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Biomedical subjects

J Tan

Publications and source records attributed to J Tan.

At least 73 records · Page 4Linked to original sources
PubMed2000

Controlling human polymorphonuclear leukocytes motility using microfabrication technology.

We describe a new approach for controlling cell motility on a material surface. Transparent, photosensitive polyimide materials were used to fabricate physical structures on glass; cell motility was then followed over time using optical microscopy. Arrays of pillars and holes with 2 micron square, 4-microm height (or depth) separated by 10 microm were successfully patterned using photolithography. Neutrophils attached and spread on the smooth glass surface and surfaces with pillars. In contrast, cells were rounded and did not adhere to either smooth polyimide film or films with holes. The migration of neutrophils was much faster on holes than on polyimide surface, but it was significantly slower on pillars than on glass. These results suggest that physical patterning may be an effective tool to manipulate cell migration in the design of biomaterials for tissue engineering.

Biocompatible Materials↗
PubMed2000

Estrogen targets genes involved in protein processing, calcium homeostasis, and Wnt signaling in the mouse uterus independent of estrogen receptor-alpha and -beta.

Estrogen actions in target organs are normally mediated via activation of nuclear estrogen receptors (ERs). By using mRNA differential display technique, we show, herein, that estradiol-17beta (E(2)) and its catechol metabolite 4-hydroxy-E(2) (4OHE(2)) can modulate uterine gene expression in ERalpha(-/-) mice. Whereas administration of E(2) or 4OHE(2) rapidly up-regulated (4-8-fold) the expression of immunoglobulin heavy chain binding protein (Bip), calpactin I (CalP), calmodulin (CalM), and Sik similar protein (Sik-SP) genes in ovariectomized wild-type or ERalpha(-/-) mice, the expression of secreted frizzled related protein-2 (SFRP-2) gene was down-regulated (4-fold). Bip, CalP, and CalM are calcium-binding proteins and implicated in calcium homeostasis, whereas SFRP-2 is a negative regulator of Wnt signaling. Bip and Sik-SP also possess chaperone-like functions. Administration of ICI-182,780 or cycloheximide failed to influence these estrogenic responses, demonstrating that these effects occur independent of ERalpha, ERbeta, or protein synthesis. In situ hybridization showed differential cell-specific expression of these genes in wild-type and ERalpha(-/-) uteri. Although progesterone can antagonize or synergize estrogen actions, it had minimal effects on these estrogenic responses. Collectively, the results demonstrate that estrogens have a unique ability to influence specific genes in the uterus not involving classical nuclear ERs.

Animals↗
PubMed2000

Anilides of (R)-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase.

The optimization of a series of anilide derivatives of (R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase (PDHK) is described that started from N-phenyl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide 1 (IC(50) = 35 +/- 1.4 microM). It was found that small electron-withdrawing groups on the ortho position of the anilide, i.e., chloro, acetyl, or bromo, increased potency 20-40-fold. The oral bioavailability of the compounds in this series is optimal (as measured by AUC) when the anilide is substituted at the 4-position with an electron-withdrawing group (i.e., carboxyl, carboxyamide, and sulfoxyamide). N-(2-Chloro-4-isobutylsulfamoylphenyl)-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropionamide (10a) inhibits PDHK in the primary enzymatic assay with an IC(50) of 13 +/- 1.5 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts, lowers blood lactate levels significantly 2.5 and 5 h after oral doses as low as 30 micromol/kg, and increases the ex vivo activity of PDH in muscle, kidney, liver, and heart tissues. However, in contrast to sodium dichloroacetate (DCA), these PDHK inhibitors did not lower blood glucose levels. Nevertheless, they are effective at increasing the utilization and disposal of lactate and could be of utility to ameliorate conditions of inappropriate blood lactate elevation.

Anilides↗
PubMed2000

Azithromycin vs cefuroxime plus erythromycin for empirical treatment of community-acquired pneumonia in hospitalized patients: a prospective, randomized, multicenter trial.

OBJECTIVE: To compare the efficacy and safety of azithromycin dihydrate monotherapy with those of a combination of cefuroxime axetil plus erythromycin as empirical therapy for community-acquired pneumonia in hospitalized patients. METHODS: Patients were enrolled in a prospective, randomized, multicenter study. The standard therapy of cefuroxime plus erythromycin was consistent with the American Thoracic Society, Canadian Community-Acquired Pneumonia Consensus Group, and Infectious Disease Society of America consensus guidelines. The doses were intravenous azithromycin (500 mg once daily) followed by oral azithromycin (500 mg once daily), intravenous cefuroxime (750 mg every 8 hours), followed by oral cefuroxime axetil (500 mg twice daily), and erythromycin (500-1000 mg) intravenously or orally every 6 hours. Randomization was stratified by severity of illness and age. Patients who were immunosuppressed or residing in nursing homes were excluded. RESULTS: Data from 145 patients (67 received azithromycin and 78 received cefuroxime plus erythromycin) were evaluable. Streptococcus pneumoniae and Haemophilus influenzae were isolated in 19% (28/145) and 13% (19/145), respectively. The atypical pathogens accounted for 33% (48/145) of the etiologic diagnoses; Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae were identified in 14% (20/ 145), 10% (15/145), and 9% (13/145), respectively. Clinical cure was achieved in 91% (61/67) of the patients in the azithromycin group and 91% (71/78) in the cefuroxime plus erythromycin group. Adverse events (intravenous catheter site reactions, gastrointestinal tract disturbances) were significantly more common in patients who received cefuroxime plus erythromycin (49% [30/78]) than in patients who received azithromycin (12% [8/67]) (P<.001). CONCLUSIONS: Treatment with azithromycin was as effective as cefuroxime plus erythromycin in the empirical management of community-acquired pneumonia in immunocompetent patients who were hospitalized. Azithromycin was well tolerated.

Anti-Bacterial Agents↗
PubMed2000

Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling.

Female reproductive hormones control mammary gland morphogenesis. In the absence of the progesterone receptor (PR) from the mammary epithelium, ductal side-branching fails to occur. We can overcome this defect by ectopic expression of the protooncogene Wnt-1. Transplantation of mammary epithelia from Wnt-4(-)/(-) mice shows that Wnt-4 has an essential role in side-branching early in pregnancy. PR and Wnt-4 mRNAs colocalize to the luminal compartment of the ductal epithelium. Progesterone induces Wnt-4 in mammary epithelial cells and is required for increased Wnt-4 expression during pregnancy. Thus, Wnt signaling is essential in mediating progesterone function during mammary gland morphogenesis.

Animals↗
PubMed2000

Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action.

Potent and selective non-peptidic inhibitors of human endothelin-converting enzyme-1 (ECE-1) have been designed as potential modulators of endothelin (ET-1) production in vivo. Because of its unique structural characteristics and long duration of action in vivo, the dual ECE-1 and neutral endopeptidase 24.11 (NEP) inhibitor, CGS 26303, was selected as an attractive lead for further optimization of potency and selectivity. Replacement of the P(1)' biphenyl substituent of CGS 26303 by a conformationally restricted 3-dibenzofuranyl group led to more potent and more selective ECE-1 inhibitors, such as the tetrazole 27. The remarkable effect of this P(1)' modification allowed for the first time phosphonomethylcarboxylic acids, such as 29, to display both potent (IC(50) = 22 nM) and selective (104-fold vs NEP) ECE-1 inhibition. Chemoenzymatic syntheses of the new alpha-amino acid (S)-3-dibenzofuran-3-ylalanine intermediate were developed, and improved procedures to generate substituted alpha-aminoalkylphosphonic acids were devised to support the production of various analogues. Although additional gains in intrinsic ECE-1 inhibitory potency could occasionally be achieved by addition of a P(1) side chain, these compounds (e.g. 43a) showed poor functional activity in vivo in the big ET-1 pressor test. Phosphonoalkyl dipeptides featuring 3-dibenzofuranyl groups in both the P(1)' and P(2)' positions were also very potent ECE-1 inhibitors, albeit lacking the desired selectivity against NEP. Functionally, 27and 29 were the two most efficacious compounds from this study, producing sustained inhibition of ECE-1 activity in rats, as measured by their ability to block the hypertensive effects induced by big ET-1. This profile was similar to that of a potent ET(A)/ET(B) dual receptor antagonist, SB 209670. Due to their favorable in vitro and in vivo profiles, 27 (CGS 34043) and 29 (CGS 35066) constitute new pharmacological tools useful in assessing the role of ECE-1 in pathological conditions.

Animals↗
PubMed2000

Gastropharyngeal and gastroesophageal reflux in globus and hoarseness.

BACKGROUND: The role of gastropharyngeal reflux in patients with globus pharyngeus and hoarseness remains unclear. OBJECTIVE: To evaluate patients with complaints of globus, hoarseness, or globus and hoarseness combined for the presence of gastropharyngeal and gastroesophageal reflux. DESIGN: Prospective clinical cohort study of 3 groups of patients undergoing ambulatory 24-hour double-probe pH monitoring. In patients with pathologic gastroesophageal reflux, an upper gastrointestinal endoscopy was also performed. SETTING: Tertiary care, outpatient clinic. PATIENTS: Twenty-seven patients with globus alone, 20 patients with hoarseness alone, and 25 patients with globus and hoarseness combined. RESULTS: Patients with well-defined pathologic reflux (ie, gastroesophageal reflux with or without gastropharyngeal reflux) were present mainly in the group of patients with globus combined with hoarseness: 18 (72%) of 25 patients, compared with 7 (35%) of 20 patients with hoarseness alone and 8 (30%) of 27 with globus alone. Seven (10%) of all 72 patients had prolonged acid exposure at the laryngopharyngeal junction in the presence of a normal gastroesophageal pH registration. Abnormal findings in the esophagus were found at endoscopy in 17 (65%) of 26 patients with pathologic gastroesophageal reflux (with or without gastropharyngeal reflux). CONCLUSIONS: We found a high prevalence of pathologic reflux in patients with both globus and hoarseness. Based on these findings, we strongly advise upper gastrointestinal endoscopy for symptomatic otolaryngological patients with pathologic gastroesophageal reflux.

Adult↗
PubMed2000

Primary melanocytic schwannoma of cervical sympathetic chain.

BACKGROUND: Primary melanocytic schwannoma arising from the cervical sympathetic chain is a rare pigmented nerve sheath tumor. Two cases are presented from an academic medical center. Patients and Methods Patients were initially seen with an enlarging neck mass associated with sympathetic nervous system dysfunction. Radiography demonstrated a mass located posterior to the carotid sheath. Primary therapy consisted of surgical excision and postoperative radiation therapy. RESULTS: The tumors were found to be melanocytic schwannomas arising from the cervical sympathetic chain. The pathologic characteristics of this neoplasm are reviewed. One patient remained disease free for 12 years after treatment, whereas 1 patient died as a result of local recurrence and distant metastases. CONCLUSIONS: Melanocytic schwannoma of the cervical sympathetic chain is a rare nerve sheath tumor of the head and neck that may be misdiagnosed as malignant melanoma. The clinical behavior of this neoplasm is variable. Preoperative neurologic findings, anatomic location, electron microscopy, and immunohistochemistry findings help to establish the diagnosis, and electron microscopy may have a role in distinguishing between benign and malignant lesions. Complete surgical excision is the treatment of choice.

Adult↗
PubMed2000

The role of echocardiographic harmonic imaging and contrast enhancement for improvement of endocardial border delineation.

Despite advances in imaging technology, many myocardial segments remain poorly visualized with echocardiography; however, both contrast enhancement and harmonic imaging have shown promise for improving endocardial definition. Fifty subjects with technically limited echocardiograms were studied with fundamental and harmonic imaging as well as during echocardiographic contrast injection. Overall endocardial visualization scores improved with both techniques compared with fundamental imaging. Harmonic imaging improved endocardial visualization in 43% of all segments and in 57% of segments nonvisualized with fundamental imaging. The benefit of harmonic imaging was seen in all segments. Contrast echocardiography had similar overall improvements in visualization (42% of all segments, 67% of segments nonvisualized with fundamental imaging) but was not helpful in all regions. Harmonic imaging outperformed contrast in 9 of 22 segments, whereas contrast was superior in 4 of 22. In a subgroup of patients with very poor images, contrast enhancement was superior, with a greater increase in overall score and a higher salvage rate than harmonic (68% vs 40%).

Albumins↗
PubMed2000

Conformational determinants of structures in stereoisomeric cis-opened anti-benzo[a]pyrene diol epoxide adducts to adenine in DNA.

As part of a comprehensive effort to understand the origins of the variety of structural motifs adopted by (+)- and (-)-cis- and trans-anti-[BP]-N(2)-dG and -N(6)-dA adducts, with the goal of contributing to the elucidation of the structure-function relationship, we present results of our comprehensive computational investigation of the C10R (+)-cis- and C10S (-)-cis-anti-[BP]-N(6)-dA adducts on the nucleoside level. We have surveyed the potential energy surface of these two adducts by varying systematically, at 5 degrees intervals in combination, the three key torsion angle determinants of conformational flexibility (chi, alpha', and beta') in each adduct, creating 373 248 structures, and evaluating each of their energies. This has permitted us to map the entire potential energy surface of each adduct and to delineate the low-energy regions. The energy maps possess a symmetric relationship in the (+)/(-) adduct pair. This symmetry in the maps stems from the mirror image configuration of the benzylic rings in the two adducts, which produces opposite orientations of the BP residues in the C10R and C10S adducts on the nucleoside level. These opposite orientations result from primary steric hindrance between the base and the BP moiety which ensues when a (+) stereoisomer is rotated to the conformation favored by the (-) stereoisomer, and vice versa. Moreover, this steric hindrance manifested on the nucleoside level governs the structure on the duplex DNA level, accounting for observed opposite orientations in high-resolution NMR studies of C10R/C10S adduct pairs.

Adenine↗
PubMed2000

Bing de ling, a Chinese herbal formula, stimulates multifaceted immunologic responses in mice.

Bing de ling is a Chinese herbal formula most commonly used in complementary medical settings against viral disorders. We have found that bing de ling potentiates upregulation of immune activity when administered to mice in dosages proportional to those used clinically. These mice demonstrated significant elevation of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production in splenocytes and enhancement of macrophage, natural killer cell, and lymphokine-activated killer cell cytotoxicity. These data are consistent with bing de ling's clinically observed efficacy against viruses and identify the formula as a promising candidate for clinical trials against diverse diseases that may respond to increased immunologic activity.

Adjuvants, Immunologic↗
PubMed2000

Improvement of Schwann cell attachment and proliferation on modified hyaluronic acid strands by polylysine.

Hyaluronic acid (HyA) has the intrinsic ability to promote cell proliferation and reduce scar formation. However, the clinical use of HyA has so far been limited because of its water solubility and nonadhesive characteristics. Increasing interest in HyA as a clinically useful biomaterial has prompted our study of altering HyA's physical properties to render it a potential component of nerve grafts. In this study, strands of HyA were cross-linked by glutaraldehyde (Glut), coated with polylysine, and then inoculated with Schwann cells (SCs). Results in vivo and in vitro demonstrated that cross-linked HyA strands were water insoluble and thus less biodegradable. Poly-D-lysine-resurfaced strands showed significant SC attachment of 350-400 cells/mm(2), compared to uncoated controls (0-10 cells/mm(2), p < 0.01). Fibroblast control groups showed an attachment of 40-100 cells/mm(2) on coated strands. Immunostaining for proliferating cells showed SCs as and fibroblasts as +. Cells neither adhered to nor proliferated on the modified HyA strands that were not resurfaced. The results suggest that polylysine promotes SC attachment and proliferation to glutaraldehyde-cross-linked HyA strands, the product being a three-dimensional composite with low solubility that may have potential application in nerve grafts.

Animals↗
PubMed2000

Patency of different arterial and venous end-to-side microanastomosis techniques in a rat model.

Microvascular anastomotic patency is the most important factor in determining a successful outcome in free-flap transfers. End-to-end and end-to-side techniques have been shown to provide equivalent arterial patency rates in clinical and basic science studies, and end-to-side anastomoses have been used extensively in microsurgical reconstruction. Nevertheless, the effect of venotomy shape on the patency of venous end-to-side anastomoses has not been previously reported. The purpose of this study was to compare the patency rates of end-to-side anastomoses using different techniques in both arteries and veins. In total, 104 Sprague-Dawley rats were subdivided into four groups. The rats were anesthetized, and anastomosis was performed on either the femoral artery or vein on the right with the left used as control. Vesselotomy was varied between an end-to-side hole and an end-to-side slit with patency measured immediately following surgery and at 2 weeks. No significant difference in patency or histology between these techniques was demonstrated in any group. We conclude there is no difference in patency rate between the two techniques in arterial or venous vesselotomies; however, in small vessels < 1.5 mm, the slit technique is technically easier, and clinical recommendations are given.

Anastomosis, Surgical↗
PubMed2000

Sequence and functional analysis of EBNA-LP and EBNA2 proteins from nonhuman primate lymphocryptoviruses.

The Epstein-Barr virus (EBV) EBNA-LP and EBNA2 proteins are the first to be synthesized during establishment of latent infection in B lymphocytes. EBNA2 is a key transcriptional regulator of both viral and cellular gene expression and is essential for EBV-induced immortalization of B lymphocytes. EBNA-LP is also important for EBV-induced immortalization of B lymphocytes, but far less is known about the functional domains and cellular cofactors that mediate EBNA-LP function. While recent studies suggest that serine phosphorylation of EBNA-LP and coactivation of EBNA2-mediated transactivation are important, more detailed mutational and genetic studies are complicated by the repeat regions that comprise the majority of the EBNA-LP sequence. Therefore, we have used a comparative approach by studying the EBNA-LP homologues from baboon and rhesus macaque lymphocryptoviruses (LCVs) (baboon LCV and rhesus LCV). The predicted baboon and rhesus LCV EBNA-LP amino acid sequences are 61 and 64% identical to the EBV EBNA-LP W1 and W2 exons and 51% identical to the EBV EBNA-LP Y1 and Y2 exons. Five evolutionarily conserved regions can be defined, and four of eight potential serine residues are conserved among all three EBNA-LPs. The major internal repeat sequence also revealed a highly conserved Wp EBNA promoter with strong conservation of upstream activating sequences important for Wp transcriptional regulation. To test whether transcriptional coactivating properties were common to the rhesus LCV EBNA-LP, a rhesus LCV EBNA2 homologue was cloned and expressed. The rhesus LCV EBNA2 transcriptionally transactivates EBNA2-responsive promoters through a CBF1-dependent mechanism. The rhesus LCV EBNA-LP was able to further enhance rhesus LCV or EBV EBNA2 transactivation 5- to 12-fold. Thus, there is strong structural and functional conservation among the simian EBNA-LP homologues. Identification of evolutionarily conserved serine residues and regions in EBNA-LP homologues provides important clues for identifying the cellular cofactors and molecular mechanisms mediating these conserved viral functions.

Amino Acid Sequence↗
PubMed2000

Regulation of the Epstein-Barr virus C promoter by AUF1 and the cyclic AMP/protein kinase A signaling pathway.

EBNA2 is an Epstein-Barr virus (EBV)-encoded protein that regulates the expression of viral and cellular genes required for EBV-driven B-cell immortalization. Elucidating the mechanisms by which EBNA2 regulates viral and cellular gene expression is necessary to understand EBV-induced B-cell immortalization and viral latency in humans. EBNA2 targets to the latency C promoter (Cp) through an interaction with the cellular DNA binding protein CBF1 (RBPJk). The EBNA2 enhancer in Cp also binds another cellular factor, C promoter binding factor 2 (CBF2), whose protein product(s) has not yet been identified. Within the EBNA2 enhancer in Cp, we have previously identified the DNA sequence required for CBF2 binding and also determined that this element is required for efficient activation of Cp by EBNA2. In this study, the CBF2 activity was biochemically purified and microsequenced. The peptides sequenced were identical to the hnRNP protein AUF1. Antibodies against AUF1 but not antibodies to related hnRNP proteins reacted with CBF2 in gel mobility shift assays. In addition, stimulation of the cellular cyclic AMP (cAMP)/protein kinase A (PKA) signal transduction pathway results in an increase in detectable CBF2/AUF1 binding activity extracted from stimulated cells. Furthermore, the CBF2 binding site was able to confer EBNA2 responsiveness to a heterologous promoter when transfected cells were treated with compounds that activate PKA or by cotransfection of plasmids expressing a constitutively active catalytic subunit of PKA. EBNA2-mediated stimulation of the latency Cp is also increased in similar cotransfection assays. These results further support an important role for CBF2 in mediating EBNA2 transactivation; they identify the hnRNP protein AUF1 as a major component of CBF2 and are also the first evidence of a cis-acting sequence other than a CBF1 binding element that is able to confer responsiveness to EBNA2.

Amino Acid Sequence↗