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Use of an optimality model to solve the immunological puzzle of concomitant infection.

Immunological data indicate that different subsets of T-helper cells work best against different types of infection. Concomitant infection of a host may thus impose either conflicting or synergistic immune response requirements, depending upon the extent to which the component optimal immune responses differ. Drawing upon empirically-determined optimal responses to single-species infections, an optimality model is here used to generate testable hypotheses for optimal responses to concomitant infection. The model is based upon the principle that the joint immune response will minimize divergence from each of the optima for single-species infections, but that it will also be weighted by the importance of mounting the correct response against each infectious organism. The model thus predicts a weighted average response as the optimal response to concomitant infection. Data on concomitant infection of murine hosts by the parasites Schistosoma mansoni and Toxoplasma gondii will provide the first test of the optimality model. If the weighted average hypothesis holds true, then there are no emergent immunological properties of concomitant infections and we may be able to understand immune responses to concomitant infection directly via our understanding of single-species infections.

Animals↗

Comparison of the OptiMAL rapid test with routine microscopic examination of Giemsa-Stained Thick Blood Film for diagnosis of malaria.

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.

Animals↗

[The optimal mating time in the bitch based on the progesterone concentration in peripheral blood. A comparison of reliability between three ELISA test kits and a 125-iodine radioimmunoassay].

During oestrus the plasma progesterone concentration can be used to determine the optimal time for mating in the dog. In this study, the optimal time for mating for 26 bitches was determined by measuring progesterone concentrations with three ELISA test kits and a 125I-radioimmunoassay (125I-RIA). Two observers evaluated the ELISA results simultaneously. They graded the results independently and did not know which dog was being tested. For both observers, the optimal time for mating, based on progesterone concentrations measured with the Progesterone Small Rapid ELISA test and the Status-Pro test, differed significantly from that based on progesterone concentrations measured by 125I-RIA. Although the optimal time for mating based on the Ovucheck Premate test did not differ significantly from that based on the 125I-RIA, three out of 14 dogs (21%) for observer one and four out of 14 dogs (29%) for observer two would have been mated on a different day than that determined on the basis of results obtained with the 125I-RIA. The results did not change when the advised period for mating based on the RIA results was extended by two days. It is concluded that the progesterone concentrations measured with the ELISA test kits are too inaccurate for clinical use to determine the optimal time for mating. The only reliable results for determining the optimal mating period are obtained when plasma progesterone concentrations are measured with a RIA.

Animals↗

[The evaluation of the postmortem body weight with special reference to the optimal weight (author's transl)].

The investigation was based on 405 men and 482 women. In all cases the optimal weight depending on the metric index and the body weight estimated by means of the Brocaindex was calculated. The comparison of all data revealed the following: 1. Persons deceased have always a lower body weight than living persons of equal age, constitution and sex independant of the method used. That means that diagnosis of generalized adipositas is more difficult in persons autopsied than in persons living. 2. The calculation of the optimal weight and of the Brocaindex does not yield the same results. In the majority of the cases the optimal weight is lower. Therefore, the pathologist must know which method of evaluation of body weight the clinician used. 3. The optimal weight depends on the constitution. This applies to persons deceased as well as living. 4. There is a statistical correlation between postmortem optimal weight and basic disease. For the dicision whether generalized adipositas or extreme cachexia being the cause of death the optimal weight should be considered.

Adult↗

Optimizing Unilateral Electroconvulsive Therapy.

Review of the unilateral-bilateral literature cannot identify the factors that optimize the efficacy of right unilateral electroconvulsive therapy (ECT) (RUL), and we should not confuse hunches with facts. With the exception of stimulus dosing, there is little experimental support that the conditions suggested by Dr. J.-O. Ottosson affect RUL efficacy. The theoretical position that eliciting a full, maximally generalized seizure provides the basis for optimal efficacy also lacks experimental support and is imprecise. Further, the conditions proposed to optimize RUL efficacy also augment its side effect profile. We do not know whether an optimal form of RUL will retain cognitive advantages if compared to optimal bilateral ECT. We also lack a clinically useful marker that an optimal form of RUL has been delivered. Under these conditions, it seems appropriate that the choice of electrode placement be made on an informed case-by-case basis.

Journal Article↗

Problems in the optimal management of myasthenia gravis patients--a prospective clinical survey at Kalafong Hospital.

OBJECTIVES: This study forms part of a clinical survey of problems in the optimal management of patients with inherited neuromuscular diseases seen at Kalafong Hospital in Pretoria. Our objectives were to determine the problems associated with providing patients with optimal management until true remission (cure), and to apply the findings to ongoing improvement of optimal management. This is the first report of the series. METHODS: Twenty-six patients were studied prospectively from 1986 to 1998. Early sternal-splitting thymectomy on class II-V patients as well as anticholinesterases, corticosteroids, azathioprine, plasma exchange, intensive care and various combinations of these constituted part of the optimal management. An assessment of the total monthly income and distance from hospital was done for each patient. RESULTS: Five of the 15 thymectomised patients (33.3%) were lost to follow-up after reaching remission. Of the remaining 10 patients, 6 (40%) are in true remission and the remaining 4 (26.7%) are in pharmacological remission. Four of the 11 patients (36%) treated non-surgically were lost to follow-up. Of the remaining patients, 1 (9.1%) is in true remission and the remaining 6 (54.5%) are in pharmacological remission. The average monthly income of patients lost to follow-up in the thymectomised group was lower than that of patients who continued follow-up, and their homes were further away from hospital. In the non-surgical group the average monthly income of patients lost to follow-up was higher than that of patients who continued follow-up and their homes were nearer to the hospital. CONCLUSION: Early thymectomy (the aggressive approach) resulted in 40% cures, 26.7% pharmacological remissions, no mortality, minimal morbidity, and early discharge. Loss to follow-up was one of the biggest problems in providing optimal management for these patients. We modified optimal management in response to our patients' concerns without sacrificing excellence, and found that poverty and poor access to tertiary hospitals were possible contributory factors to loss to follow-up. Suggestions are made with regard to tackling the problems. Myasthenia gravis (MG) is a disorder of neuromuscular function resulting from an immunologically based premature destruction of acetylcholine receptors.

Adult↗

An optimized individual target brain in the Talairach coordinate system.

The goal of regional spatial normalization is to remove anatomical differences between individual three-dimensional brain images by warping them to match features of a single target brain. Current target brains are either an average, suitable for low-resolution brain mapping studies, or a single brain. While a single high-resolution target brain is desirable to match anatomical detail, it can lead to bias in anatomical studies. An optimization method to reduce the individual anatomical bias of the ICBM high-resolution brain template (HRBT), a high-resolution MRI target brain image used in many laboratories, is presented. The HRBT was warped to all images in a group of 27 normal subjects. Displacement fields were averaged to calculate the "minimal deformation target" (MDT) transformation for optimization. The greatest anatomical changes in the HRBT, following optimization, were observed in the superior precentral and postcentral gyri on the right, the right inferior occipital, the right posterior temporal lobes, and the lateral ventricles. Compared with the original HRBT, the optimized HRBT showed better anatomical matching to the group of 27 brains. This was quantified by the improvements in spatial cross-correlation and between the group of brains and the optimized HRBT (P < 0.05). An intended use of this processing is to create a digital volumetric atlas that represents anatomy of a normal adult brain by optimizing the HRBT to the group consisting of 100+ normal subjects.

Adult↗

[Application of genetic algorithm in optimization of mobile phase composition in high performance liquid chromatography].

Referring to traditional optimal methods, a method for the optimization of isocratic elution mobile phase composition in high performance liquid chromatography has been developed. In this method, the genetic algorithm based on line-crossover and plane-mutation is used. The principle of genetic algorithm and the process of optimization of mobile phase composition in reversed-phase ion-pair high performance liquid chromatography using genetic algorithm are introduced in details. With the concentrations of acetonitrile and ion-pair reagent sodium octane sulfonate chosen as the optimal parameters, the optimum was obtained by three times of optimization procedures. The mean relative error between the predicted and experimental values was 0.75% at the optimum and the optimization results were satisfactory.

Algorithms↗

[Comparison between OptiMAL and the thick smear tests for malaria diagnosis in an endemic area during a non-epidemic period].

The capacity of Optimal to diagnose malaria was compared with the thick smear test in two representative samples, one with acute febrile syndrome (AFS) n = 107, and another diagnosed by thick smear test (AFS + M) n = 82. The samples were chosen from patients at the malaria diagnostic clinic in Turbo, Antioquia, Colombia, between June and August 2000. The study was designed to be descriptive, prospective, and cross-sectional. The two tests were applied simultaneously in the AFS group (parallel, double blind design), and in sequential form in the AFS + M group. The thick smear test was the standard test. Optimal tests were carried out according to the manufacturer's instructions. In the parallel design, Optimal showed, for Plasmodium falciparum, a sensitivity of 40% [95% CI: 18-67], a specificity of 98% (95% CI: 92-100) and positive and negative predictive values of 75% (95% CI: 36-96) and 91% (95% CI: 83-96%), respectively. For Plasmodium vivax, it showed a sensitivity of 97% (95% CI: 82-100), a specificity of 89% (95% CI: 80-95) and positive and negative predictive values of 79% (95% CI: 62-90) and 98% (95% CI: 91-100). With the sequential design, Optimal showed a sensitivity of 67% (95% CI: 52-79) and 97% (95% CI: 83-100) for P. falciparum and P. vivax, respectively. For P. falciparum, the sensitivity was directly proportional to the parasitemia, while the sensitivity for P. vivax was independent from the parasitemia. The diagnostic values and operative characteristics of the thick smear test surpassed the Optimal test in its sensitivity for P. falciparum; the specificities were similar. Both tests were nearly identical in their diagnostic capacity for P. vivax. These results recommend that the thick smear test be retained as a routine or reference test for malaria diagnosis, with Optimal used as an ancillary test.

Adolescent↗

[Dosage regimen optimization in cancer chemotherapy using a mathematical model].

In cancer chemotherapy, it is important to design treatment strategies that ensure a desired rate of tumor cell kill without unacceptable toxicity. To optimize treatment, we used a mathematical model describing the pharmacokinetics of anticancer drugs, antitumor efficacy, and drug toxicity. This model was associated with constraints on the allowed plasma concentrations, drug exposure, and leukopenia. Given a schedule of drug administrations, the mathematical model optimized the drug doses that could minimize the tumor burden while limiting toxicity on the white blood cells. Simulation suggests that the optimal drug administration is an initial high dose chemotherapy up to saturation of constraints associated with normal cell toxicity followed by a maintenance continuous infusion at a moderate rate. Data related to etoposide investigations were next used in a feasibility study. Simulations made with the usual clinical protocols and optimized protocols revealed that model-based optimal drug doses lead to greater cytoreduction. Also, examples showed how to use this new approach for the dose ranging problem and they evaluated the sensitivity of the optimized protocols with respect to the clinical constraints.

Antineoplastic Agents↗

Optimization of the gamma probe-guided parathyroidectomy.

The objective of this study was to determine the patient-specific optimal time to surgery preoperatively to improve operative success in gamma probe-guided parathyroid localization. Fifteen patients with hyperparathyroidism underwent a double-phase Tc99m-MIBI (15-20 mCi) parathyroid scintigraphy to study the Tc99m-MIBI clearance kinetics from parathyroid and thyroid glands and to determine the time point at which the optimal target-to-background ratio was achieved. Optimal time to surgery was determined on the basis of the time at which the target-to-background ratio was maximal. On the day of surgery the patients received the same dose of Tc99m-MIBI and were taken to the operating room at the time of optimal target-to-background ratio. A four-gland exploration was performed with identification and excision of hot lesions using a gamma probe. Ex vivo lesion-to-background ratios were determined. Histopathologic confirmation of a successful parathyroidectomy was obtained intraoperatively by frozen section. The total operative time and the time to localize and excise the parathyroid glands were recorded. The mean surgery time was compared with that of previous parathyroidectomies performed by the same surgical team without use of preoperative scintigraphy and intraoperative gamma probe. Scintigraphy correctly localized parathyroid pathology in 12 of 15 (80%) patients. Intraoperative gamma probe was successful in 15 of 15 (100%). The optimal time to surgery was found to be different for each patient, and the mean time was calculated as 136 +/- 43 minutes. Mean surgery time for the excision of parathyroid gland was 91 +/- 46 minutes, which was significantly shorter than previous four-gland exploration without use of scintigraphy and gamma probe (160 +/- 61 minutes; t = 3.021, P = 0.007). The mean ex vivo lesion-to-background gamma probe count ratio of abnormal parathyroid glands (77.35) was found to be significantly higher than that of all other lesions with abnormal Tc99m-MIBI uptake (5.05) (U = 10.5, P < 0.0001). Optimal target-to-background ratio is essential for the success of gamma probe-guided parathyroidectomy. This ratio was highly variable among the patients in this study. Individualization of the best surgical exploration time after Tc99m-MIBI injection will improve the surgical success of this operation.

Adult↗

Search-based optimization.

The problem of determining the minimum cost hypothetical ancestral sequences for a given cladogram is known to be NP-complete (Wang and Jiang, 1994). Traditionally, point estimations of hypothetical ancestral sequences have been used to gain heuristic, upper bounds on cladogram cost. These include procedures with such diverse approaches as non-additive optimization of multiple sequence alignment, direct optimization (Wheeler, 1996), and fixed-state character optimization (Wheeler, 1999). A method is proposed here which, by extending fixed-state character optimization, replaces the estimation process with a search. This form of optimization examines a diversity of potential state solutions for cost-efficient hypothetical ancestral sequences and can result in greatly more parsimonious cladograms. Additionally, such an approach can be applied to other NP-complete phylogenetic optimization problems such as genomic break-point analysis.

Animals↗

CT-MRI automatic surface-based registration schemes combining global and local optimization techniques.

Medical image registration is commonly required in order to combine the complementary information provided by different medical imaging modalities. In this paper, a new automatic registration scheme is proposed to register 3-D CT-MR head images and is currently tested on a clinical environment. The proposed scheme, after the preprocessing and the outer surface extraction of the data, is based on the use the rigid transformation method, in conjunction with a combination of global and local optimization techniques. Analytically, the paper exploits the optimization efficiency of three widely used optimization techniques, in obtaining the parameters of the rigid transformation model: the Downhill Simplex Method, the Genetic Algorithms and the Simulated Annealing. These optimization techniques are further combined by the sequential application of the Powell optimization method in order to refine the registration and increase its accuracy. A comparative study involving these optimization techniques in conjunction with the rigid transformation, and two other methods, the ICP and the manual methods, is also presented, for a sufficient number of clinical CT-MR brain images. Finally, quantitative and qualitative results are also presented to validate the performance of these automatic surface-based registration schemes, in terms of consistency and accuracy. Throughout of this study, the automatic registration scheme comprising of the rigid transformation in conjunction with the Simulated Annealing method sequentially combined with the Powell method has been performed superior regarding all the other compared registration schemes.

Algorithms↗

[How to increase the optimal rate of secondary cytoreductive surgery in recurrent epithelial ovarian cancer].

BACKGROUND & OBJECTIVE: Optimal secondary cytoreduction is of prognostic importance for recurrent epithelial ovarian cancer. To increase the optimal rate of secondary cytoreductive surgery in these patients is helpful for improving the prognosis of recurrent epithelial ovarian cancer patients. In this retrospective study, we investigated how to increase the optimal rate of secondary cytoreductive surgery in recurrent epithelial ovarian cancer patients. METHODS: The clinical data of 54 patients with recurrent epithelial ovarian cancer were analyzed retrospectively, who received secondary cytoreductive surgery during March 1 1997 to March 31 2003 in Cancer Center, Sun Yat-sen University. Nineteen patients had tumors only in pelvis, and 35 patients both in pelvis and abdomen. Single tumor was found in 16 patients and multiple tumors in 38 patients. Thirty-eight patients had ascites and 16 patients no ascites. Preoperative chemotherapy was given to 20 cases, and responses were observed in 12 patients and no response in 8. Multivariate logistic regression was carried out to investigate the relationship of residual diseases of secondary cytoreduction with age, time to recurrence, recurrent sites, ascites, and preoperative salvage chemotherapy. RESULTS: Optimal surgical cytoreduction was obtained in 81.5% (44/54) of the patients, with no macroscopic residual diseases in 53.7% (29/54) and residual diseases <or=2 cm in 27.8% (15/54). Logistic regression showed that recurrent sites and ascites were the significant factors for residual diseases after secondary cytoreductive surrey (both P <or= 0.05). Optimal cytoreduction was obtained in 100% (12/12) of the patients whose salvage chemotherapy before secondary cytoreduction was effective and in 37.5% (3/8) cases whose chemotherapy before secondary cytoreduction was ineffective (P<or=0.05, Chi(2) test). Complicated surgical procedures involving gastrointestinal tract, urinary tract, liver or spleen were carried out in 40.7% (22/54) of the patients. Post-operation complications occurred in 16.6% (9/54) and post-operation death rate was 1.9% (1/54). CONCLUSION: It could be helpful for obtaining optimal secondary cytoreduction and avoiding helpless laparotomy to select patients properly according to the border of recurrent tumor, recurrent site, with or without ascites and the response of salvage chemotherapy before secondary cytoreduction and to do careful preoperative preparations.

Adult↗

Non invasive hemodynamic monitorization for AV interval optimization in patients with ventricular resynchronization therapy.

INTRODUCTION AND OBJECTIVE: In patients (pts) with dilated cardiomyopathy and intraventricular conduction disturbances, resynchronization therapy improves cardiac function and functional capacity. Determination of the optimal AV interval is essential to optimize the therapy results and various methods have been used in daily practice to obtain such an interval. The aim of this work is to assess optimal AV determined by impedance cardiography and compare it to the interval previously obtained by transmitral flow Doppler echocardiography. PATIENTS: Seven pts were evaluated, five men, mean age of 61 +/- 10 years, with dilated cardiomyopathy, intra-ventricular conduction disturbances and heart failure, New York Heart Association functional class III or IV. Four pts had ischemic cardiomyopathy and three idiopathic. All pts had an implanted cardioverter-defibrillator with cardiac resynchronization. METHODS: The optimal AV delay was estimated by transmitral flow pulsed Doppler using the method previously described by Ritter. Subsequently, cardiac output (CO) was determined by impedance cardiography. CO was estimated for different AV delays, beginning with 80 ms until occurrence of fusion QRS. The optimal AV delay was defined as the value corresponding to the highest measured CO. The ideal AV interval was compared between the two methods used. RESULTS: The AV delay determined by echocardiography varied between 120 and 170 ms (134 +/- 17 ms). The optimum AV delay based on CO estimation varied between 110 and 190 ms (137 +/- 26 ms). There was a correlation between the delays determined by the two methods (r = 0.844; p = 0.017). CONCLUSIONS: In pts undergoing ventricular resynchronization therapy, AV delay optimization based on CO determined by impedance cardiography is comparable to that measured by transmitral flow pulsed Doppler. However, impedance cardiography seems a more objective and simpler technique.

Aged↗

[Survival strategy of photosynthetic organisms. 1. Variability of the extent of light-harvesting pigment aggregation as a structural factor optimizing the function of oligomeric photosynthetic antenna. Model calculations].

In accordance with our concept of rigorous optimization of photosynthetic machinery by a functional criterion, this series of papers continues purposeful search in natural photosynthetic units (PSU) for the basic principles of their organization that we predicted theoretically for optimal model light-harvesting systems. This approach allowed us to determine the basic principles for the organization of a PSU of any fixed size. This series of papers deals with the problem of structural optimization of light-harvesting antenna of variable size controlled in vivo by the light intensity during the growth of organisms, which accentuates the problem of antenna structure optimization because optimization requirements become more stringent as the PSU increases in size. In this work, using mathematical modeling for the functioning of natural PSUs, we have shown that the aggregation of pigments of model light-harvesting antenna, being one of universal optimizing factors, furthermore allows controlling the antenna efficiency if the extent of pigment aggregation is a variable parameter. In this case, the efficiency of antenna increases with the size of the elementary antenna aggregate, thus ensuring the high efficiency of the PSU irrespective of its size; i.e., variation in the extent of pigment aggregation controlled by the size of light-harvesting antenna is biologically expedient.

Models, Theoretical↗

Clinical significance of optimal red cell mass and plasma volume estimation methods.

BACKGROUND: The aim of this study was to present and compare the results of proposed methods for optimal red cell mass and plasma volume (RCM&PV) estimation, and their influence on the interpretation of obtained results. MATERIAL AND METHODS: In 120/280 patients with polycythaemia rubra vera, subjected to RCM&PV determination with autologous erythrocytes in vitro labelled with 51Cr-sodium chromate, optimal volumes were determined using: 1. traditional ml/kg of: --the real body weight method (ml/kg RBW); --the optimal body weight method (ml/kg OBW). 2. the body weight, height, and sex based method (Retzlaff's tables), 3. the method recommended by the International Council for Standardization in Haematology (ICSH), based on body surface area. RESULTS: Different interpretation of the same results of 120 RCM&PV measurements was registered in 48/120 patients (40%). The greatest disagreement existed between ml/kg RBW and ml/kg OBW methods (in 39/120 subjects, 32.5%). In underweight patients the ml/kg RBW method, and in overweight patients the ml/kg OBW method, offered better agreement with ICSH&Retzlaff's methods. The ml/kg RBW method disagreed with ICSH&Retzlaff's methods and ml/kg OBW in 25% and 19.2% of patients respectively. ICSH and Retzlaff's methods disagreed in 10/120 patients (8.3%). The ICSH method yielded significantly lower optimal volumes than Retzlaff's. CONCLUSION: Three methods for optimal RCM&PV estimation lead to different interpretations of the same results of RCM&PV measurements with 51Cr-erythrocytes in 40% of patients. Two ml/kg body weight methods show greater disagreement in comparison with ICSH and Retzlaff's methods, which differ significantly. The ICSH method yields lower optimal values compared to Retzlaff's.

Adult↗

Comparison of optimal malarial test with light microscopy for the diagnosis of malaria.

OBJECTIVE: To evaluate the efficacy of a parasite lactate dehydrogenase-based immunochromatographic antigen detection assay (optimal) against conventional light microscopy in the diagnosis of malaria at Military Hospital, Rawalpindi and Department of Pathology Army Medical College Rawalpindi from August to October 2002 in patients reporting sick with history suggestive of malaria. METHODS: The blood samples were collected from 215 patients reporting with symptoms suggestive of malaria. Thick and thin blood films were prepared, stained with Leishman's stain and examined by light microscopy for the presence of malarial parasites. Parasitaemia was estimated on all positive slides. All samples were tested for presence of malarial parasite by optimal dipstick method according to the manufacturer's instructions. RESULTS: A total of 215 cases were studied. Malarial parasites were visualized in 98 (45.5%) cases with light microscopy. Optimal test revealed 93 (43.2%) of these samples as positive. Microscopy showed 61 out of 98 positive cases to be P. vivax and 37 P. falciparum. The Optimal dipstick method revealed that 58 out of 93 were positive for P. vivax and 35 positive for P. falciparum. These results demonstrated that Optimal had sensitivities of 95% and 94.5% for P. vivax and P. falciparum respectively. It has 100% specificity for both malarial species, when compared to conventional microscopy. CONCLUSION: Optimal test showed excellent correlation with microscopy in the diagnosis of P. vivax and P. falciparum. It is expensive but it has an advantage of being simple, rapid and effective test in the diagnosis of malaria especially where well trained microscopists are not available or work load is too high.

Animals↗