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Biomedical subjects

B Nguyen

Publications and source records attributed to B Nguyen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Architecture of a K+ channel inner pore revealed by stoichiometric covalent modification.

Inwardly rectifying K+ channels bind intracellular magnesium and polyamines to generate inward rectification. We have examined the architecture of the inner pore of Kir2.1 channels by covalently attaching a constrained number (from one to four) of positively charged moieties of different sizes to the channel. Our results indicate that the inner pore is formed solely by the second transmembrane segment and is unprecedentedly wide. At a position critical for inward rectification (D172), the pore is sufficiently wide to bind three Mg2+ ions or polyamine molecules simultaneously. Single-channel recordings directly demonstrate that partially modified channels exhibit distinct subconductance levels. Such a wide inner pore may greatly facilitate ion permeation and high-affinity binding of multiple pore blockers to generate strong inward rectification.

Amino Acid Sequence↗
PubMed1999

Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ET(A) receptor selectivity.

Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET(A) and ET(B) receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET(B) receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET(A)-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET(A)-selective, ET(B)-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET(A) selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity.

Animals↗
PubMed1999

Different techniques of distal aortic repair in acute type A dissection: impact on late aortic morphology and reoperation.

OBJECTIVE: To compare three different techniques of distal aortic repair in acute type A (de Bakey type I) aortic dissection and to evaluate their impact on the late morphology of the aortic arch and descending aorta and on the incidence of reoperation. METHODS: From 65 patients operated on due to an acute type A aortic dissection between 1989 and 1993, 54 long-term survivors underwent clinical and radiologic follow-up examination after a mean postoperative interval of 62+/-16 months. The surgical techniques of distal aortic reconstruction included closed repair using Teflon felt reinforcement under moderate hypothermic cardiopulmonary bypass (n = 20) and open repair in deep hypothermic circulatory arrest using either Teflon felt reinforcement (n = 16) or gelatin-resorcin-formaldehyde (GRF) glue (n = 18) to readapt the dissected aortic layers. In all patients, MR imaging was performed on a 1.5-T whole body imaging system for the evaluation of the morphology and function of the heart, aorta and supraaortic branches. RESULTS: Overall hospital mortality following surgical repair of type A aortic dissection was 15.4% during this time period. The highest rate of persistent false lumen perfusion (17/20, 85%) and presence of an intimal flap in the aortic arch (13/20, 65%) was observed in patients following closed repair of acute ascending aortic dissection, whereas the lowest rate of such findings was demonstrated in patients who had undergone open distal aortic repair using biological glue (false lumen perfusion 10/18, 55% and intimal flap in the arch 2/18, 11%). Redo-surgery was significantly reduced in the open repair group using GRF glue (1/18, 5.5%) as compared with the Teflon felt repair group (3/16, 18%) and the closed repair group (6/20, 30%). CONCLUSIONS: In patients with acute type A dissection, open distal aortic repair using GRF-glue favourably influences both (1) the severity of late morphologic alterations in the downstream aorta and (2) the incidence of reoperation.

Aortic Dissection↗
PubMed1999

Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate. PATIENTS AND METHODS: A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m2 IV days 1 to 3 along with cisplatin 100 mg/m2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response. RESULTS: The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P = .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P = .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P = .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm. CONCLUSION: Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC.

Adult↗
PubMed1999

Intracellular mechanisms involved in dopamine-induced actin cytoskeleton organization and maintenance of a round phenotype in cultured rat lactotrope cells.

The participation of the actin cytoskeleton in the control of PRL secretion by dopamine (DA) is not yet fully understood. Recently, we demonstrated that DA induces cortical actin assembly and stabilization in anterior pituitary PRL-secreting cells (lactotropes) that can be linked to DA-induced inhibition of PRL secretion. Here we show that DA prevents cell flattening and the formation of cytoplasmic actin cables in cultured rat lactotropes. The effects of DA were reversible, mediated by D2 receptors, exclusive to lactotropes, and independent of other anterior pituitary cells present in the cultures. Because cAMP and Ca2+ mediate DA-induced inhibition of PRL secretion and synthesis, we investigated whether morphological responses to DA were dependent on these second messengers. Either inhibition of protein kinase A activity with the specific inhibitor KT5720 or blockade of Ca2+ channels with nifedipine inhibited cell flattening and induced cytoplasmic actin filament breakdown. Nifedipine was as effective as DA, but KT5720 was less effective than DA. Increased intracellular cAMP levels provoked cell flattening, which was blocked by nifedipine and KT5720, but not by DA. The results suggest that Ca2+-dependent pathways control cell shape in most lactotropes; however, in a subpopulation of lactotropes, cAMP-dependent pathways may also contribute to DA morphological responses. Next, we studied the participation of the Rho family of guanosine triphosphatases, which is known to regulate the dynamics of actin filaments. Inactivation of Rho by C3 exoenzyme induced cytoplasmic actin cable disassembly and lactotrope rounding up. No additive effects were observed among Rho-, cAMP-, and Ca2+-dependent pathways. However, C3-induced morphological responses were blocked by increased cAMP levels, suggesting that Rho-dependent steps are upstream cAMP-dependent steps. DA-induced actin cytoskeleton reorganization in lactotropes may involve modifications in the expression and localization of actin-binding proteins. DA increased expression of the actin anchoring proteins talin and alpha-actinin, but not of vinculin. DA enhanced association of talin to cell membranes. Increased talin-membrane interaction may be implicated in DA-induced maintenance of a round phenotype in lactotrope cells.

Actins↗
PubMed1999

Assessment of an outreach program that links children who use New York City immunization clinics to primary care.

BACKGROUND: Many children who obtain immunizations at the New York City (NYC) Department of Health (DOH) Immunization Clinics do not have medical coverage and therefore do not have access to primary care. A consequence of this is increased morbidity of diseases which are best managed in an outpatient setting. In 1996, Every Child By Year 2000 (ECY2000), an outreach program, was launched to educate and link families to primary care and ensure that children are referred to their primary care providers for their health care needs. METHODOLOGY: Families using the NYCDOH Immunization Clinics were interviewed and enrolled in either Child Health Plus (CHP)--a New York State sponsored health insurance program or Medicaid (MA). A survey was designed to determine the number of children, socioeconomic factors of the families that were linked to CHP or MA and factors affecting children's accessibility to primary care and immunization. RESULTS: A total of 4024 children had come into contact with the program in the first half of 1997. A total of 693 children were surveyed and 365 (52.7%) of them were enrolled in CHP or MA. Families who were aware that CHP was a free/low cost health insurance program for children were more likely to have CHP insurance. Children who were enrolled in CHP were more likely to have regular primary care, to receive up-to-date immunization shots and immunization information from their primary providers. CONCLUSION: More public health primary care outreach and education programs should be targeted to recent immigrants and low income families and these programs should be culturally sensitive.

Adolescent↗
PubMed1999

Effect of riluzole on the neurological and neuropathological changes in an animal model of cardiac arrest-induced movement disorder.

Posthypoxic myoclonus and seizures precipitate as secondary neurological consequences in ischemic/hypoxic insults of the central nervous system. Neuronal hyperexcitation may be due to excessive activation of glutamatergic neurotransmission, an effect that has been shown to follow ischemic/hypoxic events. Therefore, riluzole, an anticonvulsant that inhibits the release of glutamate by stabilizing the inactivated state of activated voltage-sensitive sodium channels, was tested for its antimyoclonic and neuroprotective properties in the cardiac arrest-induced animal model of posthypoxic myoclonus. Riluzole (4-12 mg/kg i.p.) dose-dependently attenuated the audiogenic seizures and action myoclonus seen in this animal model. Histological examination using Nissl staining and the novel Fluoro-Jade histochemistry in cardiac-arrested animals showed an extensive neuronal degeneration in the hippocampus and cerebellum. Riluzole treatment almost completely prevented the neuronal degeneration in these brain areas. The neuroprotective effect was more pronounced in hippocampal pyramidal neurons and cerebellar Purkinje cells. These effects were seen at therapeutically relevant doses of riluzole, and the animals tolerated the treatment well. These findings indicate that the pathogenesis of posthypoxic myoclonus and seizure may involve excessive activation of glutamate neurotransmission, and that riluzole may serve as an effective pharmacological agent with neuroprotective potential for the treatment of neurological conditions associated with cardiac arrest in humans.

Animals↗
PubMed1999

Restricted natural language processing for case simulation tools.

For Interactive Patient II, a multimedia case simulation designed to improve history-taking skills, we created a new natural language interface called GRASP (General Recognition and Analysis of Sentences and Phrases) that allows students to interact with the program at a higher level of realism. Requirements included the ability to handle ambiguous word senses and to match user questions/queries to unique Canonical Phrases, which are used to identify case findings in our knowledge database. In a simulation of fifty user queries, some of which contained ambiguous words, this tool was 96% accurate in identifying concepts.

Computer Simulation↗
PubMed1999

Role of antioxidants in the survival of normal and vitiliginous avian melanocytes.

Mutant feather melanocytes from Barred Plymouth Rock (BPR) and White Leghorn (WL) chickens are currently being used as avian models of vitiligo. Feather melanocytes in BPR and WL chickens die prematurely in vivo due to low (50-66%) antioxidant glutathione and superoxide dismutase levels when compared to the wild type Jungle Fowl (JF) melanocytes. Excess superoxide anions, generated by xanthine:xanthine oxidase (X:XO), caused a 15-20% increase in mortality after 1 and 2 hrs. in all three genotypes of in vitro melanocytes as compared to control values that received no X:XO. Overall, the JF wild type melanocytes had the lowest mortality rate, WL melanocytes had the highest mortality rate and the BPR melanocytes had an intermediate mortality rate. Superoxide anion and hydroxyl radical production in the WL feather were double the production in the JF wild type feather. The production of reactive oxygen species in BPR was intermediate to the other two genotypes. In an effort to mimic the low antioxidant levels of the BPR and WL feathers in the JF feather, JF in vitro feather melanocytes were treated with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor. With BSO added to the medium, the JF mortality rates increased by 20-25%, reaching the mortality levels of the mutant BPR melanocytes. The addition of iron to the JF melanocyte X:XO medium increased their mortality rate by 20%, probably via the Fenton reaction. Thus, antioxidants play an extremely important role in both the viability of normal avian melanocytes and the premature death of the vitiliginous avian melanocytes. A working hypothesis, supported in part by the current results, is that the premature death of the mutant melanocytes could be precipitated in the poorly vascularized feather by low antioxidant protection due to both low turnover of tissue fluids which contain SOD and to genetically determined low levels of internal antioxidant protection in these melanocytes. This same mechanistic hypothesis could apply as "a" cause of premature melanocyte cell death in human vitiligo wherein the vitiliginous melanocytes may have a genetic defect in their antioxidant protection system and blood flow to an area may be restricted.

Animals↗
PubMed1999

Fatal basilar artery thrombosis after traumatic cervical facet dislocation. Case report.

The authors detail a rare case of basilar artery thrombosis in a patient with traumatic cervical spine facet dislocation. Although the patient's deficits could initially be explained by the spinal injury, deterioration to a "locked-in-state" could not. In addition to vertebral artery injuries, the basilar artery can also be indirectly involved in cases of cervical spine trauma. In the rare viable patient, immediate reduction of cervical spine dislocation may allow endovascular thrombolysis, if not otherwise contraindicated.

Adult↗
PubMed1998

Pyrrolidine-3-carboxylic acids as endothelin antagonists. 3. Discovery of a potent, 2-nonaryl, highly selective ETA antagonist (A-216546).

Previously we have reported the discovery of ABT-627 (1, A-147627, active enantiomer of A-127722), a 2,4-diaryl substituted pyrrolidine-3-carboxylic acid based endothelin receptor-A antagonist. This compound binds to the ETA receptor with an affinity (Ki) of 0. 034 nM and with a 2000-fold selectivity for the ETA receptor versus the ETB receptor. We have expanded our structure-activity studies in this series, in an attempt to further increase the ETA selectivity. When the p-anisyl group of 1 was replaced by an n-pentyl group, the resultant antagonist 3 exhibited substantially increased ETB/ETA activity ratio, but a decreased ETA affinity. Structure-activity studies revealed that substitution and geometry of this alkyl group, and substitution on the benzodioxolyl ring, are important in optimizing this series of highly ETA selective antagonists. In particular, the combination of a (E)-2,2-dimethyl-3-pentenyl group and a 7-methoxy-1,3-benzodioxol-5-yl group provided hydrophobic compound 10b with subnanomolar affinity for human ETA receptor subtype and with an ETB/ETA activity ratio of over 130000. Meanwhile, synthetic efforts en route to olefinic compounds led to the discovery that 2-pyridylethyl (9o) and 2-(2-oxopyrrolidinyl)ethyl (9u) replacement of the p-anisyl group of 1yielded very hydrophilic ETA antagonists with potency and selectivity equal to those of 10b. On the basis of overall superior affinity, high selectivity for the ETA receptor (Ki, 0.46 nM for ETA and 13000 nM for ETB), and good oral bioavailability (48% in rats), A-216546 (10a) was selected as a potential clinical backup for 1.

Administration, Oral↗
PubMed1998

Decreased survival in rat liver transplantation with extended cold preservation: role of portal vein clamping time.

Primary liver graft dysfunction is currently related to cold ischemia-reperfusion injury, although a wide survival range has been reported using 24-hour preservation in cold University of Wisconsin (UW) solution. We hypothesized that the portal vein clamping time (PVCT) played a more important role than cold preservation injury in the postoperative outcome. Rat liver transplantation was performed using different clamping times after 24-hour cold ischemia in the UW solution. Survival rates, plasma tumor necrosis factor (TNF), and nitrate/nitrite levels were examined. Subsequently, the effect of clamping time was evaluated on hepatocyte and sinusoidal endothelial cell (SEC) function using isolated perfused livers. Survival rate was directly related to clamping time length. Marked increases in TNF and nitrate/nitrite levels were found after surgery, particularly after long clamping times. In perfusion studies, the SEC function was already markedly altered after preservation alone and was not further modified by transplantation. By contrast, the hepatocyte function was moderately altered after transplantation, irrespective of clamping times, even when rats operated with long clamping times were in terminal conditions. In rats, 24-hour preservation in cold UW solution is not a severely compromising condition leading to primary liver nonfunction. Long PVCTs are associated with an endotoxemia-like syndrome more related to a warm intestinal ischemia than to cold ischemia injury of the liver.

Animals↗
PubMed1998

Phase II trial of oral beta-all trans-retinoic acid in hepatocellular carcinoma (SWOG 9157).

Twenty-nine chemotherapy-naive patients with primary hepatocellular carcinoma were treated with oral beta-all trans-retinoic acid (retinoic acid, TRA 50 mg/m2 t.i.d.) on a 3-week on/one week off schedule until progression or grade 3 or 4 toxicity. Eligibility requirements allowed abnormal liver function tests as long as the creatinine and bilirubin levels were normal. No responses were seen and the median survival was four months. Grade 3 side effects occurred in II patients and grade 4 in four and included a wide range of toxicities. The results indicate that oral TRA is ineffective against primary hepatocellular carcinoma and suggest that dose-modification of this retinoid may be required in patients with significant malignant hepatic involvement.

Administration, Oral↗
PubMed1998

Nasal response in subjects undergoing challenges by inhaling occupational agents causing asthma through the nose and mouth.

BACKGROUND: Subjects with occupational asthma (OA) often report nasal symptoms, but nasal reactions to inhalation challenges with occupational agents have not been well characterized. METHODS: Fifteen subjects with OA (eight due to high-molecular-weight agents--flour and guar gum--and seven due to isocyanates) underwent inhalational challenges using closed-circuit devices (dry particles for high-molecular-weight agents and gas generator for isocyanates) on two occasions, 2-4 weeks apart in a random fashion. On one occasion, they inhaled through the nose and, on another, through the mouth. The FEV1 was monitored for up to 8 h afterward, and symptoms were documented with a standardized questionnaire on nasal symptomatology, assessment of nasal resistance by rhinomanometry, and nasal lavage for the examination of cells and mediators. RESULTS: Inhaling through the mouth and through the nose: 1) yielded similar asthmatic responses (25+/-8% and 22+/-10% maximum changes in FEV1) 2) more than doubled the peak nasal symptoms and nasal resistance when the maximum daily response was compared with prechallenge results. This increase occurred on the days of inhalational challenges through the mouth and through the nose. There were some significant responses assessed by nasal lavage in terms of cells and mediators, again with no differences between the days of challenges through the mouth and through the nose. CONCLUSIONS: Inhaling occupational agents of high or low molecular weight, including isocyanates, whether through the mouth or nose: 1) results in a similar asthmatic response 2) causes a significant nasal response in terms of symptoms and an increase in nasal resistance 3) causes some significant changes in inflammatory cells and mediators.

Administration, Inhalation↗
PubMed1998

Determinants of the bronchial response to high molecular weight occupational agents in a dry aerosol form.

In occupational challenge tests with isocyanate vapours, bronchial responsiveness is determined by the total dose rather than the concentration or duration of exposure. Whether the same applies for high molecular weight (HMW) agents in powder form is unknown. The aim of this study was to determine whether the total dose of HMW agents in powder form is responsible for the immediate reaction documented in specific challenge tests. Included in the study were nine subjects (seven males and two females) with a diagnosis of occupational asthma proved by specific challenge tests carried out on a preliminary visit. Two challenge tests (using a closed-circuit exposure chamber) were performed at an interval of 2 weeks; the concentrations administered in a random order on these two visits were half and double the one that had caused a 20% fall in forced expiratory volume in one second (FEV1) on a preliminary visit. The duration of exposure was adjusted until a significant fall in FEV1 (target of 20%) occurred. The two concentrations obtained were significantly different, by 2.07+/-0.36-fold (SD). The observed durations of exposure leading to a 20% fall in FEV1 on the two visits also differed significantly by 0.46+/-0.32-fold. Consequently, the cumulative efficient doses were not significantly different between the two visits: 12+/-5.4 and 9+/-5 mg x mL(-1) x min(-1), respectively. The corresponding cumulative dose ratio was 0.96+/-0.61. The expected duration of exposure (10.8+/-24 min) was not significantly different from the observed duration (5.4+/-9 min). The mean and 95% confidence interval for the difference in concentration between the two visits was 1.83-fold (1.48-2.21). In conclusion, the total dose rather than the concentration or duration of exposure per se determines bronchial responsiveness to high molecular weight agents in powder form.

Adult↗
PubMed1998

Combined cisplatin and gemcitabine for non-small cell lung cancer: influence of scheduling on toxicity and drug delivery.

The scheduling of cytotoxic chemotherapy has important bearing on the toxicity and ability to deliver chemotherapy at or close to full dose. We report new data on the influence of different schedules of cisplatin and gemcitabine on toxicity and drug delivery in phase II studies of non-small cell lung cancer. Patients in six phase II studies had standard entry criteria for advanced non-small cell lung cancer. Whereas gemcitabine was given on days 1, 8, and 15 of a 28-day cycle in all these studies, the scheduling of cisplatin varied and was given either on day 1, day 2, day 15 (in two studies), or days 1, 8, and 15 (in two studies). The protocol dose per infusion for gemcitabine was 1,000 mg/m2 (five studies) and 1,500 mg/m2 (one study); for cisplatin, it was 100 mg/m2 when given once per cycle and 30 mg/m2 when given on days 1, 8, and 15. Similar dose reduction schedules were implemented in the event of grade 3 or higher drug toxicity for all studies except for the day 1 cisplatin study, in which the dose was omitted for grade 2 thrombocytopenia. Nonhematologic toxicity was very low. Hematologic toxicity was moderate, and in patients who developed grade 3 or 4 toxicity, there was no hemorrhage from thrombocytopenia and neutropenic sepsis was rare. The incidence of grade 3 or 4 thrombocytopenia with the day 1, day 2, day 15 (two studies combined), and days 1, 8, and 15 (two studies combined) cisplatin regimens was 50%, 52%, 26%, and 38%. The incidence of grade 3 or 4 neutropenia with these four regimens was 51%, 37%, 56%, and 49%, respectively. Although the hematologic toxicity might appear relatively similar, it represents the toxicity at the administered rather than the intended (protocol) dose, because drug delivery was reduced or omitted in the event of grade 3 or 4 toxicity. Differences between the schedules are revealed by analysis of the actual dosages delivered. The median dosage of gemcitabine per scheduled infusion was statistically higher with the day 15 cisplatin regimens (combined) compared with any of the other regimens treating at 1,000 mg/m2 (P < .003, z-score). The dose with the day 1, day 2, day 15, and days 1, 8, and 15 cisplatin regimens was 664, 829, 889, and 774 mg/m2, respectively. Both the percentages of cycles in which gemcitabine infusions were given at full dose and in which there were no omissions of gemcitabine infusions (including infusions with dose reductions) were statistically higher in the day 15 cisplatin regimen than with any of the other regimens (P < .0001, chi-square test). The percentage of cycles containing full-dose gemcitabine with the day 1, day 2, day 15, and days 1, 8, and 15 cisplatin regimens was 24%, 44%, 75%, and 46%, respectively. The percentage of cycles in which there were no omissions of gemcitabine infusions for the four regimens above was 32%, 55%, 83%, and 72%, respectively. Apart from the once-weekly regimen (days 1, 8, and 15) in which the protocol gemcitabine dose was 1,250 mg/m2, the day 15 cisplatin schedule allowed for the highest median concentration of gemcitabine. More importantly, the day 15 cisplatin schedule provided the longest duration of gemcitabine exposure, which is particularly important for its activity as gemcitabine is a phase-specific agent. The day 15 cisplatin schedule is associated with the best dose intensity and the longest median duration of exposure to gemcitabine, and best meets the goal of administering both agents at full doses in combination.

Adult↗