Small molecule inhibitors of IgE synthesis.
A novel series of small molecule inhibitors of IgE synthesis are described. Compounds were optimized for potency, metabolic stability and absence of genetic toxicology.
Cytochrome P-450 CYP1A1↗
Biomedical subjects
Alan Brown
Publications and source records attributed to Alan Brown.
Dose-ranging study for trials of therapeutic infection with Necator americanus in humans.
Epidemiological studies suggest that a hookworm infection producing 50 eggs/gram of feces may protect against asthma. We conducted a dose-ranging study to identify the dose of hookworm larvae necessary to achieve 50 eggs/gram of feces for therapeutic trials of asthma. Ten healthy subjects without asthma or airway hyperresponsiveness to inhaled methacholine received 10, 25, 50, or 100 Necator americanus larvae administered double blind to an area of skin on the arm. Subjects were seen weekly for 12 weeks and were then treated with mebendazole. Skin itching at the entry site and gastrointestinal symptoms were common at higher doses. Lung function did not change. Levels of blood eosinophils and IgE increased transiently, and levels of IgG increased progressively. All doses resulted in at least 50 eggs/gram of feces in the eight subjects who completed the study. Infection with 10 N. americanus larvae is well tolerated, elicits a modest host eosinophil response, and is potentially suitable for use in preliminary clinical therapeutic trials.
Adult↗
President's page: The practice of medicine: many hands, light work.
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Cardiology↗
Histone structures: targets for modifications by molecular assemblies.
The core histone proteins contain modification sites that are key elements in the regulation of the cell cycle, DNA replication and repair with histone assembly, control of gene expression, and transcriptional elongation. Much work has been done on the various molecular assemblies that remodel nucleosomes, methylate, ubiquitinate, and cause ADP-ribosylation of histones, and acetylate and phosphorylate core histone tails. The core histones are the final targets of the enzymes in the molecular assemblies. What structural changes in the histones are correlated with these modifications? This paper considers the high-resolution structure of the histone octamer and stresses the importance of histone docking sequences in the binding of the two (H2A-H2B) dimers to the (H3-H4)(2) tetramer. There is an extensive acid-base area of interaction between histone octamers in crystals at high salt, which may have implications for nucleosome remodeling. We show that there are regions of high alpha-helix probability in all core histone N-terminal tails in regions where lysine acetylation occurs. There are also consensus sequences spanning up to eight amino acid residues between some histone tail regions. Circular dichroism studies using synchrotron radiation at wavelengths as low as 130 nm are promising for the accurate measurement of changes of histone secondary structure related to function.
Amino Acid Sequence↗
House dust mite Der p 1 downregulates defenses of the lung by inactivating elastase inhibitors.
House dust mites (HDM) are the most common source of aeroallergens and in genetic susceptible individuals can cause symptoms ranging from atopic dermatitis to bronchial asthma. Der p 1, a major target of the human immune responses to HDM, through its enzymatic properties can modulate the adaptive immune system by the cleavage of CD23 and CD25. The consequences of this would be to promote allergic inflammatory responses. Furthermore, by disrupting epithelial tight junctions Der p 1 facilitates the transport of allergen across the epithelium. Here, we report that Der p 1 has additional effects on the innate defense mechanisms of the lung, by inactivating in vitro and ex vivo the elastase inhibitors human (h) alpha1-proteinase inhibitor (h-A1-Pi), mouse (m-), (but not human [h])-SLPI and h-elafin. We confirm that Der p 1 contain both cysteine and serine proteinases, and extend this finding to demonstrate for the first time that h-elafin is particularly sensitive to the biological activity of the latter. Because these elastase inhibitors have antimicrobial, as well as antielastase activity, our results suggest that inactivation of these innate components of the lung defense system by Der p 1 may increase the susceptibility of patients with allergic inflammation to infection.
Acute Disease↗
Innate and cognate mechanisms of pulmonary eosinophilia in helminth infection.
Passage of helminth larvae through the lungs can cause pulmonary eosinophilia that may have evolved as a means of parasite attrition. If allergic responses represent a misdirected activation of this arm of the immune system, then mechanisms governing eosinophil recruitment during infection would be expected to be closely related to those seen in allergy. We studied primary Necator americanus infection and compared this to multiply-infected or vaccinated mice. The arrival of larvae in the lungs triggered rapid eosinophil recruitment, which was greatly enhanced in previously sensitized mice. Interestingly, the presence of larvae in the lung was sufficient to trigger eosinophil chemoattractant production, including the chemokines eotaxin and MIP-1alpha, and was not enhanced by prior exposure to the parasites. Infection stimulated IL-5 production in all groups; however, this and IgE production were greatly enhanced in sensitized animals. Elevated IL-5 increased bone marrow production of eosinophils, and eosinophilia was abrogated by treatment with anti-IL-5 antibody. Therefore, trapping of larvae in the pulmonary vasculature is sufficient to trigger eosinophil recruitment, by induction of chemokines and IL-5. Primed cognate Th2 immunity does not increase local chemokine production, but does increase IL-5 production, which greatly enhances the availability of eosinophils for recruitment to the lung.
Animals↗
Schizophrenia risk and paternal age: a potential role for de novo mutations in schizophrenia vulnerability genes.
How schizophrenia (SZ) is maintained at roughly 1% of the population despite diminished reproduction is one puzzle currently facing researchers. De novo mutations were first proposed over half a century ago as a source for new SZ genes. Current evidence linking advancing paternal age to SZ risk makes revisiting this hypothesis important. Advancing paternal age is the major source of new mutations in the human population. This article will examine potential mechanisms whereby parental age may impact new mutations, as well as review recent data supporting such a hypothesis.
Journal Article↗