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Biomedical subjects

K Nguyen

Publications and source records attributed to K Nguyen.

At least 19 recordsLinked to original sources
PubMed2000

Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP.

Interferon-gamma (IFN-gamma) is critical for defense against pathogens, but the molecules that mediate its antimicrobial responses are largely unknown. IGTP is the prototype for a family of IFN-gamma-regulated genes that encode 48-kDa GTP-binding proteins that localize to the endoplasmic reticulum. We have generated IGTP-deficient mice and found that, despite normal immune cell development and normal clearance of Listeria monocytogenes and cytomegalovirus infections, the mice displayed a profound loss of host resistance to acute infections of the protozoan parasite Toxoplasma gondii. By contrast, IFN-gamma receptor-deficient mice have increased susceptibility to all three pathogens. Thus, IGTP defines an IFN-gamma-regulated pathway with a specialized role in antimicrobial resistance.

Animals↗
PubMed2000

Gallstones and common bile duct calculi in infancy and childhood.

BACKGROUND: Gallstones and common bile duct calculi have been increasingly diagnosed in recent years in infants and children. The present study aims to review the spectrum of this disorder in the last two decades. METHODS: During the period 1979-96 a total of 102 consecutive infants and children were diagnosed in Royal Alexandra Hospital for Children with gallstones or common bile duct calculi. A detailed retrospective analysis and follow-up of these children form the basis of the present report. RESULTS: The median age at presentation was 10 years. Recurrent right upper quadrant pain was the most common clinical presentation. The male-to-female ratio was 3:2 and this male predominance was noted in all the age groups. Aetiologically three identifiable groupings were noted: idiopathic disease (n = 66), haematological diseases (n = 23) and specific non-haematological disease (n = 13). The incidence of idiopathic and haematological stones had increased two-fold in the second half of the study. The majority of children (86%) underwent surgical correction. Choledocholithiasis (CDL) was noted in 18 children (18%). Jaundice was commonly associated with abdominal pain in this group. A higher incidence of common bile duct calculi was noted in females and children less than 5 years of age (P < 0.01). Common bile duct calculi were accurately diagnosed by pre-operative imaging in all 18 children. Surgical correction was required in all except two. CONCLUSIONS: The present study suggests an increasing incidence of gallstones in children. Cholelithiasis in children occurs commonly in boys, is idiopathic in aetiology and presents with a vague right upper quadrant pain. Choledocholithiasis is not uncommon in children, occurs more commonly in girls aged < 5 years and presents with jaundice or abnormal liver function tests.

Adolescent↗
PubMed1999

Exploratory solid-phase synthesis of factor Xa inhibitors: discovery and application of p3-heterocyclic amides as novel types of non-basic arginine surrogates.

A series of novel FXa inhibitors 2a-m and 3a-f was discovered that feature heterocyclic carboxamides tethered to a d-diaminobutyric acid sidechain. These neutral amide derivatives serve as novel P3 d-arginine mimics. Pyrazine carboxamide scaffolds afforded the most potent FXa inhibitors (e.g., 2b IC50 = 4.6 nM). The synthesis and biological activity of two focused libraries are reported.

Amides↗
PubMed1999

Imaging adenoviral-directed reporter gene expression in living animals with positron emission tomography.

We are developing quantitative assays to repeatedly and noninvasively image expression of reporter genes in living animals, using positron emission tomography (PET). We synthesized positron-emitting 8-[18F]fluoroganciclovir (FGCV) and demonstrated that this compound is a substrate for the herpes simplex virus 1 thymidine kinase enzyme (HSV1-TK). Using positron-emitting FGCV as a PET reporter probe, we imaged adenovirus-directed hepatic expression of the HSV1-tk reporter gene in living mice. There is a significant positive correlation between the percent injected dose of FGCV retained per gram of liver and the levels of hepatic HSV1-tk reporter gene expression (r2 > 0.80). Over a similar range of HSV1-tk expression in vivo, the percent injected dose retained per gram of liver was 0-23% for ganciclovir and 0-3% for FGCV. Repeated, noninvasive, and quantitative imaging of PET reporter gene expression should be a valuable tool for studies of human gene therapy, of organ/cell transplantation, and of both environmental and behavioral modulation of gene expression in transgenic mice.

Animals↗
PubMed1999

Risk factors for rupture of chronic type B dissections.

OBJECTIVE: This study was an attempt to determine risk factors for rupture and to improve management of patients with type B aortic dissection who survive the acute phase without operation. METHODS: We studied 50 patients by means of serial computer-generated 3-dimensional computed tomographic scans. All patients who did not undergo operative treatment before the completion of at least 2 computed tomographic scans a minimum of 3 months apart after an acute type B dissection were included in the study. The median duration of follow-up was 40 months (range 0.9-112 months). Only 1 patient died of causes unrelated to the aneurysm during follow-up. Nine patients had fatal rupture (18%); 10 patients underwent elective aneurysm resection because of rapid expansion or development of symptoms, and 31 patients remained alive without operation or rupture. Possible risk factors for rupture in patients in the rupture, operative, and event-free groups were compared, as were dimensional data from first follow-up and last computed tomographic scans. RESULTS: Older age, chronic obstructive pulmonary disease, and elevated mean blood pressures were unequivocally associated with rupture (rupture versus event-free survival, P <.05), and pain was marginally significantly associated. Analysis of dimensional factors contributing to rupture was complicated by the fact that patients who underwent elective operation had significantly larger aneurysms and faster expansion rates than did either of the other groups, leaving comparisons of aneurysmal diameter between groups with and without rupture showing only marginal statistical significance. The last median descending aortic diameter before rupture in the rupture group was 5.4 cm (range 3.2-6. 7 cm). CONCLUSIONS: In an environment in which patients with large and rapidly expanding aneurysms are usually referred for surgical treatment, older patients with chronic type B dissections, especially if they have uncontrolled hypertension and a history of chronic obstructive pulmonary disease, are significantly more likely to have rupture than are younger, normotensive patients without lung disease. Neither the presence of a persistently patent false lumen nor a large abdominal aortic diameter appears to increase the risk of rupture. Overall, our nondimensional data strikingly resemble the natural history of patients with nondissecting aneurysms, suggesting that calculations derived from data on chronic descending thoracic and thoracoabdominal aneurysms would provide an overly conservative individual estimate of rupture risk for patients with chronic type B dissection, who tend toward earlier rupture of smaller aneurysms. A more aggressive surgical approach toward treatment of patients with chronic type B dissection seems warranted.

Age Factors↗
PubMed1999

Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families.

The tumor-suppressor activity of the retinoblastoma protein (RB) is encoded within a protein-binding ("pocket") domain that is targeted for mutations in all cases of familial retinoblastoma and in many common adult cancers. Although familial retinoblastoma is a paradigm for a highly penetrant, recessive model of tumorigenesis, the molecular basis for the phenotype of incomplete penetrance of familial retinoblastoma is undefined. We studied the RB pocket-binding properties of three independent, mutant RB alleles that are present in the germline of 12 kindreds with the phenotype of incomplete penetrance of familial retinoblastoma. Each arises from alterations of single codons within the RB pocket domain (designated "delta 480," "661W," or "712R"). Under the same conditions, we studied the properties of wild-type (WT) RB, an RB point mutant isolated from a lung carcinoma sample (706F) and an adjacent, in vitro-generated point mutant (707W). The delta 480, 661W, and 712R mutants lack pocket protein-binding activity in vitro but retain the WT ability to undergo cyclin-mediated phosphorylation in vivo. Each of the low-penetrant RB mutants exhibits marked enhancement of pocket protein binding when the cells are grown at reduced temperature. In contrast, in this temperature range, no change in binding activity is seen with WT RB, the 706F mutant, or the 707W mutant. We have demonstrated that many families with incomplete penetrance of familial retinoblastoma carry unstable, mutant RB alleles with temperature-sensitive pocket protein-binding activity. The variable frequency for tumor development in these families may result from reversible fluctuations in a threshold level of RB pocket-binding activity.

Alleles↗
PubMed1998

Experimentally induced lysosomal dysfunction disrupts processing of hypothalamic releasing factors.

Previous studies have shown that experimentally induced lysosomal dysfunction elicits various features of aging in the cortical telencephalon. The present study used cultured slices to test if: (1) it causes similar changes in the hypothalamus, and/or (2) modifies the processing of two releasing factors important to aging. A 2-day exposure to N-CBZ-L-phenylalanyl-L-alanine-diazomethylketone (ZPAD), a selective inhibitor of cathepsins B and L, triggered a pronounced increase in the numbers of lysosomes in the ventromedial and dorsomedial nuclei, and in lateral hypothalamus. Continued incubation with the inhibitor for 3-12 days resulted in the spread of endosomes-lysosomes into dendrites and, in the lateral hypothalamus, the formation of massive, lysosome-filled expansions of neuronal processes (meganeurites). These effects did not occur in the arcuate nucleus, making it the first region so far examined in which lysosomal proliferation is not initiated by hydrolase inhibitors. Despite this, a dense plexus of axons and terminals in the median eminence was partially depleted of growth hormone releasing hormone (GHRH) within 48 hours after addition of ZPAD. Moreover, the inhibitor caused axonal GHRH to become collected into large puncta, an effect highly suggestive of a partial failure in axonal transport. GHRH mRNA levels were not greatly affected by 6 days of ZPAD exposure, indicating that reduced expression did not play a major role in the peptide changes seen at 48 hours. Similar but less pronounced immunocytochemical changes were recorded for the somatostatin system in the arcuate and periventricular nucleus. It is concluded that lysosome dysfunction: (1) has different consequences for the arcuate nucleus than other brain regions, and (2) disrupts transport of hypothalamic releasing factors. The potential significance of the results to endocrine senescence is discussed.

Animals↗
PubMed1998

Survival in neonatal biventricular repair of left-sided cardiac obstructive lesions associated with hypoplastic left ventricle.

Patients with left ventricular hypoplasia and left-sided heart obstructive lesions other than critical aortic stenosis may be inappropriately subjected to single ventricular repair because their assessment is based on faulty qualitative evaluations or on quantitative methods developed for critical aortic stenosis. Patients with left ventricular hypoplasia and left-sided heart obstructions other than critical aortic stenosis successfully underwent biventricular repair despite "failing" to pass established criteria for critical aortic stenosis.

Aortic Coarctation↗
PubMed1998

High-level expression of eukaryotic polypeptides from bacterial chromosomes.

Attractive economics and short development timelines have often been cited as reasons for using bacteria to express eukaryotic proteins on a commercial scale. Nevertheless, routine techniques for bacterial expression of heterologous proteins are beset by a variety of technical and legal difficulties. In particular, the use of plasmids to express foreign proteins, popular promoter systems, protein fusion partners, and histidine tags and the recovery of proteins from inclusion bodies are affected by a host of issued patents. Chromosomally encoded leaderless fusions (CELF) offer a variety of technical and legal advantages over existing bacterial expression systems. In this study, we show that CELF can be used to produce a wide assortment of eukaryotic proteins at 10-liter fermentation scale.

Bacteriophage T7↗
PubMed1998

Modified ultrafiltration improves left ventricular systolic function in infants after cardiopulmonary bypass.

OBJECTIVE: Our objective was to test the hypothesis that use of modified ultrafiltration after cardiopulmonary bypass improves intrinsic left ventricular systolic function in children. METHODS: Twenty-one infants undergoing cardiopulmonary bypass were instrumented with ultrasonic dimension transducers, to measure the anteroposterior minor axis diameter, and a left ventricular micromanometer. Patients were randomized to modified ultrafiltration (n = 11, age 226 +/- 355 days, weight 6.7 +/- 3.1 kg) or control (n = 10, age 300 +/- 240 days, weight 7.0 +/- 2.5 kg) (all differences p > 0.05 between groups). Left ventricular systolic function was assessed by means of the slope of the preload-recruitable stroke work index. Myocardial cross-sectional area was measured by echocardiography. Data were acquired immediately after separation from bypass, at steady state, and during transient vena caval occlusion. Data acquisition was repeated after 13 +/- 5 minutes of modified ultrafiltration or after 12 +/- 5 minutes without modified ultrafiltration in the control group. Inotropic drug support was the same at both study points. RESULTS: In the modified ultrafiltration group, the filtrate volume was 363 +/- 262 ml. The hematocrit value increased from 26.0% +/- 2.7% to 36.7% +/- 9.5% (p = 0.018), myocardial cross-sectional area decreased from 3.72 +/- 0.35 cm2 to 3.63 +/- 0.36 cm2 (p = 0.04), end-diastolic length increased from 25.6 +/- 9.0 mm to 28.8 +/- 9.9 mm (p = 0.01), and end-diastolic pressure fell from 5.6 +/- 0.8 mm Hg to 4.2 +/- 0.8 mm Hg (p = 0.005), suggesting an improved diastolic compliance. In the control group, the hematocrit value, myocardial cross-sectional area, end-diastolic length, and pressure did not change (all p > 0.05). Mean ejection pressure increased in the ultrafiltration group (p = 0.001) but did not change in the control group (p = 0.22). The slope of the preload-recruitable stroke work index increased after ultrafiltration from 52.3 +/- 52.0 to 74.2 +/- 66.0 (10[3] erg/cm3) (p = 0.02) but did not change in the control group (p = 0.07). One patient from each group died in the postoperative period. Patients in the ultrafiltration group received less inotropic drug support in the first 24 hours after the operation (156.62 +/- 92.31 microg/kg in 24 hours) than patients in the control group (865.33 +/- 1772.26 microg/kg in 24 hours, p = 0.03). CONCLUSIONS: Use of modified ultrafiltration after cardiopulmonary bypass improves intrinsic left ventricular systolic function, improves diastolic compliance, increases blood pressure, and decreases inotropic drug use in the early postoperative period.

Cardiopulmonary Bypass↗
PubMed1997

B7.2 expressed by T cells does not induce CD28-mediated costimulatory activity but retains CTLA4 binding: implications for induction of antitumor immunity to T cell tumors.

The B7 family of costimulatory molecules provides the second signal necessary for activation of T cells. In the absence of the second signal, responding T cells become anergic. Although predominantly expressed on professional APCs, recent evidence shows that the B7 molecules are also expressed on T cells. To study the functions of B7 molecules on T cells, we transfected murine B7.1 (CD80) and B7.2 (CD86) cDNAs into the EL4 T cell thymoma cell line and examined the transfectants for their ability to costimulate T cell proliferation in vitro and to induce antitumor immunity in vivo. Here we show that although EL4-B7.1 cells costimulate T cells and induce tumor regression, EL4-B7.2 transfectants failed to costimulate T cell proliferation or induce tumor regression. To understand the cellular basis for this difference, we examined the binding of EL4-B7.1 and EL4-B7.2 to CTLA4 and CD28. Whereas EL4-B7.1 cells bound both CTLA4-Ig and CD28-Ig, EL4-B7.2 transfectants preferentially bound CTLA4-Ig, but not CD28-Ig. Similar binding data were obtained with freshly isolated murine T cells, which have been shown to constitutively express B7.2. Our data suggest, therefore, that B7.2 expressed on T cells may not costimulate but instead inhibit the T cell response by preferential binding to CTLA4.

Abatacept↗
PubMed1997

Norepinephrine induced growth and expression of virulence associated factors in enterotoxigenic and enterohemorrhagic strains of Escherichia coli.

The small intestine is richly innervated by the sympathetic nervous system. High concentrations of monoamines, most notably norepinephrine, are found throughout the various intestinal layers. In order to determine whether norepinephrine is capable of influencing bacterial pathogenesis, the growth and production of virulence factors in ETEC and EHEC were examined in a physiologically relevant medium utilizing very low initial bacterial inoculums to more closely mimie in vivo conditions. The growth of ETEC strain B44 and the production of the K99 pilus adhesin on a protein equivalent basis was greatly increased in the presence of norepinephrine. Growth of EHEC O157:H7 was also increased in norepinephrine containing medium as well as production of SLT-I and SLT-II. The ability of norepinephrine to increase both bacterial growth and expression of virulence factors was shown to be non-nutritional in nature. Given the abundant adrenergic innervation in the small intestine, these in vitro results suggest that the neurohumoral environment of the host may play a role in bacterial growth and expression of virulence factors.

Antigens, Surface↗
PubMed1997

Four exemplary preceptors' strategies for efficient teaching in managed care settings.

To identify time-efficient and educationally effective methods for teaching in ambulatory care and managed care settings, the authors studied four exemplary preceptors who taught family medicine clerks in managed care clinics. They interviewed all four preceptors and observed three of them. All of these preceptors claimed to practice more efficiently with students than without them. Analysis of 33 patients encounters involving students revealed that each of the five students observed spent an average of 12.0 minutes conducting a history and physical examination, 2.2 minutes presenting the case to the preceptor, 7.9 minutes observing the preceptor reviewing and/or repeating the examination with the patient, and 1.8 minutes receiving direct instruction and feedback from the preceptor. The total time per patient encounter was 23.7 minutes, 11.7 minutes of which directly involved the preceptor. The authors then compared these 33 encounters with encounters involving the preceptors alone; these encounters took an average of 10.6 minutes of the preceptors' time. The 1.1-minute difference between the amount of time preceptors spent in encounters involving students and the amount of time they spent in encounters on their own was not statistically significant as measured by t-test (p < .05). However, in calculating this time difference, possible time saved by students' assistance with charting was not accounted for. In interviews the preceptors identified three major instructional strategies for time-efficient teaching; planning and preparing; teaching with patients; and charting, giving feedback, and reflecting. Students described these preceptors as enthusiastic teachers and good role models; however, they also felt that their first two years of education had not prepared them for seeing patients in fast-paced ambulatory care settings. The challenge for medical schools is to better prepare both students and preceptors for learning and teaching in productivity driven ambulatory care and managed care environments.

Ambulatory Care↗
PubMed1997

Cytokine control of PMN phagocytosis: regulatory effects of hypoxemia and hypoxemia-reoxygenation.

We investigated the effects of hypoxemia and hypoxemia-reoxygenation (H/R) on interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), or IL-1beta stimulation of whole blood polymorphonuclear leukocyte (PMN) phagocytosis and bactericidal activity. Whole blood PMN were rendered hypoxemic (venous PO2 < 15 mmHg), normoxic (venous PO2 60-80 mmHg), or reoxygenated after hypoxemia (H/ R = venous PO2 150-200 mmHg) and were incubated with IL-8, TNF-alpha, or IL-1beta before sequential addition of serum-opsonized fluorescent microspheres and fluorescein isothiocyanate-conjugated mouse anti-human CD64, CD32w, CD16, CD35, or CD11b/CD18. Concomitant two-color flow cytometric analyses were then performed measuring mean channel fluorescence and the percentage of PMN positive for phagocytosis, with simultaneous subset receptor analysis on populations of PMN that exceeded control levels of phagocytosis. During hypoxemia, whole blood PMN phagocytosis in the presence of IL-8, TNF-alpha, or IL-1beta was increased compared with normoxia. Northern blot analyses revealed an increase in steady-state mRNA levels for CD32w during hypoxemia + IL-8 and CD64 during hypoxemia + IL-1beta. During reoxygenation, both whole blood PMN phagocytosis and bactericidal activity were reduced in the presence of IL-8, TNF-alpha, or IL-1beta, and in subsets of PMN with reduced phagocytosis H/R reduced CD64, CD32w, CD16, CD35, and CD11b/CD18 expression in the presence of each cytokine. Northern blot analyses revealed that H/R reduced mRNA levels for opsonic receptors primarily for IL-1beta-stimulated PMN. These results demonstrate a direct regulatory effect of hypoxemia and H/R on whole blood PMN phagocytosis, receptor expression, and steady-state mRNA levels of both Fc(gamma) and complement receptors.

Animals↗
PubMed1997

Lung neutrophil retention and injury after intestinal ischemia/reperfusion.

OBJECTIVE: To define the mechanisms responsible for the lung leukosequestration and injury elicited by intestinal ischemia/reperfusion (I/R). METHODS: The effect of 120 minutes of superior mesenteric artery occlusion and 90 minutes of reperfusion on neutrophil deformability, lung neutrophil retention, and pulmonary microvascular permeability was determined. RESULTS: Compared with control surgery, intestinal I/R resulted in a significant increase in neutrophil stiffness (mean yield pressure [Pyield], 1.533 +/- 0.075 and 2.302 +/- 0.288 cm H2O, respectively) and lung neutrophil content (6.3 +/- 1.4 and 31.5 +/- 6.4 U/g wet weight, respectively). These changes were not affected by inhibition of neutrophil adherence before gut reperfusion. However, the increased lung microvascular permeability elicited by gut I/R (0.111 +/- 0.020 [control surgery] and 0.255 +/- 0.041 [I/R] mL/min/cm H2O/100 g lung tissue) was significantly attenuated by administration of antibodies directed against neutrophil or endothelial determinants of leukocyte adhesion. CONCLUSIONS: The results of this study suggest that intestinal I/R is a potent inflammatory stimulus that elicits an increase in neutrophil stiffness and lung neutrophil retention independent of neutrophil-endothelial cell adhesion. In contrast, the increased lung microvascular permeability elicited by gut I/R is attenuated by strategies that interfere with neutrophil-endothelial cell adhesion.

Animals↗