A 33-year-old man with a facial rash.
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Acyclovir↗
Biomedical subjects
John Fleming
Publications and source records attributed to John Fleming.
Simulation of the regional manifestation of asthma.
Asthma presents serious medical problems of global proportions. Clinical data suggest that the disease occurs preferentially at regions designated by large (0 </= I </= 5), central (6 </= I </= 11), and small (12 </= I </= 16) airways, where I defines branching generations within lungs. Our straightforward hypothesis, therefore, was that the efficacies of pharmacologic drugs proposed for the treatment and prophylaxis of asthma would be enhanced via their targeted delivery to appropriate sites. Hence, we have developed a mathematical model describing the behavior and fate of inhaled aerosols. Original algorithms have been derived to detail the physical manifestation of asthma as distinct components of smooth muscle constriction and inflammation. We have conducted a systematic analysis of the relative effects of morphology, ventilation, and particle size on aerosol deposition. Different intensities of asthma were simulated by reducing airway diameters by prescribed amounts. To show the real clinical applications of modeling, we have also simulated the performance of a popular nebulizer. Regarding therapeutic implications, it is clear that disease-induced changes in airway morphologies have pronounced effects on the administration of inhaled drugs. Likewise, ventilation affects both the total aerosol mass deposited and its relative spatial distribution among airways. By formulating these effects, the computer code allows drugs (e.g., bronchodilators for constriction, steroids for inflammation) to be selectively deposited. We suggest, therefore, that the code can be used in a complementary manner with clinical studies and can be integrated into aerosol therapy regimens.
Aerosols↗
Twenty propositions.
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Advance Directive Adherence↗
In silico modeling of asthma.
The incidence of asthma is increasing throughout the world, especially among children, to the extent that it has become a medical issue of serious global concern. Appropriately, numerous pharmacologic drugs and clinical protocols for the treatment and prophylaxis of the disease have been reported. From a scientific perspective, a review of the literature suggests that the targeted delivery of an aerosol would, in a real sense, enhance the efficacy of an inhaled medicine. Therefore, in accordance with published data we have developed a mathematical description of disease-induced effects of disease on airway morphology. A morphological algorithm defining the heterogeneity of asthma has been integrated with a computer code that formulates the behavior and fate of inhaled drugs. In this work, predicted drug particle deposition patterns have been compared with SPECT images from experiments with healthy human subjects (controls) and asthmatic patients. The asthma drug delivery model simulations agree with observations from human testing. The results indicate that in silico modeling provides a technical foundation for addressing effects of disease on the administration of aerosolized drugs, and suggest that modeling should be used in a complementary manner with future inhalation therapy protocols.
Administration, Inhalation↗
The code and the guide--practical instruments for practical people: a reply to Cannold.
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Aged↗
Interaction of early growth response protein 1 (Egr-1), specificity protein 1 (Sp1), and cyclic adenosine 3'5'-monophosphate response element binding protein (CREB) at a proximal response element is critical for gastrin-dependent activation of the chromogranin A promoter.
Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. Gastrin elevated cellular and nuclear Egr-1 levels in a time-dependent manner and also increased Egr-1 binding to the CgA -92/-73 region. Disruption of this site reduced gastrin responsiveness without influencing basal promoter activity, while loss of Sp1 and/or CREB binding sites diminished basal and gastrin-stimulated CgA promoter activity. Ectopic Egr-1 overexpression potently stimulated the CgA promoter, whereas coexpression of Egr-1 with Sp1 and/or CREB resulted in additive effects. Functional analysis of Sp1-, Egr-1-, or CREB-specific promoter mutations in transfection studies confirmed the tripartite organization of the CgA -92/-62 element. Signaling studies revealed that MAPK kinase 1 (MEK1)/ERK1/2 cascades are critical for gastrin-dependent Egr-1 protein accumulation as well as Egr-1 binding to the CgA promoter. Our studies for the first time identify Egr-1 as a nuclear target of gastrin and show that functional interplay of Egr-1, Sp1, and CREB is indispensable for gastrin-dependent CgA transactivation in gastric epithelial cells.
Binding Sites↗