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At least 919 records · Page 51Linked to original sources
PubMed2002

In vitro/in vivo correlations between transdermal delivery of 5-aminolaevulinic acid and cutaneous protoporphyrin IX accumulation and effect of formulation.

BACKGROUND: Photodynamic therapy (PDT) using topical application of 5-aminolaevulinic acid (ALA) has been widely reported for the treatment of a variety of neoplastic and non-neoplastic cutaneous diseases. Although different formulations containing variable amounts of ALA have been applied in PDT, the dose-response relationships between transdermal ALA delivery and cutaneous protoporphyrin IX (PpIX) accumulation have not been studied. OBJECTIVES AND METHODS: The objectives of this study were to investigate the effect of permeability barrier function, ALA concentration and formulation on the in vitro penetration of ALA through nude mouse skin and cutaneous PpIX formation at 2 h following a 2-h application of ALA to nude mouse skin in vivo, and to delineate the relationships in between. RESULTS: Results demonstrated that variations in barrier integrity, in addition to ALA concentration, profoundly influenced ALA delivery to generate PpIX. Saturable correlations were found to exist between PpIX concentrations in both the epidermis and dermis in vivo and its transdermal flux in vitro, and the relationships were well described by the Emax model. The established correlations based on pure aqueous solutions were applicable to different formulations containing hydroxypropylmethylcellulose as the gelling agent and ethylenediamine tetraacetic acid as the iron chelator. Moreover, incorporation of desferrioxamine, another iron chelator, in the formulation prolonged cutaneous PpIX accumulation in the skin in comparison with 3% ALA aqueous solution, but the peak PpIX levels were not increased. Application of a liposomal formulation resulted in similar prolongation in ALA-induced PpIX accumulation, as well as better epidermal targeting. CONCLUSIONS: Knowledge of the dose-response relationships and the effect of formulation is important for designing optimal formulations and treatment schedules for topical ALA-PDT.

Administration, Cutaneous↗
PubMed2002

Fecal incontinence in anorectal malformations, neuropathy, and miscellaneous conditions.

In the majority cases, fecal soiling in children is functional and usually associated with severe constipation. Fortunately, functional soiling is a self-limiting problem and usually disappears at puberty. Organic fecal incontinence is a consequence of congenital malformations affecting the anorectum, anal sphincters, or the spinal cord. Inability to control bowel function may be permanent, as in patients with myelodysplasia; self-limiting, as in patients who have fecal soiling after a pull-through operation for Hirschsprung's disease; or partial, as in many patients who have undergone repair of an anorectal malformation. The purpose of this report is to review the etiology, long-term outcome, and evolution of the management of different types of organic fecal incontinence in children. Knowledge of the pathophysiology of fecal incontinence has accumulated during recent decades, and this provides the basis of modern treatment modalities that have revolutionized treatment so that today most patients can be provided total or at least social continence from early childhood.

Anal Canal↗
PubMed1974

The physical state dependence of carboxypeptidase Aalpha and Agamma kinetics.

Spectrochemical probes have demonstrated that the conformations of carboxypeptidase A (EC 3.4.12.2) differ in solution and in the crystalline state. Detailed kinetic studies of carboxypeptidase A(alpha) and A(gamma) crystals and solutions now show that the physical state of the enzyme is also a critical parameter that affects the function of the A(alpha) and A(gamma) enzymes in the same manner. The kinetic profiles and the corresponding kinetic constants of substrate hydrolysis are, therefore, important functional indices of the known conformational differences of the enzyme in these two physical states. The complex kinetic behavior of this enzyme, however, precludes meaningful comparisons of activity measurements for crystals and solutions obtained at only one substrate concentration. Underlying differences in varying substrate-inhibiting or -activating binding modes can result in either high or low activity ratios, concealing the true, functional consequences of the change in physical state. Thus, for all substrates examined, crystallization of the enzyme markedly reduces catalytic efficiency, k(cat), from 20- to 1000-fold. Equally as important, the substrate inhibition, apparent in solution for some di- and depsipeptides, is abolished with crystals, while for longer substrates the normal solution kinetics may acquire activation with the crystals. Hypothetical modes of substrate-enzyme interaction, generated by superimposing substrate models on the crystal structure of carboxypeptidase to simulate kinetics in solution, have failed to detect both of these changes, which affect inhibitory or activating binding modes. The only structure of carboxypeptidase yet published and that of its functionally inert complex with the pseudosubstrate, glycyl-L-tyrosine, derive from a unique form of carboxypeptidase A(alpha) crystals. These crystals differ from all others with regard both to their spectral properties and activity toward carbobenzoxy-glycyl-L-phenylalanine, which is 30% of that in solution, though the significance of this value cannot be gauged without knowledge of the relevant kinetic constants. The rapidly accumulating evidence for functional and conformational differences between crystals and solutions and the recent stress on the nonproductive aspects of the carboxypeptidase A(alpha)-glycyl-L-tyrosine complex, based on 30% site occupancy, suggest that the functional implications of its structural features require reevaluation.

Binding Sites↗
PubMed1989

Lymphatic anatomy: functional nodal basins.

The understanding of human dermal lymphatic anatomy has rested for nearly 120 years on the original work of Sappey. Subsequently, others have added significantly to our knowledge with anatomic studies. Copious lymphoscintigraphical data have accumulated in recent years in the evaluation of cutaneous melanomas. These data suggest that the old anatomic picture of lymphatic anatomy is functionally inaccurate. Analysis of these cumulative data reveals an extensive network of feeding lymphatic connections to major nodal basins far more expansive than previously recognized. These nodal basins overlap to a significant extent, rendering drainage prediction based on location nearly impossible. Therapeutic implications are remarkable.

Drainage↗
PubMed1998

P-glycoprotein-mediated efflux transport of anticancer drugs at the blood-brain barrier.

Several lipophilic, cytotoxic drugs, or both, (including anticancer drugs [Vinca alkaloids, doxorubicin, cyclosporin A, and digoxin]) have proven to be actively effluxed by P-glycoprotein (P-gp) expressed at the luminal membrane of the brain capillary endothelial cells, resulting in the very low apparent blood-brain barrier (BBB) permeation of these P-gp substrates from the blood circulating to the brain. In rats inoculated with 9L-glioma cells into the brain, the endothelial cells of tumor-associated vessels allowed easy penetration of anticancer drugs (ranimustine and doxorubicin) in tumor regions, although the normal BBB function still operated at the normal brain region to provide a barrier to the accumulation of P-gp substrates. A detailed knowledge of the BBB function would be very helpful in developing improved delivery systems of anticancer drugs to brain tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Constitutive retinoid receptors expressed from adenovirus vectors that specifically activate chromosomal target genes required for differentiation of promyelocytic leukemia and teratocarcinoma cells.

Sufficient knowledge of transcription factor structure and function has accumulated to allow attempts at the rational design of novel transcription factors for the study of gene regulation and potential application in gene therapy. In the present studies, we have systematically evaluated the function of chimeric retinoid receptors generated by fusion with the transactivation domain of VP16 and expression in adenovirus vectors. By varying the location of fusion of the VP16 transactivation domain with the retinoic acid receptor (RAR) or retinoid X receptor (RXR), marked differences in the specificity of gene activation were obtained. Although several chimeric proteins activated both RAR and RXR target genes, fusion of the NT16 transactivation domain to the N terminus of RAR permitted specific activation of reporter genes containing retinoic acid response elements. In contrast, fusion of the VP16 transactivation domain to the C terminus of RXR permitted specific activation of reporter genes containing RXR response elements. When tested for their ability to activate chromosomal targets, the chimera consisting of VP16 linked to the N terminus of PAR was much more active in promoting the differentiation of HL-60 cells and NTera-2 cells than the chimera consisting of VP16 linked to the C terminus of RXR. These observations support the existence of two distinct retinoid signalling pathways predicted on the basis of biochemical and pharmacologic studies and provide direct evidence that the programs of differentiation elicited by retinoic acid in these cells are mediated by a specific subset of binding sites for RAR-RXR heterodimers. VP16-RAR and VP16-RXR fusion proteins should be of further use in dissecting the relative contributions of RARs and RXRs to specific programs of gene expression. Constitutive retinoid receptors may also be considered for use as novel tumor suppressor genes for genetically based treatment of retinoid-responsive cancers.

Adenoviridae↗
PubMed2002

Vascular growth factors and lymphangiogenesis.

Blood and lymphatic vessels develop in a parallel, but independent manner, and together form the circulatory system allowing the passage of fluid and delivering molecules within the body. Although the lymphatic vessels were discovered already 300 years ago, at the same time as the blood circulation was described, the lymphatic system has remained relatively neglected until recently. This is in part due to the difficulties in recognizing these vessels in tissues because of a lack of specific markers. Over the past few years, several molecules expressed specifically in the lymphatic endothelial cells have been characterized, and knowledge about the lymphatic system has started to accumulate again. The vascular endothelial growth factor (VEGF) family of growth factors and receptors is involved in the development and growth of the vascular endothelial system. Two of its family members, VEGF-C and VEGF-D, regulate the lymphatic endothelial cells via their receptor VEGFR-3. With the aid of these molecules, lymphatic endothelial cells can be isolated and cultured, allowing detailed studies of the molecular properties of these cells. Also the role of the lymphatic endothelium in immune responses and certain pathological conditions can be studied in more detail, as the blood and lymphatic vessels seem to be involved in many diseases in a coordinated manner. Discoveries made so far will be helpful in the diagnosis of certain vascular tumors, in the design of specific treatments for lymphedema, and in the prevention of metastatic tumor spread via the lymphatic system.

Animals↗
PubMed1995

Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms.

In the last few years there has been a veritable explosion of knowledge about cyclic nucleotide phosphodiesterases. In particular, the accumulating data showing that there are a large number of different phosphodiesterase isozymes have triggered an equally large increase in interest about these enzymes. At least seven different gene families of cyclic nucleotide phosphodiesterase are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the more important aspects about the structure, cellular localization, and regulation of each family of phosphodiesterases. Particular emphasis is placed on new information obtained in the last few years about how differential expression and regulation of individual phosphodiesterase isozymes relate to their function(s) in the body. A substantial discussion of the currently accepted nomenclature is also included. Finally, a brief discussion is included about how the differences among distinct phosphodiesterase isozymes are beginning to be used as the basis for developing therapeutic agents.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1999

On the role of biophysical properties of cortical neurons in binding and segmentation of visual scenes.

Neuroscience is progressing vigorously, and knowledge at different levels of description is rapidly accumulating. To establish relationships between results found at these different levels is one of the central challenges. In this simulation study, we demonstrate how microscopic cellular properties, taking the example of the action of modulatory substances onto the membrane leakage current, can provide the basis for the perceptual functions reflected in the macroscopic behavior of a cortical network. In the first part, the action of the modulatory system on cortical dynamics is investigated. First, it is demonstrated that the inclusion of these biophysical properties in a model of the primary visual cortex leads to the dynamic formation of synchronously active neuronal assemblies reflecting a context-dependent binding and segmentation of image components. Second, it is shown that the differential regulation of the leakage current can be used to bias the interactions of multiple cortical modules. This allows the flexible use of different feature domains for scene segmentation. Third, we demonstrate how, within the proposed architecture, the mapping of a moving stimulus onto the spatial dimension of the network results in an increased speed of synchronization. In the second part, we demonstrate how the differential regulation of neuromodulatory activity can be achieved in a self-consistent system. Three different mechanisms are described and investigated. This study thus demonstrates how a modulatory system, affecting the biophysical properties of single cells, can be used to achieve context-dependent processing at the system level.

Animals↗
PubMed1994

Middle ear mucosal inflammation: an in vivo model.

The inflammatory process underlies the pathogenesis of otitis media (OM). Although knowledge concerning this common childhood disease continues to accumulate, most of the basic science research is based on in vitro or ex vivo methodologies. Magnetic resonance imaging (MRI), although lauded for its ability to image soft tissue, is often neglected as a research tool providing real-time in vivo information. This study attempts to assess experimental middle ear (ME) inflammation using MRI. The vasoactive effects of histamine and its interaction with antihistamines and a glucocorticoid were evaluated. Histamine was chosen because it is one of the naturally occurring inflammatory mediators. The antagonists were selected on the basis of their antihistaminic and vasoactive effects, respectively. Certainly there is substantial clinical interest in these agents because their efficacy for the treatment of OM is still being debated. The chinchilla model was chosen since it is one of the best characterized species in the study of OM. The three parts of the study are as follows: the effects of histamine on chinchilla ME mucosa; histamine challenge following pretreatment using hydroxyzine hydrochloride (H1 antagonist), ranitidine chloride (H2 antagonist), and the combination; and histamine challenge following pretreatment with dexamethasone. Sequential T1-weighted spin-echo (SE) MRI was used to detect extravasation of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) into the middle ear effusion (MEE). The results indicate that the vasoactive effects of histamine are dose-related and can be assessed across a wide spectrum of histamine dosages inclusive of the human MEE levels. The H1 antagonist alone, or in combination with the H2 antagonist, was able to prevent the increased vascular permeability induced by histamine. When used alone, the H2 antagonist did not abolish the effects of histamine. The vasoactive effects of histamine were also ameliorated by pretreatment with a glucocorticoid. These findings indicate the utility of MRI for assessing mucosal inflammation in a real-time manner rather than as an accumulation of events. This study also validates the efficacy of an H1 antagonist and a glucocorticoid in counteracting the vasoactive effects of histamine. This methodology may be suited for evaluating the effects of other classes of antiinflammatory mediators.

Animals↗
PubMed1998

Colonization of maize grain by Fusarium moniliforme and Fusarium proliferatum in the presence of competing fungi and their impact on fumonisin production.

This study was carried out to determine the effect of water activity (aw) and temperature on the patterns of colonization of maize grain by isolates of Fusarium moniliforme and F. proliferatum in the presence of interacting spoilage fungi, such as Aspergillus flavus, A. niger, A. ochraceus, and Penicillium implicatum, over 4-week incubation periods. The impact that such interactions have on Fusarium infection of maize grain and populations and on the production of fumonisins were all evaluated. At 0.93 and 0.95 aw, interactions of the two Fusarium spp. with other species to a large extent resulted in mutual inhibition on contact or overgrowth by the Aspergillus and Penicillium spp., regardless of temperature and growth rates of the species. Seed infection by the Fusarium spp. at 25 degrees C was influenced mainly by A. flavus and A. niger, with a reduction of infection by up to 45 and 30%, respectively, after 2 weeks. At 15 degrees C and lowered aw levels, infection was reduced, and sometimes completely inhibited, by A. niger, A. ochraceus, and P. implicatum. By contrast, populations of the Fusarium spp. (CFU per gram grain) were reduced mainly by A. flavus and P. implicatum. A. niger reduced populations of the Fusarium spp. at 0.93 and 0.95 aw, particularly after 4 weeks of incubation. Interaction with A. niger, A. ochraceus, and A. flavus at 15 and 25 degrees C and 0.98 aw resulted in a significant stimulation in fumonisin production by both Fusarium spp. Interaction with P. implicatum resulted in a decrease in fumonisin production by F. moniliforme. However, interaction with F. proliferatum resulted in an enhanced production at both temperatures and 0.95 and 0.98 aw. This study has shown that fungal interactions may act as an additional control factor in Fusarium spp. development on grain. However, although interactions lead to a decreased colonization by Fusarium, mainly at lower aw, a decrease in fumonisin production accumulation does not occur at the same time. Knowledge of these interactions is essential for improving effective control procedures for preventing growth and mycotoxin production by such fungi.

Aspergillus↗
PubMed2000

The role of free radicals, oxidative stress and antioxidant systems in diabetic vascular disease.

Recent experimental findings suggest that overproduction of reactive oxygen and nitrogen species (ROS/RNS), lowered antioxidant defense and alterations of enzymatic pathways in humans with poorly controlled diabetes mellitus can contribute to endothelial, vascular and neurovascular dysfunction. Over the past decade, there has been substantial interest in oxidative stress and its potential role in diabetogenesis, development of diabetic complications, atherosclerosis and associated cardiovascular disease. Consequences of oxidative stress are damage to DNA, lipids, proteins, disruption in cellular homeostasis and accumulation of damaged molecules. This review summarizes recent knowledge on the pathomechanism of ROS/RNS in vascular oxidative stress and Maillard reactions. Evidence suggests that Maillard reactions act as amplifier of oxidative damage in aging and diabetes. Furthermore, results of experimental observations with antioxidant systems and antioxidant pharmacotherapy in the treatment of diabetes mellitus are discussed. These data indicate that the targeting therapy to specific macromolecules, tissues and organs of diabetics by specific antioxidants or combined drug preparates could become a relevant adjuvant pharmacotherapy with improved glycaemic control, blood pressure control and management of dyslipidemia for the treatment or prevention of progression of micro- and macrovascular diabetic complications. Supplementation with antioxidants as a promising complementary treatment can exert beneficial effects in diabetes. Some antidiabetic drugs may have antioxidant properties independently of their main role on glycaemia control. Therapeutic potential of inhibitors of AGEs formation for delaying of diabetic complications is now intensively studied in several laboratories. Furthermore, for functional outcomes of the intervention with antioxidants is also important development of accurate and sensitive methods for early detection of oxidative damage in diabetes. (Tab. 6, Fig. 3, Ref. 117.)

Antioxidants↗
PubMed2001

[Supragenomic strategies. Cancer research after HUGO].

Vast knowledge concerning genetic alterations in cancer cells has accumulated in recent years. The results raise hopes of better and more refined therapy. However, some researchers fear that it will take a long time until we get the main picture using a reductionistic approach. The hallmark of cancer is genomic instability. Other research groups use supragenomic strategies and focus on the interactions between tumor cells and cells of the surrounding stroma, e.g. inhibition of angiogenesis, production of extracellular proteases and activation of growth factors. Tumor cells are also dependent on proteoglycans and in many cases specific forms with specific degradation pathways dominate. Proteoglycans control growth factor activity and polyamine uptake. Proteoglycans are suitable targets for antitumor therapy because they are supragenomic products and their biosynthesis can be manipulated with xylosides.

Antineoplastic Agents↗
PubMed1985

Prospects for treatment of human retrovirus-associated diseases.

Overwhelming evidence has been obtained over the past 2 years that human T-cell leukemia virus type III (HTLV-III) is the primary cause of acquired immunodeficiency syndrome. The direct cytopathic effect of the virus on T4 helper cells demonstrated in vitro is probably responsible for the depletion of this critical population of cells in affected individuals which results in a series of devastating immunological abnormalities. It follows that any approaches effective in suppressing the virulent virus would be of benefit to the infected patient. The vast amount of knowledge about retroviruses in general, and the rapidly accumulating information about HTLV-III in particular, makes it likely that a targeted approach for development of antiviral agents will bear fruit. General strategies further making use of chemical and biological agents as well as genetic manipulations are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1978

Properties of cardioinhibitory factors produced in shock.

The widespread occurrence of circulating cardioinhibitory factors in many types of circulatory shock and in a variety of mammalian species is impressive. This review summarizes the properties of the nine best-known factors with regard to their occurrence, chemical properties, sites of origin, biological actions, and pharmacological modification. Cardioinhibitory factors appear to play a significant role in the pathogenesis of circulatory shock. There now are pharmacological means available with which to prevent the formation of such factors. With knowledge on the chemistry of cardioinhibitory factors rapidly accumulating, it is anticipated that specific antagonists to the action of these factors will become available in the near future.

Animals↗
PubMed1983

[Anti-angiogenesis, a possible new modality of cancer treatment].

During the past decade a number of pioneering knowledge of neovascularization induced by neoplasm have been accumulated and a clinical application of anti-angiogenesis treatment seems to be launched within very near future. While the most Japanese research workers in the medical field are still dreaming of immunological approaches to cancers. But now we should stand on the wide view of basic biology of cancer and open searches for newer attacking targets of cancers. Such a newer modality may be included in biological treatment against not only tumor growth but also invasion, angiogenesis, and metastasis. As an example of a search for newer attacking target of cancer, here I proposed a view point regarding tumor angiogenesis as a symbiotic system of tumor cells and endothelial cells and I reviewed briefly on recent aspects of angiogenesis and anti-angiogenesis, introducing works of Drs. Folkman, Fenselau, Kumar, Weiss, Rifkin, Langer, Eisenstein, Gullino, and others. I hope this short review may attract many more research workers to the "virgin" field of angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2006

Metabolite production in degradation of pyrene alone or in a mixture with another polycyclic aromatic hydrocarbon by Mycobacterium sp.

Degradation of pyrene (PYR) alone and in the presence of phenanthrene or fluoranthene by Mycobacterium sp. strain A1-PYR isolated from mangrove sediments was investigated. When PYR was the only polycyclic aromatic hydrocarbon compound and the sole carbon source, only 33% of the added PYR was slowly degraded during 7 d of incubation. Seven metabolites were obtained, including four-ring metabolites (monohydroxypyrene and three different dihydroxypyrenes) and three-ring metabolites (dihydroxyphenanthrene, 4-phenanthrene-carboxylic acid, and 4-phenanthrol), of which more four-ring metabolites accumulated compared with three-ring metabolites. To our knowledge, this is the first report in which PYR was initially attacked by Mycobacterium sp. to form three different dihydroxypyrenes. Pyrene degradation was significantly stimulated when mixed with phenanthrene or fluoranthene. In the presence of fluoranthene, PYR was rapidly degraded (up to 57%), and significant amounts of dihydroxypyrene were formed within 3 d of incubation, followed by a period of minimal PYR degradation from 3 to 7 d with disappearance of four-ring metabolites and accumulation of three-ring metabolites. In contrast, PYR was removed completely, and little evidence of metabolites was detected in the presence of phenanthrene. These results showed that PYR was degraded to a larger extent when mixed with another polycyclic aromatic hydrocarbon concomitant with a higher turnover of PYR metabolites. The induction of complex enzyme systems and increase in biomass possibly affected the transformation of PYR metabolites in the mixture with phenanthrene or fluoranthene.

Biodegradation, Environmental↗
PubMedDate not supplied

Fatty liver: imaging patterns and pitfalls.

Fat accumulation is one of the most common abnormalities of the liver depicted on cross-sectional images. Common patterns include diffuse fat accumulation, diffuse fat accumulation with focal sparing, and focal fat accumulation in an otherwise normal liver. Unusual patterns that may cause diagnostic confusion by mimicking neoplastic, inflammatory, or vascular conditions include multinodular and perivascular accumulation. All of these patterns involve the heterogeneous or nonuniform distribution of fat. To help prevent diagnostic errors and guide appropriate work-up and management, radiologists should be aware of the different patterns of fat accumulation in the liver, especially as they are depicted at ultrasonography, computed tomography, and magnetic resonance imaging. In addition, knowledge of the risk factors and the pathophysiologic, histologic, and epidemiologic features of fat accumulation may be useful for avoiding diagnostic pitfalls and planning an appropriate work-up in difficult cases.

Diagnosis, Differential↗