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Enhancement of misonidazole chemopotentiation by mild hyperthermia (41 degrees C) in vitro and selective enhancement in vivo.

Experiments were designed to test the hypothesis that mild heat treatment would selectively increase misonidazole (MISO) chemopotentiation of CCNU toxicity in hypoxic versus aerobic cells in vitro and in tumours in vivo via an augmentation of nitroreduction. EMT-6 cells were exposed to CCNU +/- 1.0 mM MISO under aerobic or hypoxic conditions for 4 h either at a constant 37 degrees C or at 41 degrees C for the first hour followed by 37 degrees C for the remaining 3 h. Chemopotentiation was not observed under aerobic conditions and heat treatment did not modify CCNU toxicity. Co-incubation with MISO and CCNU under hypoxic conditions resulted in enhanced toxicity (i.e. chemopotentiation) with either incubation protocol; however, the magnitude of the enhancement was significantly larger (P less than 0.025) when 41 degrees C incubation was included. Systemic heat treatment produced a similar enhancement of chemopotentiation in KHT tumours in C3H/HeN mice treated with MISO (0.5 mg g-1) and whole body hyperthermia (41 degrees C, 1 h) prior to administration of CCNU (15 mg kg-1). Heating had no effect on CCNU response but doubled the median growth delay produced by the CCNU-MISO combination. Heat treatment did not enhance myelosuppression of the combination. Both the in vitro and in vivo data indicate that mild hyperthermia can selectively enhance the magnitude of MISO chemopotentiation.

Aerobiosis↗

A quantitative study of the enhancing effect of nickel ions on the taste response to sodium ions of single fibers of the frog glossopharyngeal nerve: competitive inhibition by calcium ions of the nickel-enhanced response to sodium ions.

Single water fibers of the frog glossopharyngeal nerve respond to relatively high concentrations of NaCl ( > 80 mM). NiCl2 at 1 mM enhanced the Na+ response and reduced the threshold concentration for NaCl to 20 mM. CaCl2 at 0.5-1 mM induced an inhibition of the Ni2+ -enhanced response to Na+ ions. A quantitative explanations for these results is provided by the hypothesis that Ni2+ ions secondarily affect a sodium receptor or channel (designated XNa*) that is responsible for the Na+ response and that Ca2+ ions inhibit the Ni2+ -enhanced response to Na+ ions by competing with Na+ ions for XNa*. Double-reciprocal plots of the experimental data indicate that the affinity of XNa* for both Na+ ions (agonist) and Ca2+ ions (competitive antagonist) in the presence of 1 mM NiCl2 was five times higher than the previously reported values obtained in the absence of NiCl2 (Kitada, 1991). Ni2+ ions at 1 mM enhanced the maximal response to Na+ ions by 190%. It appears that a sodium receptor (or channel) interacts with a Ni2+ -binding element that is affected by Ni2+ ions and, thus, Ni2+ ions can induce both an increase in the affinity of the sodium receptor for the respective cations and an enhancement of the Na+ response.

Animals↗

Enhancing effect of nickel ions on the response to magnesium ions of single fibers of the frog glossopharyngeal nerve: competitive inhibition by calcium ions of the nickel-enhanced response to magnesium ions.

Single fibers of the frog glossopharyngeal nerve respond to MgCl2 at concentrations exceeding 10 mM. NiCl2 at 1 mM enhanced the Mg2+ response. CaCl2 at 0.5-2 mM induced an inhibition of the Ni(2+)-enhanced response to Mg2+ ions. A quantitative explanation for these results is provided by the hypothesis that Ni2+ ions secondarily affect a magnesium receptor (designated X*Mg) that is responsible for the Mg2+ response and that Ca2+ ions inhibit the Ni(2+)-enhanced response to Mg2+ ions by competing with Mg2+ ions for X*Mg. Double-reciprocal plots of the experimental data indicate that Ni2+ ions do not affect the affinities of X*Mg for both Mg2+ ions (agonist) and Ca2+ ions (competitive antagonist) appreciably, and that Ni2+ ions at 1 mM enhanced the maximal response to Mg2+ ions by 270%. It appears that a magnesium receptor interacts with an Ni(2+)-binding element that is affected by Ni2+ ions and, thus, Ni2+ ions can induce an enhancement of the Mg2+ response.

Animals↗

Hepatocellular carcinoma: correlation between vascular endothelial growth factor level and degree of enhancement by multiphase contrast-enhanced computed tomography.

RATIONALE AND OBJECTIVES: To determine whether vascular endothelial growth factor (VEGF) is a histopathological factor influencing contrast enhancement of hepatocellular carcinoma (HCC) on computed tomography (CT). METHODS: Twenty-two nodular HCCs underwent multiphase helical CT and surgery. Tumor size, histological grading of differentiation, and type of hepatitis were evaluated. Tumor attenuation was graded as hyperattenuated, isoattenuated, and hypoattenuated. Immunohistochemical staining with anti-VEGF antibody was performed and scored as weak, intermediate, or strong. Spearman's rank correlation test was used. RESULTS: Tumors ranged from 1.0 to 12.0 cm (mean 5.1 cm). The degree of enhancement during the hepatic arterial phase was significantly correlated with VEGF expression. Size was negatively correlated with VEGF expression and the degree of enhancement, but histological grade and type of hepatitis were not correlated with VEGF expression, tumor size, or degree of enhancement. CONCLUSIONS: In HCC, VEGF expression is correlated with the degree of contrast enhancement during arterial-phase CT.

Adult↗

Contrast-enhanced spiral CT of the liver: effect of injection time on time to peak hepatic enhancement.

PURPOSE: On contrast-enhanced hepatic CT, maximum tumor detection of liver metastases from colorectal cancer is achieved at peak hepatic enhancement. We investigated the relationship between injection time of contrast medium and time to peak hepatic enhancement (TPHE) after the end of injection. METHOD: One hundred nineteen patients without a cardiovascular disorder were enrolled in this study. Before the spiral CT was performed, a small amount of contrast medium was injected and a single level dynamic CT was performed to evaluate aortic enhancement and to determine the scan start time of the spiral examination. Patients were divided into three groups; contrast medium was injected over 30 s in 40 patients (Group A), 45 s in 39 patients (Group B), and 60 s in 40 patients (Group C). The TPHE after the end of injection was measured, and the difference among the groups was compared using one-way analysis of variance. A p value of <0.05 was considered a statistically significant difference. RESULTS: The TPHEs of the groups were 25.3 +/- 4.6 s (Group A), 27.0 +/- 5.8 s (Group B), and 24.4 +/- 4.6 s (Group C) and were similar in value. No statistically significant difference was observed (p = 0.067). CONCLUSION: Hepatic enhancement reaches its peak at approximately 25 s after the end of contrast medium injection irrespective of injection time.

Adult↗

Enhanced penetration of mitomycin C through hairless mouse and rat skin by enhancers with terpene moieties.

The effects of four new percutaneous absorption enhancers containing an azacyclo ring and terpene chain (1-geranylazacycloheptan-2-one (GAH), 1-farnesylazacycloheptan-2-one (FAH), 1-geranylazacyclopentan-2,5-dione (GAPD), and 1-farnesylazacyclopentan-2-one (FAP] and 1-dodecylazacycloheptan-2-one (Azone) on the percutaneous penetration of mitomycin C (MMC) through hairless mouse and rat skin in-vitro has been investigated. GAH, FAH, FAP and Azone enhanced MMC penetration by 20 to 60 times that of the control (ethanol). During the early part of the experiments, when the sink condition was maintained, FAH was the most effective for hairless mouse skin, whereas Azone showed the highest effect in the rat skin. The enhancing effect of GAPD was only about half that of the other enhancers, suggesting the importance of the polar group of the ring moiety in these compounds. The penetration of MMC through rat skin was also increased by pretreatment with these compounds, suggesting that the enhancers had a direct effect on the skin.

Animals↗

Effectiveness and toxicity screening of various absorption enhancers in the rat small intestine: effects of absorption enhancers on the intestinal absorption of phenol red and the release of protein and phospholipids from the intestinal membrane.

Sodium glycocholate, sodium taurocholate, sodium deoxycholate, EDTA, sodium salicylate, sodium caprate, diethyl maleate, N-lauryl-beta-D-maltopyranoside, linoleic acid polyoxyethylated (60 mol) mixed micelles (all 20 mM) have been ranked in order of their effectiveness as enhancers of the absorption of drugs in the rat small intestine, by use of an in-situ loop model with phenol red as a model drug. Local toxicity in rats was examined by assessing protein and phospholipid release as biological markers. Of the absorption enhancers, sodium deoxycholate, EDTA and N-lauryl-beta-D-maltopyranoside were the most effective; sodium deoxycholate and EDTA, however, caused significant release of protein and phospholipids. N-lauryl-beta-D-maltopyranoside, on the other hand, did not damage the small intestinal membrane. Sodium taurocholate enhanced phenol red absorption from the small intestine and resulted in little or no protein and phospholipids release. Sodium salicylate, diethyl maleate and the mixed micelles had no absorption-promoting effects on phenol red. There was good correlation between the area under the plasma concentration-time curve for phenol red and the amounts of protein and phospholipid released in the presence of absorption enhancers. From these results it might be concluded that N-lauryl-beta-D-maltopyranoside and sodium taurocholate are effective absorption enhancers which have low toxicity levels at a concentration of 20 mM.

Animals↗

Enhanced resolution of pituitary fossa by three-dimensional fat-suppressed gradient-echo magnetic resonance: before and after gadolinium enhancement.

In imaging small anatomical parts such as the pituitary fossa, thin sections enhance the spatial resolution. Gradient recalled images (GRASS) using three-dimensional volume data produce ultrathin contiguous sections with a high signal-to-noise ratio. In this study, conventional spin-echo magnetic resonance images (MRIs) of the pituitary fossa were compared to three-dimensional gradient recalled MRI in 5 volunteers and 10 patients suspected of having pituitary gland abnormalities. Utility of fat suppression was also assessed, along with gadolinium enhancement. Conventional spin-echo and three-dimensional spoiled GRASS images, three-dimensional spoiled GRASS images without and with fat suppression (Group II), and three-dimensional spoiled GRASS images with fat suppression before and after gadolinium enhancement were compared. Three-dimensional spoiled GRASS images provided better delineation of the pituitary fossa structures. There was differential enhancement between the normal gland and pituitary tumors. The fat suppression technique following gadolinium administration helped separate the high signal of tumor from the high signal of the clivus marrow. In conclusion, T1-weighted three dimensional gradient-echo images with fat suppression following gadolinium enhancement appear promising in evaluation.

Adenoma↗

Scrotal disorders: evaluation of testicular enhancement patterns at dynamic contrast-enhanced subtraction MR imaging.

PURPOSE: To evaluate testicular enhancement patterns in various scrotal disorders at dynamic contrast medium-enhanced subtraction magnetic resonance (MR) imaging. MATERIALS AND METHODS: Forty-two patients with scrotal symptoms (22 testicular diseases, 20 extratesticular scrotal disorders) underwent three-dimensional (3D) fast field-echo or fast spin-echo dynamic subtraction MR imaging after injection of paramagnetic contrast medium. The relative percentages of peak height and mean slope of the testes on the affected side were compared with those on the unaffected side by using time-signal intensity curves. RESULTS: Extratesticular scrotal disorders (time-signal intensity curve mean peak height, 93.1%; mean slope, 89.8%) showed gradual and progressive increase in homogeneous testicular contrast enhancement in all normal testes. Relative percentages of peak height and mean slope of testicular torsion (mean peak height, 17.3%; mean slope, 10.6%), infarction (mean peak height, 30.4%; mean slope, 19.8%), traumatic hemorrhagic necrosis (mean peak height, -3.5%; mean slope, -12.0%), and epidermoid cyst (mean peak height, -6.6%; mean slope, -14.2%) were significantly lower than those of extratesticular scrotal disorders. Acute mumps orchitis (mean peak height, 135.1%; mean slope, 307.5%) and malignant testicular tumor (mean peak height, 178.7%; mean slope, 467.6%) showed higher relative percentages of peak height and mean slope. CONCLUSION: Dynamic contrast-enhanced subtraction MR imaging can provide information about testicular perfusion on the basis of contrast enhancement and can be used to differentiate testicular diseases from scrotal disorders.

Adolescent↗

Formulation of an HPMC gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing in vitro transdermal delivery of nicorandil.

The objective of the present study was to formulate a hydroxypropyl methylcellulose (HPMC) gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing the transdermal delivery of nicorandil so as to develop and fabricate a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation of nicorandil was determined across rat abdominal skin from a solvent system consisting of ethanol or various proportions of ethanol and water. The ethanol-water (70:30 v/v) solvent system that provided an optimal transdermal permeation was used in formulating an HPMC gel drug reservoir system with selected concentrations (0% w/w, 4% w/w, 6% w/w, 8% w/w or 10% w/w) of limonene as a penetration enhancer for further enhancement of transdermal permeation of nicorandil. The amount of nicorandil permeated in 24 h was found increased with an increase in the concentration of limonene in the drug reservoir system up to a concentration of 6% w/w, but beyond this concentration there was no further increase in the amount of drug permeated. The flux of nicorandil was 370.9 +/- 4.2 microg/cm2 x h from the drug reservoir system with 6% w/w of limonene, which is about 2.6 times the required flux to be obtained across rat abdominal skin for producing the desired plasma concentration for the predetermined period in humans. The results of a Fourier Transform Infrared study indicated that limonene enhanced the percutaneous permeation of nicorandil by partially extracting the stratum corneum lipids. It is concluded that the HPMC gel drug reservoir system prepared with a 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene is useful in designing and fabricating a membrane-moderated TTS of nicorandil.

Administration, Cutaneous↗

Regulation of human monocyte/macrophage function by extracellular matrix. Adherence of monocytes to collagen matrices enhances phagocytosis of opsonized bacteria by activation of complement receptors and enhancement of Fc receptor function.

In inflammation monocytes emigrate from the peripheral circulation into an extravascular area rich in extracellular matrix proteins. In this milieu, phagocytes ingest and kill invading pathogens. In the present studies, we found that monocytes adhered to type I collagen gels phagocytized 2.5-12-fold more opsonized Escherichia coli, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae than plastic-adherent monocytes. The rate of phagocytosis and the number of bacteria ingested by collagen-adherent monocytes was equal to, or greater than, the number of bacteria ingested by 7-d cultured macrophages (M phi). Although both collagen- and plastic-adherent monocytes were bactericidal for E. coli and S. aureus, more bacteria were killed by collagen-adherent monocytes by virtue of their enhanced phagocytic capacity. Cultured M phi only were bacteriostatic. Adherence of monocytes to collagen gels activated C receptors (CR) types 1 and 3 for phagocytosis, and enhanced Fc receptor (FcR)-mediated phagocytosis. Collagen- and plastic-adherent monocytes produced equivalent amounts of superoxide anion in response to phorbol myristate acetate and opsonized zymosan. Thus, the enhanced phagocytosis and killing of opsonized bacteria by collagen-adherent monocytes appear to be by regulation of the function of membrane CR and FcR, without apparent enhancement of the respiratory burst. These data suggest that adherence of monocytes to the extracellular matrix during inflammation may rapidly activate these cells for enhanced phagocytic bactericidal activity.

Blood Bactericidal Activity↗

Skin penetration enhancement of acyclovir by prodrug-enhancer combination.

The effectiveness of prodrug-enhancer combination in skin penetration enhancement was studied using acyclovir and its lipophilic prodrug, acyclovir butyrate, with octanol/water partition coefficient of 0.0123 and 0.402, respectively. In the in vitro diffusion experiment with rat skin, the total amount of acyclovir appearing in the receptor phase after administration of the aqueous suspension of acyclovir butyrate was smaller than that obtained after administration of acyclovir, but their permeability coefficients were almost equal. An enhancer, 1-geranylazacycloheptan-2-one (GACH) did not show a large penetration enhancement of acyclovir (3.37-fold) but demonstrated extensive enhancement effect on the prodrug (12.3-fold). Most of the prodrug appeared in the form of acyclovir in the receptor phase without GACH, but the appearance ratio of acyclovir to total flux decreased with an increase in pretreatment doses of GACH.

Acyclovir↗

Contrast enhancement for electronic speckle pattern interferometry fringes by the differential equation enhancement method.

Electronic speckle pattern interferometry fringe patterns usually have poor contrast so it is important to enhance fringe contrast for the extraction of phase from a single fringe pattern. We present new enhancement methods based on differential equations (called DE enhancement methods) to electronic speckle pattern interferometry fringes. The DE enhancement methods transform the image processing to solve differential equations. With the proposed methods, the visibility of the correlation speckle fringe patterns can be improved significantly. We tested the proposed methods on computer-simulated speckle correlation fringes and experimentally obtained fringes, and we compared the new method with other contrast enhancement techniques. The experimental results illustrate the performance of this approach.

Journal Article↗

Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo.

Hemopoiesis is regulated in part by survival/apoptosis of hemopoietic stem/progenitor cells. Exogenously added stromal cell-derived factor-1 ((SDF-1)/CXC chemokine ligand (CXCL)12) enhances survival/antiapoptosis of myeloid progenitor cells in vitro. To further evaluate SDF-1/CXCL12 effects on progenitor cell survival, transgenic mice endogenously expressing SDF-1/CXCL12 under a Rous sarcoma virus promoter were produced. Myeloid progenitors (CFU-granulocyte-macrophage, burst-forming unit-erythroid, CFU-granulocyte-erythrocyte-megakaryocyte-monocyte) from transgenic mice were studied for in vitro survival in the context of delayed addition of growth factors. SDF-1-expressing transgenic myeloid progenitors were enhanced in survival and antiapoptosis compared with their wild-type littermate counterparts. Survival-enhancing effects were due to release of low levels of SDF-1/CXCL12 and mediated through CXCR4 and G(alpha)i proteins as determined by ELISA, an antagonist to CXCR4, Abs to CXCR4 and SDF-1, and pertussis toxin. Transgenic effects of low SDF-1/CXCR4 may be due to synergy of SDF-1/CXCL12 with other cytokines; low SDF-1/CXCL12 synergizes with low concentrations of other cytokines to enhance survival of normal mouse myeloid progenitors. Consistent with in vitro results, progenitors from SDF-1/CXCL12 transgenic mice displayed enhanced marrow and splenic myelopoiesis: greatly increased progenitor cell cycling and significant increases in progenitor cell numbers. These results substantiate survival effects of SDF-1/CXCL12, now extended to progenitors engineered to endogenously produce low levels of this cytokine, and demonstrate activity in vivo for SDF-1/CXCL12 in addition to cell trafficking.

Adjuvants, Immunologic↗

Contrast-enhanced ultrasonography of small solid pseudopapillary tumors of the pancreas: enhancement pattern and pathologic correlation of 2 cases.

OBJECTIVE: The purpose of this series is to describe the value of contrast-enhanced ultrasonography (CEUS) in the characterization of small pseudopapillary tumors (SPTs) of the pancreas. METHODS: Two cases of SPTs found on conventional ultrasonography, both located at the pancreatic body, were studied with spiral computed tomography, magnetic resonance imaging, and CEUS. A final diagnosis was obtained with histologic analysis after distal pancreatectomy. Immunohistochemical analysis of the tumors with the CD34 antigen was performed. RESULTS: At CEUS, the 2 SPTs had a slight peripheral rim enhancement in the early dynamic phases. The presence of this enhancement pattern at CEUS, not clear at spiral computed tomography or at magnetic resonance imaging, suggested the diagnosis of SPTs with a peripheral pseudocapsule deriving from the compression of the pancreatic parenchyma. The presence of a perilesional pseudocapsule was proved at immunohistochemical analysis of the tumors with the CD34 antigen. CONCLUSIONS: Contrast-enhanced ultrasonography can improve the characterization of SPTs by showing the typical rim enhancement of these pancreatic tumors.

Adolescent↗

Interleukin-1beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: functional evidence for enhancement of electrographic seizures.

Using immunocytochemistry and ELISA, we investigated the production of interleukin (IL)-1beta in the rat hippocampus after focal application of kainic acid inducing electroencephalographic (EEG) seizures and CA3 neuronal cell loss. Next, we studied whether EEG seizures per se induced IL-1beta and microglia changes in the hippocampus using bicuculline as a nonexcitotoxic convulsant agent. Finally, to address the functional role of this cytokine, we measured the effect of human recombinant (hr)IL-1beta on seizure activity as one marker of the response to kainate. Three and 24 hr after unilateral intrahippocampal application of 0.19 nmol of kainate, IL-1beta immunoreactivity was enhanced in glia in the injected and the contralateral hippocampi. At 24 hr, IL-1beta concentration increased by 16-fold (p < 0.01) in the injected hippocampus. Reactive microglia was enhanced with a pattern similar to IL-1beta immunoreactivity. Intrahippocampal application of 0.77 nmol of bicuculline methiodide, which induces EEG seizures but not cell loss, enhanced IL-1beta immunoreactivity and microglia, although to a less extent and for a shorter time compared with kainate. One nanogram of (hr)IL-1beta intrahippocampally injected 10 min before kainate enhanced by 226% the time spent in seizures (p < 0.01). This effect was blocked by coinjection of 1 microgram (hr)IL-1beta receptor antagonist or 0.1 ng of 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate, selective antagonists of IL-1beta and NMDA receptors, respectively. Thus, convulsant and/or excitotoxic stimuli increase the production of IL-1beta in microglia-like cells in the hippocampus. In addition, exogenous application of IL-1beta prolongs kainate-induced hippocampal EEG seizures by enhancing glutamatergic neurotransmission.

Animals↗

Small solitary pulmonary nodules: assessment of enhancement and enhancement patterns in benign and malignant tumours by high resolution computed tomography.

Our aim was to determine the accuracy of quantitative and qualitative findings of contrast-enhanced computed tomography (CT) by means of differential analysis of small uncalcified solitary pulmonary nodules and to compare the CT diagnosis with the results of transthoracic needle biopsies (TTNB). We assessed a consecutive series of 109 patients with 66 malignant or 45 benign pulmonary nodules before TTNB and surgery with contrast and high resolution computed tomography (HRCT). Pulmonary nodules were classified as small when equal to or smaller than 15 mm and large when larger than 15 mm. Diagnostic accuracy of CT qualitative evaluation was 95% for large nodules and 92% for small nodules. Specificity was 92% for small nodules, 80% for large nodules. Enhancing regular septa were observed in 28 hamartomas (80%) while except for two cases (3%), inner septa were absent or irregular in malignant tumours. TTNB accuracy was 70% for small nodules and 94% for large ones. Low-enhancing hamartomas are more frequent in Italy than in the US where the prevalence of high-enhancing granulomas in benign nodules reduces the specificity of quantitative CT analysis. We propose that certain geographic areas would benefit from enhanced-CT in place of TTNB in managing lung nodules equal to or less than 1.5 cm.

Adenocarcinoma↗

[The influence of absorption enhancer and preparation of paclitaxel on its intestinal mucous membrane permeation detected by enhancement by using electron spin resonance technique].

AIM: To investigate the permeation mechanism of paclitaxel by enhancers and preparation factors. METHODS: The fluidity of mucous membrane and membrane protein conformation changes were determined by using electron spin resonance (ESR) when mucous membrane was treated by several enhancers. At the same time, the factors of penetration of lower dissolution drug across the intestinal mucous membrane were studied in three formulas inclusion complex, microemulsion and injection. RESULTS: Polyethylene glycol (PEG) 1500, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and phospholipid as enhancers could reinforce the permeation of paclitaxle because of loosening of protein conformation in intestinal mucous membrane. Paclitaxel-HP-beta-CD inclusion complex and paclitaxel microemulsion as vehicle could significantly increased permeation kinetic rate of paclitaxel with fluid diffuse method. CONCLUSION: Characteristics of enhancing intestinal absorption of poor dissolution drug had been provided with enhancer the change of membrane fluid.

2-Hydroxypropyl-beta-cyclodextrin↗