Contrasting frequencies of CCR5delta32 and CCR2-64I alleles in the Tunisian population.
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Alleles↗
Biomedical subjects
L Hong
Publications and source records attributed to L Hong.
Determination of assay and impurities of gamma irradiated chloramphenicol in eye ointment.
A sample preparation method was developed to isolate chloramphenicol and its radiolytic products from an oily ointment base. The isolation method suspended the eye ointment in n-hexane at 45 degrees C, and isolated the target compounds as residue by centrifugation. It was found that the main element to ensure a satisfactory isolation was keeping the sample solution at 45 degrees C during sample preparation. Linearity, precision, accuracy and suitability of the method were confirmed valid for both assay and impurity tests. This isolation method was ideal for assay, unique for extraction of unexpected and complex radiolysis products, and had a number of advantages compared to the pretreatment methods described in The United Stares Pharmacopoeia and British Pharmacopoeia, in terms of accuracy, precision, and easy handling. The effect of gamma-irradiation on chloramphenicol eye ointment was studied by HPLC, after applying the developed sample preparation method. The present assay and impurity test methods with HPLC were confirmed to be suitable for irradiated chloramphenicol in eye ointment. Formation of radiolytic products induced by gamma-irradiation was evidenced by the impurity test. The assay test showed that active ingredient of chloramphenicol eye ointment decreased by 3.3% at an irradiation dose of 25 kGy and by 11.1% at 50 kGy.
Centrifugation↗
The growth of highly proliferative acute lymphoblastic leukemia may be independent of stroma and/or angiogenesis.
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Adolescent↗
Enhanced formation of fibrosis in a rabbit aneurysm by gelatin hydrogel incorporating basic fibroblast growth factor.
OBJECTIVE: This study was undertaken to analyze whether the controlled release of basic fibroblast growth factor (bFGF) can promote intrasaccular thrombosis in an experimental aneurysmal model. METHODS: Carotid aneurysms were constructed in 80 rabbits with venous pouches and treated by placing gelatin hydrogels into each aneurysm incorporating 0, 25, 50, or 100 microg of bFGF or incorporating 100 microg of bFGF with different water contents. In the controls, the venous pouches either were not treated or were treated with gauze alone. Gelatin hydrogel was used for the controlled release of bFGF into the aneurysms. The formation of fibrosis in the aneurysms was histologically viewed to assess the area occupied by the fibrous tissues at 3 and 6 weeks after the hydrogel application. The effect of the bFGF dose and water content on obliterating the aneurysm by the hydrogels incorporating bFGF was also investigated. RESULTS: Six weeks after the application of gelatin hydrogels with a water content of 95 wt% incorporating 100 microg of bFGF, the lateral pouch orifice was completely closed, obliterating the aneurysm at the level of tissue appearance, in contrast to hydrogels incorporating lower doses of bFGF and other control agents. The venous pouch aneurysm was histologically occupied with the newly formed fibrous tissue, and the fibrous tissue area and percentage of the aneurysmal lumen occupied by the fibrosis-gauze complex were significantly larger than those of other hydrogel applications (P < 0.05). The neointima tissue was homogeneously covered with a monolayer of Factor VIII-positive cells. The fact that there was no difference in the water content in the fibrosis formation induced by the bFGF-incorporated gelatin hydrogels indicated that the hydrogel biodegradability did not affect the obliteration of the aneurysm. CONCLUSION: Local controlled release of bFGF stimulated the formation of in vivo fibrosis, resulting in obliteration of the aneurysm. The long-term results of the fibrous organization remain speculative.
Animals↗
A trial to prepare biodegradable collagen-hydroxyapatite composites for bone repair.
This paper is a trial to prepare collagen-hydroxyapatite composites in vitro by an alternate immersion method. Collagen sponges of different biodegradabilities were prepared through chemical cross-linking of Type I collagen with glutaraldehyde (GA) at concentrations of 0.2, 1.0, and 2.0 wt%. The sponges were immersed at 37 degrees C in Tris-HCl-buffered solution containing 200 mM CaCl2 (pH 7.4) for 2 h and then in an aqueous solution of 120 mM Na2HPO4 (pH 9.3) for a 2 h further (one immersion cycle). The alternate immersion cycle was repeated for different times to obtain collagen-hydroxyapatite composites. The characterization of the resulting composites was performed by Fourier transform infrared spectroscopy (FT-IR). X-ray diffraction (XRD), and scanning electron microscopy (SEM). The weight of composites increased with an increase in immersion cycles and the rate of increase became greater with higher GA cross-linking levels for collagen sponge preparation. The pH of the phosphate solution decreased with the immersion cycle, which suggests H+ generation accompanied hydroxyapatite formation. Irrespective of the GA concentration and immersion cycle, every composite showed IR absorption bands attributable to phosphate and hydroxyl groups at 950-1100 or 550-650 and 3000-3500 cm(-1) and broad peaks specific to hydroxyapatite on the XRD charts. SEM study revealed small white clusters of hydroxyapatite interspersed uniformly on/in the collagen framework without any preferential orientation. The composite prepared from 0.2 wt% GA cross-linked collagen sponge which showed favourable characteristics was applied to a rat skull defect to evaluate its osteoconductivity as well as biodegradability. The formation of new bone tissue was histologically observed at the defect 12 weeks after application in marked contrast to the collagen sponge alone. The composite degraded without any inflammation reaction. It is concluded that the collagen-hydroxyapatite composite prepared by the present method is a biodegradable biomaterial of osteoconductivity applicable to bone repair.
Animals↗
Inhibitory effects of nitric oxide on estrogen production and cAMP levels in rat granulosa cell cultures.
Previous studies demonstrated inhibitory effects of nitric oxide (NO) and cGMP on ovarian steroidogenesis. This study examined the effects of NO on estrogen levels and cAMP accumulation from immature cultured rat granulosa cells. Granulosa cells were incubated with media alone (control), FSH or FSH plus increasing concentrations of the NO generator, (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO). While FSH increased estrogen levels 15-fold compared with controls, DETA/NO inhibited FSH-stimulated aromatase activity in a dose-dependent manner. Time-course studies revealed that the inhibitory effects of DETA/NO on aromatase activity persisted throughout the 72 h culture period. Treatment with DETA/NO also inhibited the stimulatory effects of forskolin on estrogen production, indicating that NO can influence steroidogenesis by actions downstream of the FSH receptor. Incubation of cells with FSH plus DETA/NO increased cGMP accumulation over 100-fold, compared with cells treated with media or FSH alone. In this regard, a cGMP analog mimicked the inhibitory effects of NO on FSH- and forskolin-stimulated estrogen production, indicating a potential mechanism of NO action. NO also decreased FSH-stimulated (cAMP) accumulation from cultured cells, indicating an antagonistic effect of NO on the second messenger mediating FSH actions. These findings demonstrate that NO inhibits estrogen production from rat granulosa cells, potentially reflecting actions on the second messengers cGMP and cAMP.
Animals↗
Regional difference of muscle oxygen saturation and blood volume during exercise determined by near infrared imaging device.
UNLABELLED: Using a near infrared (NIR) imaging device, we tested the hypothesis that regional differences in oxygen status could be detected in the gastrocnemius muscle during exercise and recovery. Six healthy subjects performed the standing plantar flexion exercises for 2 min; the frequency was one contraction per second. The NIR imaging device was placed over the medial head of the right gastrocnemius muscle and the signals from two optical sensors situated on the middle proximal and middle distal portions were used. The NIR-O(2) saturation (difference between deoxygenated and oxygenated Hb signals) and NIR-blood volume (sum of the oxygenated and deoxygenated Hb signals) were calculated in optical density units. Plantar flexion resulted in more deoxygenation during exercise and more reoxygenation during recovery in the distal portion compared with the proximal portion. The changes in NIR-O(2) between rest and a 2 min exercise, and between a 2 min exercise and a 3 min recovery were 0.11 and -0.23, respectively, in the distal portion, which were significantly larger than proximal values (0.05 and -0.10, p < 0.05). Plantar flexion resulted in lower NIR-blood volumes during exercise and greater recovery of blood after exercise in the distal portion compared with the proximal portion. The changes in NIR blood volume between rest and a 2 min exercise and between a 2 min exercise and a 3 min recovery were -0.19 and 0.31, respectively, in the distal portion, significantly larger than proximal values (-0.07 and 0.12, p < 0.05 for all comparisons). These findings indicate that the distal portion of the medial gastrocnemius had larger changes in NIR-O(2) saturation and NIR-blood volume than the proximal portion had. This is consistent with the distal portion having a greater impairment of blood flow possibly because of the higher intramuscular pressure during exercise. IN CONCLUSION: (1) regional differences in oxygen status in the gastrocnemius muscle were detected with exercise, with the distal portion having greater NIR-O(2) saturation and NIR-blood volume changes, and (2) the NIR imaging device might be a useful method to detect the regional differences of oxygen status in the muscle.
Adult↗
Synthesis and biological activity of novel 5-fluoro-2'-deoxyuridine phosphoramidate prodrugs.
A series of novel haloethyl and piperidyl phosphoramidate FdUMP prodrug analogues has been synthesized, and the growth inhibitory activity of these compounds has been evaluated against L1210 mouse leukemia cells. All compounds exhibited potent inhibition of L1210 cell proliferation with IC(50) values in the nanomolar range. Growth inhibition was reversed by the addition of 5 microM thymidine, suggesting a mechanism of action involving the intracellular release of FdUMP. (31)P NMR studies carried out on model haloethyl phosphoramidates confirm the release of nucleotide via cyclization of the phosphoramidate anion to the aziridinium ion intermediate followed by hydrolysis of the P-N bond. The data suggests that <50% of the prodrug is converted to FdUMP intracellularly by this pathway. Piperidyl phosphoramidate analogues are also converted to nucleotide intracellularly, presumably by the action of an endogenous phosphoramidase.
Amides↗
High-throughput scanning of the rat genome using interspersed repetitive sequence-PCR markers.
We report the establishment of a hybridization-based marker system for the rat genome based on the PCR amplification of interspersed repetitive sequences (IRS). Overall, 351 IRS markers were mapped within the rat genome. The IRS marker panel consists of 210 nonpolymorphic and 141 polymorphic markers that were screened for presence/absence polymorphism patterns in 38 different rat strains and substrains that are commonly used in biomedical research. The IRS marker panel was demonstrated to be useful for rapid genome screening in experimental rat crosses and high-throughput characterization of large-insert genomic library clones. Information on corresponding YAC clones is made available for this IRS marker set distributed over the whole rat genome. The two existing rat radiation hybrid maps were integrated by placing the IRS markers in both maps. The genetic and physical mapping data presented provide substantial information for ongoing positional cloning projects in the rat.
Animals↗
Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor.
Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease involved in the production of beta-amyloid peptide in Alzheimer's disease and is a major target for drug design. We determined the crystal structure of the protease domain of human memapsin 2 complexed to an eight-residue inhibitor at 1.9 angstrom resolution. The active site of memapsin 2 is more open and less hydrophobic than that of other human aspartic proteases. The subsite locations from S4 to S2' are well defined. A kink of the inhibitor chain at P2' and the change of chain direction of P3' and P4' may be mimicked to provide inhibitor selectivity.
Amyloid Precursor Protein Secretases↗
IL-11 selectively inhibits aeroallergen-induced pulmonary eosinophilia and Th2 cytokine production.
IL-11 is a pleiotropic cytokine that induces tissue remodeling with subepithelial fibrosis when expressed in the airway. Its effects on the Th2-dominated airway inflammation that is characteristic of asthma, however, are poorly understood. To characterize the effects of IL-11 on Th2 tissue inflammation, we compared the inflammatory responses elicited by OVA in sensitized mice in which IL-11 is overexpressed in a lung-specific fashion (CC10-IL-11) with that in transgene- wild-type littermate controls. Transgene- and CC10-IL-11 transgene+ mice had comparable levels of circulating Ag-specific IgE after sensitization. OVA challenge of sensitized transgene- mice caused airway and parenchymal eosinophilic inflammation, Th2 cell accumulation, and mucus hypersecretion with mucus metaplasia. Exaggerated levels of immunoreactive endothelial cell VCAM-1, mucin (Muc) 5ac gene expression and bronchoalveolar lavage and lung IL-4, IL-5, and IL-13 protein and mRNA were also noted. In contrast, OVA challenge in CC10-IL-11 animals elicited impressively lower levels of tissue and bronchoalveolar lavage inflammation, eosinophilia, and Th2 cell accumulation, and significantly lower levels of VCAM-1 and IL-4, IL-5, and IL-13 mRNA and protein. IL-11 did not cause a comparable decrease in mucus hypersecretion, Muc 5ac gene expression, or the level of expression of RANTES, monocyte chemoattractant protein-2, or monocyte chemoattractant protein-3. In addition, IL-11 did not augment IFN-gamma production demonstrating that the inhibitory effects of IL-11 were not due to a shift toward Th1 inflammation. These studies demonstrate that IL-11 selectively inhibits Ag-induced eosinophilia, Th2 inflammation, and VCAM-1 gene expression in pulmonary tissues.
Administration, Inhalation↗
Global distribution of the CCR2-64I/CCR5-59653T HIV-1 disease-protective haplotype.
OBJECTIVES: Several natural polymorphisms in the genes for the human CC-chemokine receptors CCR5 and CCR2 are associated with HIV-1 disease. The CCR2-64I genetic variant [a G to A substitution resulting in a valine (V) to isoleucine (I) change at position 64] is in strong linkage disequilibrium with a mutation within the CCR5 regulatory region (CCR5-59653T). Individuals with two CCR2-64I alleles are not resistant to sexual transmission of HIV-1, but progress significantly more slowly to HIV-1 disease. It is therefore important to determine the global distributions of CCR2-64I and CCR5-59653T genetic variants and define the degree of linkage between them. DESIGN AND METHODS: We have developed molecular beacon-based, real-time PCR allele discrimination assays for all three chemokine receptor mutations, and used these spectral genotyping assays to genotype 3923 individuals from a globally distributed set of 53 populations. RESULTS: CCR2-64I and CCR5-59653T genetic variants are found in almost all populations studied: their allele frequencies are greatest (approximately 35%) in Africa and Asia but decrease in Northern Europe. We confirm that CCR2-64I is in strong linkage disequilibrium with CCR5-59653T (96.92% of individuals had the same genotype for both CCR2-64I and CCR5-59653T polymorphisms). CONCLUSIONS: The greater geographical distribution of the CCR2-64I/CCR5-59653T haplotype compared with that of CCR5-delta32 suggests that it is a much older mutation whose origin predates the dispersal of modern humans.
Alleles↗
A Drosophila complementary DNA resource.
Collections of nonredundant, full-length complementary DNA (cDNA) clones for each of the model organisms and humans will be important resources for studies of gene structure and function. We describe a general strategy for producing such collections and its implementation, which so far has generated a set of cDNAs corresponding to over 40% of the genes in the fruit fly Drosophila melanogaster.
3' Untranslated Regions↗
Bone regeneration by transforming growth factor beta1 released from a biodegradable hydrogel.
This paper describes the sustained release of transforming growth factor beta1 (TGF-beta1) from a biodegradable hydrogel based on polyion complexation for the enhancement of bone regeneration activity. Basic TGF-beta1 was adsorbed onto the biodegradable hydrogel of acidic gelatin with an isoelectric point of 5.0 by an electrostatic interaction. The TGF-beta1 could not be adsorbed onto basic gelatin. When acidic gelatin hydrogels incorporating 125I-labeled TGF-beta1 were implanted into the back subcutis of mice, the radioactivity decreased with time and the in vivo retention of TGF-beta1 was prolonged with a decrease in the water content of hydrogels. The higher the water content of hydrogels, the faster their biodegradation. The in vivo retention of TGF-beta1 correlated well with that of gelatin hydrogels, indicating that TGF-beta1 was released from the gelatin hydrogel as a result of hydrogel biodegradation. The ability of TGF-beta1-incorporated into acidic gelatin hydrogels to induce bone regeneration was evaluated in a rabbit calvarial defect model. Eight weeks after treatment, the gelatin hydrogels with water contents of 90 and 95 wt% induced significantly high bone regeneration compared with those with lower and higher water contents and free TGF-beta1. This indicates that the sustained release of TGF-beta1 from the hydrogel with suitable in vivo degradability is necessary to effectively enhance its osteoinductive function. Rapid hydrogel degradation will result in a retention time of TGF-beta1 which is too short to induce bone regeneration. It is possible that the slow degradation of the hydrogel physically blocked TGF-beta1-induced bone regeneration at the skull defect. It can be concluded that the gelatin hydrogel is a promising matrix of TGF-beta1 release to induce skull bone regeneration.
Absorbable Implants↗
Atypical fatal hypocomplementemic urticarial vasculitis with involvement of native and homograft aortic valves in an African American man.
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Adult↗
Toward a transformed approach to prevention: breaking the link between masculinity and violence.
Men are disproportionately overrepresented among both perpetrators and victims of violent crime. Scholars from the men's studies movement have documented a clear link between socialization into stereotypical norms of hegemonic masculinity and an increased risk for experiencing violence. Despite this evidence, most campus prevention programs fail to recognize the link between men and violence and use only traditional approaches to violence prevention. The most that on-campus prevention programs provide are self-defense seminars for potential female victims of rape and general campus safety measures. In this article, the author describes a comprehensive, transformed approach to violence prevention. Data from a year-long case study of Men Against Violence, a peer education organization at a large university in the South, demonstrate the feasibility of meaningfully expanding male students' conceptions of manhood and appropriate gender roles and, thus, reducing the likelihood of men's engaging in sexually or physically violent behavior.
Adult↗
Promoted bone healing at a rabbit skull gap between autologous bone fragment and the surrounding intact bone with biodegradable microspheres containing transforming growth factor-beta1.
This study is a trial to promote repairing of the rabbit skull bone gap between an autologous bone flap and the intact bone with biodegradable gelatin microspheres containing transforming growth factor-beta1 (TGF-beta1). A 10-mm diameter bone defect was prepared in rabbit skulls by drilling out a bone flap of 6 mm in diameter. After a surrounding gap defect of 2 mm was created and treated with 0.5 microg of free TGF-beta1 and gelatin microspheres containing 0.5 microg of free TGF-beta1, the circular autologous bone flap was placed in the center. Significant bone healing at the gap defect was observed 3 weeks after implantation of the TGF-beta1-containing gelatin microspheres. The bone mineral density (BMD) was significantly higher than that of other experimental groups. On the contrary, when applied with free TGF-beta1, a fibrous tissue initially infiltrated into the gap defect, resulting in impairing bone healing. The tissue response was similar to that at the defect implanted with empty gelatin microspheres and TGF-beta1-free phosphate-buffered saline solution alone. There was more space in the gap-filling bone in the 16-week view than the 3-week view. It is possible that this was an intermediate step along the way toward normal healing and formation of cancellous bone. We conclude that gelatin microspheres containing TGF-beta1 show promise as an agent to promote bone regeneration of subcritical size defects between surgically positioned autologous bone flaps and surrounding host bone.
Animals↗
Crystal structure of an in vivo HIV-1 protease mutant in complex with saquinavir: insights into the mechanisms of drug resistance.
Saquinavir is a widely used HIV-1 protease inhibitor drug for AIDS therapy. Its effectiveness, however, has been hindered by the emergence of resistant mutations, a common problem for inhibitor drugs that target HIV-1 viral enzymes. Three HIV-1 protease mutant species, G48V, L90M, and G48V/L90M double mutant, are associated in vivo with saquinavir resistance by the enzyme (Jacobsen et al., 1996). Kinetic studies on these mutants demonstrate a 13.5-, 3-, and 419-fold increase in Ki values, respectively, compared to the wild-type enzyme (Ermolieff J, Lin X, Tang J, 1997, Biochemistry 36:12364-12370). To gain an understanding of how these mutations modulate inhibitor binding, we have solved the HIV-1 protease crystal structure of the G48V/L90M double mutant in complex with saquinavir at 2.6 A resolution. This mutant complex is compared with that of the wild-type enzyme bound to the same inhibitor (Krohn A, Redshaw S, Richie JC, Graves BJ, Hatada MH, 1991, J Med Chem 34:3340-3342). Our analysis shows that to accommodate a valine side chain at position 48, the inhibitor moves away from the protease, resulting in the formation of larger gaps between the inhibitor P3 subsite and the flap region of the enzyme. Other subsites also demonstrate reduced inhibitor interaction due to an overall change of inhibitor conformation. The new methionine side chain at position 90 has van der Waals interactions with main-chain atoms of the active site residues resulting in a decrease in the volume and the structural flexibility of S1/S1' substrate binding pockets. Indirect interactions between the mutant methionine side chain and the substrate scissile bond or the isostere part of the inhibitor may differ from those of the wild-type enzyme and therefore may facilitate catalysis by the resistant mutant.
Amino Acid Substitution↗