Structure-activity relationships for 1-phenylbenzimidazoles as selective ATP site inhibitors of the platelet-derived growth factor receptor

1-Phenylbenzimidazoles are shown to be a new class of ATP-site inhibitors of the platelet-derived growth factor receptor (PDGFR). Structure-activity relationships (SARs) are narrow, with closely related heterocycles being inactive. A systematic study of substituted 1-phenylbenzimidazoles showed clear SARs. Substituents at the 4'- and 3'-positions of the phenyl ring are tolerated but do not significantly improve activity, while substituents at the 2'-position abolish it. Substituents in the 2-, 4-, and 7-positions of the benzimidazole ring (with the exception of 4-OH) also abolish activity. Most substituents at the 5- and 6-positions maintain or increase activity, with the 5-OH, 5-OMe, 5-COMe, and 5-CO2Me analogues being >10-fold more potent than the parent 1-phenylbenzimidazole. The 5-OMe analogue was both the most potent inhibitor, and showed the highest selectivity (50-fold) between PDGFR and FGFR isolated enzymes, and also a moderately effective inhibitor (IC50 = 1.9 microM) of PDGF-stimulated PDGFR autophosphorylation in rat aorta smooth muscle cells.     

A longitudinal study of AIDS conversations between mothers and adolescents

This paper presents the results of a study on the introduced, free-ranging patas monkey population of Southwestern Puerto Rico (SWPR). It describes information on the population size, social group composition, diet, daily ranging patterns, and patas home range during a 3 year period. The patas monkey population in the study area consisted of approximately 120 individuals in four heterosexual groups and several all-male bands. Within their home ranges (26.8 km2), the population density was 4.47 individuals/km2. Home range size among the population's four heterosexual groups varied from 3.72 km2 to 15.39 km2, and minimum daily distance traveled ranged from 0.8-2.0 km. In general, the social structure and mating system of this population parallels what has been described for African populations. However, habitat use, ranging behavior, and the quality of intergroup interactions suggests that patas of this population exhibit territorial behavior.     

Use of parallel Erlang density functions to analyze first-pass pulmonary uptake of multiple indicators in dogs

The gamma and Erlang density functions describe a large class of lagged, right-skewed distributions. The Erlang distribution has been shown to be the analytic solution for a chain of compartments with identical rate constants. This relationship makes it useful for the analysis of first-pass pulmonary drug uptake data following intravenous bolus administration and the incorporation of this analysis into an overall systemic drug disposition model. However, others have shown that one Erlang density function characterizes the residence time distribution of solutes in single tissues with significant systematic error. We propose a model of two Erlang density functions in parallel that does characterize well the arterial appearance of indocyanine green, antipyrine, and alfentanil administered simultaneously by right atrial bolus injection. We derive the equations that permit calculation of the higher order moments of a system consisting of two parallel Erlang density functions and use the results of these calculations from the data for all three indicators to estimate pulmonary capillary blood volume and mean transit time in the dog.     

Malaria chemosuppression in pregnancy. V. Placenta malarial changes among three different prophylaxis groups

The effect of malaria chemoprophylaxis during pregnancy on placenta malarial changes (PMCs) was investigated in 170 tissue sections. Women of 63 sections received daily proguanil (PROG), 61 once weekly chloroquine (CQ) and 46 the two drug combination (CQ+PROG). All were residents of a malaria hyperendemic area in Muheza District, Tanzania. Supervised prophylaxis started early in pregnancy till delivery. Parasitaemias and clinical episodes were detected early and radically treated. Overall, PMCs were mostly infrequent and light viz: fibrinous deposits (98%), fibrinoid necrosis (60%), leucocytic infiltrations (59%), macrophage containing pigment (16%), and malaria parasites (8%). The type, prevalence, and severity of the PMCs in the three prophylaxis groups were comparable. This was despite the fact that PROG and CQ+PROG were prophylactically more efficacious than CQ and despite the expectation that the prevalence and severity of the PMCs would be high in the CQ group. Prompt diagnosis and effective treatment of parasitaemias in this group contributed to the low prevalence and less severity. It is concluded that effective malaria chemoprophylaxis or prompt diagnosis and effective treatment of malaria parasitaemias have significant impact on the prevalence of PMCs. Due to various operational constraints in most developing countries, chemoprophylaxis remains the only feasible broad option for malaria control in pregnancy.     

Rectal gland of Bactrocera papayae: ultrastructure, anatomy, and sequestration of autofluorescent compounds upon methyl eugenol consumption by the male fruit fly

Sexually mature males of Bactrocera papayae are strongly attracted to and consume methyl eugenol (ME). Upon consumption, ME is biotransformed to two phenylpropanoids, 2-allyl-4,5-dimethoxyphenol (DMP) and (E)-coniferyl alcohol (CF), that are transported in the hemolymph, sequestered and stored in the rectal glands, and subsequently released as sex and aggregation pheromones during courtship. To date, very little work on the ultrastructure and anatomy of the rectal gland has been done, and the accumulation of phenylpropanoids in the rectal glands of males has not been observed visually. Our objectives are to describe the anatomy and fine structures of the rectal glands of males and females and to observe the accumulation of autofluorescent compounds in the rectal glands of males. The rectal glands of males and females have four rectal papillae with each papilla attached to a rectal pad. The rectal pads protrude from the rectal gland as the only surfaces of the gland that are not surrounded by muscles. The rectal papillae of ME-fed males had oil droplets and autofluorescent compounds that were absent from those of ME-deprived males. The autofluorescent compounds accumulated in the rectal sac, which is an evagination that is not found in rectal glands of females. The accumulation of these compounds increased with time and reached maximum at a day post-ME feeding and decreased thereafter. This trend is similar to the accumulation pattern of phenylpropanoids, CF and DMP in the rectal gland.     

BCL-2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice

The proto-oncogene, BCL-2, has been suggested to participate in cell survival during development of, and after injury to, the CNS. Transgenic (TG) mice overexpressing human Bcl-2 (n = 21) and their wild-type (WT) littermates (n = 18) were subjected to lateral controlled cortical impact brain injury. Lateral controlled cortical impact brain injury resulted in the formation of a contusion in the injured cortex at 2 days, which developed into a well-defined cavity by 7 days in both WT and TG mice. At 7 days after injury, brain-injured TG mice had a significantly reduced cortical lesion (volume = 1.99 mm3) compared with that of the injured WT mice (volume = 5.1 mm3, P < 0.01). In contrast, overexpression of BCL-2 did not affect the extent of hippocampal cell death after lateral controlled cortical impact brain injury. Analysis of motor function revealed that both brain-injured WT and TG mice exhibited significant right-sided deficits at 2 and 7 days after injury (P < 0.05 compared with the uninjured controls). Although composite neuroscores (sum of scores from forelimb and hind limb flexion, lateral pulsion, and inclined plane tests) were not different between WT and TG brain-injured mice, TG mice had a slightly but significantly reduced deficit in the inclined plane test (P < 0.05 compared to the WT mice). These data suggest that the cell death regulatory gene, BCL-2, may play a protective role in the pathophysiology of traumatic brain injury.