Short report: polymorphisms in the chloroquine resistance transporter gene in Plasmodium falciparum isolates from Lombok, Indonesia.

The polymorphisms in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) and P. falciparum chloroquine resistance transporter (pfcrt) genes, which are associated with chloroquine resistance, were examined in 48 P. falciparum isolates from uncomplicated malaria patients from the West Lombok District in Indonesia. The point mutation N86Y in pfmdr1 was present in 35.4% of the isolates and mutation K76T in pfcrt was found in all but one of the samples studied. Identified pfcrt haplotypes were mainly identical to the Papua New Guinea type SagtVMNT (42 of 48, 87.5%), and a few isolates had the Southeast Asia type CVIET (5 of 48, 10.4%). Moreover, one P. falciparum isolate harbored the K76N mutation, giving rise to the haplotype CVMNN, which was not previously reported in field isolates. Our findings suggest that chloroquine resistance in this area might have the same origin as in Papua New Guinea

Short report: polymorphisms in the chloroquine resistance transporter gene in Plasmodium falciparum isolates from Lombok, Indonesia.

The polymorphisms in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) and P. falciparum chloroquine resistance transporter (pfcrt) genes, which are associated with chloroquine resistance, were examined in 48 P. falciparum isolates from uncomplicated malaria patients from the West Lombok District in Indonesia. The point mutation N86Y in pfmdr1 was present in 35.4% of the isolates and mutation K76T in pfcrt was found in all but one of the samples studied. Identified pfcrt haplotypes were mainly identical to the Papua New Guinea type SagtVMNT (42 of 48, 87.5%), and a few isolates had the Southeast Asia type CVIET (5 of 48, 10.4%). Moreover, one P. falciparum isolate harbored the K76N mutation, giving rise to the haplotype CVMNN, which was not previously reported in field isolates. Our findings suggest that chloroquine resistance in this area might have the same origin as in Papua New Guinea

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インドネシア・ロンボク島のマラリア浸淫地におけるハマダラカ蚊相とマラリア媒介蚊の究明

A systematic mosquito collection was carried out for 3 years from November 2001 to September 2004 in western Lombok Island, Indonesia to clarify Anopheles fauna, and to confirm vector species in malaria endemic areas. Adult mosquitoes were collected at 14 sites in the study area by using double-walled mesh nets with human or cow bait. A total of 11 species were encountered. Anopheles vagus was the most predominant. The second most abundant species differed among the sub-study areas; An. sundaicus was abundant in the coastal plain area, and An. balabacensis in the mountainous area. Anopheles balabacensis showed high anthropophily and exophagy and An. sundaicus moderate anthropophily and exophagy. Malaria parasite detection from the collected mosquitoes was also carried out through the detection of circumsporozoite protein by the VecTest^. Fourteen and 4 samples, which were positive for Plasmodium falciparum and P. vivax antigen respectively, were found from An. subpictus, An. sundaicus and An. balabacensis. We conclude that malaria in the coastal plain area is transmitted by An. sundaicus and An. subpictus, whereas An. balabacensis is the primary vector in the mountainous area of Lombok Island.2001年11月から2004年9月までインドネシア・ロンボク島・ムニンティング郡においてマラリア媒介蚊調査を行った.合計11種のハマダラカを沿岸,丘陵地,平地,山間部の異なる4地域で採取した.沿岸と山間部で採取した10種について,Vectestを用いてマラリア原虫抗原検出試験を行った結果,森林部で採取したAn.balabacensis,沿岸部で採取したAn.sundaicusとAn.subpictusから陽性反応が得られた.特にAn.balabacensisから多くの陽性反応を得た.これら3種は屋外吸血性,人嗜好性が認められ,マラリア患者との発生時期や分布地域とも一致したため,マラリア媒介蚊と判断した.ロンボク島でのAn.balabacensisによるマラリア媒介は,本研究が初めて明らかにした

Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma

Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan\u27s method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-indcued point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A,. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens

High-contrast PET imaging of vasopressin V1B receptors with a novel radioligand, 11C-TASP699

Vasopressin 1B receptors (V1BRs) are abundantly expressed in the pituitary, and in vivo positron emission tomography (PET) of V1BRs was recently enabled by our development of a specific radioligand, 11C-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4-one analog, N-tert-butyl-2-[2-(6-11C-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (11C-TASP0410699, hereafter referred to as 11C-TASP699), as a potent V1BR radioligand producing a higher image contrast for the target than 11C-TASP0434299. Methods: In vitro properties of TASP699 were assessed by assaying its affinity for human V1BR and its selectivity for off-target molecules. Radioactive uptakes in the pituitary were analyzed using PET in rhesus monkeys after intravenous administration of 11C-TASP699. Serial doses of a selective V1BR antagonist, 2-[2-(3-chloro-4-fluorophenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]-N-isopropylacetamide hydrochloride (TASP0390325), were administered prior to the radioligand injection. Autoradiographic labeling of monkey pituitary slices with 11C-TASP699 was conducted with or without nonradioactive V1BR antagonists. Results: The half maximal inhibitory concentration (IC50) of TASP699 for human V1BRs (0.165 nM) was lower than that of TASP0434299 (0.526 nM), whereas its IC50 values for off-target molecules exceeded 1 μM. PET imaging in monkeys demonstrated that the peak pituitary uptake of 11C-TASP699 was almost equivalent to that of 11C-TASP0434299 and that pretreatment with TASP0390325 inhibited the retention of 11C-TASP699 in a dose-dependent manner, inducing nearly full occupancy at 0.3 mg/kg. Specific radioligand binding was determined as a specific-to-nondisplaceable uptake ratio at equilibrium using radioactivity retentions at 60 min in baseline and blocking studies. This ratio for 11C-TASP699 was approximately 2.5-fold greater than that of 11C-TASP0434299. A reverse-phase high performance liquid chromatography (HPLC) study identified the parent and polar radiometabolites. Affinities of two predicted metabolite candidates for V1BRs were more than ten times weaker than that of the parent. Intense autoradiographic labeling of the anterior pituitary with 11C-TASP699 was inhibited with TASP0390325 in a concentration-dependent manner. Conclusion:11C-TASP699 yielded PET images of pituitary V1BRs with a higher contrast than 11C-TASP0434299, supporting the applicability of 11C-TASP699 in the assessment of neuropsychiatric diseases and dose findings for test drugs in clinical trials