 1.42-5.66 million times annually and kills 190,000-974,000 (> 13% CFR) children < 5 years of age annually. Respiratory distress, hypoglycemia, and overlapping clinical manifestations cause 1.12-1.99 million cases and > 225,000 (> 18% CFR) additional deaths among African children with malaria. Maternal, placental, or fetal malaria infection during pregnancy adversely affects development and survival of fetuses and newborns through low birth weight (LBW), maternal anemia, and possibly abortion and stillbirth. Between 167,000 and 967,000 cases of malaria-associated LBW occur yearly; malaria-induced LBW kills 62,000-363,000 (> 38% CFR) newborns each year. All the gaps in the burden comprise 0.4-1.7 million deaths annually, > 50% of which are due to severe malarial anemia. These malaria-induced medical problems constitute major clinical, public health, and research challenges in that they may contribute to more than double the mortality than is generally acknowledged. [References: 94]

3382.    Odeh M. The role of tumour necrosis factor-alpha in the pathogenesis of complicated falciparum malaria. [Review] [121 refs]  Cytokine.  14(1):11-8, 2001 Apr 7.


  Plasmodium falciparum malaria is the most important parasitic infection of humans and is one of the most serious health problems facing the inhabitants of developing countries. It is responsible for about 2 million deaths every year. To date there is no specific treatment for the disease apart from anti-malarials. The declining sensitivity to these drugs is a serious therapeutic problem, while no safe and effective vaccine is likely to be available for general use in the near future. There is now abundant laboratory and clinical evidence to suggest that tumour necrosis factor-alpha (TNF-alpha) plays a major role in the pathogenesis of complicated falciparum malaria. Modulation of TNF-alpha response in combination with the current anti-malarial drugs, may represent a novel approach to the treatment of the serious complications associated with the disease. Copyright 2001 Academic Press. [References: 121]


3383.    Odunukwe NN.  Tuberculosis masquerading as 'constant malaria'.  West African Journal of Medicine.  20(1):22-7, 2001 Jan-Mar.


  Four hundred adults aged 20-60 years, (200 females and 200 males) were studied. All the subjects were residing in the urban areas of Lagos, Nigeria. Thirteen percent claimed they were having "constant malaria" (> 8 times per year), 5% (20) claimed to have cough mostly during the cold period, 2.5% (10) produced mucoid sputum, 2.5% unproductive cough, 13% were AFB smear positive, 1.5% had positive chest X-ray for pulmonary Tuberculosis (PTB), 1.5% were HIV positive and 50% were mantoux positive (> 10 mm induration). All who complained of "constant malaria" were AFB positive. Malaria parasite density was lower in those who complained of "constant malaria" than those who did not complain (P = 0.003). The complaint of frequent malaria attack decreased after Antituberculosis therapy for 6 months. This study revealed that in a malaria and tuberculosis endemic region, early stage of tuberculosis can masquerade as "constant malaria". Therefore any such complaint should be fully investigated.


3384.    Okoko BJ.  Wesuperuma LH.  Ota MO.  Banya WA.  Pinder M.  Gomez FS.  Osinusi K.  Hart AC. Influence of placental malaria infection and maternal hypergammaglobulinaemia on materno-foetal transfer of measles and tetanus antibodies in a rural west African population.  Journal of Health, Population & Nutrition.  19(2):59-65, 2001 Jun.


  Placental malaria infection jeopardizes pregnancy outcome, and its influence may also impair the transplacental transfer of some antibodies. Two hundred and thirteen Gambian mother-baby pairs were studied to determine the influence of placental malaria infection and maternal hypergammaglobulinaemia on transplacental transfer of measles and tetanus antibodies in Gambian population. Placental blood and tissue were collected for placental malaria diagnosis. Cord and maternal sera were tested for total IgG concentration by laser nephelometry and for IgG antibody to tetanus toxoid and measles by ELISA. The prevalence of placental malaria infection was 51.1%. Mothers whose placentae were parasitized had a significantly higher mean total serum IgG (22.0 g/L vs 11.3 g/L, p < 0.001) and measles antibody level (4.02 IU/mL vs 1.21 IU/mL, p < 0.01), but not tetanus antibody, than mothers with non-parasitized placentae. Results of multiple regression analysis showed that placental malaria infection and maternal hypergammaglobulinaemia were associated with the reduction of 72% (95% CI 67.84) and 86% (95% CI 76.91) in transplacental transfer of measles antibody respectively but did not influence the transfer of tetanus antibody. It is concluded that the combined influence of placental malaria infection and maternal hypergammaglobulinaemia is significantly associated with the transfer of impaired measles antibody in this population.


3385.   Pestell K.  Dodgy malaria drugs. Trends in Pharmacological Sciences.  22(8):402, 2001 Aug.


3386.   Shanks GD.  Kain KC.  Keystone JS.  Malaria chemoprophylaxis in the age of drug resistance. II. Drugs that may be available in the future. [Review] [20 refs] Clinical Infectious Diseases.  33(3):381-5, 2001 Aug 1.


  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. [References: 20]


3387.   Steketee RW.  Nahlen BL.  Parise ME.  Menendez C. The burden of malaria in pregnancy in malaria-endemic areas. [Review] [70 refs] American Journal of Tropical Medicine & Hygiene.  64(1-2 Suppl):28-35, 2001 Jan-Feb.


  Pregnant women in malarious areas may experience a variety of adverse consequences from malaria infection including maternal anemia, placental accumulation of parasites, low birth weight (LBW) from prematurity and intrauterine growth retardation (IUGR), fetal parasite exposure and congenital infection, and infant mortality (IM) linked to preterm-LBW and IUGR-LBW. We reviewed studies between 1985 and 2000 and summarized the malaria population attributable risk (PAR) that accounts for both the prevalence of the risk factors in the population and the magnitude of the associated risk for anemia, LBW, and IM. Consequences from anemia and human immunodeficiency virus infection in these studies were also considered. Population attributable risks were substantial: malaria was associated with anemia (PAR range = 3-15%), LBW (8-14%), preterm-LBW (8-36%), IUGR-LBW (13-70%), and IM (3-8%). Human immunodeficiency virus was associated with anemia (PAR range = 12-14%), LBW (11-38%), and direct transmission in 20-40% of newborns, with direct mortality consequences. Maternal anemia was associated with LBW (PAR range = 7-18%), and fetal anemia was associated with increased IM (PAR not available). We estimate that each year 75,000 to 200,000 infant deaths are associated with malaria infection in pregnancy. The failure to apply known effective antimalarial interventions through antenatal programs continues to contribute substantially to infant deaths globally. [References: 70]


3388.    Sunyer J.  Mendendez C.  Ventura PJ.  Aponte JJ.  Schellenberg D.  Kahigwa E.  Acosta C.  Anto JM.  Alonso PL. Prenatal risk factors of wheezing at the age of four years in Tanzania. Thorax.  56(4):290-5, 2001 Apr.


  BACKGROUND: A study was undertaken to assess the interactions between prenatal exposures, early life infections, atopic predisposition, and allergen exposures in the development of wheezing up to the age of 4 years in a tropical region of Africa. METHODS: The study subjects comprised children born at the district hospital in Ifakara, Tanzania during a 1 year period who were participating in a trial of iron supplementation and malaria chemoprophylaxis during the first year of life and followed for up to 4 years. From this group of subjects, 658 (79%) participated in the interview at 18 months and 528 (64%) in a second interview at 4 years. Wheezing was measured with the ISAAC questionnaire. A hospital based inpatient and outpatient surveillance system was set up to document all attendance by study children for any cause, including episodes of clinical malaria and lower respiratory tract infections. Total IgE levels and malaria parasites were measured in maternal and cord blood. Total IgE was also measured at 18 months of age. Indoor environmental levels of Der p I and Fel d I were determined using an enzyme linked immunosorbent assay at the same time as the interview at the age of 18 months. RESULTS: The prevalence of wheezing at 4 years is common in Ifakara (14%, range 13-15%). The presence of malaria parasites in cord blood (odds ratio, OR = 6.84, 95% CI 1.84 to 24.0) and maternal asthma (OR = 8.47, 95% CI 2.72 to 26.2) were positively associated with wheezing at the age of 4 years, and cord blood total IgE was negatively associated (OR = 0.24, 95% CI 0.07 to 0.85) (all p<0.05). Parasitaemia at birth was not related to total IgE levels in cord blood (p=0.6). Clinical episodes of malaria during infancy were not associated with wheezing, and nor were levels of indoor aeroallergens. CONCLUSION: These findings suggest that events occurring during pregnancy may play a role in the future appearance of wheezing, although the results must be interpreted with caution because of the small numbers studied.


3389.    Taylor-Robinson A.  Parasite variation provides hope for malaria vaccine design. Trends in Microbiology.  9(4):157-8, 2001 Apr.

3390.    Temkin NR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: meta-analysis of controlled trials.  Epilepsia.  42(4):515-24, 2001 Apr.


  PURPOSE: To synthesize evidence concerning the effect of antiepileptic drugs (AEDs) for seizure prevention and to contrast their effectiveness for provoked versus unprovoked seizures. METHODS: Medline, Embase, and The Cochrane Clinical Trials Register were the primary sources of trials, but all trials found were included. Minimal requirements: seizure-prevention outcome given as fraction of cases; AED or control assigned by random or quasi-random mechanism. Single Abstracter. Aggregate relative risk and heterogeneity evaluated using Mantel-Haenszel analyses; random effects model used if heterogeneity was significant. RESULTS: Forty-seven trials evaluated seven drugs or combinations for preventing seizures associated with fever, alcohol, malaria, perinatal asphyxia, contrast media, tumors, craniotomy, and traumatic brain injury. Effective: Phenobarbital for recurrence of febrile seizures [relative risk (RR), 0.51; 95% confidence interval (CI), 0.32-0.82) and cerebral malaria (RR, 0.36; CI, 0.23-0.56). Diazepam for contrast media-associated seizures (RR, 0.10; CI, 0.01-0.79). Phenytoin for provoked seizures after craniotomy or traumatic brain injury (craniotomy: RR, 0.42; CI, 0.25-0.71; TBI: RR, 0.33; CI, 0.19-0.59). Carbamazepine for provoked seizures after traumatic brain injury (RR, 0.39; CI, 0.17-0.92). Lorazepam for alcohol-related seizures (RR, 0.12; CI, 0.04-0.40). More than 25% reduction ruled out valproate for unprovoked seizures after traumatic brain injury (RR, 1.28; CI, 0.76-2.16), and carbamazepine for unprovoked seizures after craniotomy (RR, 1.30; CI, 0.75-2.25). CONCLUSIONS: Effective or promising results predominate for provoked (acute, symptomatic) seizures. For unprovoked (epileptic) seizures, no drug has been shown to be effective, and some have had a clinically important effect ruled out.


3391.    Ulmer JB.  Tuberculosis DNA vaccines. [Review] [26 refs]  Scandinavian Journal of Infectious Diseases.  33(4):246-8, 2001.


  DNA vaccines have been the subject of intense investigation for the past 10 y, during which time several tuberculosis (TB) DNA vaccines have been shown to confer protective immunity in animal models. So far, proof of principle for priming of immune responses by a naked DNA vaccine (malaria) has been demonstrated in humans, but potency remains a significant limitation. However, new DNA vaccine formulations and delivery systems are being developed with markedly improved potency in animal models. Therefore, there is a clear path to the human clinical testing of TB DNA vaccines. [References: 26]

3392.     Virk A.  Medical advice for international travelers. [Review] [32 refs]  Mayo Clinic Proceedings.  76(8):831-40, 2001 Aug.


  Each year, approximately 30 to 40 million Americans travel outside the United States. Although the most popular destinations are Europe, Central America, and the Caribbean, travel to Africa and Asia is increasing substantially. International travel, particularly to developing countries, can be associated with the risk of infectious and noninfectious diseases. These risks can be decreased, eliminated, or modified with vaccinations, prophylactic medications, and education. Optimally, pretravel advice must be individualized to a person's medical history, itinerary, and risk behavior. In addition to risk assessment-based immunizations, issues such as traveler's diarrhea, malaria prophylaxis, sexually transmitted diseases, and management of underlying medical problems must form a part of pretravel management. Adventure or prolonged travel or persons with underlying medical diseases such as insulin-dependent diabetes mellitus, transplantation, immunodeficiencies, and dialysis warrant additional preventive measures. This review primarily updates pretravel management of adults. [References: 32]



3393.    Wheeler C.  Berkley S. Initial lessons from public-private partnerships in drug and vaccine development. Bulletin of the World Health Organization.  79(8):728-34, 2001.


  In recent years, venture capital approaches have delivered impressive results in identifying and funding promising health discoveries and bringing them to market. This success has inspired public sector experiments with "social venture capital" approaches to address the dearth of affordable treatment and prevention for diseases of the developing world. Employing the same focus on well-defined and measurable objectives, and the same type of connections to pool and deploy resources as their for-profit counterparts, social venture capitalists seek to use the tools and incentives of capitalism to solve one of its biggest failures: the lack of drugs and vaccines for diseases endemic to low-income populations. As part of a larger trend of partnerships emerging in health product donation and distribution, public-private partnerships for pharmaceutical development have led research and development (R&D) efforts to generate more accessible and efficacious products for diseases such as malaria, tuberculosis, and AIDS. In this article, three R&D-focused partnerships are explored: the International AIDS Vaccine Initiative; the Medicines for Malaria Venture; and the newly formed Global Alliance for TB Drug Development. The article highlights key elements essential to the success of these ventures.


3394.    Yeboah-Antwi K.  Gyapong JO.  Asare IK.  Barnish G.  Evans DB.  Adjei S.  Impact of prepackaging antimalarial drugs on cost to patients and compliance with treatment. Bulletin of the World Health Organization.  79(5):394-9, 2001.


  OBJECTIVE: To examine the extent to which district health teams could reduce the burden of malaria, a continuing major cause of mortality and morbidity, in a situation where severe resource constraints existed and integrated care was provided. METHODS: Antimalarial drugs were prepackaged into unit doses in an attempt to improve compliance with full courses of chemotherapy. FINDINGS: Compliance improved by approximately 20% in both adults and children. There were 50% reductions in cost to patients, waiting time at dispensaries and drug wastage at facilities. The intervention, which tended to improve both case and drug management at facilities, was well accepted by health staff and did not involve them in additional working time. CONCLUSION: The prepackaging of antimalarials at the district level offers the prospect of improved compliance and a reduction in the spread of resistance.

3395.    Zhong KJ.  Salas CJ.  Shafer R.  Gubanov A.  Gasser RA Jr.  Magill AJ.  Forney JR.  Kain KC. Comparison of IsoCode STIX and FTA Gene Guard collection matrices as whole-blood storage and processing devices for diagnosis of malaria by PCR. Journal of Clinical Microbiology.  39(3):1195-6, 2001 Mar.


  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).


3396. - 3400. No abstract 


Apr 02


  1. Alessio M. Cytoadherence of Plasmodium falciparum-infected erythrocytes is mediated by a redox-dependent conformational fraction of CD36. J Immunol  2001 Dec 1;167(11):6510-7. Abstract. The adherence of Plasmodium falciparum-infected RBC (IRBC) to postcapillary venular endothelium is an important determinant of the pathogenesis of severe malaria complications. Cytoadherence of IRBC to endothelial cells involves specific receptor/ligand interactions. The glycoprotein CD36 expressed on endothelial cells is the major receptor involved in this interaction. Treatment of CD36-expressing cells with reducing agents, such as DTT and N-acetylcysteine, was followed by CD36 conformational change monitorable by the appearance of the Mo91 mAb epitope. Only a fraction of the surface expressed CD36 molecules became Mo91 positive, suggesting the presence of two subpopulations of molecules with different sensitivities to reduction. The Mo91 epitope has been localized on a peptide (residues 260-279) of the C-terminal, cysteine-rich region of CD36. Treatment with reducing agents inhibited the CD36-dependent cytoadherence of IRBC to CD36-expressing cells and dissolved pre-existent CD36-mediated IRBC/CD36-expressing cell aggregates. CD36 reduction did not impair the functionality of CD36, since the reactivity of other anti-CD36 mAbs as well as the binding of oxidized low density lipoprotein, a CD36 ligand, were maintained. The modifications induced by reduction were reversible. After 14 h CD36 was reoxidized, the cells did not express the Mo91 epitope, and cytoadherence to IRBC was restored. The results indicate that IRBCs bind only to a redox-modulated fraction of CD36 molecules expressed on the cell surface. The present data indicate the therapeutic potential of reducing agents, such as the nontoxic drug N-acetylcysteine, to prevent or treat malaria complications due to IRBC cytoadhesion.

  2. Amaral L, Viveiros M, Kristiansen JE. Phenothiazines: potential alternatives for the management of antibiotic resistant infections of tuberculosis and malaria in developing countries. Trop Med Int Health  2001 Dec;6(12):1016-22. Abstract. The in vitro and in vivo activity of phenothiazines against antibiotic susceptible and antibiotic resistant Mycobacterium tuberculosis and malaria-causing Plasmodia is reviewed. Given the facts that pulmonary tuberculosis and malaria are the major causes of death in developing countries, that both of these infections continue to escalate in their resistance to antibiotics, that the cost for the management of these infections is beyond that afforded by most developing nations, and lastly, that new and effective agents are not forthcoming from the pharmaceutical industry, the scientific rationale for the potential use of select phenothiazines for the management of these infections is presented.

  3. Arevalo-Herrera M, Herrera S. Plasmodium  vivax malaria vaccine development. Mol Immunol  2001 Dec;38(6):443-55. Abstract. Plasmodium vivax represents the most widespread malaria parasite worldwide. Although it does not result in as high a mortality rate as P. falciparum, it inflicts debilitating morbidity and consequent economic impact in endemic communities. In addition, the relapsing behavior of this malaria parasite and the recent resistance to anti-malarials contribute to making its control more difficult. Although the biology of P. vivax is different from that of P. falciparum and the human immune response to this parasite species has been rather poorly studied, significant progress is being made to develop a P. vivax-specific vaccine based on the information and experience gained in the search for a P. falciparum vaccine. We have devoted great effort to antigenically characterize the P. vivax CS protein and to test its immunogenicity using the Aotus monkey model. Together with other groups we are also assessing the immunogenicity and protective efficacy of the asexual blood stage vaccine candidates MSP-1 and DBP in the monkey model, as well as the immunogenicity of Pvs25 and Pvs28 ookinete surface proteins. The transmission-blocking efficacy of the responses induced by these latter antigens is being assessed using Anopheles albimanus mosquitoes. The current status of these vaccine candidates and other antigens currently being studied is described.

  4. B, Gay F, Looareesuwan S. Association of splenomegaly with cerebral malaria and decreased concentrations of reactive nitrogen intermediates in Thailand. Am J Trop Med Hyg  2001 Nov;65(5):639-43. Abstract.  The role of the spleen during Plasmodium falciparum malaria in humans is unclear. In Thailand, malaria transmission is low and splenomegaly is rarer than in high transmission areas. We compared the prevalence of splenomegaly between 52 cerebral malaria patients and 191 patients without complications despite a high parasite biomass. We also measured concentrations of reactive nitrogen intermediates (RNIs) in a fraction of these cases recruited in 1998 (24 cerebral malaria and 56 controls). Splenomegaly was significantly associated with cerebral malaria (adjusted odds ratio = 2.07 [95% confidence interval = 1-4.2]; P = 0.048). There was a linear trend for this association (P = 0.0003). After adjusting for potential confounders, concentrations of RNIs were significantly lower in the presence of splenomegaly (P = 0.01). These results suggest that in humans, as in animal models, the spleen may be involved in the pathogenesis of cerebral malaria. The relationship between RNI concentrations and the spleen suggest that nitric oxide may have a regulating role in the complex physiology of the spleen during malaria.

  5. Basco LK, Ringwald P. Molecular epidemiology of malaria in Yaounde, Cameroon. VIII. Multiple Plasmodium falciparum infections in symptomatic patients. Am J Trop Med Hyg  2001 Dec;65(6):798-803. Abstract. The extent of genetically distinct parasite populations coinfecting individual human hosts (i.e., multiplicity) was studied by polymerase chain reaction amplification of 3 polymorphic genetic markers, circumsporozoite protein and merozoite surface antigens (MSA) 1 and 2, in symptomatic children and adults and analyzed in relation with age and initial parasitemia. Of the total of 177 DNA samples analyzed (of which 115 were paired pre- and posttreatment samples), 101 (57%) were composed of multiclonal infections, with up to 7 distinguishable parasite populations. Among the 3 polymorphic markers, msa-2 yielded the highest proportion of clinical isolates with multiclonal populations. Patients with multiclonal infections before treatment had, on average, 2.9 genetically distinct parasite populations. The extent of multiplicity decreased significantly (P < 0.05) in recrudescent parasites, but not with reinfections, as compared with the pretreatment samples. Neither age (5-60 years) nor initial parasitemia was correlated with multiplicity. Further studies in different epidemiological settings are required to understand the role of multiclonal Plasmodium falciparum infections in influencing malaria transmission.

  6. Bhat GP, Surolia N. In vitro antimalarial activity of extracts of three plants used in the traditional medicine of India. Am J Trop Med Hyg  2001 Oct;65(4):304-8 . Abstract. In an attempt to search for new antimalarial drugs, we studied plants used by traditional healers of southwest India to treat malaria. Aqueous and organic solvent extracts obtained from specific parts of the plants Swertia chirata, Carica papaya, and Citrus sinensis were tested on malaria strain Plasmodium falciparum FCK 2 in vitro. The temperatures of extraction were the same as that used by the traditional healers in their plant preparations. Visual evaluation of the antimalarial activity of the plant extracts on thin blood smears was followed by quantification of the activity by use of [35S]-methionine incorporation into parasite proteins to determine the value that inhibits 50% (IC50). Among the 3 plants tested, 2 had significant inhibitory effect on P. falciparum in vitro.

  7. Biswas R, Sengupta G, Mundle M: Controlled study  on haemograms of  malaria patients in Calcutta. Indian J Malar 1999, 36(1-2), 42-8. (015287) Aug 1, 2001 . Abstract. Study was carried out at the Urban Health Centre, Chetla, Calcutta to evaluate the efficacy of quantitative buffy coat (QBC) analysis of haemograms in malaria patients suffering from fever with bodyahe and chill and /or rigour attending the Fever Treatment Depot during a three months period (March-June 1996) who had undergone both malaria parasite study and haematological investigation by the QBC method, from blood samples collected finger prick. To avoid bias, malaria parasite studies and haemograms were done separately, and investigators were kept ‘blind’ about the results of other investigation. The haematological dinfings obtained of 180 slide negative malaria cases were compared with a sample of 177 age- and sex-matched slide-negative controls selected random smpling. The results revealed that haemoglobin levels (g%), haematocrit values (%)., WBC and platelet counts of malaria cases were significantly lower than in the matched controls. Thus, QBC estimation correlates well with existing knowledge about malarial haematology. This relatively easier, quicker and reliable method of taking haemograms may be recommended for filed testing for assessing haematological parameters of malaria cases under field condition, before its introduction for large-scale use.

  8. Bradbury J. Haemoglobin C protection against  malaria. Lancet  2001 Nov 17;358(9294):1702  No abstract.

  9. Brice GT, Graber NL, Hoffman SL, Doolan DL. Expression of the chemokine MIG is a sensitive and predictive marker for antigen-specific, genetically restricted IFN-gamma production and IFN-gamma-secreting cells. J Immunol Methods  2001 Nov 1;257(1-2):55-69 . Abstract. The evaluation of antigen-specific immune responses is critical for understanding the mechanisms of immune protection and for establishing the efficacy of candidate vaccines. Here, we describe a novel assay for IFN-gamma activity which is based on the flow cytometric detection of the chemokine, monokine induced by gamma interferon (MIG) as a sensitive and predictive measure of IFN-gamma-mediated effector function, and a surrogate marker for IFN-gamma-producing cells. Upregulation of MIG expression was demonstrated following in vitro activation of peripheral blood mononuclear cells (PBMCs) with defined CD8+ T-cell epitopes derived from influenza virus, cytomegalovirus (CMV), or Epstein-Barr virus (EBV) and was antigen-specific, genetically restricted and dependent on both CD8+ T cells and IFN-gamma. Furthermore, antigen-specific MIG expression was also demonstrated with Plasmodium falciparum circumsporozoite protein (CSP) peptides, using PBMCs from volunteers immunized with irradiated P. falciparum sporozoites. In multiple parallel experiments, the MIG assay was compared to conventional IFN-gamma ELISPOT, IFN-gamma ELISA, MIG ELISA and intracellular cytokine staining assays. The level of MIG expression was shown to be directly associated with the number of IFN-gamma spot-forming cells (SFCs) detected by ELISPOT (r2=0.94). Moreover, in all instances where cultures were considered positive by ELISPOT, a higher stimulation index was noted with the MIG assay as compared with the ELISPOT assay (on average at least threefold higher) and, in some cases, responses as detected by the MIG assay were significant, but the corresponding response as measured by ELISPOT was not significant. Finally, the flow-based MIG assay offers a number of practical and technical advantages over the ELISPOT assay. Our data validate this novel method for the detection of low as well as high levels of antigen-specific and genetically restricted IFN-gamma activity.

  10. Brower V. Tackling the most difficult diseases. Genetics and genomics open new strategies to fight vector-borne diseases. EMBO Rep  2001 Oct;2(10):875-7 No abstract.

  11. Bryceson A. A policy for leishmaniasis with respect to the prevention and control of drug resistance. Trop Med Int Health  2001 Nov;6(11):928-34  . Abstract. At the moment no country has a policy designed to control or prevent drug resistance in leishmaniasis. The risk of resistance is high in areas of anthroponotic visceral leishmaniasis, for example North Bihar, India, where the rate in some areas is 60%. Post-epidemic Sudan is also at risk. Zoonotic areas in which HIV co-infection is common could also be at risk as sandflies can become infected from co-infected individuals. Many factors determine the choice of drug for the treatment of visceral leishmaniasis, and drug resistance may not be the over-riding priority. In anthroponotic areas reduction in transmission through public health measures will be important, but the use of two drugs in combination should be seriously considered. Pharmacokinetic and other features of the drugs available, relevant to their use in combination are discussed and tentative suggestions made concerning trials of possible combinations. These include miltefosine plus paromomycin and allopurinol plus an azole. Lessons may be learnt from the experiences of similar problems in malaria, leprosy and tuberculosis. Guidelines are offered for the introduction of policies to use drugs in combination, which differ between anthroponotic and zoonotic areas of transmission.

  12. Burgess DC, Kain KC. The performance and utility of rapid diagnostic assays for Plasmodium falciparum malaria in a field setting in the Lao People's Democratic Republic. Ann Trop Med Parasitol  2001 Oct;95(7):671-7 . Abstract. 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.

  13. Chongsuphajaisiddhi T, White NJ. Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg  2001 Nov;65(5):614-22 . Abstract. The factors contributing to anemia in falciparum malaria were characterized in 4,007 prospectively studied patients on the western border of Thailand. Of these, 727 patients (18%) presented with anemia (haematocrit < 30%), and 1% (55 of 5,253) required blood transfusion. The following were found to be independent risk factors for anemia at admission: age < 5 years, a palpable spleen, a palpable liver, recrudescent infections, being female, a prolonged history of illness (> 2 days) before admission, and pure Plasmodium falciparum infections rather than mixed P. falciparum and Plasmodium vivax infections. The mean maximum fractional fall in hematocrit after antimalarial treatment was 14.1% of the baseline value (95% confidence interval [CI], 13.6-14.6). This reduction was significantly greater in young children (aged < 5 years) and in patients with a prolonged illness, high parasitemia, or delayed parasite clearance. Loss of parasitized erythrocytes accounted for < 10% of overall red blood cell loss. Hematological recovery was usually complete within 6 weeks, but it was slower in patients who were anemic at admission (adjusted hazards ratio [AHR], 1.9, 95% CI, 1.5-2.3), and those whose infections recrudesced (AHR, 1.2, 95% CI, 1.01-1.5). Half the patients with treatment failure were anemic at 6 weeks compared with 19% of successfully treated patients (relative risk, 2.8, 95% CI, 2.0-3.8). Patients coinfected with P. vivax (16% of the total) were 1.8 (95% CI, 1.2-2.6) times less likely to become anemic and recovered 1.3 (95% CI, 1.0-1.5) times faster than those with P. falciparum only. Anemia is related to drug resistance and treatment failure in uncomplicated malaria. Children aged < 5 years of age were more likely than older children or adults to become anemic. Coinfection with P. vivax attenuates the anemia of falciparum malaria, presumably by modifying the severity of the infection.

  14. Cian F, Declich S. HIV, malaria parasites, and acute febrile episodes in Ugandan adults: a case-control study. AIDS  2001 Dec 7;15(18):2445-50. Abstract. BACKGROUND: In sub-Saharan Africa, co-infection with HIV and malaria is probably very common. Although an interaction between the two infections is biologically plausible, it has not been investigated thoroughly. OBJECTIVES: To evaluate the association firstly between co-infection with HIV and malaria parasites and the occurrence of acute fever, and secondly between HIV infection and clinical malaria, defined as the presence of acute fever and malaria parasites. METHODS: A hospital-based case-control study was conducted in Gulu District (northern Uganda), an area endemic for malaria and with a high HIV prevalence. HIV testing and malaria parasite quantification were performed on 167 consecutive adult out-patients with acute fever and no signs or symptoms of localized infection, and on 134 consecutive adult in-patients without fever who were admitted for non-HIV-related trauma or elective surgery. RESULTS: No significant association with acute fever was observed for single infection with either malaria parasites [adjusted odds ratio (AOR), 1.75; 95% confidence interval (CI), 0.73 4.21] or HIV (AOR, 1.01; 95% CI, 0.51-2.03), whereas a significant association was observed for co-infection (AOR, 9.75; 95% CI, 1.19 80.00). An association was found between HIV infection and clinical malaria (AOR, 2.34; 95% CI, 0.89-6.17); the association became statistically significant when the definition of clinical malaria included a cut-off for parasite density (50th percentile; i.e., 586 parasites/microl; AOR, 3.61; 95% CI, 1.04-12.52). CONCLUSIONS: Despite the limited statistical power, the results of our study show an association between HIV infection and clinical malaria; if confirmed, this finding could be important for public health in sub-Saharan Africa.

  15. Corbellino M. Subacute malaria due to Plasmodium falciparum and the role of polymerase chain reaction. Clin Infect Dis  2001 Nov 1;33(9):1614-5  No abstract.

  16. Cunha MG, Rodrigues MM, Soares IS. Comparison of the immunogenic properties of recombinant proteins representing the Plasmodium vivax vaccine candidate MSP1(19) expressed in distinct bacterial vectors. Vaccine  2001 Nov 12;20(3-4):385-96 . Abstract. The 19kDa C-terminal region of the merozoite surface protein 1 (MSP1(19)) is one of the most promising vaccine candidates against the erythrocytic forms of malaria. In the present study, we used three different Escherichia coli expression vectors to generate five recombinant proteins representing the MSP1(19) of Plasmodium vivax. These proteins were compared for reactivity with a panel of sera from individuals naturally exposed to P. vivax and for their immunogenicity in mice. Among the proteins studied, MSP1(19) expressed by the vector pET (His(6)-MSP1(19)) was better recognized by the antibodies of several individuals exposed to P. vivax. The addition of the T-cell Pan-allelic DR epitope (PADRE) did not alter the recognition of this recombinant protein by human antibodies. Although recombinant proteins were immunogenic to mice, immunization with MSP1(19) expressed by the pET or pGEX vectors induced significantly higher antibody titers than a protein produced by the pMAL vector. The antibody immune response elicited by His(6)-MSP1(19) containing the PADRE epitope was compared using different adjuvant formulations. After only two immunizing doses, antibody titers induced in the presence of the adjuvants TiterMax, MPL/TDM/CWS or alum plus CpG ODN 1826 were as high as titers generated by complete Freund's adjuvant. We concluded that, among the bacterial recombinant proteins, MSP1(19) expressed by the vector pET should be selected for further evaluation in pre-clinical immunizations against P. vivax.

  17. D'Alessandro U, Buttiens H. History and importance of antimalarial drug resistance. Trop Med Int Health  2001 Nov;6(11):845-8 . Abstract. The emergence of Plasmodium falciparum resistance to widely used antimalarial drugs such as chloroquine (CQ) has made malaria control and treatment much more difficult. This is particularly dramatic for Africa, as few affordable alternatives are available. Drug pressure has been identified as one of the key factors for the emergence and spread of resistance. The contribution of the extensive use and misuse of antimalarial drugs to the selection of resistant parasites became particularly evident during the Global Malaria Eradication campaign, launched by World Health Organization (WHO) in 1955. The first reports confirming P. falciparum resistance to CQ came almost simultaneously in the early 1960s from South America and South-East Asia, where direct or indirect (through use of medicated cooking salt) mass drug administration (MDA) had been implemented. Similar approaches were very limited in Africa, where P. falciparum resistance to CQ was first reported from the eastern region in the late 1970s and spread progressively west. Most African countries still rely heavily on CQ as first-line treatment despite various levels of resistance, although some states have changed to sulphadoxine-pyrimethamine (SP) as the first-line drug. Unfortunately, the predicted SP useful therapeutic life might be very short, probably because of its prolonged half-life, causing a higher probability of selecting resistant strains and a consequent fast development of resistance. CQ resistance is not evenly distributed and important differences can be found within and between countries. It seems to have spread more rapidly in East than in West Africa. Considering the high level of CQ use in West Africa, other factors such as intensity of transmission, population immunity or population movements should be considered when explaining the different levels of resistance. Understanding such factors may help us in devising strategies to contain the spread of drug resistance.

  18. Foca A, Matera G, Barreca GS, Gagliardi F, Apuzzo G, Guaglianone L. Imported malaria in pregnancy due to Plasmodium falciparum. J Travel Med  2001 Nov-Dec;8(6):331-2 No abstract.

  19. Goodman CA, Coleman PG, Mills AJ. Changing the first line drug for malaria treatment--cost-effectiveness analysis with highly uncertain inter-temporal trade-offs. Health Econ  2001 Dec;10(8):731-49 . Abstract. Access to effective treatment would substantially reduce the burden of malaria in sub-Saharan Africa, but resistance to chloroquine, the most commonly used first line drug, is now widespread. There has been considerable debate over the level of chloroquine resistance at which a new first line drug should be adopted. Two issues make this an extremely complex decision: it involves trade-offs in costs and health outcomes over time; and many of the parameters are uncertain. A modelling approach was identified as appropriate for addressing these issues. The costs and effects of changing from chloroquine to sulphadoxine-pyrimethamine (SP) as the first line drug were modelled over 10 years, allowing for growth in drug resistance. Probabilistic sensitivity analysis was used to allow for the high levels of parameter uncertainty. The optimal year of switch was highly dependent on both empirical values, such as initial resistance and resistance growth rates, and on subjective values, such as the time preferences of policy-makers. It was not possible to provide policy-makers with a definitive threshold resistance level at which to switch, but the model can be used as an analytical tool to structure the problem, explore trade-offs, and identify areas for which data are lacking. Copyright 2001 John Wiley & Sons, Ltd.

  20. Gupta D, Chugh K, Sachdev A, Soni A. ICU management of  severe malaria. Indian J Pediatr  2001 Nov;68(11):1057-61 . Abstract. Malaria is very common in India. First step in management of malaria is to establish the diagnosis. It is established by using traditional smear or method like dipstick antigen captures assay which is simpler, accurate and doesn't require expertise. Next step is to look for signs and symptoms, which help cases of severe malaria should be admitted in intensive care unit (ICU) and antimalarial chemotherapy should be started through parenteral route. Complications like coma, anemia, renal failure, pulmonary edema, disseminated intravascular coagulation are not very uncommon. These complications should be anticipated and treated in time. There is no role of corticosteroids, mannitol in the treatment of cerebral edema. Therapeutic monitoring of severe malaria should involve quantitative estimation of parasite load.

  21. Haldar K, Samuel BU, Mohandas N, Harrison T, Hiller NL. Transport mechanisms in Plasmodium-infected erythrocytes: lipid rafts and a tubovesicular network. Int J Parasitol  2001 Oct;31(12):1393-401 . Abstract. The mature human erythrocyte is a simple cell that is devoid of intracellular organelles and does not show endocytic or phagocytic activity at the plasma membrane. However, following infection by Plasmodium, the erythrocyte undergoes several morphological and functional changes. Parasite-derived proteins are exported into the erythrocyte cytoplasm and to the membrane, while several proteins are localised to the parasitophorous vacuolar membrane and to the tubovesicular membranous network structures surrounding the parasite. Recent evidence indicates that multiple host proteins, independent of the type of their membrane anchor, that exist in detergent-resistant membrane (DRM) rafts or microdomains enter this apicomplexan vacuole. The internalised host components along with the parasite-encoded transmembrane protein PfEXP1 can be detected as DRM rafts in the vacuole. It appears that in Plasmodium-infected erythrocytes lipid rafts may play a role in endovacuolation and macromolecular transport.

  22. Hemingway J. Identification of a novel class of insect glutathione S-transferases involved in resistance to DDT in the malaria vector Anopheles gambiae. Biochem J  2001 Oct 15;359(Pt 2):295-304 . Abstract. The sequence and cytological location of five Anopheles gambiae glutathione S-transferase (GST) genes are described. Three of these genes, aggst1-8, aggst1-9 and aggst1-10, belong to the insect class I family and are located on chromosome 2R, in close proximity to previously described members of this gene family. The remaining two genes, aggst3-1 and aggst3-2, have a low sequence similarity to either of the two previously recognized classes of insect GSTs and this prompted a re-evaluation of the classification of insect GST enzymes. We provide evidence for seven possible classes of insect protein with GST-like subunits. Four of these contain sequences with significant similarities to mammalian GSTs. The largest novel insect GST class, class III, contains functional GST enzymes including two of the A. gambiae GSTs described in this report and GSTs from Drosophila melanogaster, Musca domestica, Manduca sexta and Plutella xylostella. The genes encoding the class III GST of A. gambiae map to a region of the genome on chromosome 3R that contains a major DDT [1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane] resistance gene, suggesting that this gene family is involved in GST-based resistance in this important malaria vector. In further support of their role in resistance, we show that the mRNA levels of aggst3-2 are approx. 5-fold higher in a DDT resistant strain than in the susceptible strain and demonstrate that recombinant AgGST3-2 has very high DDT dehydrochlorinase activity.

  23. Kaushik A, Gahlot S, Kaushik  S, Verma B L. Rapid manual test for falciparum malaria. Indian Pediat 2001, 38(6), 650-4. (017313).1 Sept 2001. No abstract.

  24. Kawamoto F. Detection of Plasmodium ovale by the ICT malaria P.f/P.v. immunochromatographic test. Acta Trop  2001 Dec 21;80(3):283-4  No abstract.

  25. Kirk K.  Malaria. A voracious creature. Lancet  2001 Dec;358 Suppl:S41 No abstract.

  26. Krettli AU, Andrade-Neto VF, Brandao MG, Ferrari WM. The search for new antimalarial drugs from plants used to treat fever and malaria or plants ramdomly selected: a review. Mem Inst Oswaldo Cruz  2001 Nov;96(8):1033-42 . Abstract. In this review we discuss the ongoing situation of human malaria in the Brazilian Amazon, where it is endemic causing over 610,000 new acute cases yearly, a number which is on the increase. This is partly a result of drug resistant parasites and new antimalarial drugs are urgently needed. The approaches we have used in the search of new drugs during decades are now reviewed and include ethnopharmocology, plants randomly selected, extracts or isolated substances from plants shown to be active against the blood stage parasites in our previous studies. Emphasis is given on the medicinal plant Bidens pilosa, proven to be active against the parasite blood stages in tests using freshly prepared plant extracts. The anti-sporozoite activity of one plant used in the Brazilian endemic area to prevent malaria is also described, the so called "Indian beer" (Ampelozizyphus amazonicus, Rhamnaceae). Freshly prepared extracts from the roots of this plant were totally inactive against blood stage parasites, but active against sporozoites of Plasmodium gallinaceum or the primary exoerythrocytic stages reducing tissue parasitism in inoculated chickens. This result will be of practical importance if confirmed in mammalian malaria. Problems and perspectives in the search for antimalarial drugs are discussed as well as the toxicological and clinical trials to validate some of the active plants for public health use in Brazil.

  27. L, Sergheraert C, Grellier P, Schirmer RH, Becker K. A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline. J Med Chem  2001 Nov 22;44(24):4268-76 . Abstract. Glutathione (GSH), which is known to guard Plasmodium falciparum from oxidative damage, may have an additional protective role by promoting heme catabolism. An elevation of GSH content in parasites leads to increased resistance to chloroquine (CQ), while GSH depletion in resistant P. falciparum strains is expected to restore the sensitivity to CQ. High intracellular GSH levels depend inter alia on the efficient reduction of GSSG by glutathione reductase (GR). On the basis of this hypothesis, we have developed a new strategy for overcoming glutathione-dependent 4-aminoquinoline resistance. To direct both a 4-aminoquinoline and a GR inhibitor to the parasite, double-drugs were designed and synthesized. Quinoline-based alcohols (with known antimalarial activity) were combined with a GR inhibitor via a metabolically labile ester bond to give double-headed prodrugs. The biochemically most active double-drug 7 of this series was then evaluated as a growth inhibitor against six Plasmodium falciparum strains that differed in their degree of resistance to CQ; the ED(50) values for CQ ranged from 14 to 183 nM. While the inhibitory activity of the original 4-aminoquinoline-based alcohol followed that of CQ in these tests, the double-drug exhibited similar efficiency against all strains, the ED(50) being as low as 28 nM. For the ester 7, a dose-dependent decrease in glutathione content and GR activity and an increase in glutathione-S-transferase activity were determined in treated parasites. The drug was subsequently tested for its antimalarial action in vivo using murine malaria models infected with P. berghei. A 178% excess mean survival time was determined for the animals treated with 40 mg/kg 7 for 4 days. No cytotoxicity due to this compound was observed. Work is in progress to extend and validate the strategy outlined here.

  28. Leke RG. The state of immunology in Africa: HIV/AIDS and malaria. Curr Opin Immunol  2001 Oct;13(5):523-7 . Abstract. HIV and malaria are two major infections that are responsible for the greatest burden of diseases, morbidity and mortality in the African population. Successful research has been undertaken in Africa into novel means of monitoring HIV disease progression and in identifying vaccine candidates. The role of IgG isotypes in malaria has been investigated, as have parasite adhesion molecules important for pathogenesis. It is hoped that vaccines for malaria will soon prove successful. However, many problems still face immunology research in Africa.

  29. Mayxay M, Chotivanich K, Pukrittayakamee S, Newton P, Looareesuwan S, White NJ. Contribution of humoral immunity to the therapeutic response in falciparum malaria. Am J Trop Med Hyg  2001 Dec;65(6):918-23 . Abstract. The contribution of humoral immunity to the therapeutic response in acute falciparum malaria was assessed in a case-control study. Forty adult Thai patients with acute falciparum malaria who had subsequent recrudescent infections and 40 patients matched for age, therapeutic regimen, and disease severity who were cured by Day 28 were studied. All cured patients had positive immunoglobulin (Ig) G to ring-infected erythrocyte surface antigen (RESA) in their admission plasma, compared with only 60% of patients who failed to respond to treatment (P < 0.001). The proportion of IgM-positive cases at admission was also higher in the successfully treated group than in the group with failure (70% versus 30%) (P < 0.001). The geometric mean (95% confidence interval) reciprocal IgG titer at admission was significantly higher in cured patients (187.0 [83.5-418.3]) compared with those who experienced treatment failure (11.6 [5.1-26.5]) (P < 0.001). The patients with uncomplicated malaria who were both IgG and IgM positive at admission had significantly shorter fever clearance times and lower admission parasitemia levels compared with those who were negative (P = 0.01 and P = 0.02, respectively). The median (range) in vitro parasite multiplication rate was significantly lower in cultures containing positive anti-RESA antibody plasma compared with those containing normal plasma (0.7 [0.1-3.5] versus 2.6 [0.1-12.1]; P < 0.001). These results suggest that antimalarial antibodies may play an important supportive role in the therapeutic response to antimalarial drugs during acute falciparum malaria.

  30. Merten M, Thiagarajan P. Role for sulfatides  in platelet aggregation. Circulation  2001 Dec 11;104(24):2955-60 . Abstract. BACKGROUND: Sulfatides are sulfated glycosphingolipids present on the surface of oligodendrocytes, renal tubular cells, and certain tumor cells. They appear to be involved in nerve conduction and cell adhesion, but their precise physiological function is not known. METHODS AND RESULTS: Here, we show a novel role for sulfatides as a major ligand for P-selectin in platelet adhesion and aggregation. Sulfatides are expressed on the platelet surface, and platelets expressing sulfatides adhere to P-selectin. Both sulfatide micelles and sulfatide-binding recombinant malaria circumsporozoite protein (MCSP) inhibit this adhesion. In parallel, platelets and CHO cells expressing P-selectin adhere to sulfatides, and anti-P-selectin antibodies inhibit this adhesion. Furthermore, both anti-P-selectin antibodies and sulfatide antagonist MCSP significantly reverse platelet aggregation induced by ADP, collagen, or thrombin receptor-activating peptide, suggesting that sulfatide-P-selectin interactions are necessary for the formation of stable platelet aggregates. CONCLUSIONS: These results show that sulfatide interactions with P-selectin are important in platelet adhesion and platelet aggregation. The sulfatide interactions with P-selectin stabilize platelet aggregates, representing a new mechanism of platelet aggregation that may play a significant role in hemostasis and thrombosis.

  31. Modiano D. Antimalarial  antibody levels and IL4 polymorphism in the Fulani of West Africa. Genes Immun  2001 Nov;2(7):411-4 . Abstract. The Fulani are less clinically susceptible and more immunologically responsive to malaria than neighbouring ethnic groups. Here we report that anti-malarial antibody levels show a wide distribution amongst the Fulani themselves, raising the possibility that quantitative analysis within the Fulani may be an efficient way of screening for important genetic factors. The Th2 cytokine interleukin-4 is an obvious candidate: in Fulani, the IL4-524 T allele is at high frequency and is associated with elevated antibody levels against malaria antigens. These data highlight the possibility of combining inter- and intra-ethnic comparisons to characterize critical determinants of malarial immunity in a natural setting.

  32. Nacer A, Berry L, Slomianny C, Mattei D. Plasmodium falciparum signal sequences: simply sequences or special signals? Int J Parasitol  2001 Oct;31(12):1371-9 . Abstract. The malaria parasite, Plasmodium falciparum, synthesises and exports several proteins inducing morphological and biochemical modifications of erythrocytes during the erythrocytic cycle. The protein trafficking machinery of the parasite is similar to that of other eukaryotic cells in several ways. However, some unusual features are also observed. The secretion of various polypeptides was inhibited when P. falciparum infected erythrocytes were incubated with Brefeldin A. Immunoelectron microscopy studies revealed substantial morphological changes in the endoplasmic reticulum following exposure of parasitised erythrocytes to the drug. Immunofluorescence studies of Brefeldin A-treated parasites suggest that polypeptide sorting to different intracellular destinations begins at the endoplasmic reticulum. The parasite also secretes polypeptides by a Brefeldin A-insensitive route that bypasses the classical endoplasmic reticulum-Golgi complex pathway.

  33. Oguariri RM, Borrmann S, Klinkert MQ, Kremsner PG, Kun JF. High prevalence of human antibodies to recombinant Duffy binding-like alpha domains of the Plasmodium falciparum-infected erythrocyte membrane protein 1 in semi-immune adults compared to that in nonimmune children. Infect Immun  2001 Dec;69(12):7603-9 . Abstract. We used a panel of nine fusion proteins that contain different Duffy binding-like alpha (DBL-alpha) domains of Plasmodium falciparum infected erythrocyte membrane protein 1 to assess the levels of antibody activity in serum samples obtained from semi-immune or nonimmune individuals from Lambarene, Gabon. Recognition was measured in terms of either the prevalence or the magnitude of the response. A strong correlation between the immune status of the patients and reactivity with recombinant proteins was observed, which was interpreted as a reflection of the number of infections acquired over time. The antibody responses were predominantly directed toward variable epitopes of the DBL-alpha domain. Antibody responses could be reduced by preincubation of the sera with various fusion proteins. A portion of individuals who exhibited high-level responses to all fusion proteins also had antibodies which recognized conserved epitopes. The possibility that a synergizing effect of anti-DBL-alpha domain antibodies could support chemotherapy is discussed.

  34. Okech BA, Nalunkuma A, Okello D, Pang XL, Suzue K, Li J, Horii T, Egwang TG. Natural human immunoglobulin G subclass responses to Plasmodium falciparum serine repeat antigen in Uganda. Am J Trop Med Hyg  2001 Dec;65(6):912-7 . Abstract. Serum samples from Ugandan residents of a malaria-hyperendemic region were tested by enzyme-linked immunosorbent assay for reactivity against recombinant constructs of the 47 (SE47')- and 50 (SE50A)-kDa fragments of Plasmodium falciparum serine repeat antigen (SERA). Immunoglobulin (Ig) G3 and IgG1 were the predominant subclass responses to SE47' and SE50A, respectively. The geometric mean optical density (OD) for IgG3 anti-SE47' was significantly lower in children < 15 years compared with adults > or = 15 years (P < 0.0001). By contrast, the geometric mean IgG1 anti-SE50A was slightly higher in children compared with adults (P < 0.01). The proportion of high responders (ODs > 0.5) to SE47' was significantly lower in children compared with adults (P < 0.001), whereas the proportion of high responders to SE50A was comparable in children and adults (P = 0.07). This first detailed study of SERA in a malaria-hyperendemic region suggests that natural human IgG3 anti-SE47' might be associated with immunity to malaria.

  35. Olliaro P, Taylor WR, Rigal J. Controlling malaria: challenges and solutions. Trop Med Int Health  2001 Nov;6(11):922-7. . Abstract. Antimalarial drug resistance is a major public health challenge and the principal reason for the erosion of efficacious treatments. Cost and the limited number of antimalarial drugs in current use impose considerable constraints on malaria control, especially in sub-Saharan Africa. The paper describes a multilateral, multidisciplinary research project on artemisinin-based combination therapy, which offers a new and potentially highly effective way to prevent or retard the development of drug resistance.

  36. Ouellette M. Biochemical and molecular mechanisms of drug  resistance in parasites. Trop Med Int Health  2001 Nov;6(11):874-82 . Abstract.  Drug resistance is complicating the treatment of parasitic diseases. We review here the basic mechanisms of parasite resistance in malaria, sleeping sickness, leishmaniasis and common helminthiases. Parasites resort to multiple biochemical means to achieve resistance and we have begun to isolate and characterize the genes/proteins implicated in resistance. Understanding drug resistance is essential for the control of parasitic diseases.

  37. Pennisi E. Genes and disease. Genetic change wards off malaria. Science  2001 Nov 16;294(5546):1439  No abstract.

  38. Pinder M, Hill AV, Plebanski M.  Unique T cell effector functions elicited by Plasmodium falciparum epitopes in malaria-exposed Africans tested by three T cell assays. J Immunol  2001 Oct 15;167(8):4729-37 . Abstract. Natural immunity to malaria is characterized by low level CD4 T cell reactivity detected by either lymphoproliferation or IFN-gamma secretion. Here we show a doubling in the detection rate of responders to the carboxyl terminus of circumsporozoite protein (CS) of Plasmodium falciparum by employing three T cell assays simultaneously: rapid IFN-gamma secretion (ex vivo ELISPOT), IFN-gamma secretion after reactivation of memory T cells and expansion in vitro (cultured ELISPOT), and lymphoproliferation. Remarkably, for no individual peptide did a positive response for one T cell effector function correlate with any other. Thus these CS epitopes elicited unique T cell response patterns in malaria-exposed donors. Novel or important epitope responses may therefore be missed if only one T cell assay is employed. A borderline correlation was found between anti-CS Ab levels and proliferative responses, but no correlation was found with ex vivo or cultured IFN-gamma responses. This suggested that the proliferating population, but not the IFN-gamma-secreting cells, contained cells that provide help for Ab production. The data suggest that natural immunity to malaria is a complex function of T cell subgroups with different effector functions and has important implications for future studies of natural T cell immunity.

  39. Rajagopal  V, Appavoon N C, Sarangapani T D, Mani S: Comparative study on microscopic detection of malaria parasites under conventional thick film and concentration by saponin haemolysis.Indian J Malar 1999, 36(1-2), 49-51. (015249), Aug 1, 2023 No abstract.

  40. Rajesh Kumar: Study of consequences of malaria among sicklers. Proc Indian Sci Congr Ass- Pt II, Sect- II 1999, 28-9. (016449). Aug 16, 2001. . Abstract. Except tribals and African black people, other population group also possesses the gene of Sickle Cell. In other words the genes of Sickle Cell transmitting from one population group to other or its occurrence by mutation is still continue due to its selective advantages. It provides protection against the severe consequences of Malaria. Indian continent and its people are sensitive in connection with Malaria as well as Sickle Cell gene. Madhya Pradesh Statw and Mandla district is heart place of the country. 43 percent people of Mehra (Jharia) caste fo Mandla district possess sickle cell gene, frequency of genes (Sickle Cell gene) is 0.2450 in this population. It is concluded from the investigation that 44.18 percent Sicklers and 47.37 percent normal individuals are affected by the malarial parasite before the recent year, either once or twice. The Sicklers (23.25 per cent ) more affected once in last one year, as compared to normal individuals (17.54 percent). The percentage of never affected  individuals found more among normal individuals (17.54 per cent) as compared to Sicklers (9.30 percent). The investigation shows that there are not any selective advantages for Sicklers against the parasite of Plasmodium malarialii, plasmodium ovale and plasmodium vivex but they hardly suffer from plasmodium falsiparum.

  41. Rhee MS, Akanmori BD, Waterfall M, Riley EM. Changes in cytokine production associated with acquired immunity to Plasmodium falciparum malaria. Clin Exp Immunol  2001 Dec;126(3):503-10 . Abstract. Individuals living in malaria-endemic areas eventually develop clinical immunity to Plasmodium falciparum. That is, they are able to limit blood parasite densities to extremely low levels and fail to show symptoms of infection. As the clinical symptoms of malaria infection are mediated in part by pro-inflammatory cytokines it is not clear whether the acquisition of clinical immunity is due simply to the development of antiparasitic mechanisms or whether the ability to regulate inflammatory cytokine production is also involved. We hypothesize that there is a correlation between risk of developing clinical malaria and the tendency to produce high levels of proinflammatory cytokines in response to malaria infection. In order to test this hypothesis, we have compared the ability of peripheral blood mononuclear cells from malaria-naive and malaria-exposed adult donors to proliferate and to secrete IFN-gamma in response to P. falciparum schizont extract (PfSE). In order to determine how PfSE-induced IFN-gamma production is regulated, we have also measured production of IL-12p40 and IL-10 from PfSE-stimulated PBMC and investigated the role of neutralizing antibody to IL-12 in modulating IFN-gamma production. We find that cells from naive donors produce moderate amounts of IFN-gamma in response to PfSE and that IFN-gamma production is strongly IL-12 dependent. Cells from malaria-exposed donors living in an area of low malaria endemicity produce much higher levels of IFN-gamma and this response is also at least partially IL-12 dependent. In complete contrast, cells from donors living in an area of very high endemicity produce minimal amounts of IFN-gamma. No significant differences were detected between the groups in IL-10 production, suggesting that this cytokine does not play a major role in regulating malaria-induced IFN-gamma production. The data from this study thus strongly support the hypothesis that down-regulation of inflammatory cytokine production may be a component of acquired clinical immunity to malaria but the mechanism by which this is achieved remains to be elucidated.

  42. Rowe AK, Onikpo F, Lama M, Cokou F, Deming MS. Management of childhood illness at health facilities in Benin: problems and their causes. Am J Public Health  2001 Oct;91(10):1625-35 . Abstract. OBJECTIVES: To prepare for the implementation of Integrated Management of Childhood Illness (IMCI) in Benin, we studied the management of ill children younger than 5 years at outpatient health facilities. METHODS: We observed a representative sample of consultations; after each consultation, we interviewed caregivers and reexamined children. Health workers' performance was evaluated against IMCI guidelines. To identify determinants of performance, statistical modeling was performed and 6 focus groups with health workers were conducted to solicit their opinions. RESULTS: Altogether, 584 children were enrolled and 101 health workers were observed; 130 health workers participated in focus group discussions. Many serious deficiencies were found: incomplete assessment of children's signs and symptoms, incorrect diagnosis and treatment of potentially life-threatening illnesses, inappropriate prescription of dangerous sedatives, missed opportunities to vaccinate, and failure to refer severely ill children for hospitalization. Quantitative and qualitative analyses showed various health facility-, health worker-, caregiver-, and child-related factors as possible determinants of health worker performance. CONCLUSIONS: Action is urgently needed. Our results suggest that to improve health care delivery, interventions should target both the health system and the community level.

  43. Rubio JM, Berzosa PJ, Benito A. Amplified fragment length polymorphism (AFLP) protocol for genotyping the malarial parasite Plasmodium falciparum. Parasitology  2001 Oct;123(Pt 4):331-6 . Abstract. We have established an amplified fragment length polymorphism (AFLP) protocol for identifying anonymous polymorphic loci of the malarial parasite, Plasmodium falciparum. The method consists of the following steps (i) digestion and ligation in one reaction; (ii) selective fluorescence forward primers labelled; (iii) PCR products resolved in polyacrylamide gels using the ABIPRISM 377 XL DNA sequencer and, (iv) the use of Genescan software to size the fragments. This standardized protocol distinguished between 2 standard reference clones of P. falciparum from West African and Southeast Asian and 2 Central African isolates from patients with clinical malaria. The AFLP protocol resulted in evenly distributed and reproducible band patterns for amplified fragments ranking from 163 to 489 bp long +/-0.5 S.D. The primer Tru ACA labelled with the phosphoramidite 6-carboxifluorescein (FAM-blue) was easy to interpret, with a maximum of 53 bands per clone and of 81 per isolate (mixed falciparum populations) whereas the primer Tru AG labelled with the hexachlorinated analogue (HEX-green) showed a less clear pattern of bands and reproducibility than Tru ACA.

  44. Saito-Ito A, Akai Y, He S, Kimura M, Kawabata M. A rapid, simple and sensitive flow cytometric system for detection of Plasmodium falciparum. Parasitol Int  2001 Nov;50(4):249-57 . Abstract. We have established a rapid, simple and sensitive flow cytometric system for the detection of Plasmodium falciparum that involves lysing erythrocytes and staining parasites at the same time using a newly developed hemolysing and staining solution containing dodecyl methyl ammonium chloride and acridine orange. In this system, freed parasites of P. falciparum could be plotted separately from erythrocyte ghosts, white blood cells and platelets on the two-dimensional scattergram of forward-angle light scatter and green fluorescence by flow cytometry with an argon laser. It took only 2-3 min per sample to obtain the scattergram and analyze the data, including the time of sample preparation for flow cytometric analysis. Sample preparation with this method does not require any difficult handling procedures. The threshold of parasite detection was almost equal to that of microscopic examination for cultured P. falciparum. The results of drug-susceptibility assays using this system were also almost identical to those obtained using microscopic examination. In this system, parasites at different erythrocytic stages could be easily distinguished. This system must prove useful and practical for basic laboratory studies of P. falciparum including those requiring the differential measurement of parasites at specific erythrocytic stages.

  45. Senior K. "Imperfect" vaccines may encourage more potent pathogens, model suggests. Lancet  2001 Dec 15;358(9298):2055  No abstract.

  46. Snounou G. Association of genetic mutations in Plasmodium vivax dhfr with resistance to sulfadoxine-pyrimethamine: geographical and clinical correlates. Antimicrob Agents Chemother  2001 Nov;45(11):3122-7 . Abstract. Mutations in the Plasmodium falciparum gene (dhfr) encoding dihydrofolate reductase are associated with resistance to antifols. Plasmodium vivax, the more prevalent malaria parasite in Asia and the Americas, is considered antifol resistant. Functional polymorphisms in the dhfr gene of P. vivax (pvdhfr) were assessed by PCR-restriction fragment length polymorphism using blood samples taken from 125 patients with acute vivax malaria from three widely separated locations, Thailand (n = 100), India (n = 16), and Madagascar and the Comoros Islands (n = 9). Upon evaluation of the three important codons (encoding residues 57, 58, and 117) of P. vivax dhfr (pvdhfr), double- or triple-mutation genotypes were found in all but one case from Thailand (99%), in only three cases from India (19%) and in no cases from Madagascar or the Comoros Islands (P < 0.0001). The dhfr PCR products of P. vivax from 32 Thai patients treated with the antifolate sulfadoxine-pyrimethamine (S-P) were investigated. All samples showed either double (53%) or triple (47%) mutations. Following treatment, 34% of the patients had early treatment failures and only 10 (31%) of the patients cleared their parasitemias for 28 days. There were no significant differences in cure rates, but parasite reduction ratios at 48 h were significantly lower for patients whose samples showed triple mutations than for those whose samples showed double mutations (P = 0.01). The three mutations at the pvdhfr codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in P. vivax. These mutations presumably arose from selection pressure.

  47. Tarimo DS, Minjas JN, Bygbjerg IC. Perception of chloroquine efficacy and alternative treatments for uncomplicated malaria in children in a holoendemic area of Tanzania: implications for the change of treatment policy. Trop Med Int Health  2001 Dec;6(12):992-7 . Abstract. Prior to policy change from chloroquine (CQ) to sulphadoxine/pyrimethamine (S/P; Fansidar) we assessed the perception of CQ efficacy and the alternative treatment options for malaria in children among parents/guardians (N=527) of under-fives attending first level health facilities on account of fever. It was hypothesized that the long experience with CQ and its antipyretic effect (lacking in S/P) might impede acceptance of S/P for wider use as first-line drug. Malarial fevers in children were most commonly treated with CQ (92.8%), followed by quinine (60.7%) and S/P (28.7%). A 63.2% knew the reasons for non-response to antimalarial treatment, and only 50% were aware that CQ could fail to treat malaria, and 57.1% knew alternative treatment options, namely quinine (52.2%) and S/P (20.5%). Generally, decreased efficacy of CQ had been noticed, and quinine was prescribed for both suspected and proven CQ failures in first level health facilities and the district hospital. S/P was judged to be more effective than quinine, but too strong for children, and was the least known drug in the study area. All formulations of S/P cost more per dose for a child and an adult than CQ. The implications of these findings on the change of malaria treatment policy are discussed.

  48. Tjitra E, Suprianto S, Currie BJ, Morris PS, Saunders JR, Anstey NM. Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia. Am J Trop Med Hyg  2001 Oct;65(4):309-17 . Abstract. Combining artesunate with existing antimalarial drugs may improve cure rates, delay emergence of resistance, and reduce transmission. We performed a randomized comparative trial to quantify the effect of adding artesunate to sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria in Indonesia. Using a modified 1997 World Health Organization protocol for assessment of therapeutic efficacy of antimalarial drugs, 105 patients (stratified by age/ethnic group) were randomized: 53 received artesunate orally, 4 mg/kg of body weight, a single daily dose for three days, plus sulfadoxine pyrimethamine orally (1.25 mg of pyrimethamine/kg of body weight), a single dose on day 0, and 52 patients received sulfadoxine-pyrimethamine alone. Six from the combination group were withdrawn from analysis, as were six of the sulfadoxine-pyrimethamine group. Treatment failure rates on day 14 were 0% in the artesunate plus sulfadoxine-pyrimethamine group and 8.7% in the sulfadoxine-pyrimethamine group (P = 0.12). Treatment failure rates on day 28 were 4.4% and 15.2%, respectively (P = 0.16). Relative risk of treatment failure at 28 days was 0.3 (95% confidence interval [CI] = 0.1-1.3). Mean fever clearance time (1.3 versus 1.7 days) and mean parasite clearance time (1.4 versus 2.0 days) were both faster in the artesunate plus sulfadoxine-pyrimethamine group than in the sulfadoxine-pyrimethamine group (P = 0.08 and P < 0.0001, respectively). Only 20 (39.2%) of 51 patients treated with artesunate plus sulfadoxine-pyrimethamine were still parasitemic on day 1 compared with 45 (86.5%) of 52 patients treated with sulfadoxine-pyrimethamine alone (P = 0.000001, relative risk [RR] = 0.4, 95% CI = 0.3-0.6). Gametocyte carriage was lower following artesunate plus sulfadoxine-pyrimethamine than following sulfadoxine-pyrimethamine (RR = 0.5, 95% CI = 0.2-1.0 on day 7 and RR = 0.5, 95% CI = 0.2-1.1 on day 14). Mild diarrhea, rash, and itching resolved without treatment. Combined artesunate plus sulfadoxine-pyrimethamine resulted in more rapid fever and parasiteclearance, was well tolerated, reduced risk of treatment failure, and lowered gametocyte carriage.

  49. Tjitra E, Suprianto S, Dyer ME, Currie BJ, Anstey NM. Detection of histidine rich protein 2 and panmalarial ICT Malaria Pf/Pv test antigens after chloroquine treatment of uncomplicated falciparum malaria does not reliably predict treatment outcome in eastern Indonesia. Am J Trop Med Hyg  2001 Nov;65(5):593-8 . Abstract. In regions with drug-resistant malaria, the ability to rapidly detect or predict treatment failure (TF) soon after a course of standard therapy for Plasmodium falciparum malaria would facilitate the prompt institution of second-line therapy. We thus evaluated longitudinally the ability of the ICT Malaria Pf/Pv immunochromatographic test to predict treatment outcome. Sixty-six Sumbanese Indonesians with uncomplicated falciparum malaria were treated with chloroquine and followed for 28 days by use of 1997 World Health Organization criteria for assessment of therapeutic efficacy of antimalarial drugs. The ICT Pf/Pv testing could be compared with microscopy in approximately half of the patients on each day of follow-up. Although strongly positive histidine rich protein 2 (HRP2) line intensities (equal to or greater than the control band) in convalescence were highly predictive of TF, any degree of positivity for the HRP2 and panmalarial antigens in convalescence was only moderately predictive of TE Positive predictive values of the HRP2 and panmalarial antigens for TF were 76.9% and 87.0%, respectively, on Day 3, 82.4% and 87.5% on Day 7, and 78.9% and 78.9% on Day 14. Negative HRP2 and panmalarial antigen results in convalescence were even less predictive of an adequate clinical response, and false-negative HRP2 and panmalarial antigen test results were found in one-sixth (6 of 37) of recrudescent infections diagnosed by microscopy among patients with late treatment failure. To reliably predict treatment outcome with rapid antigen tests, further development appears necessary to improve sensitivity for viable asexual parasites while avoiding detection of both gametocytes and persistent antigen in convalescence.

  50. Toure FS, Mavoungou E, Ndong JM, Tshipamba P, Deloron P. Erythrocyte binding antigen (EBA-175) of Plasmodium falciparum: improved genotype determination by nested polymerase chain reaction. Trop Med Int Health  2001 Oct;6(10):767-9 . Abstract. We have designed primers to the conserved region of the erythrocyte binding antigen (EBA)-175 gene which amplify specifically the two alleles by polymerase chain reaction (PCR) and by nested PCR. This approach provides a specific, sensitive and rapid method for genotype determination in a large number of Plasmodium falciparum field isolates.

  51. Trial Team. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet  2001 Dec 8;358(9297):1927-34 . Abstract. BACKGROUND: RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P. falciparum infection in semi-immune adult men in The Gambia. METHODS: 306 men aged 18-45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P. falciparum. Analysis was per protocol. FINDINGS: 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P. falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0-53, p=0.014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037). INTERPRETATION: RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P. falciparum infection.

  52. Tsuji M, Zavala F. Peptide-based subunit vaccines against pre-erythrocytic stages of malaria parasites. Mol Immunol  2001 Dec;38(6):433-42 . Abstract. Malaria currently ranks among the most prevalent infections in tropical and sub-tropical areas throughout the world with relatively high morbidity and mortality particularly in young children. The widespread occurrence and the increased incidence of malaria in many countries, caused by drug-resistant parasites (Plasmodium falciparum and P. vivax) and insecticide-resistant vectors (Anopheles mosquitoes), indicate the need to develop new methods of controlling this disease. Experimental vaccination with radiation-attenuated sporozoites can protect animals and humans against the disease, demonstrating the feasibility of developing an effective malaria vaccine. However, vaccines based on radiation-attenuated sporozoites are not feasible for large scale application due to lack of in vitro culture system. Therefore, the development of peptide-based subunit vaccines has been undertaken as an alternative approach. Synthetic peptides containing defined B- and T-cell epitopes of different antigens expressed in sporozoites and/or liver stages have been used as subunit vaccines in experimental animal models. They have been shown to be highly immunogenic and capable of inducing protective immunity mediated by antibodies, as well as CD4+ and CD8+ T-cells.

  53. Urquiza M, Ocampo M, Patarroyo ME, Patarroyo MA. Plasmodium vivax: functional analysis of a highly conserved PvRBP-1 protein region. Mol Biochem Parasitol  2001 Oct;117(2):229-34 No abstract.

  54. Yapabandara AM, Curtis CF, Wickramasinghe MB, Fernando WP. Control of malaria vectors with the insect growth regulator pyriproxyfen in a gem-mining area in Sri Lanka. Acta Trop  2001 Dec 21;80(3):265-76. Abstract. The study was conducted in eight adjacent villages in central Sri Lanka where there are many shallow pits dug by gem miners that fill with water. These become breeding places of the main malarial vector Anopheles culicifacies, and of the second most important vector Anopheles subpictus, but not of Anopheles varuna, the third most important vector. With the help of local volunteers, data on the adult populations of these three species was collected by various standard methods, and data on the incidence of malaria cases was collected by two clinics set up for the project and through the existing hospitals. Prevalence of malaria infection in symptom-less people was investigated by mass blood surveys. On the basis of a year's pre-intervention data the villages were stratified into four with high levels of malaria transmission and four with lower transmission. Within each stratum two villages were randomly assigned for mosquito control by treating all the gem pits, as well as river bed pools, with a granular formulation of the insect growth regulator pyriproxyfen at a target dose of 0.01 mg a.i./litre. The intervention caused significant reductions in the adult populations of An. culicifacies and An. subpictus. Similarly, incidence of malaria was reduced in the intervention villages to about 24% (95% c.l. 20-29%) of that in the controls. Prevalence of parasitaemia also declined significantly. It is concluded that in this situation where, with active community participation, the breeding sites of the main vectors could be located; vector control by a highly active and persistent insect growth regulator can be a very effective means of malaria control.


July 02


4714.                     Bonnet S, Paul RE, Gouagna C, Safeukui I, Meunier JY, Gounoue R, Boudin C.  Level and dynamics of malaria transmission and morbidity in an equatorial area of South Cameroon. Trop Med Int Health. 2002 Mar;7(3):249-56.


We conducted parasitological and entomological malaria surveys among the population of Mengang district in southern Cameroon to analyse the relationship between malaria transmission intensity and malaria morbidity. We investigated two adjacent areas which differ 10-fold in transmission intensity [annual entomological inoculation rate (EIR) 17 vs. 170], but have very similar Plasmodium falciparum malariometric profiles with parasite prevalences of 58 vs. 64%, high parasitaemia prevalences (> 1000 parasites/microl) of 15 vs. 16% and the same morbidity of 0.17-0.5 attacks/person/year. Plasmodium malariae prevalence was 14 vs. 16%. One possible explanation is that the similarity of the duration of the short and high transmission seasons in both areas is equally, if not more, significant for parasitological and clinical profiles as the annual EIR. We discuss the relationships between variations in transmission levels, parasitaemia and clinical incidence, and draw parallels to similar situations elsewhere.


4715.                     Bull PC, Marsh K.  The role of antibodies to Plasmodium falciparum-infected-erythrocyte surface antigens in naturally acquired immunity to malaria. Trends Microbiol. 2002 Feb;10(2):55-8. Review.


Plasmodium falciparum, the most virulent species of human malaria parasite, causes 1-3 million deaths per year. Because this parasite is susceptible to naturally acquired host immunity the main burden of diseases falls on young children. The mechanism of this immunity is still unclear. However, the parasite makes a considerable investment in the insertion of highly polymorphic antigens (parasite-infected-erythrocyte surface antigens, PIESA) on the infected erythrocyte surface, and these antigens are potentially important immune targets.


4716.                     Bynum WF.  Portraits of science. Mosquitoes bite more than once. Science. 2002 Jan 4;295(5552):47-8.


Ronald Ross discovered that the plasmodium parasite--'Laveran's germ'—was transmitted by anopheline mosquitoes to human beings to cause malaria. This discovery won him a Nobel Prize in 1902, but the route to this success was by no means clear. He was an indifferent student, he liked to write novels and poems and only just managed to gain a medical qualification. Fortuitously he was mediocre enough to enter the least prestigious section of the Indian Medical Service, which put him directly in contact with the parasites that were to become his passion. Despite honours being showered on him, life after the Prize also was not straightforward, he was irrascible and his innovative mathematical and economic approaches to disease control were overlooked.


4717.                     Chaisavaneeyakorn S, Moore JM, Otieno J, Chaiyaroj SC, Perkins DJ, Shi YP, Nahlen BL, Lal AA, Udhayakumar V.  Immunity to placental malaria. III. Impairment of interleukin(IL)-12, not IL-18, and interferon-inducible protein-10 responses in the placental intervillous blood of human immunodeficiency virus/malaria-coinfected women. J Infect Dis. 2002 Jan 1;185(1):127-31.


Pregnant women are highly susceptible to malaria, and human immunodeficiency virus (HIV) infection increases this susceptibility. In our previous studies, placental malaria (PM), HIV infection, and HIV/PM coinfection were all associated with decreased interferon (IFN)-gamma production by maternal placental (intervillous) blood mononuclear cells (IVBMC). This study investigated whether in vitro production of the IFN-gamma regulatory cytokines interleukin (IL)-12 and IL-18 and the chemokine IFN-inducible protein (IP)-10 by IVBMC is altered in women who have been exposed to malaria and are infected with HIV. IL-12 production from IVBMC was significantly lower in HIV-positive women, regardless of PM status, in contrast to HIV-negative, PM-negative women. IL-18 and IP-10 production by IVBMC was reduced in HIV-positive, PM-negative women but elevated in HIV-positive, PM-positive women. These results reveal a substantial impairment of IL-12 production by IVBMC in HIV-positive women, implicating this cytokine as a potentially critical regulator of malaria antigen-specific IFN-gamma responses in HIV-infected and HIV/PM-coinfected women.


4718.                     Chandramohan D, Jaffar S, Greenwood B.  Use of clinical algorithms for diagnosing malaria. Trop Med Int Health. 2002 Jan;7(1):45-52. Review.


Several attempts have been made to identify symptoms and signs based algorithms for diagnosing malaria. In this paper, we review the results of published studies and assess the risks and benefits of this approach in different epidemiological settings. Although in areas with a low prevalence the risk of failure to treat malaria resulting from the use of algorithms was low, the reduction in the wastage of drugs was trivial. The odds of wastage of drugs increased by 1.49 (95% confidence limit 1.45-1.51) for each 10% decrease in the prevalence of malaria. In highly endemic areas the algorithms had a high risk of failure to treat malaria. The odds of failure to treat increased by 1.57 (95% confidence limit 1.50-1.65) for each 10% increase in the prevalence. Furthermore, the best clinical algorithms for diagnosing malaria were site-specific. We conclude that the accuracy of clinical algorithms for diagnosing malaria is not sufficient to determine whether antimalarial drugs should be given to children presenting with febrile illness. In highly endemic areas where laboratory support is not available, the policy of offering antimalarial drugs to all children presenting with a febrile illness recommended by the integrated child management initiative is appropriate.


4719.                     Cho-Min-Naing, Gatton ML.  Performance appraisal of rapid on-site malaria diagnosis (ICT malaria Pf/Pv test) in relation to human resources at village level in Myanmar. Acta Trop. 2002 Jan;81(1):13-9.


Logistic, economic and technical factors limit rapid access to microscopic confirmation of symptomatic diagnosis of malaria in many rural areas in endemic countries such as Myanmar. A study was conducted to evaluate a rapid on-site immunochromatographic test (ICT Malaria Pf/Pv) for detection of Plasmodium falciparum and P. vivax in two villages in the Taikkyi region of Myanmar. The ICT Malaria tests were performed by a volunteer health worker (VHW) in Yae-Aye-San village and by a professionally trained midwife (MW) in Kankone village. A total of 1000 symptomatic patients participated in the study by providing blood samples for an ICT test and for microscopy. The ICT performance indices, relative to microscopy, were better for the trained MW compared with the less experienced VHW. For P. falciparum and/or P. vivax infections, the sensitivities were 82.7% for the VHW compared with 93.7% for the MW. For P. falciparum infections, the sensitivities were 82.2% for the VHW and 91.3% for the MW, while the corresponding values for P. vivax infections were 66.7 and 79%, respectively. Although the test kit appeared to perform better in more experienced hands, this study questions whether this difference is related to the use of the ICT Malaria Pf/Pv test kit, or related to other factors such as differences in the quality of blood slides prepared by the VHW and MW for microscopic examination. Overall, the results suggest that a rapid diagnostic assay such as the ICT Malaria Pf/Pv test kit can be used in rural settings by relatively inexperienced persons, such as VHWs, with a reasonable degree of sensitivity, thus providing on-site confirmation of symptomatic diagnosis of malaria.



4720.                     Fischer PR, Bialek R.  Prevention of malaria in children. Clin Infect Dis. 2002 Feb 15;34(4):493-8.


Although malaria kills approximately 1 million children each year, preventive measures can be effective in limiting the mortality and morbidity associated with malaria. Mosquito bites can be avoided by use of appropriate environmental control and use of protective clothing, bed nets, repellents, and insecticide. Chemoprophylaxis is a mainstay of malaria prevention, and new, effective agents are increasingly available. Rapid, accurate diagnosis and effective medical treatment can help people who become ill with malaria despite their preventive efforts. With careful attention to preventive efforts, malaria should be extremely rare in travelers; similarly, broader implementation of preventive measures could decrease the burden of malaria on residents in areas where it is endemic.


4721.                     Greenwood B, Mutabingwa T.  Malaria in 2002. Nature. 2002 Feb 7;415(6872):670-2. Review.


The burden of malaria is increasing, especially in sub-Saharan Africa, because of drug and insecticide resistance and social and environmental changes. Thus, there is an urgent need for vaccines, new drugs and insecticides. Parasite, mosquito and human genome projects are helping in the search for new control tools and international donors are developing new funding mechanisms that could make them available to poor countries. But these new tools will achieve their maximum impact only if additional resources are deployed to strengthen malaria research and control communities in countries where the new tools will be used.


4722.                     Hoffman SL, Subramanian GM, Collins FH, Venter JC.  Plasmodium, human and Anopheles genomics and malaria. Nature. 2002 Feb 7;415(6872):702-9. Review.


The Plasmodium spp. parasites that cause malaria are transmitted to humans by Anopheles spp. mosquitoes. Scientists have now amassed a great body of knowledge about the parasite, its mosquito vector and human host. Yet this year there will be 300-500 million new malaria infections and 1-3 million deaths caused by the disease. We believe that integrated analyses of genome sequence, DNA polymorphisms, and messenger RNA and protein expression profiles will lead to greater understanding of the molecular basis of vector-human and host-parasite interactions and provide strategies to build upon these insights to develop interventions to mitigate human morbidity and mortality from malaria.



4723.                     Irion A, Beck HP, Smith T.  Assessment of positivity in immuno-assays with variability in background measurements: a new approach applied to the antibody response to Plasmodium falciparum MSP2. J Immunol Methods. 2002 Jan 1;259(1-2):111-8.


Measurements of immune responses often exhibit considerable heterogeneity, making it impossible to clearly distinguish responders and nonresponders to particular antigens. Typically, in, for example, enzyme-linked immunosorbent assay (ELISA) procedures, a nonexposed control group is used to assign a cutoff value of positivity, calculated as the mean plus either 2 or 3 standard deviations (S.D.). This can cause extremely biased estimates of response rates when the background is variable, and especially when there is overlap between the distribution of the control levels and that of responders. This problem is compounded when results of assays with different background levels are compared. We illustrate this with hypothetical data sets reflecting frequent patterns seen in laboratory and epidemiological studies.We propose that such data should be analysed by statistical modelling of the ratio of numbers of test samples/control samples as a function of the readout from the assay. Rather than classifying samples dichotomously as negative or positive, this provides estimates of the prevalence of positivity lambda, and the probability, for each sample, that the measured activity is above background. Several statistical methods can provide such estimates. Analyses of simulated data sets using our preferred estimation method [a latent class model (LCM)] demonstrate that this gives more reliable results than the traditional assignment using cutoff values. We have applied this approach to the analysis of ELISA assessments of antibodies against distinct regions of the Plasmodium falciparum merozoite surface protein 2 (MSP2) in human sera from Tanzania.



4724.                     King CL, Malhotra I, Wamachi A, Kioko J, Mungai P, Wahab SA, Koech D, Zimmerman P, Ouma J, Kazura JW.  Acquired immune responses to Plasmodium falciparum merozoite surface protein-1 in the human fetus. J Immunol. 2002 Jan 1;168(1):356-64.


Infants born in areas of stable malaria transmission are relatively protected against severe morbidity and high density Plasmodium falciparum blood-stage infection. This protection may involve prenatal sensitization and immunologic reactivity to malaria surface ligands that participate in invasion of red cells. We examined cord blood T and B cell immunity to P. falciparum merozoite surface protein-1 (MSP-1) in infants born in an area of stable malaria transmission in Kenya. T cell cytokine responses to the C-terminal 19-kDa fragment of MSP-1 (MSP-1(19)) were detected in 24 of 92 (26%) newborns (4-192 IFN-gamma and 3-88 IL-4-secreting cells per 10(6)/cord blood lymphocytes). Peptide epitopes in the N-terminal block 3 region of MSP-1 also drove IFN-gamma and/or IL-13 production. There was no evidence of prenatal T cell sensitization to liver-stage Ag-1. A total of 5 of 86 (6%) newborns had cord blood anti-MSP-1(19) IgM Abs, an Ig isotype that does not cross the placenta and is therefore of fetal origin. The frequency of neonatal B cell sensitization was higher than that indicated by serology alone, as 5 of 27 (18%) cord blood samples contained B cells that produced IgG when stimulated with MSP-1(19) in vitro. Neonatal B cell IgG responses were restricted to the Q-KNG allele of MSP-1(19), the major variant in this endemic area, whereas T cells responded to all four MSP-1(19) alleles evaluated. In utero sensitization to MSP-1 correlated with the presence of malaria parasites in cord blood (chi(2) = 20, p < 0.0001). These data indicate that prenatal sensitization to blood-stage Ags occurs in infants born in malaria endemic areas.


4725.                     Kublin JG, Dzinjalamala FK, Kamwendo DD, Malkin EM, Cortese JF, Martino LM, Mukadam RA, Rogerson SJ, Lescano AG, Molyneux ME, Winstanley PA, Chimpeni P, Taylor TE, Plowe CV.  Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. J Infect Dis. 2002 Feb 1;185(3):380-8.


Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.


4726.                     Lee EA, Palmer DR, Flanagan KL, Reece WH, Odhiambo K, Marsh K, Pinder M, Gravenor MB, Keitel WA, Kester KE, Diggs C, Kaslow D, Apostolopoulos V, Ballou WR, Hill AV, Krzych U, Plebanski M.  Induction of T helper type 1 and 2 responses to 19-kilodalton merozoite surface protein 1 in vaccinated healthy volunteers and adults naturally exposed to malaria. Infect Immun. 2002 Mar;70(3):1417-21.


Plasmodium falciparum malaria is a major cause of death in the tropics. The 19-kDa subunit of P. falciparum merozoite surface protein 1 (MSP-1(19)), a major blood stage vaccine candidate, is the target of cellular and humoral immune responses in animals and humans. In this phase I trial of MSP-1(19), immunization of nonexposed human volunteers with either of the two allelic forms of recombinant MSP-1(19) induced high levels of antigen-specific Th1 (gamma interferon) and Th2 (interleukin 4 [IL-4] and IL-10) type lymphokines. The adjustment of the antigen dose and number of immunizations regulated the level of specificity of immune responses and Th1/Th2 bias of responses induced by vaccination. Novel conserved and allelic T-cell epitopes which induced cross-strain immune responses were identified. Importantly, responses to many of these novel epitopes were also present in adults exposed to malaria, both in east (Kenya) and west Africa (The Gambia). These data suggest that epitope-specific naturally acquired MSP-1(19) immune responses in endemic populations can be boosted by vaccination.

4727.                     Mankhambo L, Kanjala M, Rudman S, Lema VM, Rogerson SJ.  Evaluation of the OptiMAL rapid antigen test and species-specific PCR to detect placental Plasmodium falciparum infection at delivery. J Clin Microbiol. 2002 Jan;40(1):155-8.


During pregnancy, Plasmodium falciparum infection of the placenta frequently occurs in the absence of parasites in peripheral blood. We investigated the abilities of the OptiMAL rapid immunochromatographic strip test for P. falciparum lactate dehydrogenase and species-specific PCR performed on peripheral blood to detect placental infection or malaria-associated low birth weight. Of 509 Malawian women screened by microscopy, 76 had malaria infection. Among these 509 women, the frequency of peripheral blood parasitemia was low. The OptiMAL test gave positive results in 37 of 171 women tested (one of whom had placental but not peripheral blood parasitemia) and had sensitivities of 71% for peripheral parasitemia and 38% for placental parasitemia compared to the microscopy values. The specificity for peripheral parasitemia was 94%. In 135 women, PCR had sensitivities of 94% for peripheral blood malaria detected by microscopy and 72% for placental infection. In samples examined by PCR, the prevalence of malaria in peripheral blood increased from 26.7% by microscopy to 51.9%. Women with placental malaria and women with malaria in peripheral blood samples by microscopy or OptiMAL testing, but not women with malaria detected only by PCR, had lower-birth-weight babies than did women without malaria by these criteria. Positive results by PCR in the absence of microscopic parasitemia were not associated with low birth weight. Neither OptiMAL nor PCR testing of peripheral blood is adequately sensitive to detect all placental malaria infection, but a positive result by OptiMAL testing identifies women with a high proportion of low-birth-weight babies.


4728.                     Marchant T, Schellenberg JA, Edgar T, Nathan R, Abdulla S, Mukasa O, Mponda H, Lengeler C.  Socially marketed insecticide-treated nets improve malaria and anaemia in pregnancy in southern Tanzania. Trop Med Int Health. 2002 Feb;7(2):149-58.


OBJECTIVES: To study the uptake of socially marketed insecticide-treated nets (ITNs) and their impact on malaria and anaemia in pregnancy; and to report on a discount voucher system which aimed to increase coverage in pregnancy. METHODS: A 12-month cross-sectional study of women in the second or third trimester of pregnancy. ITN use and other factors were assessed by questionnaire and a blood sample taken for malaria parasitaemia and anaemia. 'Non-users' of ITNs included both women not using any net and women using untreated nets. RESULTS: Fifty three per cent of pregnant women used ITNs. Women aged 15-19, primigravidae, unmarried women, and those with no access to cash had the lowest ITN use. Fewer ITN users were positive for malaria than ITN non-users (25 vs. 33%: P=0.06), and the protective efficacy (PE) for parasitaemia was 23% (CI 2-41). Multiparous ITN users had a twofold decrease in parasite density compared with multiparous non-ITN users (625 parasites/microl vs. 1173 parasited/microl: P=0.01). Fewer ITN users were anaemic (Hb < 11 g/dl) than ITN non-users (72 vs. 82%: P=0.01). ITNs had a PE of 12% (CI 2-21) against mild anaemia and a PE of 38% (CI 4-60) against severe anaemia (Hb < 8 g/dl). There was a trend in the prevalence of severe, mild and no anaemia, and of high density, low density and no malaria infection by ITN status. Recently treated nets were most effective at preventing malaria and anaemia (prevalence of mild anaemia was 68% compared with 82% for those without nets (P=0.002); prevalence of malaria was 22% compared with 33% for those without nets (P=0.02). Knowledge and reported use of the discount voucher system were low. Further qualitative research is ongoing. CONCLUSIONS: A modest impact of ITNs on pregnancy malaria and anaemia was shown in our high malaria transmission setting. The development of ITN programmes for malaria control should include pregnant women as a specific target group.


4729.                     Mawili-Mboumba DP, Kun JF, Lell B, Kremsner PG, Ntoumi F.  Pfmdr1 alleles and response to ultralow-dose mefloquine treatment in Gabonese patients. Antimicrob Agents Chemother. 2002 Jan;46(1):166-70.


The identification of parasite molecular markers involved in resistance to antimalarial compounds is of great interest for monitoring the development and spread of resistance in the field. Polymorphisms in Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) have been associated with chloroquine resistance and mefloquine susceptibility. In the present study, carried out in Lambarene, Gabon, we investigated the relationship between the presence of mutations at codons 86, 184, 1034, 1042, and 1246 in the pfmdr1 gene and the success of ultralow-dose mefloquine treatment (1.1 mg/kg of body weight). Sixty-nine patients were included in the study, and depending on the level of in vivo resistance to mefloquine, they were classified as sensitive responders (S), patients with low-grade resistance (RI), and nonresponders (NR). We found that the prevalences of the Tyr-86 mutation among isolates from patients in groups S, RI, and NR were 100, 96, and 90%, respectively, and that the prevalence of the Phe-184 mutation among the isolates was 80% in each group. A prevalence of about 10% point mutations at codons 1042 and 1246 was detected only in isolates from patients in groups RI and NR. There was no statistically significant association between the presence of the Tyr-86 mutation and the in vivo response (P = 0.79). Among the parasite isolates from patients with drug-resistant infections, 83% had the wild-type pfmdr1 genotype (S(1034)-N(1042)-D(1246)). No link between the presence of this genotype and parasite resistance was detected (P = 0.42). Among the isolates analyzed, 85 had double mutations (Y(86)-F(184) or Y(86)-Y(1246)) and 11 had triple mutations (Y(86)-D(1042)-Y(1246), Y(86)-F(184)-Y(1246), or Y(86)-F(184)-D(1042)). These findings are not consistent with those of previous in vitro studies and suggest that further evaluation of pfmdr1 gene polymorphism and in vivo mefloquine sensitivity are needed.


4730.                     Medana IM, Day NP, Hien TT, Mai NT, Bethell D, Phu NH, Farrar J, Esiri MM, White NJ, Turner GD.  Axonal injury in cerebral malaria. Am J Pathol. 2002 Feb;160(2):655-66.


Impairment of consciousness and other signs of cerebral dysfunction are common complications of severe Plasmodium falciparum malaria. Although the majority of patients make a complete recovery a significant minority, particularly children, have sequelae. The pathological process by which P. falciparum malaria induces severe but usually reversible neurological complications has not been elucidated. Impairment of transport within nerve fibers could induce neurological dysfunction and may have the potential either to resolve or to progress to irreversible damage. Beta-amyloid precursor protein (beta-APP) immunocytochemistry, quantified using digital image analysis, was used to detect defects in axonal transport in brain sections from 54 Vietnamese cases with P. falciparum malaria. The frequency and extent of beta-APP staining were more severe in patients with cerebral malaria than in those with no clinical cerebral involvement. Beta-APP staining was often associated with hemorrhages and areas of demyelination, suggesting that multiple processes may be involved in neuronal injury. The age of focal axonal damage, as determined by the extent of the associated microglial response, varied considerably within tissue sections from individual patients. These findings suggest that axons are vulnerable to a broad range of cerebral insults that occur during P. falciparum malaria infection. Disruption in axonal transport may represent a final common pathway leading to neurological dysfunction in cerebral malaria.


4731.                     Miller LH, Baruch DI, Marsh K, Doumbo OK.  The pathogenic basis of malaria. Nature. 2002 Feb 7;415(6872):673-9. Review.


Malaria is today a disease of poverty and underdeveloped countries. In Africa, mortality remains high because there is limited access to treatment in the villages. We should follow in Pasteur's footsteps by using basic research to develop better tools for the control and cure of malaria. Insight into the complexity of malaria pathogenesis is vital for understanding the disease and will provide a major step towards controlling it. Those of us who work on pathogenesis must widen our approach and think in terms of new tools such as vaccines to reduce disease. The inability of many countries to fund expensive campaigns and antimalarial treatment requires these tools to be highly effective and affordable.

4732.                     Mockenhaupt FP, Ulmen U, von Gaertner C, Bedu-Addo G, Bienzle U.  Diagnosis of placental malaria. J Clin Microbiol. 2002 Jan;40(1):306-8.


In a group of 596 delivering Ghanaian women, the sensitivities of peripheral blood thick film microscopy, ICT Malaria P.f/P.v test, and PCR in detecting microscopically confirmed placental Plasmodium falciparum infection were 42, 80, and 97%, respectively. In addition to the gross underestimation of placental malaria by peripheral blood film microscopy, submicroscopic infections were found to be a risk factor for maternal anemia.

4733.                     Mohapatra MK; Mitra I; Das SP; Kar LK. Haematological and coagulation profile in malaria The Indian Practitioner 2002 Feb; 55(2): 75-8


ABSTRACT: The haematological and coagulation profile was studied in 60 patients of falciparum malaria and 40 patients of vivax malaria The diagnosis of malaria was made by detection of parasite in the peripheral smear. The mean haemoglobin in complicated and uncomplicated falciparum malaria was 6.2 plus minus 2.02 gm percent and 8.4 plus minus 1.99 gm percent which was lower than vivax malaria (10.26 plus minus 2.16 gm percent) and control (p<0.05). Leukocytosis was found in 12 (20 percent) cases of complicated falciparum malaria. Peripheral pancytopenia was found in 2(3.3 percent) cases. The bleeding time was increased in complicated falciparum malaria. Raised FDP was found in 5 (8.3 percent) cases. Inspite of thrombocytopenia and raised FDP, bleeding manifestations are uncommon.


4734.                     Moody A.  Rapid diagnostic tests for malaria parasites. Clin Microbiol Rev. 2002 Jan;15(1):66-78. Review.


Malaria presents a diagnostic challenge to laboratories in most countries. Endemic malaria, population movements, and travelers all contribute to presenting the laboratory with diagnostic problems for which it may have little expertise available. Drug resistance and genetic variation has altered many accepted morphological appearances of malaria species, and new technology has given an opportunity to review available procedures. Concurrently the World Health Organization has opened a dialogue with scientists, clinicians, and manufacturers on the realistic possibilities for developing accurate, sensitive, and cost-effective rapid diagnostic tests for malaria, capable of detecting 100 parasites/microl from all species and with a semiquantitative measurement for monitoring successful drug treatment. New technology has to be compared with an accepted "gold standard" that makes comparisons of sensitivity and specificity between different methods. The majority of malaria is found in countries where cost-effectiveness is an important factor and ease of performance and training is a major consideration. Most new technology for malaria diagnosis incorporates immunochromatographic capture procedures, with conjugated monoclonal antibodies providing the indicator of infection. Preferred targeted antigens are those which are abundant in all asexual and sexual stages of the parasite and are currently centered on detection of HRP-2 from Plasmodium falciparum and parasite-specific lactate dehydrogenase or Plasmodium aldolase from the parasite glycolytic pathway found in all species. Clinical studies allow effective comparisons between different formats, and the reality of nonmicroscopic diagnoses of malaria is considered.


4735.                     Mukanganyama S, Widersten M, Naik YS, Mannervik B, Hasler JA.  Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.


A strategy to overcome multidrug resistance in cancer cells involves

Treatment with a combination of the antineoplastic agent and a chemomodulator that inhibits the activity of the resistance-causing protein. The aim of our study was to investigate the effects of antimalarial drugs on human recombinant glutathione S-transferase (GSTs) activity in the context of searching for effective and clinically acceptable inhibitors of these enzymes. Human recombinant GSTs heterologously expressed in Escherichia coli were used for inhibition studies. GST A1-1 activity was inhibited by artemisinin with an IC(50) of 6 microM, whilst GST M1-1 was inhibited by quinidine and its diastereoisomer quinine with IC(50)s of 12 microM and 17 microM, respectively. GST M3-3 was inhibited by tetracycline only with an IC(50) of 47 microM. GST P1-1 was the most susceptible enzyme to inhibition by antimalarials with IC(50) values of 1, 2, 1, 4, and 13 microM for pyrimethamine, artemisinin, quinidine, quinine and tetracycline, respectively. The IC(50) values obtained for artemisinin, quinine, quinidine and tetracycline are below peak plasma concentrations obtained during therapy of malaria with these drugs. It seems likely, therefore, that GSTs may be inhibited in vivo at doses normally used in clinical practice. Using the substrate ethacrynic acid, a diuretic drug also used as a modulator to overcome drug resistance in tumour cells, GST P1-1 activity was inhibited by tetracycline, quinine, pyrimethamine and quinidine with IC(50) values of 18, 27, 45 and 70 microM, respectively. The ubiquitous expression of GSTs in different malignancies suggests that the addition of nontoxic reversing agents such as antimalarials could enhance the efficacy of a variety of alkylating agents. Copyright 2001 Wiley-Liss, Inc.


4736.                     Mya MM; Saxena RK; Roy A. Sensitivity and specificity of isolated antigen from Plasmodium Falciparum culture supernatant Indian Journal of Clinical Biochemistry 2002 Jan; 17(1): 75-82

ABSTRACT: Immunological sensitivity and specificity properties of isolated Plasmodium falciparum (GPL) antigen from culture supernatant have been measured and compared with malarial antigens and non malarial filtered paper blood sera for potency and efficacy. Latex bead coded GPL, Pf and RESA antigens immunoreaction properties of human filter paper blood samples (FPB) were studied by laser light scattering immunoassay (LIA) and Enzyme linked immunoabsorbent assay (ELISA) techniques. Results of GPL antigen sensitivity study by LIA method showed a very high malaria antibody binding response (MABR) i.e. 6 percent compared with 78 percent with RESA and 88 percent Pf antigens. Malaria detection by ELISA method also found similar results. Specificity study of GPL antigen for different non malarial filter paper blood sera (NMFS) showed no immunoreaction however Pf and RESA antigen showed few positive immunological responses. These results suggest that sensitivity and specificity properties of isolated GPL antigen is better than other antigens.


4737.                     Padhy PK; Parija BL; Tripathy BK; Ash T; Biswas G. Atypical manifestations of malaria The Antiseptic 2002 Jan; 99(1): 1-4


ABSTRACT: Adult patients suffering from fever of sudden onset were prescribed antimicrobials (100 percent), antimalarials (89.1 percent) and antipyretics (87.4 percent). Total eight categories of diseases were diagnosed, in addition to which there were patients of pyrexia of unknown origin as well as undiagnosed cases. Respiratory infections were common as a system (37.4 percent). As a single most common disease malaria was prevalent most (17.3 percent). Maximum disease prevalence was seen in patients having temperature between 100-101 degree F. Patients of pyrexia of unknown origin and undiagnosed cases were referred to specialists of other faculties as per the need. Follow up revealed varied infections (88.1 percent), cysts (5.1 percent), organic mass (5.1 percent) and acute lymphatic leukemia (1.7 percent). No diagnosis could be made in 13.2 percent of these referred patients.


4738.                     Parhate SM; Thawani VR; Altekar CS. Prescription trends and diagnostic approach in patients of fever of sudden onset The Antiseptic 2002 Jan; 99(1): 26-8


ABSTRACT: Adult patients suffering from fever of sudden onset were prescribed antimicrobials (100 percent), antimalarials (89.1 percent) and antipyretics (87.4 percent). Total eight categories of diseases were diagnosed, in addition to which there were patients of pyrexia of unknown origin as well as undiagnosed cases. Respiratory infections were common as a system (37.4 percent). As a single most common disease malaria was prevalent most (17.3 percent). Maximum disease prevalence was seen in patients having temperature between 100-101 degree F. Patients of pyrexia of unknown origin and undiagnosed cases were referred to specialists of other faculties as per the need. Follow up revealed varied infections (88.1 percent), cysts (5.1 percent), organic mass (5.1 percent) and acute lymphatic leukemia (1.7 percent). No diagnosis could be made in 13.2 percent of these referred patients.


4739.                     Potasman I, Juven Y, Weller B, Schwartz E.  Does mefloquine prophylaxis affect electroencephalographic patterns? Am J Med. 2002 Feb 1;112(2):147-9.  No Abstract.

4740.                     Richie TL, Saul A.  Progress and challenges for malaria vaccines. Nature. 2002 Feb 7;415(6872):694-701. Review.6: 


Malaria causes much physical and economic hardship in tropical regions, particularly in communities where medical care is rudimentary. Should a vaccine be developed, it is the residents of these areas that stand to benefit the most. But the vaccine, which has been promised to be 'just round the corner' for many years, remains elusive. It is important to ask why this is so, when effective vaccines exist for many other infectious diseases. What are the reasons for the slow rate of progress, and what has been learned from the first clinical trials of candidate malaria vaccines? What are the remaining challenges, and what strategies can be pursued to address them?


4741.                     Ridley RG.  Medical need, scientific opportunity and the drive for antimalarial drugs. Nature. 2002 Feb 7;415(6872):686-93. Review.


Continued and sustainable improvements in antimalarial medicines through focused research and development are essential for the world's future ability to treat and control malaria. Unfortunately, malaria is a disease of poverty, and despite a wealth of scientific knowledge there is insufficient market incentive to generate the competitive, business-driven industrial antimalarial drug research and development that is normally needed to deliver new products. Mechanisms of partnering with industry have been established to overcome this obstacle and to open up and build on scientific opportunities for improved chemotherapy in the future.


4742.                     Sachs J, Malaney P.  The economic and social burden of malaria. Nature. 2002 Feb 7;415(6872):680-5. Review.


Where malaria prospers most, human societies have prospered least. The global distribution of per-capita gross domestic product shows a striking correlation between malaria and poverty, and malaria-endemic countries also have lower rates of economic growth. There are multiple channels by which malaria impedes development, including effects on fertility, population growth, saving and investment, worker productivity, absenteeism, premature mortality and medical costs.


4743.                     Salihu HM, Naik EG, Tchuinguem G, Bosny JP, Dagne G. Weekly chloroquine prophylaxis and the effect on maternal haemoglobin status at delivery. Trop Med Int Health. 2002 Jan;7(1):29-34.


Our aim was to determine the effectiveness of chloroquine prophylaxis in reducing the frequency of malaria-induced anaemia at delivery. We estimated the haemoglobin levels of 207 parturients; 82 (39.6%) had been on chloroquine prophylaxis [treatment group (TG)] while 125 (60.4%) did not take any malaria preventive medication antenatally [control group (CG)]. The proportion of women with malaria parasitaemia was significantly higher in CG than TG [risk ratio (RR=1.57, CI=1.05-2.34)]. The dose-response relationship between the severity of parasitaemia and the risk of being anaemic (P < 0.001) confirms a strong correlation between gestational malaria and maternal anaemia. There was a 35% reduction in risk for anaemia in the TG compared with the CG (RR=0.65, 0.40-1.06). The difference in risk was more pronounced after adjusting for disparity in place of residence, educational status and obstetric history (adjusted RR=0.54, CI=0.21-0.98). Primiparous mothers appeared to have benefited more from the antianaemic effects of malaria chemoprevention than mothers of higher parity (protective effectiveness 43% compared with 33%, respectively). In conclusion, despite reports of widespread Plasmodium falciparum resistance to chloroquine on the African continent, malaria chemosuppression with the drug was found beneficial in reducing the risk of anaemia at delivery among Cameroonian women.


4744.                     Sharma A, Kabilan L. Regulation of nitric oxide production by cytokines inhuman macrophages: possible role in P. vivax malaria. Indian J Biochem Biophys 2000, 37(5), 313-17.


Abstract : Production of reactive nitrogen intermediates (RNI) by macrophages in response to the malaria antigen of P. vivax and various cytokines was evaluated. Live malaria antigens, interferon-g, concanavalin A, interleukin-6 and tumour necrosis factor-a induced production of RNI in a dose dependent manner. RNI production was found to be steadily increased for a period of 72 hr and it was further enhanced when the live malaria antigen was co-incubated with interleukin-6 and interferon-g and/or tumour necrosis factor-a. L-N-monomethyl arginine (L-NMA) and polymyxin B were found to inhibit the production of RNI. Production of RNI by cAMP however, was not inhibited by polymyxin B. Dead parasites (heated) did not affect the production of RNI. Results are thus consistent with the possibility that cytokines may contribute  to the pathology of the host cells and also to the parasite immunosuppression through the production of the reactive nitrogen intermediates. 43 ref.


4745.                     Sharma P, Pillai CR, Sharma JD.  In vitro schizontocidal activity of standard antimalarial drugs on chloroquine-sensitive and chloroqine-resistant isolates of Plasmodium falciparum. Indian J expl Biol 2001, 38(11), 1129-33.


Abstract : The expanding foci of multiple drug resistant malaria and emergence of difference requires the reassessment of antimalarial activity with various drugs. In vitro response of a chloroquine sensitive and a chloroquine resistant isolate of P. falciparum to a group of 6 quinine derived and 3 artemisinin derived standard drugs has been screened, to evaluate schizontocidal activity of the drugs. In a conventional test system the IC50s were derived from the log dose response curves and evaluated by a rigorous statistical interpretation. Analysis by Tukey's test was significant for the quinine elected drugs (Q³0.01) and excludes the statistical significance of artemisinin related drugs in these isolates. The dose-responses of these two isolates vary with quinine derivatives, with some overlap at lower doses for the sensitive isolate than for the resistant one which manifested at higher doses.17 ref.


4746.                     Shete MM. Anaemia: a threat to life in malaria [editorial] The Indian Practitioner 2002 Feb; 55(2): 73-4. No Abstract.

4747.                     Stephenson J.  Sequencing of the malaria genome opens door to vaccines and new drugs. JAMA. 2002 Mar 13;287(10):1251-3. No Abstract.

4748.                     Surolia N.  Novel targets for antimalarial drug development. J Indian Inst Sci 2000, 80(1), 17-23.


Abstract : Heme as well as protein biosynthetic pathways of malaria parasite Plasmodium falciparum have been identified as crucial for the survival of the parasite. Intervention of either of the two pathways results in the death of the parasite, basically due to the pivotal role played by heme in these pathways. 12 ref.


4749.                     Turusov V, Rakitsky V, Tomatis L.  Dichlorodiphenyltrichloroethane (DDT): ubiquity, persistence, and risks. Environ Health Perspect. 2002 Feb;110(2):125-8. Review.


Due to uncontrolled use for several decades, dichlorodiphenyltrichloroethane (DDT), probably the best known and most useful insecticide in the world, has damaged wildlife and might have negative effects on human health. This review gives a brief history of the use of DDT in various countries and presents the results of epidemiologic and experimental studies of carcinogenesis. Even though its use has been prohibited in most countries for ecologic considerations, mainly because of its negative impact on wildlife, it is still used in some developing countries for essential public health purposes, and it is still produced for export in at least three countries. Due to its stability and its capacity to accumulate in adipose tissue, it is found in human tissues, and there is now not a single living organism on the planet that does not contain DDT. The possible contribution of DDT to increasing the risks for cancers at various sites and its possible role as an endocrine disruptor deserve further investigation. Although there is convincing experimental evidence for the carcinogenicity of DDT and of its main metabolites DDE and DDD, epidemiologic studies have provided contrasting or inconclusive, although prevailingly negative, results. The presence and persistence of DDT and its metabolites worldwide are still problems of great relevance to public health. Efficient pesticides that do not have the negative properties of DDT, together with the development of alternative methods to fight malaria, should be sought with the goal of completely banning DDT.


4750.                     Villamor E, Mbise R, Spiegelman D, Hertzmark E, Fataki M, Peterson KE, Ndossi G, Fawzi WW.  Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth. Pediatrics. 2002 Jan;109(1):E6.


OBJECTIVE: Evidence from animal experiments and observational studies in humans suggests that vitamin A plays a fundamental role in physical growth. However, results from vitamin A supplementation trials in children are inconsistent; whereas some did not find an overall effect on growth, others found benefits only among specific groups, including children with low concentrations of serum retinol or short duration of breastfeeding. The apparent lack of an overall effect of vitamin A on growth could be attributed to context-specific distribution of conditions that affect both growth and the response to supplementation, eg, baseline vitamin A status, deficiency of other nutrients (fat, zinc), and the presence of infectious diseases. Human immunodeficiency virus (HIV) infection, malaria, and diarrheal disease adversely affect growth and are associated with increased prevalence of vitamin A deficiency. We hypothesize that vitamin A supplementation could ameliorate the adverse effect of these infections on child growth. METHODS: We conducted a randomized, clinical trial among 687 Tanzanian children who were 6 to 60 months of age and admitted to the hospital with pneumonia. Children were assigned to oral doses of 200 000 IU vitamin A (half that dose if <12 months) or placebo on the day of admission, a second dose on the following day, and third and fourth doses at 4 and 8 months after discharge from the hospital, respectively. Anthropometric measurements were obtained at baseline and at monthly visits to the study clinics during 12 months after the initial hospitalization. Surveillance on the incidence and severity of diarrhea and respiratory infections was conducted during biweekly visits, alternately at a study clinic and the child's home, using a pictorial diary that the mothers were trained to use. A blood specimen was drawn at baseline for determination of HIV status, malaria infection, and hemoglobin levels. We used mixed effects models to compare estimated total weight and height increases after 1 year of follow-up between treatment arms, overall and within levels of HIV status, malaria, and other possible baseline effect modifiers. We also assessed the potential modulating effect of vitamin A on the risk of stunting (height-for-age <-2 standard deviations of the gender-specific National Center for Health Statistics median reference) attributable to diarrheal and respiratory infections during follow-up, in the subset of children who were not stunted at baseline. A similar approach was followed for wasting (weight-for-height <-2 standard deviations of the reference median). Cox regression models were used to estimate relative risks and 95% confidence intervals (CI), treating episodes of infection as time-dependent covariates. RESULTS: A total of 554 children had at least 2 follow-up measurements of height or weight and constituted the study base. Baseline characteristics did not differ significantly by treatment arm. Seventy-three percent of the children were <2 years of age, and 37% were <12 months; 31% were stunted at baseline and 9% were wasted. Malaria (Plasmodium falciparum) and HIV infection were found in 24% and 9% of the children, respectively. Median duration of follow-up was 351 days, with 10 measurements/child, on average, irrespectively of treatment assignment. Supplementation with vitamin A among children who had HIV infection and were <18 months of age resulted in a significant length increase. Four months after the first dose, infants who were HIV positive in the vitamin A arm had gained, on average, 2.8 cm (95% CI: 1.0-4.6) more than children who received placebo, whereas no effect was observed among infants who were HIV negative (difference at 4 months: -0.2 cm; 95% CI: -0.8-0.5). Children who were <12 months of age and had malaria at enrollment experienced a 747-g (95% CI: 71-1423) higher yearly weight gain attributable to vitamin A; among children without malaria, however, the supplements did not have a significant effect (-57 g; 95% CI: -461-348). These results remained unchanged after controlling for indicators of the socioeconomic and nutritional status at baseline. Linear growth was also improved by vitamin A among children from households with poor water supply (0.8 cm/year; 95% CI: 0-1.5) but not in children with tap water in the house or compound (-1.0 cm/year; 95% CI: -1.9-0). Weight gain was greater among children with mid-upper arm circumference below the 25th percentile of the age-specific distribution at baseline (458 g/year; 95% CI: 1-905), but no benefit was evident among children with higher mid-upper arm circumference. The risk of stunting associated with episodes of persistent diarrhea (lasting 14 or more days) during follow-up was virtually eliminated by vitamin A supplements. Among children in the placebo group, the average risk of stunting associated with 1 or more episodes of persistent diarrhea between 2 consecutive visits was 5.2 times higher (95% CI: 2.4-11.2) than that of children without diarrhea or with acute episodes. In contrast, among children who received vitamin A, there was virtually no risk of stunting associated with persistent diarrhea (relative risk: 1.0; 95% CI: 0.3-1.3). This effect was slightly attenuated after controlling for the number of household possessions, gender, baseline low arm circumference, HIV infection, and presence of malaria parasites in blood. Vitamin A supplements did not modify the associations between respiratory infections and the risk of stunting or wasting. CONCLUSIONS: Vitamin A supplementation improves linear and ponderal growth in infants who are infected with HIV and malaria, respectively, and decreases the risk of stunting associated with persistent diarrhea. Supplementation could constitute a low-cost, effective intervention to decrease the burden of growth retardation in settings where infectious diseases are highly prevalent.


4751.                     Wengelnik K, Vidal V, Ancelin ML, Cathiard AM, Morgat JL, Kocken CH, Calas M, Herrera S, Thomas AW, Vial HJ.  A class of potent antimalarials and their specific accumulation in infected erythrocytes. Science. 2002 Feb 15;295(5558):1311-4.


During asexual development within erythrocytes, malaria parasites synthesize considerable amounts of membrane. This activity provides an attractive target for chemotherapy because it is absent from mature erythrocytes. We found that compounds that inhibit phosphatidylcholine biosynthesis de novo from choline were potent antimalarial drugs. The lead compound, G25, potently inhibited in vitro growth of the human malaria parasites Plasmodium falciparum and P. vivax and was 1000-fold less toxic to mammalian cell lines. A radioactive derivative specifically accumulated in infected erythrocytes to levels several hundredfold higher than in the surrounding medium, and very low dose G25 therapy completely cured monkeys infected with P. falciparum and P. cynomolgi.


Oct 2002

5499.                     Acosta AR, Dominguez ND, Asguilar I, Giron ME. Detection of glutamate dehydrogenase enzyme activity in Plasmodium falciparum infection. Indian J med Res 1999 April; 109: 152-6. 
Describes the separation of an active glutamate dehydrogenase [GDH (NADP+)] enzyme from the plasma of patients with P. falciparum infection using columns of sepharose anti-GDH (NADP+) of Proteus spp. The activity of this enzyme was also detected in P. falciparum culture supernatant. The parasitic origin of this enzyme was suggested by western blot analysis using anti-P. falciparam culture supernatant and anti-whole parasite anti-bodies. The differential inhibition of the P. falciparum GDH (NADP+) indicates that some epitopes recognised by the antibodies in both preparations may by different. The determination of P. falciparum GDH (NADP+) activity could be developed into a specific technique for the diagnosis of falciparum malaria.


5500.                     Ansari KU. Mefloquine – a new antimalarial against resistant malaria II. Antiseptic, Madurai 2001; 98(10), 393-4. Mefloquine is a derivative of 4 quinolone methanol chemically related to quinine which emerged from eventual clinical trial as a readily tolerated antimalarial drug that is highly active against both the usual and the multi-drug resistant strains of P. falciparum.  


5501.                     Arya SC. Chemotherapeutic failures in Plasmodium falciparum infections. Trop Doct. 2002 Apr;32(2):121-2.  No Abstract.

5502.                     Clark I, Awburn M. Migration inhibitory factor in the cerebral and systemic endothelium in sepsis and malaria. Crit Care Med. 2002 May;30(5 Suppl):S263-7. Review.
OBJECTIVE: We have included migration inhibitory factor (MIF) in an ongoing immunohistochemical study comparing the site and intensity of the generation of inflammatory mediators in falciparum malaria, sepsis, and other causes of pediatric death in Africa. We wanted to determine whether it could account for our observation that inducible nitric oxide synthase is less strongly induced in the cerebral, compared with the systemic, vasculature. DATA SOURCES: Comparisons of tissue samples taken from blood vessel walls from the brain and the axillary space in a series of sepsis and falciparum malaria autopsies of African children. DATA SUMMARY: Intense staining for MIF has been detected in endothelial cells of axillary region vessels of all sepsis cases and most of the malaria cases examined. This parallels our findings with inducible nitric oxide synthase staining. African and Western control tissues from noninfectious causes of death stained lightly or not at all. In contrast, MIF could not be detected in vascular endothelial cells within the brain, where inducible nitric oxide synthase staining was much less intense. Detection of both MIF and inducible nitric oxide synthase in ependymal and glial cells in the same brains served as an internal positive staining control. CONCLUSION: These outcomes add weight to the proposal that endothelial cells are a site of intense inflammatory mediator activity in sepsis and malaria. They also suggest that suppression of anti-inflammatory glucocorticoids by MIF may be lower in the brain than elsewhere in the body. The lack of MIF in cerebral vasculature endothelial cells may be linked to the absence of thrombomodulin in these cells. The systemic cellular distribution and intensity of MIF in human systemic inflammatory states has not been described.

5503.                     Das LK. Malaria during pregnancy and its effect on foetus in a tribal area of Koraput District, Orissa. Indian J Malar. 2000; 37(1-2).
Malaria during pregnancy and its maternal and foetal complications was sutdied in Koraput district Orissa – a tribal area, endemic for malaria. A total of 209 pregnant women with 738 pregnancy months were studied. The parasitic index among the pregnant women ranged between 10.8 and 25.6 per cent with peak incidence during post-monsoon months. There was a significant difference in parasite incidence between the primi- and multigravidae (p<0.05) but difference was not observed between the trimesters. The mean haemoglobin (Hb) concentration declined to 8.4 g/dl (range 7.2-10.2 g/dl) at full-term and parturition  from its initial level of 9.6 g/dl (range 7.2 – 12.8 g/dl). There was a significant difference (p<0.05) in Hb concentration among the trimesters of pregnancy. There was no significant difference the outcome of pregnancies in women with or without malaria parasites in their peripheral blood. There was no significant difference in Hb concentrations between malaria parasite positive and negative pregnant women (p<0.05). significant difference was observed in the proportion of newborn positives from mothers with or without malaria parasites indicating a high degree of transplacental transmission. The overall foetal mortality rate was 21.5 per cent. The miscarriage, stillbirth, premature delivery leading to foetal and neonatal along with perinatal mortality constituted for 24.4, 13.3, 20 and 17.7 per cent of all mortalitites.


5504.                     Das NG, Bhuyan M, Das SC. Entomological and epidemiological studies on malaria in Rajmahal range, Bihar. Indian J Malar. 2000; 37(3-4), 88-96. Abstract: Epidemiological investigations carried out in six tribal villages in Rajmahal range hill in south Binar revealed average slide positivity rate (SPR) 25.1 ranging between 9.8 and 37.8 percent. Plasmodium falcium was the dominant parasite which accounted 64.2 per cent of the total infections. Result of mass blood survey indicates the presence of high percentage of asymptomatic carriers of malaria parasite in the local populace. In an antomological survey, 25 species of mosquitoes under five genera  were collected in 20 trap nights. The average density of mosquitoes alone accounted 72.8 per cent of the total collection whereas malaria vectors Anopheles maculates, An. Minius, An. Philippinensis, An. Annularis accounted 32.8 per cent of the anophelines collected. Both anopheline and culicine mosquitoes were found susceptible to DDT (4 per cent) and malathion (5 per cent) in 30 min exposure. Dissection of malaria vectors An. Minimus, An. Maculates and An. Philippnensis revealed very high percentage age of parity rate (77.8 per cent) which gives a strong indication about their vectorial status in the transmission of malarial. Poor socio-economic condition, lack of sense of hygiene worsen the situation in the presince of asymptomatic carriers.      

5505.                     Ghosh  K, Mukherjee MB, Surve RR, Shankarkumar U, Kate SL, Nagtilak SB, Colah RB, Tamankar AA, Mohanty D. Splenomegaly in school children in a remote tribal area of Dhule District, Maharashtra. Indian J Malar. 2000; 37(3-4), 64-73.
Sickle-cell gene is known to protect against P. falciparum infection and provides a selective survival advantage in those areas where P. falciparum infection is endemic. This protection is not absolute and many other factor, inherited and acquired also contribute to the immunity against P. falciparam infection. Investigates incidence of splenomegaly and typical history of malarial in the past two years in apparently healthy school children in tribal area in Dhule District in Maharashtra to see whether the incidence of malaria (splenomegaly and typical history) was different in children having sickle-cell trait to that of these who did not have this trait. A total of 480 school children were clinically examined for splenomegaly and history of typical malarial fever and/or blood slide positivity for malaria in the past two years. About 9.55 per cent of normal population had either splenomegaly or convincing history of malarial infection in the past two years, which is not statistically different from the sickle-cell trait patients having evidence of past malaria (8.79 per cent; p<0.05).


5506.                     Gogtay NJ, Dalvi SS, Desai S, Narayana RV, Shah PU. Cerebellar syndrome in a case of uncomplicated Plasmodium falciparum malaria. Neurol India. 2001; 49(2), 213-14. No Abstract.

5507.                     Hati AK, Mondal B, Chaudhuri P, Purkayashta S, Mukherjee H, Mukhopadhyay AK. Estimating parasite density in patients suffering from falciparum malaria in an endemic area in Kolkata. Indian J Malar. 2000; 37(3-4), 82-7. Parasite density of one hundred patients suffering from falciparam malaria in an endemic area in Kolkata was determined using three different methods. In the first of these, parasite density per microlitre of blood in a patient was determined using parasite count adjusted by average WBC count (i.e. 8000/ml) observed in microscopic fields of the thick film. In the remaining two methods, only raw (i.e. unadjusted) parasite counts in the microscopic fields of the same slide were used. A statistical analysis was carried out to compare these methods based on raw and adjusted parasites is of primary importance in determining the severity of infection. Furthermore, parasite density can help in identifying short-treatment and long-treatment failure vis-a-vis detection of development of resistance in P. falciparam against the drug used. This article reports some findings that indicate the existence of a potentially dangerous situation in the study area.


5508.                     Huong NM, Davis TM, Hewitt S, Huong NV, Uyen TT, Nhan DH, Cong le D. Comparison of three antigen detection methods for diagnosis and therapeutic monitoring of malaria: a field study from southern Vietnam. Trop Med Int Health. 2002 Apr;7(4):304-8.


OBJECTIVES: To compare the sensitivity, specificity and post-treatment

persistence of three commonly used rapid antigen detection methods. METHOD: We studied 252 Vietnamese patients aged from 4 to 60 years, 157 with falciparum and 95 with vivax malaria and 160 healthy volunteers. An initial blood sample was taken for microscopy, and OptiMAL, immunochromatographic test (ICT) malaria P.f./P.v. and Paracheck-Pf tests. Patients with falciparum malaria were treated with an artesunate-based combination regimen and those with vivax malaria received chloroquine. Eighty-seven patients with falciparum malaria who were initially positive for one of the antigen tests and who remained blood smear-negative underwent follow-up testing over 28 days. RESULTS: Paracheck-Pf was the most sensitive test for Plasmodium falciparum (95.8% vs. 82.6% for ICT malaria P.f./P.v. and 49.7% for OptiMAL). Specificities were all 100%. For vivax malaria, OptiMAL performed better than ICT malaria P.f./P.v. (sensitivities 73.7% and 20.0%, respectively), with 100% specificity in both cases. All tests had low sensitivities (< or = 75.0%) at parasitaemias < 1000/microl regardless of malaria species. During follow-up, Paracheck-Pf remained positive in the greatest proportion of patients, especially at higher parasitaemias (> 10,000/microl). Residual OptiMAL positivity occurred only in a relatively small proportion of patients (< 10%) with parasitaemias > 10,000/microl during the first 2 weeks after treatment. CONCLUSIONS: Although microscopy remains the gold standard for malaria diagnosis, Paracheck-Pf may prove a useful adjunctive test in uncomplicated falciparum malaria in southern Vietnam. OptiMAL had the lowest sensitivity for P. falciparum but it might have a use in the diagnosis of vivax malaria and perhaps to monitor efficacy of treatment for falciparum malaria where microscopy is unavailable.


5509.                     Hussain T, Sharma SK, Mahanta J. Antibodies reacting with chloroquine in human sera. Indian J med Res 1999 March; 109: 100-02. No Abstract.

5510.                     Jani IV, Janossy G, Brown DW, Mandy F. Multiplexed immunoassays by flow cytometry for diagnosis and surveillance of infectious diseases in resource-poor settings. Lancet Infect Dis. 2002 Apr;2(4):243-50. Review.


An accurate, rapid and cost-effective diagnosis is the cornerstone of efficient clinical and epidemiological management of infections. Here we discuss the relevance of an emerging technology, multiplexed immunoassays read by flow cytometry, for the diagnosis of infectious diseases. In these assays, multiple fluorescent microspheres, conjugated to different antigens or antibodies, constitute the solid phase for detecting antibodies or antigens in biological samples. These assays seem to be more sensitive than traditional immunoassays, have a high throughput capacity, and provide a wide analytical dynamic range. Additionally, they have multiplexing ability-ie, they are capable of measuring multiple antibodies or antigens simultaneously. We discuss four different areas where this technology could make an impact in resource-poor settings: (i) infections causing rash and fever in children; (ii) sero-epidemiological studies on vaccine-preventable diseases; (iii) management of genital ulcers and vaginal discharge; and (iv) screening of infections in blood banking. We predict a widespread use for a new breed of small, affordable, practical flow cytometers as field instruments for replacing ELISA and RIA tests, which will also be capable of doing cellular immunological tests such as CD4+ T-cell enumeration and Plasmodium falciparum detection in whole blood.


5511.                     Li J, Matsuoka H, Mitamura T, Horii T. Characterization of proteases involved in the processing of Plasmodium falciparum serine repeat antigen (SERA). Mol Biochem Parasitol. 2002 Apr 9;120(2):177-86.The Plasmodium falciparum serine repeat antigen (SERA), a malaria vaccine candidate, is processed into several fragments (P73, P47, P56, P50, and P18) at the late schizont stage prior to schizont rupture in the erythrocytic cycle of the parasite. We have established an in vitro cell-free system using a baculovirus-expressed recombinant SERA (bvSERA) that mimics the SERA processing that occurs in parasitized erythrocytes. SERA processing was mediated by parasite-derived trans-acting proteases, but not an autocatalytic event. The processing activities appeared at late schizont stage. The proteases are membrane associated, correlating with the secretion and accumulation of SERA within the parasitophorous vacuole membrane (PVM). The activity responsible for the primary processing step of SERA to P47 and P73 was inhibited by serine protease inhibitor DFP. In contrast, the activity responsible for the conversion of P56 into P50 was inhibited by each of the cysteine protease inhibitors E-64, leupeptin and iodoacetoamide. Moreover, addition of DFP, E-64 or leupeptin to the cultures of schizont-stage parasites blocked schizont rupture and release of merozoites from PVM. These results indicate that SERA processing correlates to schizont rupture and the processing is mediated by at least three distinct proteases.

5512.                     Mahesh RK, Jauhari RK. Incrimination of Anopheles fluviatilis james, 1902 as a vector of malaria in forested areas of Doon valley. Indian J For.  2001; 24(1), 72-6.
Effects of different combinations of plant growth regulators on callus induction and formation of multiple shoots from various explants of Rauwolfia serpentina were studied. Maximum callus induction (91.66%) was found on MS basal medium containing 2, 4-D (2.0 mg/l) and BAP (0.2 mg/l) when leaf was the explant. Callus growth could be improved with adequate concentrations of auxin and cytokinin to MS medium without the addition of casein hydrolysate, coconut milk and yeast extract. Multiple shoots (2-4) were induced from the shoot apices and nodal segmetns on MS medium supplemented with BAP and NAA. A substantial positive correlation between biomass and crude alkaloid fraction (CAF) indicated an increase in alkaloid accumulation. Medium optimization may thus lead to enhancement of tissue culture response and alkaloid contents of sarpagandha.


5513.                     Nand N, Balani N, Aggrawal H, Sharma M. Singh M. Renal dysfunction in malaria. Surr med Trends. 2001; 5(1), 855-63. Clinical profile and renal functions were evaluated in sixty adult patients of malaria. Routine investigations, liver function test, renal profile and haematological investigations were done on admission, day 4 and day 7. There were fourteen cases of Plasmodium vivax, forty one of falciparum, two of mixed and three of unclassifiable species. The mean haemoglobin was 7.4±2.8 gm%(vivax 9.6±1.6 gm% and falciparum 6.7±2.8 gm, p<0.01). eighteen patients had increased serum creatinine (mean 3.9±2.5 mg% ), forty four had decreased createnine clearance (mean 42.6±26.1 ml/min) and albuminuria was observed in forty seven patients (mean 0.52±8 g/day). The creatinine clearance was 91.9±25.4 and 53.7±35.0 ml/min in vivax and falciparum subgroups respectively (p<0.001). Histopathology showed evidence of glomerular and tubular changes in the form of mesengial prominence (45%), gromerular hyperlobulation (9%), tubular degeneration (18%), hydropic changes (18%) and a variety of casts (36%). Renal dysfunction was more in patients of falciparum malaria with heavy infestation. Proteinuria observed in 78% cases was mild and transient and observed in absence of overt renal failure…………..



5514.                     Padhy PK, Parija BL, Hui PK, Tripathy SK, Ash Tm Biswas ASG. Atypical manifestations of malaria. Antiseptic, Madurai. 2002; 99(1), 1-4.
Describing atypical or unusual manifestations of malaria is twofold. First to alert clinicians and other health workers to the symptoms and signs which are associated with progression to life threatening disease. Urgent and special treatment is required including parenteral chemotherapy or referral to a level of health services where this can be given. Secondly to indicate the clinical features which should be looked for and systematically recorded in any research study. This should allow  comparison of study population in different geographical areas and interpretation of data to assess morbidity, mortality and long term sequelae.

5515.                     Rajshekhar M, Nandakumar NV. Occupational malaria and health risk among select occupational health care employee groups in an urban hospital at Tirupati, A. P. Indian J Malar. 2003, 37(3-4), 53-60. Attempt was made to see the occupational risk of malaria among health care workers of Sri Venkateswara Ramnarayan Ruia Government General Hospital (SVRRGGH), Tirupati, Andhra Pradesh. The cohort studies revealed association between exposure to occupational (hospital) environment and malaria among hospital staff. Retrospective cohort studies were made. 1354 subjects namely hospital staff exposed to occupational environment included civil assistant surgeons and physicians, the students of medicine, the students of nursing, permanent nursing sthaff and the class IV employees (class IV included janitorial, male nursing orderlies, female nursing orderlies, attenders, laundry workers and the rest). Retrospective empidemiological studies were carried put for four years on the cohorts and the hospital staff. The data showed statistically significant relative risk and attributable risk for malaria. Physicians and civil assistant surgeons showed no incidence of malarial. The relative risk for malaria in the class IV employees was 1.27, 0, 5.8 and 2.9 for the years 1995-98. These results provide and evidence for an association between occupational environment and malaria for  the hospital staff and is more prevalent among certain group of the hospital staff.

5516.                     Ram Rakhiani N, Singhvi D, Jain A, Rakhiani R, Sharma V, Singhvi A. Clinical profile and hepatic dysfunction in malaria. Antiseptic, Madurai. 2001; 98(10), 390-2.
Clinical profile and hepatic functions were evaluated in sixty adult patients of malaria. Detailed history and clinical examination of each patient was don. There were fourteen cases of Plasmodium vivax, forty one of falciparum, two of mixed and three of unclassifiable species. Main clinical presintation included fever (60) alterations in sensorium (28), clinical jaundice (28), oliguria (7), splenomegaly (36), hepatomegaly (20) and dark coloured urine (6). The mean haemoglobin was 7.4
±2.8 g%, (vivax 9.6±1.6g and falciparum 6.7±2.8 g% p<0.01). decreased platelets count were found in six patients. Fibrin degradation products (FDP) were positive in five; prothrombin index (PTI) was decreased in seventeen and serum bilirubin was raised in thirty one (mean 7.6±8.8 mg%). Transaminases were raised in forty one patients (mean AST 120±134, ALT 130±164 IU/L).  


5517.                     Rosner I. Uses of error: early and late. Lancet. 2002 Apr 20;359(9315):1422. No Abstract.

5518.                     Saparia B, Solanki A, Murthy RSR. Sustained release implants of chloroquine phosphate for possible use in chemoprophylaxis of malaria. Indian J expl Biol. 2001. 39(9), 902-05.
Implants of chloroquine phosphate (CQP) using biodegradeable polymer, gelatin (G) and crossed-linked gelatin (CLG) were prepared and evaluated to assess their physicochemical properties and in vitro release profile. The mechanics and kinetics were studied to correlate the release phenomenon with the formulation parameters. Out of the many batches of the implants investigated, the implant prepared with 20% gelatin at 2:1 drug polymer ratio, 10% crosslinking agent at 2% plasticizer (Batch J) was found to provide optimum release behaviour conforming to the requirement of a long term implant for a week. In vivo studies conducted on albino rats showed consistent therapeutic blood level over a period of 7 days. Mean residence time (MRT) of the drug release in the body, calculated as the ratio of the area under concentration time curve (AUC) was 72 hr implant against 2.42 hr for subcutaneous injection      


5519.                     Sharma I, Rawat DS, Pasha ST, Biswas S, Sharma YD. Complete nucleotide sequence of the 6 kb  element and conserved cytochrome b gene sequence among Indian isolates of Plasmodium falciparam. Int J Parasite. 2001; 31(10), 1107-13.
Malaria parasite contains a nuclear genome with 14 chromosome and two extrachromosomal DNA molecules of 6 kb element or mitochondrial DNA, has been sequenced from several  Plasmodium falciparum isolates because this is a potential drug target. Here describe the complete nucleotide sequence of this element from an Indian isolate of P. falciparam. It is 5967 bp in size and shows 99.6% homology with the 6 kb element of other isolates. The element contains three open reading frames for mitochondrial proteins-cytochrome oxidase subunit I (CoI), submit II (CoIII) and cytochrome b (Cyb) which were found to be expressed during blood stages of the parasite. Also sequenced the entire Cyb gene from several Indian isolates of P. falciparum. Th rate of  mutation in this gene was very low since 12 of 14 isolates showed the identical sequence. Only one isolate showed a maximum change in five amino acids where as the other isolate showed only one amino acid change. However, none of the Indian isolates showed any change in those amino acids of cyb which are associated with resistance to various drugs as these drugs are not yet commonly used in India.


5520.                     Singh KB, Anand K, Krishna T, Kant S, Ray T, Kapoor SK. Outbreak of malaria in a village in Faridabad District, Haryana. Indian J Malar. 2000, 37(3-4), 106-10. No Abstract.

5521.                     Singh S, Chatterjee S, Sohoni R, Badakere S, Sharma S. Sera from lupus patients inhibit growth of P-Falciparum in culture. Autoimmunity. 2001; 33(4), 253-63.
Large number of malaria immune persons from Eastern India were found to possess antibodies to the ribosomal phosphoprotin PO (PfPO) of the human malarial parasite Plasmodium falciparum. The characterization of PfPO has been reported recently, and it has been shown that antibodies against PfPO inhibit P. Falciparum in vitro. About 10-15% of the patients suffering from the autoimmune disorder systemic Lupus Erythematosus (SLE) possess autoantibodies to the human ribosomal P protein. In order to test the cross-reactivity of the human and Plasmodium falciparum PO proteins and to compared the SLE  patients and malaria immune persons response, sera from 41 Indian SLE patients were tested against the P. falciparum PfPO by Western blot analysis. Four of these samples (9.75%) were found to be cross-reactive to the carboxy-terminal domain of PfPO, but not to the amino-terminal domain of PfPO. The PfPO reactive SLE sera inhibited the growth of Plasmodium falciparum in vitro. IgG purified from one such cross-reactive serum sample inhibited the growth of P. falciparum. Depletion of anti-PO antibodies from this IgG preparation resulted in the removal of growth inhibition. Sera samples were collected from one of the PfPF positive SLE patient from Mumbai, India, at different stages of the disease progression, and screen for the presence of anti-PfPO antibodies. This patients serum inhibited the parasited growth in vitro only during the phase.

5522.                   Singh S, Singh N, Handa R. Tumor necrosis factor – alpha in patients with malaria. Indian J Malar. 2000; 37(1-2), 27-33.
Serum concentrated of Tumor Nerosis Factor-alpha (TNF-
a) was observed in 54 parasitologically confirmed cases of malaria. Of them, 15 cases were Plasmodium falciparum with cerebral involvement, three cases with mixed infections of P. falciparum and P. vivax, 32 cases of P. vivax, three cases of P. malaria and one case of P. ovale. Five out of 15 patients of P. falciparum (33.3 per cent), one out of 54 patients with mixed infection of P. falciparum and P. malariae (1.8 per cent) had fatal outcome. The serum TNF-a measured by avidin-biotin sandwich ELISA, was found to be significantly raised in P. falciparum and more so in fatal infections. The degree of parasitaematic, due to single or double infection, had positive effect on cytokine production. The mean TNF-a concentration was statistically significantly higher (p<0.001) in P. falciparum then in P. vivax parasites infection. The mean TNF-a values in P. falciparum and P. vivax were 915 and 280.6 against the values in normal healthy controls of 12.9 pcg/ml respectively (p<0.001). The study thus showed that the serum concentration of TNF-a correlated well with severity of malaria and these values could be used as an important prognostic marker of the disease.


5523.                     Soni CL, Kumar MR, Gupta BK, Singh VB, Srimali L, Nayak KC, Chadda VS. Prognostic implication of hypocalcemia and QTc interval in malaria. Indian J  Malar. 2000. 37(3-4), 61-7.
Hundred confirmed cases of malaria were included in the present study to determine the clinical and prognostic implications of hypocalcemia and corrected QT interval (QTc) prolongation in malaria. Peripheral blood smear examination was done to determine the parasite species and the parasite load. Serum calcium level and QTc measurements in electrocardiogram were done for each patient fifty patients were of P. falciparum malaria (38 complicated and 12 uncomplicated), 40 of vivax malaria and 10 patients were having mixed (P. falciparum and P. vivax) infection. Hypocalcimia was found in 26 cases in which QTc was prolonged. Ten patients who had convulsions, all of them were having QTc prolongation and four had hypocalcemia. A total number of eight patients had muscle spasm, of which six had QTc prolongation and four had hypocalcemia. There were 34 cases of cerebral malaria, of which 18 had hypocalcemia as well as QTc prolongation, 12 of them developed renal failure and 14 had high parasitaemia. Four patients died who had hypocalcemia and QTc prolongation due to hepatorenal syndrome. The mean parasite load, QTc interval and serum calcium were 2.69
±1.0, 0.468±0.055 sec and 8.16±0.86 mg/dl respectively in complicated mixed falciparum malaria; 1.6±0.55, 0.442±0.043 sec and 8.72®0.97 mg/dl in complicated mixed (Pf+Pv) infection.       


5524.                     Srivastava A, Nagpal BN, Saxena R, Subbarao SK. Predictive habitat modelling for forest malaria vector species A. dirus in India – a GIS-based approach. Curr Sci. 2001; 80(9), 1129-34.
Anopheles dirus is found in deep-forested areas where manual surveys are very difficult because of inaccessibility. Geographic Information System (GIS) and a Boolean operator have been used to map areas where the species is likely to be found. Being a forest-based species, thematic maps of forest cover, altitude, rainfall and temperature were prepared. Overlaying and integration of thematic maps were done using Arc/Info NT and analysis by Arc/view 3.1 (GIS ESR) software. The results were validated through reported distribution and were found correct. The technique can cover vast and inaccessible areas, fast and easily duplicable in other parts of the world. Once the vector distribution is known, species-specific control measures can be formulated.


5525.                     Srivastava HC, Sharma SK. Chloroquine resistant Plasmodium falciparum in migrant population. Indian J Malar. 2000; 37(1-2), 39-42. No Abstract.

5526.                     Wongsrichanalai C, Miller RS. Malaria rapid tests: a public health perspective. Lancet. 2002 May 18;359(9319):1781. No Abstract.

5527.                     Yadav RS, Sampath RR, Sharam VP. Deltamenthrin treated bednets for control of malaria transmitted by Anopheles culcifacies (Diptera: Culicidae) in India. J Med Ent. 2001; 38(5), 613-22. In November 1990, nylon bednets treated with deltamethrin at 25 mg/m2 were given out in two villages (population 1062), untreated bed nets were given out in five villages (population 1226) and in one village (population 786) nets were not given. Nets were retreated in October 1991 and June 1992 in treated net villages. The trial continued until October 1992. The treated nets caused significant reduction in indoor resting density, biting (landing), light lap catches, human engorgement rate, and parous rate of malaria vector Anopheles culicifacies Giles as compared with untreated nets or no nets.  Untreated nets also caused reduction in biting and indoor density. Treated nets treated insecticidal action well over 6 mo. In the final year, malaria incidence was reduced 8.9% in and 59.1% in villages with treated nets. The relative risk of malaria and parasite rates declined significantly in the villages with  treated nets. Pediatric splenomegaly rate did not change in the no-net village, increased significantly in villages with nets. Treated nets also reduced anemia rates, but Hb concentration increased in all villages. Considering the benefits of treated bednets and development of resistance among vectors to DDT and malathion.


5528.                     Abdel-Wahab A, Abdel-Muhsin AM, Ali E, Suleiman S, Ahmed S, Walliker D, Babiker HA. Dynamics of gametocytes among Plasmodium falciparum clones in natural infections in an area of highly seasonal transmission. J Infect Dis. 2002 Jun 15;185(12):1838-42.


The dynamics of gametocyte production in Plasmodium falciparum clones were studied in inhabitants of an area of highly seasonal malaria transmission in eastern Sudan. Reverse-transcriptase polymerase chain reaction was used to detect expression of 2 genes that encode gametocyte-specific proteins, pfs25 and pfg377, in parasites sampled from individuals throughout one year. Some patients who acquired infections during the wet season were found to harbor subpatent gametocytemia through the following dry season in the apparent absence of mosquito transmission. Genotyping of parasites in multiclonal infections showed considerable fluctuation of gametocyte production by individual clones. The gametocytes present at the end of the dry season provide the most probable source of the genetically complex cyclical malaria outbreaks following the rainy season in this region.


5529.                     Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V.  Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet. 2002 Apr 13;359(9314):1311-2.


The high frequency of the sickle-cell haemoglobin (HbS) gene in malaria endemic regions is believed to be due to a heterozygote (HbAS) advantage against fatal malaria. Data to prospectively confirm the protection associated with HbAS against mortality are lacking. We show that HbAS provides significant protection against all-cause mortality, severe malarial anaemia, and high-density parasitaemia. This significant reduction in mortality was detected between the ages of 2 and 16 months, the highest risk period for severe malarial anaemia in this area. These data are important in understanding the role of malaria in the selection and maintenance of the sickle cell gene.

5530.                     Beebe NW, Cooper RD. Distribution and evolution of the Anopheles punctulatus group (Diptera: Culicidae) in Australia and Papua New Guinea. Int J Parasitol. 2002 May;32(5):563-74. Review.


The members of the Anopheles punctulatus group are major vectors of malaria and Bancroftian filariasis in the southwest Pacific region. The group is comprised of 12 cryptic species that require DNA-based tools for species identification. From 1984 to 1998 surveys were carried out in northern Australia, Papua New Guinea and on islands in the southwest Pacific to determine the distribution of the A. punctulatus group. The results of these surveys have now been completed and have generated distribution data from more than 1500 localities through this region. Within this region several climatic and geographical barriers were identified that restricted species distribution and gene flow between geographic populations. This information was further assessed in light of a molecular phylogeny derived from the ssrDNA (18S). Subsequently, hypotheses have been generated on the evolution and distribution of the group so that future field and laboratory studies may be approached more systematically. This study suggested that the ability for widespread dispersal was found to have appeared independently in species that show niche-specific habitat preference (Anopheles farauti s.s. and A. punctulatus) and conversely in species that showed diversity in their larval habitat (Anopheles farauti 2). Adaptation to the monsoonal climate of northern Australia and southwest Papua New Guinea was found to have appeared independently in A. farauti s.s., A. farauti 2 and Anopheles farauti 3. Shared or synapomorphic characters were identified as saltwater tolerance (A. farauti s.s. and Anopheles farauti 7) and elevational affinities above 1500 m (Anopheles farauti 5, Anopheles farauti 6 and A. farauti 2).

5531.                     Chau TT, Mai NT, Phu NH, Luxemburger C, Chuong LV, Loc PP, Trang TT, Vinh H, Cuong BM, Waller DJ, Sinh DX, Day NP, Hien TT, White NJ. Malaria in injection drug abusers in Vietnam. Clin Infect Dis. 2002 May 15;34(10):1317-22.


A prospective case-control study was conducted in a referral hospital in Ho Chi Minh City, Vietnam, to compare the clinical and laboratory features and outcome of severe falciparum malaria in injection drug abusers (IDAs) with those of patients who had acquired malaria by mosquito bite. From 1991 to 1996, 70 IDAs were admitted to the hospital, of whom at least 32 had acquired malaria by needle sharing. Although IDAs were more likely than control patients with severe malaria to be malnourished and to have coincident hepatitis B, hepatitis C, and human immunodeficiency virus infections, the overall rates of mortality, complications, and recovery were similar in the 2 groups. The route of malaria acquisition did not affect the outcome of severe malaria. The management of severe malaria in IDAs is similar to that for other patients.

5532.                     Chotivanich K, Udomsangpetch R, McGready R, Proux S, Newton P, Pukrittayakamee S, Looareesuwan S, White NJ.  Central role of the spleen in malaria parasite clearance. J Infect Dis. 2002 May 15;185(10):1538-41.

In acute malaria, red blood cells (RBCs) that have been parasitized, but no longer contain a malaria parasite, are found in the circulation (ring-infected erythrocyte surface antigen [RESA]-RBCs). These are thought to arise by splenic removal of dead or damaged intraerythrocytic parasites and return of the intact RBCs to the circulation. In a study of 5 patients with acute falciparum malaria who had previously undergone splenectomy, it was found that none of these 5 patients had any circulating RESA-RBCs, in contrast to the uniform finding of RESA-RBCs in all patients with acute malaria and intact spleens. Parasite clearance after artesunate treatment was markedly prolonged, although the parasites appeared to be dead and could not be cultured ex vivo. These observations confirm the central role of the spleen in the clearance of parasitized RBCs after antimalarial treatment with an artemisinin derivative. Current criteria for high-grade antimalarial drug resistance that are based on changes in parasitemia are not appropriate for asplenic patients.

5533.                     Ehrhardt S, Mockenhaupt FP, Agana-Nsiire P, Mathieu A, Anemana SD, Stark K, Otchwemah RN, Bienzle U.  Efficacy of chloroquine in the treatment of uncomplicated, Plasmodium falciparum malaria in northern Ghana. Ann Trop Med Parasitol. 2002 Apr;96(3):239-47.


Chloroquine (CQ) resistance in Plasmodium falciparum contributes to growing malaria-attributable morbidity and mortality in sub-Saharan Africa. However, the extent and degree of such resistance vary considerably between endemic areas. Data on CQ resistance in northern Ghana are almost entirely lacking. The therapeutic efficacy of CQ in uncomplicated malaria was therefore assessed, in a standard, 14-day protocol, in 225 children aged <5 years in Tamale, in the Northern region of Ghana. Early treatment failure (ETF) was observed in 11% of the children and late treatment failure in 18%. High initial parasite density and young age were independent predictors for ETF. Resistant parasitological responses (RI-RIII) were seen in 57% of the cases that could be classified. More than half of these responses occurred in children fulfilling the criteria for adequate clinical response (ACR), indicating a considerable lack of agreement between parasitological and clinical outcome. During the follow-up period, haemoglobin levels increased by approximately 1g/dl not only in patients with ACR but also in those who experienced clinical failure more than 1 week post-treatment. As CQ-treatment failure occurred in >25% of the children and more than half of the parasitological responses indicated resistance, current recommendations for the treatment of uncomplicated malaria in young children in northern Ghana have to be reconsidered.

5534.                     Good MF, Xu H, Batzloff M.  Adapting immunity with subunit vaccines: case studies with group A Streptococcus and malaria. Int J Parasitol. 2002 May;32(5):575-80. Review.


Although vaccines have widely been regarded as the most cost-effective way to improve public health, for some organisms new technological advances in vaccine design and delivery, incurring additional developmental costs, will be essential. These organisms are typically those for which natural immunity is either slow to develop or does not develop at all. Clearly, such organisms have evolved strategies to evade immune responses and innovative approaches will be required to induce a type of immune response which is both different to that which develops naturally and is effective. This article describes some approaches to develop vaccines for two such organisms (malaria parasites and Streptococcus pyogenes (group A Streptococcus)) that are associated with widespread mortality and morbidity, mostly in the poorest countries of the world. At this stage, the challenges are primarily scientific, but if these hurdles are surmounted then the challenges will become financial ones--developing much needed vaccines for people least able to afford them.

5535.                     Hay SI, Noor AM, Simba M, Busolo M, Guyatt HL, Ochola SA, Snow RW. Clinical epidemiology of malaria in the highlands of western Kenya. Emerg Infect Dis. 2002 Jun;8(6):543-8.


Malaria in the highlands of Kenya is traditionally regarded as unstable and limited by low temperature. Brief warm periods may facilitate malaria transmission and are therefore able to generate epidemic conditions in immunologically naive human populations living at high altitudes. The adult:child ratio (ACR) of malaria admissions is a simple tool we have used to assess the degree of functional immunity in the catchment population of a health facility. Examples of ACR are collected from inpatient admission data at facilities with a range of malaria endemicities in Kenya. Two decades of inpatient malaria admission data from three health facilities in a high-altitude area of western Kenya do not support the canonical view of unstable transmission. The malaria of the region is best described as seasonal and meso-endemic. We discuss the implications for malaria control options in the Kenyan highlands.

5536.                     le Cessie S, Verhoeff FH, Mengistie G, Kazembe P, Broadhead R, Brabin BJ. Changes in haemoglobin levels in infants in Malawi: effect of low birth weight and fetal anaemia. Arch Dis Child Fetal Neonatal Ed. 2002 May;86(3):F182-7.


OBJECTIVES: To examine the effect of low birth weight (LBW) and fetal anaemia (FA) on haemoglobin (Hb) patterns in infancy. To study the additional contribution of other risk factors known at birth. To examine the effect of iron supplementation during infancy on Hb levels. METHODS: A stratified cohort of infants in Malawi (83 with LBW (< 2500 g), 111 with FA (cord Hb < 125 g/l), 31 with both LBW and FA, and 176 controls) was followed during infancy. Hb levels were measured at about 2, 4, 6, 9, and 12 months of age. Repeated measures models were used to describe the changes in Hb levels over time. RESULTS: The mean Hb concentration in the control group was 95.5 g/l (95% confidence interval (CI) 92.5 to 98.5) at 2 months, 86.9 g/l (95% CI 84.4 to 89.4) at 9 months, and 898 g/l (95% CI 874 to 92.2) at 12 months. Differences between LBW infants and controls increased over time (difference at 12 months: 5.5 g/l (95% CI 1.3 to 9.7)). Infants with FA had borderline significantly lower Hb at 2 months (p =0.07), but at 6 months their levels were similar to those of controls. The LBW infants and those with FA had the lowest Hb levels (difference from controls at 12 months 7.9 g/l). Parity, placental and maternal malaria at delivery, and sex significantly affected Hb levels after adjustment for LBW and FA. After iron supplementation, Hb significantly increased. CONCLUSIONS: Antimalarial control and iron supplementation throughout pregnancy should be increased to reduce the incidence of infant anaemia and improve child development and survival.


5537.                     Lycett GJ, Kafatos FC. Anti-malarial mosquitoes? Nature. 2002 May 23;417(6887):387-8.  No Abstract.

5538.                     McKenzie FE, Jeffery GM, Collins WE. Plasmodium vivax blood-stage dynamics. J Parasitol. 2002 Jun;88(3):521-35.


We examine the dynamics of parasitemia and gametocytemia reflected in the preintervention charts of 221 malaria-naive U.S. neurosyphilis patients infected with the St. Elizabeth strain of Plasmodium vivax, for malariatherapy, focusing on the 109 charts for which 15 or more days of patency preceded intervention and daily records encompassed an average 98% of the duration of each infection. Our approximations of merogony cycles (via "local peaks" in parasitemia) seldom fit patterns that correspond to "textbook" tertian brood structures. Peak parasitemia was higher in trophozoite-induced infections than in sporozoite-induced ones. Relative densities of male and female gametocytes appeared to alternate, though without a discernably regular period. Successful transmission to mosquitoes did not depend on detectable gametocytemia or on absence of fever. When gametocytes were detected, transmission success depended on densities of only male gametocytes. Successful feeds occurred on average 4.7 days later in an infection than did failures. Parasitemia was lower in homologous reinfection, gametocytemia lower or absent.

5539.                     Nuwaha F. People's perception of malaria in Mbarara, Uganda. Trop Med Int Health. 2002 May;7(5):462-70.


To understand people's perceptions of malaria and their implications for control programmes, we held focus group discussions (FGDs) and conducted semi-structured interviews (SSIs) with community members in Mbarara, Uganda. Mosquitoes were perceived as the cause or transmitters of malaria but the causation/transmission model of people differed from biomedical facts. Convulsions, a common complication of malaria, were perceived as a supernatural ailment, best treated by traditional medicine, as was splenomegaly. More than 70% of the patients with malaria had treatment from non-public health sources. This included self-treatment (13%), use of traditional healers (12%) and use of private medical practitioners/pharmacists (69%). Although 26% (887/3309) used bednets to prevent malaria, only 7% of the nets were impregnated with insecticide. People who did not use bednets cited discomfort because of heat/humidity and their high cost as reasons. To improve malaria control in this area, people need to be educated on the connection between mosquitoes and malaria and on seeking biomedical treatment for convulsions. The malaria control programme could collaborate with traditional and private health care providers to increase promotion of insecticide-impregnated mosquito nets.


5540.                     Rowe JA, Kyes SA, Rogerson SJ, Babiker HA, Raza A. Identification of a conserved Plasmodium falciparum var gene implicated in malaria in pregnancy. J Infect Dis. 2002 Apr 15;185(8):1207-11.


The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family is a highly polymorphic class of variant surface antigens encoded by var genes that play an important role in malaria pathogenesis. This report describes the unexpected finding that 1 of the var genes encoding a PfEMP1 variant that binds to the host receptor chondroitin sulfate A (CSA) and is implicated in malaria in pregnancy is well conserved among P. falciparum isolates worldwide. The N-terminal domains of this PfEMP1 variant are especially highly conserved, whereas the functional CSA binding domain is more variable. Analysis of var gene expression in placental parasites from primigravid women in Malawi did not support a role for this conserved gene in placental infection but identified a second commonly occurring var gene. These results indicate the need for reevaluation of previous assumptions of a minimal overlap between var gene repertoires from different parasite isolates.


5541.                     Serghides L, Kain KC. Mechanism of protection induced by vitamin A in falciparum malaria. Lancet. 2002 Apr 20;359(9315):1404-6.


Supplementation with vitamin A potentiates host resistance to malaria, however, the underlying mechanism is unknown. We tested the effects of 9-cis-retinoic acid, a metabolite of vitamin A, on CD36 expression, non-opsonic phagocytic clearance of parasitised erythrocytes, and TNFalpha production in human monocytes and macrophages. We found reduced secretion of TNFalpha, upregulated CD36 expression, and increased phagocytosis of Plasmodium falciparum-parasitised erythrocytes. Increased parasite clearance and reduced proinflammatory cytokine responses to infection might partly explain the beneficial effects of supplementation with vitamin A in malaria.


5542.                     Wilson RJ. Progress with parasite plastids. J Mol Biol. 2002 May 31;319(2):257-74. Review. No Abstract.

5543.                     Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002 Apr;2(4):209-18. Review. No Abstract.

5544.                     Zhang K, Rathod PK. Divergent regulation of dihydrofolate reductase between malaria parasite and human host. Science. 2002 Apr 19;296(5567):545-7. No Abstract.


5545.                     Dardick K. Educating travelers about malaria: dealing with resistance and patient noncompliance. Cleve Clin J Med. 2002 Jun;69(6):469-79. Review.


Malaria is a risk to travelers in many parts of the world. Physicians need to tailor chemoprevention strategies to take into account resistance patterns. Patient education is important, especially for those travelers least likely to comply with prevention strategies. Most travelers who contract malaria do not become ill until they return home, so recognition and treatment are crucial.

5546.                     Hoffman SL, Goh LM, Luke TC, Schneider I, Le TP, Doolan DL, Sacci J, de la Vega P, Dowler M, Paul C, Gordon DM, Stoute JA, Church LW, Sedegah M, Heppner DG, Ballou WR, Richie TL. Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites. J Infect Dis. 2002 Apr 15;185(8):1155-64.


During 1989-1999, 11 volunteers were immunized by the bites of 1001-2927 irradiated mosquitoes harboring infectious sporozoites of Plasmodium falciparum (Pf) strain NF54 or clone 3D7/NF54. Ten volunteers were first challenged by the bites of Pf-infected mosquitoes 2-9 weeks after the last immunization, and all were protected. A volunteer challenged 10 weeks after the last immunization was not protected. Five previously protected volunteers were rechallenged 23-42 weeks after a secondary immunization, and 4 were protected. Two volunteers were protected when rechallenged with a heterologous Pf strain (7G8). In total, there was protection in 24 of 26 challenges. These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.


5547.                     Wallace R, Wallace RG. Immune cognition and vaccine strategy: beyond genomics. Microbes Infect. 2002 Apr;4(4):521-7. Review.


I.R. Cohen's work on immune cognition has profound implications for vaccine strategies when simple elicitation of sterilizing immunity fails, given Nisbett's analysis showing that cognition by the central nervous system is culturally determined. We reinterpret West African cultural variation in immune response to malaria, and the US cultural variation in HIV transmission, from this perspective, which does not reify 'race'.


5548.                     Nshakira N, Kristensen M, Ssali F, Whyte SR. Appropriate treatment of malaria? Use of antimalarial drugs for children's fevers in district medical units, drug shops and homes in eastern Uganda. Trop Med Int Health. 2002 Apr;7(4):309-16.


OBJECTIVE: To evaluate the quality of pharmaceutical care of malaria for children in eastern Uganda prescribed at government health units and drug shops, and administered by caretakers at home; and to assess its appropriateness in relation to national treatment guidelines, which recommend chloroquine over 3 days. METHODS: We followed 463 children under 5 years whose caretakers attended two drug shops and two government health units to seek treatment for fever. The children were examined and the caretakers interviewed on the day of enrollment in the study (day 0), and in their homes on days 3 and 7. Data was collected on drug use prior to attending the shop or health unit, the treatment provided at these study sites, and the administration of drugs at home over the following 3 days. RESULTS: Before attending the study sites, 72% of children had already been given some biomedical drugs, and 40% had received the recommended drug, chloroquine. Health workers prescribed chloroquine for 94% of the children, but only 34% of the recommended doses followed guidelines. Two-thirds of the children were prescribed an injection of chloroquine. By day 3, according to caretaker reports, about 38% of the children had received chloroquine in compliance with the instructions given by the health workers and drug shop attendants. Only 28% of the children had received chloroquine at the optimal dose of 20-30 mg/kg recommended by national policy. CONCLUSION: The methods were useful for examining adherence of both caretakers and health care providers to national guidelines and the extent to which caretakers were compliant with providers' prescriptions. Chloroquine and antipyretics were the drugs of choice for fever in these areas of rural eastern Uganda. But children did not receive the recommended dosage of chloroquine because of lack of compliance on the parts of providers as well as users of health care.


5549.                     Shiff C. Integrated approach to malaria control. Clin Microbiol Rev. 2002 Apr;15(2):278-93. Review.


Malaria draws global attention in a cyclic manner, with interest and associated financing waxing and waning according to political and humanitarian concerns. Currently we are on an upswing, which should be carefully developed. Malaria parasites have been eliminated from Europe and North America through the use of residual insecticides and manipulation of environmental and ecological characteristics; however, in many tropical and some temperate areas the incidence of disease is increasing dramatically. Much of this increase results from a breakdown of effective control methods developed and implemented in the 1960s, but it has also occurred because of a lack of trained scientists and control specialists who live and work in the areas of endemic infection. Add to this the widespread resistance to the most effective antimalarial drug, chloroquine, developing resistance to other first-line drugs such as sulfadoxine-pyrimethamine, and resistance of certain vector species of mosquito to some of the previously effective insecticides and we have a crisis situation. Vaccine research has proceeded for over 30 years, but as yet there is no effective product, although research continues in many promising areas. A global strategy for malaria control has been accepted, but there are critics who suggest that the single strategy cannot confront the wide range of conditions in which malaria exists and that reliance on chemotherapy without proper control of drug usage and diagnosis will select for drug resistant parasites, thus exacerbating the problem. An integrated approach to control using vector control strategies based on the biology of the mosquito, the epidemiology of the parasite, and human behavior patterns is needed to prevent continued upsurge in malaria in the endemic areas.

5550.                     Thong BY, Leong KP, Chng HH. Hypersensitivity syndrome associated with dapsone/pyrimethamine (Maloprim) antimalaria chemoprophylaxis. Ann Allergy Asthma Immunol. 2002 May;88(5):527-9.


BACKGROUND: Dapsone 100 mg/pyrimethamine 12.5 mg (Maloprim; Beacons Chemicals Pte Ltd, Singapore) is routinely prescribed for antimalarial chemoprophylaxis in military servicemen in Singapore who are not glucose-6-phosphate dehydrogenase-deficient. METHODS: We report a series of three male National Servicemen with hypersensitivity syndrome from Maloprim. RESULTS: The three patients were diagnosed with hypersensitivity syndrome based on the presence of features of a drug hypersensitivity syndrome including fever, lymphadenopathy, maculopapular exanthema, hepatitis, and definite exposure to weekly Maloprim alone. A mild Coombs positive hemolytic anemia was also observed in one patient. All the clinical, hematologic, and biochemical derangements normalized within 3 months of tapering regimens of moderate-dose prednisolone. CONCLUSIONS: Drug hypersensitivity syndromes can occur even on low-dose, weekly drug regimens. Hypersensitivity syndrome from weekly Maloprim is potentially reversible when recognized and treated early.




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