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Biomedical subjects

William E Collins

Publications and source records attributed to William E Collins.

At least 19 recordsLinked to original sources

A comparative study of the genetic diversity of the 42kDa fragment of the merozoite surface protein 1 in Plasmodium falciparum and P. vivax.

We investigated the genetic diversity of the 42kDa fragment of the merozoite surface protein 1 (MSP-1) antigen in Plasmodium falciparum and P. vivax, as well as in non-human primate malarial parasites. This fragment undergoes a proteolytic cleavage generating two fragments of 19kDa (MSP-1(19)) and 33kDa (MSP-1(33)) that are critical in erythrocyte invasion. We found that overall the MSP-1(33) fragment exhibits greater genetic diversity than the MSP-1(19) regardless of the species. We have found evidence for positive natural selection only in the human malaria parasites by comparing the rate of non-synonymous versus synonymous substitutions. In addition, we found clear differences between the two major human malaria parasites. In the case of P. falciparum, positive natural selection is acting on the MSP-1(19) region while the MSP-1(33) is neutral or under purifying selection. The opposite pattern was observed in P. vivax. Our results suggest different roles of this antigen in the host-parasite immune interaction in each of the major human malarial parasites.

Amino Acid Motifs↗

Studies on sporozoite-induced and chronic infections with Plasmodium fragile in Macaca mulatta and New World monkeys.

Plasmodium fragile continues to be investigated because of its biologic similarities to the human malaria parasite, Plasmodium falciparum. Two strains of P. fragile are available for study; one strain is able to infect mosquitoes, whereas the other strain is transmissible only by blood inoculation. The Sri Lanka strain of P. fragile was transmitted to Macaca mulatta, Macaca fascicularis, Aotus lemurinus griseimembra, Aotus nancymaae, Aotus vociferans, and Saimiri boliviensis monkeys via sporozoites that developed to maturity only in Anopheles dirus mosquitoes. The prepatent periods ranged from 12 to 35 days for macaques and from 15 to 30 days for New World monkeys after intravenous injection of sporozoites. Eight rhesus monkeys were infected with the Nilgiri strain and followed for 482 days. Parasitemia in 6 animals persisted at relatively high density through the period of observation. Erythrocyte, hematocrit, and hemoglobin values reached their lowest levels 3 wk after infection and slowly recovered; however, the values did not approach preinfection levels as long as parasitemia persisted in the monkeys. The mean corpuscular volume and corpuscular hemoglobin concentration reached their peak and lowest values, respectively, at day 38 and then returned to the preinfection level. The mean corpuscular hemoglobin value decreased to its lowest level at day 87 and then returned to preinfection level.

Animals↗

Assessment of transmission-blocking activity of candidate Pvs25 vaccine using gametocytes from chimpanzees.

Macaca mulatta monkeys were immunized with the candidate transmission-blocking vaccine against Plasmodium vivax, Pvs25, combined with alum or Montanide ISA 720. Efficacy was measured by combining post-immunization sera with gametocytes obtained from infections induced in chimpanzees using membrane-feeding techniques. The results indicate that immunization of M. mulatta monkeys with Pvs25 and Montanide ISA 720 was more effective than with alum in efficacy and resulted in the maintenance of a lasting transmission-blocking immunity to P. vivax. This was evident two weeks after the second immunization, and more strongly demonstrable 62 and 152 days after the second immunization. This transmission-blocking activity was strongly reinforced by a third immunization given 181 days after the primary immunization, as measured three weeks later by indirect membrane feeding. The use of gametocytes of P. vivax derived from infections induced in chimpanzees can contribute to the selection of appropriate constructs, formulations, and immunization regimens for the development of effective transmission-blocking vaccines.

Alum Compounds↗

Diagnosing infection levels of four human malaria parasite species by a polymerase chain reaction/ligase detection reaction fluorescent microsphere-based assay.

Improving strategies for diagnosing infection by the four human Plasmodium species parasites is important as field-based epidemiologic and clinical studies focused on malaria become more ambitious. Expectations for malaria diagnostic assays include rapid processing with minimal expertise, very high specificity and sensitivity, and quantitative evaluation of parasitemia to be delivered at a very low cost. Toward fulfilling many of these expectations, we have developed a post-polymerase chain reaction (PCR)/ligase detection reaction-fluorescent microsphere assay (LDR-FMA). This assay, which uses Luminex FlexMAP microspheres, provides simultaneous, semi-quantitative detection of infection by all four human malaria parasite species at a sensitivity and specificity equal to other PCR-based assays. In blinded studies using P. falciparum-infected blood from in vitro cultures, we identified infected and uninfected samples with 100% concordance. Additionally, in analyses of P. falciparum in vitro cultures and P. vivax-infected monkeys, comparisons between parasitemia and LDR-FMA signal intensity showed very strong positive correlations (r > 0.95). Application of this multiplex Plasmodium species LDR-FMA diagnostic assay will increase the speed, accuracy, and reliability of diagnosing human Plasmodium species infections in epidemiologic studies of complex malaria-endemic settings.

Animals↗

Aotus nancymaae as a potential model for the testing of anti-sporozoite and liver stage vaccines against Plasmodium falciparum.

The Santa Lucia strain of Plasmodium falciparum was transmitted to Aotus lemurinus griseimembra, A. azarae boliviensis, A. vociferans, and A. nancymaae monkeys by bite and by intravenous inoculation of sporozoites dissected from Anopheles freeborni, An. stephensi, An. gambiae, An. albimanus, and An. maculatus mosquitoes. The data obtained from these infections indicate that A. nancymaae can be considered a suitable host model when combined with the Santa Lucia strain of P. falciparum for the testing of candidate anti-sporozoite and liver stage vaccines.

Animals↗

Diagnosis of malaria by magnetic deposition microscopy.

Although malaria contributes to a significant public health burden, malaria diagnosis relies heavily on either non-specific clinical symptoms or blood smear microscopy methods developed in the 1930s. These approaches severely misrepresent the number of infected individuals and the reservoir of parasites in malaria-endemic communities and undermine efforts to control disease. Limitations of conventional microscopy-based diagnosis center on time required to examine slides, time required to attain expertise sufficient to diagnose infection accurately, and attrition from the limited number of existing malaria microscopy experts. Earlier studies described magnetic properties of Plasmodium falciparum but did not refine methods to diagnosis infection by all four human malaria parasite species. Here, following specific technical procedures, we show that it is possible to concentrate all four human malaria parasite species, at least 40-fold, on microscope slides using very inexpensive magnets through an approach termed magnetic deposition microscopy. This approach delivered greater sensitivity than a thick smear preparation while maintaining the clarity of a thin smear to simplify species-specific diagnosis. Because the magnetic force necessary to concentrate parasites on the slide is focused at a precise position relative to the magnet surface, it is possible to examine a specific region of the slide for parasitized cells and avoid the time-consuming process of scanning the entire slide surface. These results provide insight regarding new strategies for performing malaria blood smear microscopy.

Animals↗

The temporal changes of arterial blood flow dynamics.

Computer simulation of hydrodynamic models, using two dimensional T-junction geometry and experimentally determined arterial wave velocities, shows turbulent blood flow behavior of varying degrees at different critical points of the cardiac cycle. The flow disturbances get stronger when the waveform changes from systolic acceleration to diastolic deceleration. Finally, in the region of diastolic endpoints the flow demonstrates transition to stability due to subsiding blood pressure and arterial wall remodeling effect as a preparation for the start of more streamlined flow at the subsequent cycle. Such flow variations have implications on the initiation of atherosclerosis and interventional surgical procedures designed to alleviate such diseases. First, oscillating wall shear stress can induce different cell signaling pathways which can facilitate the initiation and progression of arterial diseases. Second, through advective transport of atherogenic plasma proteins, filtration to the artery wall is known to be regulated. Third, such constantly changing flows can cause early failure of arterial grafts and could also negatively affect their compatibility with the host tissue.

Animals↗

Malaria chemoprophylaxis and the serologic response to measles and diphtheria-tetanus-whole-cell pertussis vaccines.

BACKGROUND: Acute malaria has been associated with a decreased antibody response to tetanus and diphtheria toxoids, meningococcal, salmonella, and Hib vaccines. Interest in giving malaria drug therapy and prevention at the time of childhood immunizations has increased greatly following recent trials of intermittent preventive therapy during infancy (IPTi), stimulating this re-analysis of unpublished data. The effect of malaria chemoprophylaxis on vaccine response was studied following administration of measles vaccines and diphtheria-tetanus-whole cell pertussis (DTP) vaccines. METHODS: In 1975, six villages divided into two groups of children < or = 74 months of age from Burkina Faso, were assigned to receive amodiaquine hydrochloride chemoprophylaxis (CH+) every two weeks for seven months or no chemoprophylaxis (CH-). After five months, children in each group received either one dose of measles or two doses of DTP vaccines. RESULTS: For recipients of the measles vaccine, the seroconversion rates in CH+ and CH- children, respectively, were 93% and 96% (P > 0.05). The seroresponse rates in CH+ and CH- children respectively, were 73% and 86% for diphtheria (P > 0.05) and 77% and 91% for tetanus toxoid (P > 0.05). In a subset analysis, in which only children who strictly adhered to chemoprophylaxis criteria were included, there were, likewise, no significant differences in seroconversion or seroresponse for measles, diphtheria, or tetanus vaccines (P > 0.05). While analysis for pertussis showed a 43% (CH+) and 67% (CH-) response (P < 0.05), analyses using logistic regression to control for sex, age, chemoprophylaxis, weight-for-height Z-score, and pre-vaccination geometric mean titer (GMT), demonstrated that chemoprophylaxis was not associated with a significantly different conversion rate following DTP and measles vaccines. Seven months of chemoprophylaxis decreased significantly the malaria IFA and ELISA GMTs in the CH+ group. CONCLUSION: Malaria chemoprophylaxis prior to vaccination in malaria endemic settings did not improve or impair immunogenicity of DTP and measles vaccines. This is the first human study to look at the association between malaria chemoprophylaxis and the serologic response to whole-cell pertussis vaccine.

Amodiaquine↗

A monkey's tale: the origin of Plasmodium vivax as a human malaria parasite.

The high prevalence of Duffy negativity (lack of the Duffy blood group antigen) among human populations in sub-Saharan Africa has been used to argue that Plasmodium vivax originated on that continent. Here, we investigate the phylogenetic relationships among 10 species of Plasmodium that infect primates by using three genes, two nuclear (beta-tubulin and cell division cycle 2) and a gene from the plastid genome (the elongation factor Tu). We find compelling evidence that P. vivax is derived from a species that inhabited macaques in Southeast Asia. Specifically, those phylogenies that include P. vivax as an ancient lineage from which all of the macaque parasites could originate are significantly less likely to explain the data. We estimate the time to the most recent common ancestor at four neutral gene loci from Asian and South American isolates (a minimum sample of seven isolates per locus). Our analysis estimates that the extant populations of P. vivax originated between 45,680 and 81,607 years ago. The phylogeny and the estimated time frame for the origination of current P. vivax populations are consistent with an "out of Asia" origin for P. vivax as hominoid parasite. The current debate regarding how the Duffy negative trait became fixed in Africa needs to be revisited, taking into account not only human genetic data but also the genetic diversity observed in the extant P. vivax populations and the phylogeny of the genus Plasmodium.

Africa↗

Plasmodium ovale: parasite and disease.

Humans are infected by four recognized species of malaria parasites. The last of these to be recognized and described is Plasmodium ovale. Like the other malaria parasites of primates, this parasite is only transmitted via the bites of infected Anopheles mosquitoes. The prepatent period in the human ranges from 12 to 20 days. Some forms in the liver have delayed development, and relapse may occur after periods of up to 4 years after infection. The developmental cycle in the blood lasts approximately 49 h. An examination of records from induced infections indicated that there were an average of 10.3 fever episodes of > or = 101 degrees F and 4.5 fever episodes of > or = 104 degrees F. Mean maximum parasite levels were 6,944/microl for sporozoite-induced infections and 7,310/microl for trophozoite-induced infections. Exoerythrocytic stages have been demonstrated in the liver of humans, chimpanzees, and Saimiri monkeys following injection of sporozoites. Many different Anopheles species have been shown to be susceptible to infection with P. ovale, including A. gambiae, A. atroparvus, A. dirus, A. freeborni, A. albimanus, A. quadrimaculatus, A. stephensi, A. maculatus, A. subpictus, and A. farauti. An enzyme-linked immunosorbent assay has been developed to detect mosquitoes infected with P. ovale using a monoclonal antibody directed against the circumsporozoite protein. Plasmodium ovale is primarily distributed throughout sub-Saharan Africa. It has also been reported from numerous islands in the western Pacific. In more recent years, there have been reports of its distribution on the Asian mainland. Whether or not it will become a major public health problem there remains to be seen. The diagnosis of P. ovale is based primarily on the characteristics of the blood stages and its differentiation from P. vivax. The sometimes elliptical shape of the infected erythrocyte is often diagnostic when combined with other, subtler differences in morphology. The advent of molecular techniques, primarily PCR, has made diagnostic confirmation possible. The development of techniques for the long-term frozen preservation of malaria parasites has allowed the development diagnostic reference standards for P. ovale. Infections in chimpanzees are used to provide reference and diagnostic material for serologic and molecular studies because this parasite has not been shown to develop in other nonhuman primates, nor has it adapted to in vitro culture. There is no evidence to suggest that P. ovale is closely related phylogenetically to any other of the primate malaria parasites that have been examined.

Animals↗

The clinical-grade 42-kilodalton fragment of merozoite surface protein 1 of Plasmodium falciparum strain FVO expressed in Escherichia coli protects Aotus nancymai against challenge with homologous erythrocytic-stage parasites.

A 42-kDa fragment from the C terminus of major merozoite surface protein 1 (MSP1) is among the leading malaria vaccine candidates that target infection by asexual erythrocytic-stage malaria parasites. The MSP1(42) gene fragment from the Vietnam-Oak Knoll (FVO) strain of Plasmodium falciparum was expressed as a soluble protein in Escherichia coli and purified according to good manufacturing practices. This clinical-grade recombinant protein retained some important elements of correct structure, as it was reactive with several functional, conformation-dependent monoclonal antibodies raised against P. falciparum malaria parasites, it induced antibodies (Abs) that were reactive to parasites in immunofluorescent Ab tests, and it induced strong growth and invasion inhibitory antisera in New Zealand White rabbits. The antigen quality was further evaluated by vaccinating Aotus nancymai monkeys and challenging them with homologous P. falciparum FVO erythrocytic-stage malaria parasites. The trial included two control groups, one vaccinated with the sexual-stage-specific antigen of Plasmodium vivax, Pvs25, as a negative control, and the other vaccinated with baculovirus-expressed MSP1(42) (FVO) as a positive control. Enzyme-linked immunosorbent assay (ELISA) Ab titers induced by E. coli MSP1(42) were significantly higher than those induced by the baculovirus-expressed antigen. None of the six monkeys that were vaccinated with the E. coli MSP1(42) antigen required treatment for uncontrolled parasitemia, but two required treatment for anemia. Protective immunity in these monkeys correlated with the ELISA Ab titer against the p19 fragment and the epidermal growth factor (EGF)-like domain 2 fragment of MSP1(42), but not the MSP1(42) protein itself or the EGF-like domain 1 fragment. Soluble MSP1(42) (FVO) expressed in E. coli offers excellent promise as a component of a vaccine against erythrocytic-stage falciparum malaria.

Animals↗

Observations on the Vietnam Palo Alto strain of Plasmodium vivax in two species of Aotus monkeys.

Thirty-three splenectomized Aotus lemurinus griseimembra monkeys with no previous experience with malaria were infected with the Vietnam Palo Alto strain of Plasmodium vivax. The median maximum parasite count was 280,000/microl. Nine splenectomized monkeys with previous infection with Plasmodium falciparum had median maximum parasite counts of 120,000/microl. Splenectomized Aotus nancymai monkeys supported infections at a lower level. Transmission via the bites of Anopheles dirus mosquitoes was obtained in a splenectomized A. lemurinus griseimembra, with a prepatent period of 31 days. It is estimated that between 1.5 x 10(8) and 1.6 x 10(9) parasites can be removed from an infected animal for molecular or diagnostic antigenic studies.

Animals↗

Studies on two strains of Plasmodium cynomolgi in New World and Old World monkeys and mosquitoes.

Infections that cause the Gombak and Smithsonian strains of Plasmodium cynomolgi were induced in Macaca mulatta, Aotus lemurinus griseimembra, Aotus nancymai, and Saimiri boliviensis monkeys. Transmission of the Gombak strain to Aotus spp. monkeys was obtained by the injection of sporozoites dissected from the salivary glands of experimentally infected Anopheles dirus and by the bites of infected An. dirus and Anopheles farauti mosquitoes. Two S. boliviensis monkeys were infected via the injection of sporozoites dissected from An. dirus. Prepatent periods in New World monkeys ranged from 14 to 44 days, with a median of 18 days. The Smithsonian strain was transmitted via sporozoites to 1 A. lemurinus griseimembra and 9 A. nancymai monkeys. Prepatent periods ranged from 12 to 31 days.

Adaptation, Physiological↗

The Rheology of Blood Flow in a Branched Arterial System.

Blood flow rheology is a complex phenomenon. Presently there is no universally agreed upon model to represent the viscous property of blood. However, under the general classification of non-Newtonian models that simulate blood behavior to different degrees of accuracy, there are many variants. The power law, Casson and Carreau models are popular non-Newtonian models and affect hemodynamics quantities under many conditions. In this study, the finite volume method is used to investigate hemodynamics predictions of each of the models. To implement the finite volume method, the computational fluid dynamics software Fluent 6.1 is used. In this numerical study the different hemorheological models are found to predict different results of hemodynamics variables which are known to impact the genesis of atherosclerosis and formation of thrombosis. The axial velocity magnitude percentage difference of up to 2 % and radial velocity difference up to 90 % is found at different sections of the T-junction geometry. The size of flow recirculation zones and their associated separation and reattachment point's locations differ for each model. The wall shear stress also experiences up to 12 % shift in the main tube. A velocity magnitude distribution of the grid cells shows that the Newtonian model is close dynamically to the Casson model while the power law model resembles the Carreau model. ZUSAMMENFASSUNG: Die Rheologie von Blutströmungen ist ein komplexes Phänomen. Gegenwärtig existiert kein allgemein akzeptiertes Modell, um die viskosen Eigenschaften von Blut wiederzugeben. Jedoch gibt es mehrere Varianten unter der allgemeinen Klassifikation von nicht-Newtonschen Modellen, die das Verhalten von Blut mit unterschiedlicher Genauigkeit simulieren. Die Potenzgesetz-, Casson und Carreau-Modelle sind beliebte nicht-New-tonsche Modelle und beeinflussen die hämodynamischen Eigenschaften in vielen Situationen. In dieser Studie wurde die finite Volumenmethode angewandt, um die hämodynamischen Vorhersagen dieser Modelle zu untersuchen. Um die finite Volumenmethode zu implementieren, wurde die Fluiddynamiksoftware Fluent 6.1 verwendet. In dieser numerischen Studie wurde gefunden, dass die unterschiedlichen hämorheologischen Modelle unterschiedliche Resultate für die hämodynamischen Grössen vorhersagen, von denen bekannt ist, dass sie die Entstehung von Arteriosklerose und die Bildung von Thrombose beeinflussen. Es wurde gefunden, dass die relative Differenz der axialen Geschwindigkeit bis zu 2% und die der radialen Geschwindigkeit bis zu 90% in unterschiedlichen Abschnitten der T-Verbindung beträgt. Die Grösse der Strömungszirkulationszonen und ihrer dazugehörigen Trennungs- und Vereinigungspunkte differieren für jedes Modell. Die Scherspannung an der Wand erfährt ebenfalls eine Verschiebung im Hauptrohr von bis zu 12%. Der Verlauf der Geschwindigkeit auf den Gitterzellen zeigt, dass das Newtonsche Modell mit Bezug auf die Dynamik dem Casson-Modell nahe ist, während das Potenzgesetzmodell dem Carreau-Modell ähnlich ist. R#ENTITYSTARTX000E9;SUM#ENTITYSTARTX000E9;: La rhéologie de l'écoulement sanguin est un phénomène complexe. Présentement, il n'y a pas de consensus universel sur le modèle qui représente la propriété visqueuse du sang. Cependant, parmi la classification générale des modèles non-Newtoniens qui simulent le comportement du sang avec différents degrés de précision, il y a plusieurs différences. Les lois de puissance, les modèles de Casson et Carreau sont des modèles non-Newtoniens populaires et ont un effet sur les quantités hémodynamiques sous plusieurs conditions. Dans cette étude, la méthode de volume fini est utilisée pour explorer les prédictions hémodynamiques de chacun de ces modèles. Pour implémenter la méthode de volume fini, le logiciel de calcul de dynamique des fluides Fluent 6.1 a été utilisé. Dans cette étude numérique, les différents modèles hémorhéologiques tendent à prédire des résultats différents pour les variables hémodynamiques qui sont reconnues comme ayant un impact sur la genèse de l'artériosclérose et de la thrombose. Une différence jusqu'à 2% dans l'amplitude de la vélocité axiale et une différence jusqu'à 90% dans la vélocité radiale sont découverts dans différentes sections d'une géométrie de type jonction en T. La taille des zones de re-circulation d'écoulement et les localisations des points de séparation et de rattachement qui leur sont associées, diffèrent pour chacun des modèles. La contrainte de cisaillement aux parois présente également un déplacement de 12% dans le tube principal. La distribution de l'amplitude de vitesse dans les cellules du maillage montre que le modèle Newtonien est dynamiquement proche du modèle de Casson tandis que le modèle en loi de puissance ressemble au modèle de Carreau.

Journal Article↗

Plasmodium simium and Saimiri boliviensis as a model system for testing candidate vaccines against Plasmodium vivax.

Observations on Plasmodium simium infections in Saimiri boliviensis boliviensis monkeys suggest that this host-parasite combination would be a suitable model for the testing of candidate vaccines against Plasmodium vivax. To evaluate the normal course of infections, parasitemia in 52 splenectomized S. boliviensis boliviensis monkeys infected with P. simium were analyzed. The mean maximum parasite count for 31 monkeys after injection with trophozoite-infected erythrocytes was 77,580/microL. Twenty-one monkeys were infected via sporozoites, and prepatent periods ranged from 14 to 24 days with a median of 15 days. The mean maximum parasite count was 29,234/microL. The mean maximum parasite count for monkeys previously infected with Old World P. vivax was 26,337/microL versus 56,362/microL for those previously infected with New World P. vivax, possibly suggesting a closer antigenic relationship between P. simium and the Old World parasites.

Animals↗

Preliminary observations on the efficacy of a recombinant multistage Plasmodium falciparum vaccine in Aotus nancymai monkeys.

A vaccine trial was conducted to determine the efficacy of a multicomponent candidate vaccine, FALVAC-1, against Plasmodium falciparum in Aotus nancymai monkeys. After two immunizations, animals were challenged intravenously with parasites of the Vietnam Oak Knoll (FVO) strain of P. falciparum. The primary outcome was to determine the protective response of the monkeys to immunization with the FALVAC-1 antigen produced in baculovirus when combined with different adjuvants (alum, QS-21, ASO2a, CRL1005/oil, and CRL1005/saline) as compared with FALVAC-1 with FCA/FIA and antigen alone. When compared with the monkeys immunized with FALVAC-1 alone, FALVAC-1 with FCA/FIA reduced the mean parasite count (to Day 11), reduced the mean accumulated parasitemia (through Day 11), and extended the number of days to treatment. None of the other 5 antigen-adjuvant combinations were able to provide discernable levels of protection based on log(parasitemia) and log(cumulative parasitemia) to Day 11.

Adjuvants, Immunologic↗

Adaptation of Plasmodium vivax to growth in owl monkeys (Aotus nancymai).

The purpose of this study was reactivation and adaptation of a strain of Plasmodium vivax to Aotus nancymai monkeys. A need arose for malarial parasites for use in serologic and molecular studies and for teaching slides. This particular strain of parasite had been characterized previously as producing high-density parasitemia in splenectomized New World monkeys and therefore represented a good candidate for reactivation. P. vivax (Vietnam II), isolated in 1970, was reactivated after adaptation in Aotus lemurinus griseimembra monkeys nearly 33 years earlier and adapted to A. nancymai monkeys. Passage was achieved by intravenous inoculation of parasite blood stages into splenectomized A. nancymai monkeys. Parasitemia was determined by analyzing daily blood smears stained with Giemsa. Maximum parasite counts ranged from 10,630 to 94,000 parasites/microl; the mean maximum parasite count for the four animals was 39,565 parasites/microl. Parasite counts of > 10,000/microl were maintained for 2 to 64 days. After only three passages of the parasite, attempts to reactive were successful. A. nancymai proved a suitable animal model for the recovery of this parasite. In conclusion, successful reactivation and adaptation of this parasite offers the capability to perform a series of diagnostic, immunologic, and molecular studies as well as to provide otherwise potentially unavailable teaching materials to healthcare professionals.

Adaptation, Physiological↗