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Biomedical subjects

D R Brooks

Publications and source records attributed to D R Brooks.

At least 55 records · Page 3Linked to original sources
PubMed1997

The treatment of patients with infected implantable cardioverter-defibrillator systems.

OBJECTIVE: The purpose of this study was to evaluate the treatment of patients with infected implantable cardioverter-defibrillator systems. METHODS: Retrospective analysis was done of the cases of 21 patients treated for implantable cardioverter-defibrillator infection during an 11-year period. RESULTS: Of 723 cardioverter-defibrillator implantations (550 primary implants, 173 replacements), nine (1.2%) were complicated by early postoperative device-related infections. Late infections developed in two patients 19 and 22 months, respectively, after implantation. Ten other patients were transferred to our institution for treatment of cardioverter-defibrillator infection. The time from implantation to overt infection was 2.2 +/- 1.3 months, excluding the two late infections. The responsible organisms were Staphylococcus aureus (9), Staphylococcus epidermidis (6), Streptococcus hemolyticus (1), gram-negative bacteria (3), Candida albicans (1), and Corynebacterium (1). All patients were treated with intravenous antibiotic drugs. Total system removal was done in 15 patients and partial removal in 2; in 4, the cardioverter-defibrillator system was not explanted. There were no perioperative deaths. A new implantable cardioverter-defibrillator system was reimplanted in 7 patients after 2 to 6 weeks of antibiotic therapy. Ten patients were treated without reimplantation (2 arrhythmia operation, 8 antiarrhythmic drugs). Four patients (3 patients without explantation and 1 with partial system removal) were treated with maintenance long-term antibiotic therapy. During a mean follow-up of 21 +/- 2.8 months, no patient had clinical recurrence of infection. One patient treated with antiarrhythmic drugs without system reimplantation died suddenly. CONCLUSIONS: Infections that involve implantable cardioverter-defibrillator systems can be safely managed by removing the entire system with reimplantation after intravenous antibiotic therapy. In selected patients in whom the risk for system explantation is high and anticipated life expectancy is short, long-term antibiotic therapy to suppress low-virulence infections may represent an acceptable alternative.

Adult↗
PubMed1997

Six species of Acanthobothrium (Eucestoda: Tetraphyllidea) in stingrays (Chondrichthyes: Rajiformes: Myliobatoidei) from Ecuador.

Six species of Acanthobothrium, 4 described as new, are reported in stingrays from southern Ecuador. Acanthobothrium atahualpai n. sp. in Gymnura afuerae most closely resembles Acanthobothrium fogeli and Acanthobothrium parviuncinatum by having bothridial hooks with recurved prongs and short handles. It differs from A. fogeli by having bothridial hooks 163-195 microns vs. 78-114 microns long and averaging 25 vs. 32 testes per pruglottis: it differs from A. parviuncinatum by having bothridial hooks 163-195 microns vs. 87 microns long and averaging 25 vs. 13 testes per proglottis. Acanthobothrium minusculus n. sp. in Urolophus tumbesensis most resembles Acanthobothrium campbelli and Acanthobothrium vargasi by being no more than 3 mm long and having 6-30 testes per proglottis. It can be distinguished from them by having bothridial hooks averaging 86 microns vs. 108-111 microns and 130-133 microns long, and 6-10 vs. 15-23 and 22-29 testes per proglottis, respectively. Acanthobothrium monksi n. sp. in Aetobatus narinari resembles Acanthobothrium tasajerasi from Himantura schmardae by having a prominent genital atrium and a large globose cirrus sac; it differs by averaging 21 vs. 35 testes per proglottis and having bothridial hooks averaging 150 microns vs. 165 microns long. Acanthobothrium obuncus n. sp. in Dasyatis longus resembles a group of species characterized by wider than long to square immature and mature proglottides, bothridia at least partially fused to the scolex at their posterior ends, and asymmetrical ovarian arms with aporal arms extending anteriorly to the vaginal level. It resembles Acanthobothrium americanum by averaging 73 vs. 72 testes per proglottis, but differs by having bothridial hooks averaging 120-131 microns vs. 151 microns long; it resembles Acanthobothrium chilensis by having bothridial hooks averaging 120-131 microns vs. 130 microns long, but differs by averaging 73 vs. 90 testes per proglottis. Acanthobothrium campbelli in Urotrygon chilensis and Acanthobothrium costarricense in Dasyatis longus, previously known in those hosts from the Pacific coast of Costa Rica, are reported from Ecuador for the first time.

Animals↗
PubMed1997

Evolution of the schistosomes (Digenea: Schistosomatoidea): the origin of dioecy and colonization of the venous system.

Trematodes of the family Schistosomatidae are considered venous system specialists whose sister group is the vascular system generalists (Spirorchidae) of turtles. Colonization of homeotherms by vascular trematodes required precision egg laying near the conduit for egg passage to the external environment and avoidance of pathogenesis that might result in the premature death of the host. Evolution of dioecy from the hermaphroditic condition may have proceeded through androdioecy in which hermaphrodites were specialized for precision egg placement in the vascular system and larger adults became functional males. The evolution of nuclear genes suppressing female function along with cytoplasmic genes suppressing male function could then have resulted in the origin of dioecious, dimorphic populations. Schistosomes compensated for the reduction in potential reproductive partners by (1) increased overdispersion in the vertebrate host, (2) reduced egg hatching time in the external environment, (3) formation of permanent pairs mimicking the hermaphroditic condition, (4) increased longevity in the definitive host, and (5) increased fecundity. Colonization of the venous system was necessitated by (1) evolutionary radiation into terrestrial vertebrates and (2) the increased immunopathology associated with the high, constant body temperature of homeothermic vertebrates. The immune response to spirorchid and schistosome eggs appears to be qualitatively similar in their respective hosts. The arterial dwelling spirorchids release eggs in the direction of blood flow, resulting in a wide dissemination of eggs within the host. The lower body temperature of poikilotherms accompanied by the seasonal nature of the immune response in these hosts would result in a quantitatively reduced pathogenesis. Hosts that did succumb to the infection would most likely die in water, where eggs could be released by predation, scavengers, or decomposition and develop successfully. Colonization of the venous system by schistosomes would require precision egg placement because eggs are released against blood flow. Eggs are sequestered within the portal system of homeotherms, thus restricting egg dispersal and resulting pathogenesis to less sensitive organs. A significant number of eggs may escape into the external environment before a heavily infected host is incapacitated by, or dies from, the infection.

Animals↗
PubMed1997

Phylogeny of the orders of the Eucestoda (Cercomeromorphae) based on comparative morphology: historical perspectives and a new working hypothesis.

The phylogeny of the Eucestoda was evaluated based on a suite of 49 binary and multistate characters derived from comparative morphological and ontogenetic studies; attributes of adult and larval tapeworms were considered. A single most parsimonious tree (MPT) (consistency index = 0.872; retention index = 0.838; and homoplasy index = 0.527) was fully resolved and is specified by the following: (Gyrocotylidea, (Amphilinidea, ((Spathebothriidea, (Pseudophyllidea, ((Diphyllidea, (Trypanorhyncha, (Tetraphyllidea, (Lecanicephalidea, ((Nippotaeniidea, (Tetrabothriidea, Cyclophyllidea)), Proteocephalidea))))), Haplobothriidea))), Caryophyllidea))). Monophyly for the Eucestoda was firmly corroborated. Trees derived from the primary and bootstrap analyses were congruent, but low values, particularly for relationships among the tetrafossate tapeworms, indicated additional examination is warranted. The MPT was found to be the most efficient hypothesis for describing character evolution and in specifying relationships among the orders when compared to those concepts that had been developed for the tapeworms over the past century. Areas of congruence were shared among the current hypothesis and one or more of the prior hypotheses. Major conclusions include: (1) Caryophyllidea are basal and monozooy is ancestral; (2) difossate forms are primitive, and the Pseudophyllidea are the sister group of the strongly polyzoic tapeworms; (3) Nippotaeniidea are highly derived; (4) the higher tapeworms (Tetraphyllidea, Lecanicephalidea, Proteocephalidea, Nippotaeniidea, Tetrabothriidea, and Cyclophyllidea) are closely related or potentially coordinate groups: (5) Tetrabothriidea and the Cyclophyllidea are sister groups; and (6) Tetraphyllidea is paraphyletic, with the Onchobothriidae basal to the Phyllobothriidae. Character support for placement of the Tetrabothriidea continues to be contradictory, and this order may represent a key to understanding the phylogeny of the higher cestodes. The current study constitutes a complete historical review and poses a new and robust hypothesis for the phylogeny of the Eucestoda.

Animals↗
PubMed1996

Work-related injuries to Massachusetts teens, 1987-1990.

This study uses workers' compensation data to describe the work-related injury experience of Massachusetts teens, ages 14-17, from 1987 to 1990. During this period, 2,551 injuries were reported to the workers' compensation system. Injuries were more frequent among 16-17 year-olds and among males. Sprains and strains, followed by lacerations, were the most frequent type of injury. Four industries--grocery stores, restaurants, health services, and department stores--accounted for over half of all injuries. The overall injury rate was 1.9/100 full-time equivalents (FTEs), but was higher in the construction, manufacturing, and wholesale trade sectors. Teens working in apparel manufacturing and nursing homes sustained the highest rate of injuries. Geographical analysis indicated that teens living in the southeast region of the state had the highest injury rates. This study adds to the existing evidence that work-related injuries to teens are a substantial public health problem.

Accidents, Occupational↗
PubMed1996

Two new species of tetraphyllidean cestodes in Himantura pacifica (Chondrichthyes: Myliobatiformes: Dasyatididae) from the northwest coast of Costa Rica.

Two new species of tetraphyllidean cestodes inhabiting Himantura pacifica from the northwest coast of Costa Rica are apparently most closely related to species inhabiting Himantura schmardae from the Atlantic coast of Colombia. Acanthobothroides pacificus n. sp. differs from Acanthobothroides thorsoni, the only other species in the genus, primarily by having smaller lateral (98-123 microns rather than 168-198 microns long) and medial (handles 92-116 microns rather than 162-168 microns long) hooks, and more testes (up to 125 rather than up to 97) per proglottis. The generic diagnosis of Acanthobothroides is modified to include the presence of a small inner prong on the large medial bothridial hooks. Rhinebothrium geminum n. sp. and Rhinebothrium magniphallum are the only 2 species in the genus possessing unusually long cirrus sacs, extending from the genital atrium all the way to the ovarian isthmus; R. geminum averages 12 (12-14) loculi per bothridium and 11 (9-12) testes, whereas R. magniphallum averages 17 (16-18) loculi and 14 (10-16) testes per proglottis.

Animals↗
PubMed1996

A new species of Acanthobothrium van Beneden, 1849 (Eucestoda:Tetraphyllidea: Onchobothriidae) in Dasyatis longus Garman (Chondrichthyes:Myliobatiformes:Dasyatididae) from Chamela Bay, Jalisco, Mexico.

A new species of Acanthobothrium in Dasyatis longus from Chamela Bay, Jalisco, Mexico, is a member of a presumed clade of species diagnosed by being anapolytic or nearly so, having more than 100 testes per proglottis, with immature and mature proglottides wider than long to square, aspinose scolex, muscular bothridia fused to the scolex at their posterior ends, H- to V -shaped ovaries, relatively short symmetrical to asymmetrical ovarian arms that extend anteriorly to, or nearly to, the cirrus sac, and vitellaria arranged in fields rather than a single row of follicles. The new species most closely resembles Acanthobothrium terezae from the freshwater stingray Potamotrygon motoro in the following characters: bothridial hooks longer than 200 microns with inner hooks having bent asymmetrical prongs, an average of 130-140 testes per proglottis, and shallow genital atria located posterior to midline of proglottis. The new species differs from A. terezae by having outer hooks approximately the same size and shape as the inner hooks, inner hooks averaging 230 microns rather than 313 microns in total length, and cirrus sacs averaging 255 microns rather than 450 microns in length. The new species is unique among all described species of Acanthobothrium by having a cleft in the posterior margin of each apical bothridial pad. The apparent close relationship of the new species to one inhabiting a Neotropical freshwater stingray provides support for the hypothesized Pacific marine ancestry of Neotropical freshwater stingrays and raises the possibility that the Neotropical freshwater stingrays may not be monophyletic.

Animals↗
PubMed1996

Phylogenetic analysis of Opisthadena (Digenea:Hemiuridae).

Systematic study of the closely related hemiurid genera Mitrostoma, Neopisthadena and Opisthadena revealed that Opisthadena cortesi is a junior synonym of Opisthadena dimidia and Opisthadena fujianensis and Opisthadena marina are species inquirendae. Phylogenetic analysis of the 7 recognized species, based on 21 transformation series derived from comparative morphologic characters, produced a single tree with a consistency index of 0.735. The five species of the genus Opisthadena constitute a monophyletic clade and Neopisthadena habei is their sister group. Mitrostoma nototheniae is the sister group of the other 6 members of the clade. Geographic distribution suggests an ancient circum-Pacific distribution of the group. The association between kyphosids and this group of hemiurids appeared with the ancestor of Neopisthadena and Opisthadena.

Animals↗
PubMed1995

Limitations and late complications of third-generation automatic cardioverter-defibrillators.

BACKGROUND: This study examines the limitations and complex management problems associated with the use of tiered-therapy, implantable cardioverter-defibrillators (ICDs). METHODS AND RESULTS: The study group comprises the first 154 patients undergoing implantation of tiered-therapy ICDs at our institution. Pulse generators from three different manufacturers were used. In 39 patients, a complete nonthoracotomy lead system was used. The perioperative mortality was 1.3%. Of these 154 patients, 37% experienced late postoperative problems. Twenty-one patients required system revision within 36.5 months (mean, 8.57 +/- 11.3) of surgery. Reasons for revision were spurious shocks due to electrode fractures (3) or electrode adapter malfunction (2), inadequate signal from endocardial rate-sensing electrodes (3), superior vena cava or right ventricular coil migration (5), failure to correct tachyarrhythmias due to a postimplant rise in defibrillation threshold (5), or pulse generator failure (3). One of these patients required system removal for infection after revision of an endocardial lead. A further 32 patients received inappropriate shocks for atrial fibrillation with a rapid ventricular response or sinus tachycardia. Two of these patients also received shocks for ventricular tachycardia initiated by antitachycardia pacing triggered by atrial fibrillation. Ventricular pacing for bradycardia was associated with inappropriate shocks due to excessive autogain in 2 patients. CONCLUSIONS: Despite the major diagnostic and therapeutic advantages of tiered-therapy ICDs, a significant proportion of patients continue to experience hardware-related complications or receive inappropriate shocks.

Algorithms↗
PubMed1995

A mutation-specific PCR system to detect sequence variation in the dihydropteroate synthetase gene of Plasmodium falciparum.

Sulphur-based antimalarial drugs targeted at dihydropteroate synthetase (DHPS) are frequently used in synergistic combination with inhibitors of dihydrofolate reductase (DHFR) to combat chloroquine-resistant malaria. We have previously shown that lines of Plasmodium falciparum resistant to the most commonly used sulpha drug, sulphadoxine, carry point mutations in the DHPS coding region, relative to the sequence of sensitive strains (Brooks et al., Eur. J. Biochem. 224 (1994) 397-405). We have now developed PCR diagnostic assays based on allele-specific amplification that are able to detect such mutations. The four tests described can reliably discriminate all of the mutations observed to alter codons 436, 581 and 613, yielding allele-specific amplification products of different sizes in each case. Moreover, by careful adjustment of primer length and the degree of mismatch to target and non-target alleles, we were able to standardise all four tests to a single set of PCR conditions, allowing all possible mutations to be monitored simultaneously on one thermocycler. These assays should prove invaluable in further assessing the contribution of specific base changes in the DHPS gene of the parasite to the sulphadoxine resistance phenotype and to the clinical failure of the sulphadoxine/pyrimethamine combination Fansidar.

Alleles↗
PubMed1995

Proteocephalus chamelensis n. sp. (Cestoda: Proteocephalidae) from the "guavina" Gobiomorus maculatus (Osteichthyes: Eleotrididae) in Chamela Bay, Jalisco, México.

A new species of Proteocephalus inhabiting the eleotridid estuarine fish Gobiomorus maculatus is described from Chamela Bay, Jalisco State, Mexico. The new species and P. pugetensis are nearly identical in strobila length, presence of a vestigial apical organ, having vaginae only anterior to the cirrus sac, an average of 4-7 uterine diverticula per proglottis, and a ratio of cirrus sac length to proglottis width averaging approximately 1:4. Proteocephalus pugetensis differs from the new species by having an average of 35 rather than 68 testes per proglottis, vitelline follicles terminating posteriorly at the level of the anterior margin of the ovary rather than at the level of the posterior margin, and equatorial genital pores rather than genital pores located in the anterior 1/4 of the proglottis. Finally, Proteocephalus pugetensis occurs from estuarine habitats along the Pacific coast of the United States; the new species was collected from an estuarine habitat on the Pacific coast of México.

Animals↗
PubMed1995

Acanthobothrium nicoyaense n. sp. (Eucestoda: Tetraphyllidea: Onchobothriidae) in Aetobatus narinari (Euphrasen) (Chondrichthyes: Myliobatiformes: Myliobatidae) from the Gulf of Nicoya, Costa Rica.

A new species of Acanthobothrium in Aetobatus narinari from the Gulf of Nicoya, Costa Rica, most closely resembles Acanthobothrium colombianum in the same host and A. urotrygoni in Urotrygon venezuelae from Cartagena, Colombia, by having relatively few proglottides per strobila, spinose cephalic peduncles, bothridial margins free at their posterior ends, and irregularly shaped rather than spherical or elongate cirrus sacs. Acanthobothrium colombianum differs from the new species by being as much as 35 mm rather than no more than 4.7 mm long and by having 31-48 rather than 13-19 proglottides, an average of 46 rather than 15 testes per proglottis, and bothridial hooks averaging 185 microns rather than 137 microns in total length. Acanthobothrium urotrygoni differs from the new species by being as much as 15 mm rather than no more than 4.7 mm long and by having V-shaped rather than H-shaped ovaries, bothridial hooks averaging 95 microns rather than 137 microns in total length, by having an average of 28 rather than 15 testes per proglottis, and by having poral ovarian arms extending anteriorly to the posterior margin of the cirrus sac and aporal arms extending to the lateral margin of the cirrus sac.

Animals↗
PubMed1995

Phylogenetic relationships of the genera of the Pronocephalidae Looss, 1902 (Digenea: Paramphistomiformes).

Quantitative phylogenetic analysis of 20 nominal genera of the Pronocephalidae based on 47 morphological transformation series produced 6 equally parsimonious trees, each with a consistency index of 77.8%. All trees agree that Adenogaster is the sister group to the rest of the pronocephalids, and a new subfamily is proposed for it. The Pronocephalinae comprises Pronocephalus, Ruicephalus, Neopronocephalus, Macravestibulum, Choanophorus, Cetiosaccus, and Metacetabulum. The Charaxicephalinae comprises Charaxicephalus, Desmogonius, Diaschistorchis, Pleurogonius, Iguanacola, Renigonius, Parapleurogonius, Himasomum, Pyelosomum, Cricocephalus, Barisomum, and Pseudobarisomum. An amended diagnosis for Himasomum is presented. The trees differ only in the placements of Pleurogonius, Renigonius + Parapleurogonius, Iguanacola, and Himasomum relative to each other. Parapronocephalum and Notocotyloides are members of the clade containing the Notocotylidae. The phylogenetic tree supports interpretations of 3-4 transitions from marine to freshwater turtles, 3 host switches from marine turtles to the Galapagos marine iguana and 3 from marine turtles to the French angelfish, and widespread host switching among marine chelonians. No switches to non-chelonian hosts coincide with transitions from marine to freshwater.

Animals↗
PubMed1995

Phylogenetic relationships among the species of Pyelosomum Looss, 1899 (Digenea: Pronocephalidae).

Comparative morphological study of 10 nominal species of pronocephalids forming a clade diagnosed by plump rounded bodies, sinuous ceca, and short esophagi supports the recognition of 7 species, with Pyelosomum longicaecum a junior synonym of P. renicapite, and P. solum and Myosaccus chelonei species incertae sedis. Phylogenetic analysis of the 7 recognized species, based on 18 morphological transformation series, produced a single tree with a consistency index of 86%. That tree suggests that Pyelosomum is paraphyletic unless Astrorchis, Epibathra, and Myosaccus are included in it. Accordingly, all are considered junior synonyms of Pyelosomum. Epibathra stenobursata is designated Pyelosomum stenobursata comb. n.

Animals↗
PubMed1995

Serendip deborahae n. gen. and n. sp. (Eucestoda: Tetraphyllidea: Serendipidae n. fam.) in Rhinoptera steindachneri Evermann and Jenkins, 1891 (Chondrichthyes: Myliobatiformes: Myliobatidae) from southeastern Ecuador.

Cestodes collected in spiral valves of Rhinoptera steindachneri from the southern coast of Ecuador represent an undescribed species of Tetraphyllidea. The new species has bothridia possessing septa but lacking apical suckers. It is diagnosably distinct from all other tetraphyllidean genera by possessing a scolex comprising 4 triangular bothridia that are fused together forming a platelike structure, each of which is subdivided by 2 simple and 1 bifurcating septa radiating from its base and ringed by marginal loculi; therefore, a new genus is proposed for it. By exhibiting some degree of bothridial fusion, testes arranged in 2 layers in the proglottis and postovarian testes, the new species appears to be a member of a clade containing Dioecotaenia, Duplicibothrium, and Glyphobothrium. The new species possesses vitelline fields that converge dorsally in each proglottis, except for the ovarian and terminal genitalia areas, a feature that has been reported previously only in Duplicibothrium and Glyphobothrium. Furthermore, Duplicibothrium and Glyphobothrium, like the new species, are markedly protandric. Therefore, we propose that Duplicibothrium, Glyphobothrium, and the new species comprise the sister group of the Dioecotaeniidae, and propose a new family name for the clade. Tritaphros is rejected as a possible sister group for the clade; suggested alternatives include some species of Caulobothrium, Rhodobothrium, or some members of the Phyllobothrium centrurum group.

Animals↗
PubMed1995

Five new species of Acanthobothrium van Beneden, 1849 (Eucestoda: Tetraphyllidea: Onchobothriidae) in stingrays from 1he Gulf of Nicoya, Costa Rica.

Five new species of Acanthobothrium are described in stingrays from the Gulf of Nicoya, Costa Rica. Acanthobothrium costarricense n. sp. in Dasyatis longus, most similar to Acanthobothrium lilium, Acanthobothrium lineatum, and Acanthobothrium himanturi, has bothridial hooks averaging 125 microns (lateral) and 145 microns (medial) long, an average of 47 testes per proglottis, cirrus sacs averaging 187 microns long, and asymmetrical ovarian lobes with poral lobes reaching the posterior margin of the cirrus sac, and aporal lobes reaching the middle of the cirrus sac. Acanthobothrium cimari n. sp. in D. longus, most similar to A. lilium, A. lineatum, A. himanturi, A. costarricense, and Acanthobothrium semnovesiculum, has bothridial hooks averaging 117 microns (lateral) and 121 microns (medial) long, an average of 50 testes per proglottis, cirrus sacs averaging 164 microns long, and asymmetrical ovarian lobes with poral lobes reaching the posterior margin of the cirrus sac, and aporal lobes reaching the level of the vagina. Acanthobothrium puntarenasense n. sp. in D. longus, distinctive in having a very small scolex relative to the width of the cephalic peduncle similar to Acanthobothrium microcephalum, has bothridial hooks averaging 111 microns (lateral) and 117 microns (medial) long, an average of 50 testes per proglottis, cirrus sacs averaging 170 microns long, and asymmetrical ovarian lobes with poral lobes reaching the posterior margin of the cirrus sac, and aporal lobes reaching the middle of the cirrus sac. Acanthobothrium vargosi in D. longus, most similar to Acanthobothrium brevissime, Acanthobothrium tasajerasi, Acanthobothrium urotrygoni, and Acanthobothrium campbelli, has bothridial hooks averaging 130 microns (lateral) and 133 microns (medial) long, an average of 25 testes per proglottis arranged in 2 single rows, cirrus sacs averaging 91 microns long, and asymmetrical ovarian lobes with poral lobes reaching the posterior margin of the cirrus sac, and aporal lobes reaching the middle of the cirrus sac. Acanthobothrium campbelli n. sp. in Urotrygon chilensis, most similar to a A. brevissime, A. Vargasi, A. lineatum, A. himanturi, and A. urotrygoni, has bothridial hooks averaging 108 microns (lateral) and 111 microns (medial) long, an average of 19 tester per proglottis arranged in 2 nearly linear rows, cirrus sacs averaging 74 microns long, and asymmetrical ovarian lobes with the poral lobe reaching the posterior margin of the cirrus sac, and the aporal lobes reaching the middle of the cirrus sac.

Animals↗
PubMed1994

Sequence variation of the hydroxymethyldihydropterin pyrophosphokinase: dihydropteroate synthase gene in lines of the human malaria parasite, Plasmodium falciparum, with differing resistance to sulfadoxine.

Dihydropteroate synthase (H2Pte synthase) is the target of the sulfur-based antimalarial drugs, which are frequently used in synergistic combination with inhibitors of dihydrofolate reductase (H2folate reductase) to combat chloroquine-resistant malaria. We have isolated the H2Pte synthase coding sequence of the most pathogenic human parasite Plasmodium falciparum. It forms part of a longer coding sequence, located on chromosome 8, that also specifies 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (CH2OH-H2pterinPP kinase) at its 5' proximal end. This domain is unusually large, with two long insertions relative to other CH2OH-H2pterinPP kinase molecules. To investigate a possible genetic basis for clinical resistance to sulfa drugs, we sequenced the complete H2Pte synthase domains from eleven isolates of P. falciparum with diverse geographical origins and levels of sulfadoxine resistance. Overall, point mutations in five positions were observed, affecting four codons. Parasite lines exhibiting high-level resistance were found to carry either a double mutation, altering both Ser436 and Ala613, or a single mutation affecting Ala581. The mutations at positions 436 and 581 have the same location relative to each of two degenerate repeated amino acid motifs that are conserved across all other known H2Pte synthase molecules. The amino acid alteration at residue 613 is identically positioned relative to a different conserved motif. The fourth amino acid residue (437) affected by mutation, though adjacent to the apparently crucial residue 436, shows no obvious correlation with resistance. Although these mutations have no exact counterparts in any other organism, that at position 581 falls within a region of three amino acids where H2Pte synthase is modified in various ways in a number of sulfonamide-resistant pathogenic bacteria. Copy-number analysis indicated that there was no amplification of the H2Pte synthase domain in resistant parasite lines of P. falciparum, compared to sensitive lines.

Amino Acid Sequence↗