Preparation and biological activity of new substituted antimalarial diaminodiphenylsulfones

Starting from 4,4'-diamino-diphenylsulfone (DDS) as a lead structure, new 2-substituted analogues as well as new 2-substituted 4-alkylamino-4'-amino diphenylsulfones have been designed and synthetized in different ways. This has led to compounds the inhibitory activity of which against 7,8-dihydropteroic acid synthase of plasmodia and mycobacteria is clearly superior to that of sulfadoxine and in most cases to that of DDS. Of special interest is 4'-amino-4-n-propylamino-2-methyl-diphenylsulfone. Together with inhibitors of 7,8-dihydrofolate reductase in vitro and in vivo it possesses a marked synergistic inhibitory activity against plasmodia. In contrast to DDS in doses up to 200 mg/kg p.o. (cat) no methemoglobin formation is observed. The compound has been selected for further studies.     

Digit ratio and hand-grip strength in German and Mizos men: cross-cultural evidence for an organizing effect of prenatal testosterone on strength.

The ratio of the length of the second and fourth digits (2D:4D), a putative proxy of prenatal testosterone (PT), is correlated with measures of physical fitness. The relationship between the organizing effect of PT on physical fitness is likely to arise as a response to intrasexual male competition for females. Physical strength is also likely to be important in intrasexual conflict, but nothing is known concerning the relationship between 2D:4D and strength. The strength of an individual is strongly influenced by body size, and 2D:4D is strongly dependent on ethnicity. We present evidence that strength, as measured from hand-grip strength, is related to 2D:4D in samples from two ethnic groups (52 Caucasian men from Germany, and 88 Oriental Mizos men from northeast India) which differed markedly in size. We found that 1) the German men were heavier and stronger, but had higher 2D:4D (lower PT) than the Mizos men; 2) a median split for grip strength into low (LGS) and high (HGS) groups showed that for right-hand 2D:4D (but not left-hand 2D:4D), the LGS men had higher 2D:4D than the HGS men; and 3) the relationships between right 2D:4D and grip strength were independent of ethnicity, age, height, and weight. Measures of grip strength correlate strongly with strength in other muscle groups, so we conclude that PT may have an early organizing effect on strength in men, and this is likely to be widespread in human groups.     

Neutrophils play a critical role in early resistance to amebic liver abscesses in severe combined immunodeficient mice.

Animal models of liver abscess formation with Entamoeba histolytica suggest that the neutrophil is the first cell of the host immune system to interact with the invading ameba. In vitro studies have suggested that lysis of neutrophils by virulent amebae may exacerbate the damage seen in amebic liver abscesses. To investigate the role of neutrophils in vivo, we used the severe combined immunodeficient (SCID) mouse model of amebic liver abscess formation and compared liver damage in neutrophil-depleted and control mice. We found that neutrophil-depleted animals have significantly larger amebic liver abscesses at early stages of infection and that abscesses in neutrophil-depleted SCID mice lack the prominent inflammatory cell ring seen in amebic liver abscesses in control SCID mice. These data suggest that neutrophils play a protective role in the early host response to amebic infection of the liver.     

Innate recognition of bacteria: engagement of multiple receptors

Until recently, consensus was that the mechanism of action of the innate immune system was a simplified one. Current research findings in the field of innate recognition of bacteria suggest that it involves complex associations of receptors depending on cell type and bacterial stimuli, CD14, integrins, Toll-like receptors (TLRs), CD55, ion channels, and activation clusters containing heat shock proteins, chemokine receptor 4 and a plethora of other molecules have been shown to serve as key molecules in bacterial recognition. In this article, we review all the advances in the field and discuss the possibility that the repertoire for recognition of pathogens is defined by the combinational engagement of multiple receptors.     

Cryptosporidium parvum Infection of Human Intestinal Xenografts in SCID Mice Induces Production of Human Tumor Necrosis Factor Alpha and Interleukin-8

The protozoan parasite Cryptosporidium parvum invades intestinal epithelial cells and can cause life-threatening diarrhea in immunocompromised individuals. Despite the clinical importance of this organism, much remains to be learned about the pathogenesis of C. parvum-induced diarrhea. To explore the role of the intestinal inflammatory response in C. parvum disease, using C. parvum oocysts we infected human intestinal xenografts in severe combined immunodeficient (SCID) mice. Seven days after infection, we found levels of human tumor necrosis factor alpha and interleukin-8 in C. parvum-infected human intestinal xenografts that were significantly higher than those seen in uninfected control xenografts. These results demonstrate that human intestinal cells produce proinflammatory cytokines in response to C. parvum infection and establish SCID-HU-INT mice as a model system to study the interactions of C. parvum with the human intestine.     

Shigella infection in a SCID mouse-human intestinal xenograft model: role for neutrophils in containing bacterial dissemination in human intestine

Shigellae infect human intestine and cause intense inflammation and destruction of colonic and rectal mucosa. To model the interactions of shigella with human intestine in vivo, we have studied shigella infection in human intestinal xenografts in severe combined immunodeficient mice (SCID-HU-INT mice). Inoculation of shigella into human intestinal xenografts caused severe inflammation and mucosal damage, which was apparent as soon as 4 h following infection. Shigella infection was associated with human intestinal production of interleukin-1B (IL-1B) and IL-8 and a marked neutrophil influx into the graft. Depletion of neutrophils from SCID-HU-INT mice reduced inflammation in the human intestinal xenograft in response to shigella infection but failed to significantly alter tissue damage. However, the number of intracellular bacteria was more than 20-fold higher in the human intestinal xenografts from neutrophil-depleted SCID-HU-INT mice. Infection of human intestinal xenografts with an attenuated vaccine strain of shigella (CVD1203) induced lower levels of IL-1B and IL-8 than wild-type shigella and caused only moderate damage to the intestinal permeability barrier. Our studies establish the SCID-HU-INT mouse as a viable model for studying the interactions between shigella and human intestine and indicate that neutrophils are important for controlling the invasion of human intestine by shigella.     

A quantitative structure-activity relationship analysis of some 4-aminodiphenyl sulfone antibacterial agents using linear free energy and molecular modeling methods

A set of 36 congeneric 4-aminodiphenyl sulfones with measured inhibition potencies of dihydropteroate synthase were studied by using both linear free energy and molecular modeling methods. The goals of the investigation were to identify the "active" conformation for these compounds as inhibitors and, correspondingly, to contruct a quantitative structure-activity relationship (QSAR). These molecules are quite flexible and possess multiple conformational energy minima. Application of molecular shape analysis (MSA), using all intramolecular energy minima as part of the analysis, was not successful in generating a QSAR. However, the calculated intramolecular conformational entropy of these compounds was found to correlate with inhibition potency leading to a highly significant QSAR. Inhibition potency increases as entropy decreases. A decrease in entropy enhances the population of specific, symmetry-related minimum-energy conformations. In this indirect way, it was possible to postulate an "active" conformation. This investigation illustrates that specific knowledge of the "active" shape of a molecule may not provide the information needed to quantitatively explain the observed structure-activity relationship.     

Apolipoprotein E promotes the binding and uptake of β-amyloid into Chinese hamster ovary cells in an isoform-specific manner

The 4 allele of apolipoprotein E gene is a major risk factor for Alzheimer's disease. However, the mechanism by which the E4 isoform of apolipoprotein E increases the risk of Alzheimer's disease is poorly understood. To determine whether the isoform-specific effects of apolipoprotein E may be mediated via clearance of bound β-amyloid, we examined the uptake of β-amyloid 1–40 into Chinese hamster ovary cells in the presence or absence of the apolipoprotein E isoforms E2, E3 and E4. Apolipoprotein E2 and E3 treatments were associated with higher association of β-amyloid with cells as compared to treatment with E4. Heparin blocked the association of β-amyloid with cells, as did an antibody to one of the apolipoprotein E receptors (the low-density lipoprotein receptor-related protein).

Thus, the apolipoproteins E2 and E3, but not E4, may play important roles in the clearance of β-amyloid from the extracellular space via the low-density lipoprotein receptor-related protein.     

Endotoxin-induced suppression of erythropoiesis: the role of erythropoietin and a heme synthesis stimulating factor

The regulation of erythropoiesis is primarily controlled by erythropoietin (Ep). Recently, however, other factors that both stimulate and inhibit erythropoiesis have been reported. Using an in vitro liquid culture of bone marrow cells, a factor in normal mouse serum was demonstrated that markedly stimulated heme synthesis by marrow erythroid cells. In this study, the role of this heme synthesis stimulating factor (HSF) and Ep in the erythropoietic suppression caused by endotoxin administration to mice was examined. Although HSF levels did not alter appreciably after endotoxin injection, marrow erythroid cells from these animals became unresponsive to the factor. This could be reversed if Ep was added to the culture in vitro or if the hormone was injected into the mice 18 hr prior to harvesting the marrow. This marrow erythroid cell response is identical to that seen in animals in whom Ep levels are markedly reduced, such as that found in exhypoxic polycythemia, and suggest a decrease in the hormone following endotoxin administration. Additional studies demonstrated that when Ep was injected into mice 6 hr after endotoxin administration, an increase in femoral erythroid colony-forming units (CFU-E), proerythroblast number, and 59 Fe incorporation into femoral marrow cells could be demonstrated. These findings, together with the marrow erythroid cell response to the hormone, suggest that the mechanism for suppression of erythropoiesis after endotoxin injection is a reduction in the level of circulating Ep.     

Association of in utero sensitization to Schistosoma haematobium with enhanced cord blood IgE and increased frequencies of CD5- B cells in African newborns

This study investigated in utero priming as a consequence of maternal parasitic infections. Cord blood plasma samples of 63 African newborns were assessed by enzyme-linked immunosorbent assay for their content of total and schistosome-specific or filaria-specific IgE and IgG4. The frequencies of lymphocyte phenotypes in cord blood were also determined by using flow cytometry, and were compared with those of European newborns. We found significantly increased schistosome soluble egg antigen (SEA)-specific IgE in cord plasma of those born to mothers with schistosome infections and correlations between fetal and maternal SEA-specific and filaria antigen-specific IgE. These data are evidence for in utero priming of the fetal immune system to maternal helminth infections. Furthermore, we show significantly enhanced percentages of CD5- B cells in African newborns cord blood compared with Europeans, which is consistent with earlier maturation of the African fetal immune system.