Bronchiectasis: current clinical and imaging concepts.
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Bronchiectasis↗
Biomedical subjects
B Nguyen
Publications and source records attributed to B Nguyen.
Bismuth-based quadruple therapy with bismuth subcitrate, metronidazole, tetracycline and omeprazole in the eradication of Helicobacter pylori.
BACKGROUND: A previous study showed that 14 days of qid bismuth-based triple therapy with tetracycline 500 mg, metronidazole 250 mg and colloidal bismuth subcitrate 120 mg resulted in excellent Helicobacter pylori eradication rates (89.5%). The present study looked at a shorter treatment period by adding omeprazole and by reducing the dose of tetracycline. METHODS: One hundred sixty-one patients with H pylori confirmed by histology and (13)carbon urea breath test were included in the study. They were treated for seven days with bismuth subcitrate 120 mg plus metronidazole 250 mg plus tetracycline 250 mg qid plus omeprazole 20 mg bid (OBMT). Patients were 18 to 75 years of age and had dyspepsia with or without a history of peptic ulcer. Patients with irritable bowel syndrome, active ulcer or previous attempt at eradication, or those who had used antibiotics or antiulcer drugs in the previous 30 days were excluded. Eradication was determined by two (13)carbon urea breath tests done one and three months, respectively, after treatment. Strains with minimal inhibitory concentrations of 8 microg/mL or higher were considered to be resistant to metronidazole. RESULTS: The overall per protocol eradication rate was 84%-89.5% in metronidazole-sensitive and 70.8% in metronidazole-resistant strains. Modified intent-to-treat analysis resulted in a 80% eradication rate--82.5% in metronidazole-sensitive and 66.7% in metronidazole-resistant strains. Only one patient discontinued treatment because of adverse events. CONCLUSIONS: The OBMT regimen used in this study is safe and effective against metronidazole-sensitive H pylori strains.
Adolescent↗
Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead.
The interaction between leukocyte function-associated antigen-1 (LFA-1), a member of the beta(2)-integrin family of adhesion molecules, and intracellular adhesion molecule ICAM-1 (cd54) is thought to play a critical role in the inflammatory process. On the basis of an anilino diaryl sulfide screening lead 1, in combination with pharmacophore analysis of other screening hits, we have identified an adjacent binding pocket. Subsequently, a p-ethenylcarbonyl linker was discovered to be optimal for accessing this binding site. Solution-phase parallel synthesis enabled rapid optimization of the cinnamides for this pocket. In conjunction with fine-tuning of the diaryl substituents, we discovered a novel series of potent, nonpeptide inhibitors of LFA-1/ICAM-1 interaction, exemplified by A-286982 (28h), which has IC(50) values of 44 and 35 nM in an LFA-1/ICAM-1 binding assay and LFA-1-mediated cellular adhesion assay, respectively.
Animals↗
A phase II study of gemcitabine plus oral etoposide in the treatment of patients with advanced nonsmall cell lung carcinoma.
BACKGROUND: The authors have designed a non-cisplatin-based chemotherapy regimen for the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC). This regimen capitalizes on the mild toxicity of gemcitabine, a novel nucleoside analog. METHODS: A total of 46 chemotherapy-naive patients with histologically confirmed Stage IIIB or IV NSCLC were enrolled. Eligible patients were treated with gemcitabine 1000 mg/m(2) on Days 1, 8, and 15, plus oral etoposide 50 mg daily for 14 days, which was increased to 21 days if there was no World Health Organization (WHO) Grade 3 or 4 toxicity in the 1st 2 cycles (each cycle was 28 days long). All patients were included for analysis of response and survival according to an intention-to-treat principle. RESULTS: The overall response rate was 43.5% (95% confidence interval [CI], 30. 7-60.2%). There was 1 complete response (2.2%) and 19 partial responses (41.3%). The median survival was 48.0 weeks (95% CI, 38. 1-75.9 weeks) and the 1-year survival rate was 45% (95% CI, 29-62%). The median time to progression for all patients was 39.2 weeks (95% CI, 35.7-49.7 weeks). World Health Organization (WHO) Grade 3 and 4 anemia, neutropenia, and thrombocytopenia was reported in 29%, 32%, and 18% of patients, respectively. Two patients had reactivation of hepatitis B viral infection that resulted in WHO Grade 4 hepatic dysfunction. Other nonhematologic toxicities were uncommon. CONCLUSIONS: This non-cisplatin-based regimen of gemcitabine and oral etoposide achieved a high response and survival rate. Toxicity appeared to be less severe than that associated with existing cisplatin-based regimens. A randomized study of this regimen versus a cisplatin-based regimen is indicated.
Adult↗
[Meningeal metastases of ovarian cancer. Contribution of imaging].
BACKGROUND: Secondary meningeal localizations are uncommon and may disclose reactivation of a malignant disease. Most meningeal metastases occur in breast cancer, exceptionally in primary ovarian cancer. CASE REPORT: We report 2 cases of secondary meningeal localizations of ovarian cancer. The diagnosis was clinical, supported by cerebrospinal fluid analysis and computed tomography and magnetic resonance imaging. DISCUSSION: Establishing the diagnosis of carcinomatous meningitis may be difficult. Clinical signs and biological data are not always conclusive. If spinal tap is contraindicated or negative, imaging, particularly magnetic resonance imaging is highly contributive in establishing the diagnosis of secondary localization. A precise evaluation of the invaded tissues is quite helpful in guiding therapeutic management based on chemotherapy, tumor resection or radiotherapy.
Adult↗
The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation.
The checkpoint kinase Chk1 is an important mediator of cell cycle arrest following DNA damage. The 1.7 A resolution crystal structures of the human Chk1 kinase domain and its binary complex with an ATP analog has revealed an identical open kinase conformation. The secondary structure and side chain interactions stabilize the activation loop of Chk1 and enable kinase activity without phosphorylation of the catalytic domain. Molecular modeling of the interaction of a Cdc25C peptide with Chk1 has uncovered several conserved residues that are important for substrate selectivity. In addition, we found that the less conserved C-terminal region negatively impacts Chk1 kinase activity.
Catalytic Domain↗
Animal models of posthypoxic myoclonus: I. Development and validation.
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Animals↗
Pulmonary and mediastinal glomus tumors--report of five cases including a pulmonary glomangiosarcoma: a clinicopathologic study with literature review.
Pulmonary and mediastinal glomus tumors are rare lesions, with four previously reported primary pulmonary cases and three mediastinal cases. The authors report one mediastinal glomus tumor, a locally infiltrative type, and four pulmonary glomus tumors, including the first case of primary pulmonary glomangiosarcoma. These tumors show a variety of clinical and pathologic differences from the more common cutaneous variety, including later age at presentation, larger size, and more frequent atypical/malignant features. Mediastinal and pulmonary glomus tumors both have an average patient age at presentation of 45 years. However, compared with their pulmonary counterparts, mediastinal glomus tumors are less common, more often symptomatic, and are larger (average size, 5.4 cm). Additionally, mediastinal glomus tumors more often demonstrate malignant or atypical features. Pulmonary glomus tumors average 3.3 cm in greatest dimension, with the majority measuring less than 2.5 cm. The pulmonary glomangiosarcoma presented was large, measuring 9.5 cm, and showed increased mitotic count (9 mitoses/10 high-power fields), necrosis, cytologic atypia, and was associated with disseminated disease. Regardless of clinical symptoms, histologic features, and even metastases, the vast majority of all benign and malignant glomus tumors are indolent and cured surgically, with adjuvant therapy needed only for occasional patients with more advanced disease. The four patients with glomus tumors reported are currently alive and free of disease as of last follow up. The patient with the glomangiosarcoma developed widespread metastases and died of disease 68 weeks after initial therapy.
Adult↗
Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer.
PURPOSE: The Hoosier Oncology Group has previously reported the results of its phase II trial of the combination of cisplatin plus gemcitabine. In that study of 27 assessable patients with advanced or metastatic non-small-cell lung cancer (NSCLC), the response rate was 33%, with a median survival of 8.4 months. Based on such favorable results, the Hoosier Oncology Group designed this randomized phase III study of gemcitabine plus cisplatin compared with cisplatin alone in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients were randomized to receive either cisplatin (100 mg/m(2) intravenously on day 1 of a 28-day cycle) or the combination of cisplatin (100 mg/m(2) intravenously on day 1) plus gemcitabine (1,000 mg/m(2) administered intravenously on days 1, 8, and 15 of a 28-day cycle). RESULTS: From August 1995 to February 1997, 522 assessable chemotherapy-naive patients were randomized. Toxicity was predominantly hematologic and was more pronounced in the combination arm, with grade 4 neutropenia occurring in 35.3% of patients compared with 1.2% of patients on the cisplatin monotherapy arm. The incidence of neutropenic fevers was less than 5% in both arms. Grade 4 thrombocytopenia occurred in 25. 4% of patients on the combination arm compared with 0.8% of patients on the cisplatin monotherapy arm. No serious hemorrhagic events related to thrombocytopenia were reported for either arm. The combination of gemcitabine plus cisplatin demonstrated a significant improvement over single-agent cisplatin with regard to response rate (30.4% compared with 11.1%, respectively; P <.0001), median time to progressive disease (5.6 months compared with 3.7 months, respectively; P =.0013), and overall survival (9.1 months compared with 7.6 months, respectively; P =.004). CONCLUSIONS: For the first-line treatment of NSCLC, the regimen of gemcitabine plus cisplatin is superior to cisplatin alone in terms of response rate, time to disease progression, and overall survival.
Adult↗
Distribution of thrombi in acute lower extremity deep venous thrombosis: implications for sonography and CT and MR venography.
OBJECTIVE: Our objective was to determine the typical distribution of thrombi in acute lower extremity deep venous thrombosis as a means of evaluating the validity of imaging techniques that only include the common femoral and popliteal veins, but not the superficial femoral vein. MATERIALS AND METHODS: The results of 2704 lower extremity venous sonograms, obtained in 2026 consecutive patients over a 4-year interval, were reviewed retrospectively. The distribution of acute deep venous thromboses across various lower extremity venous segments was analyzed for this population, which consisted of both symptomatic and asymptomatic patients. RESULTS: Of 2704 lower extremities studied with duplex sonography, acute deep venous thrombosis was identified in 269 (9.9%). Of these 269 cases, acute deep venous thrombosis was isolated to the superficial femoral vein in 60 (22.3%). The remaining 209 cases (77.7%) showed thrombus that extended into the common femoral or popliteal veins (or both). CONCLUSION: An abbreviated imaging study that evaluates only the common femoral and popliteal veins would fail to identify more than 20% of lower extremity acute deep venous thromboses in a population like ours. Although evaluation of the superficial femoral vein requires additional time and resources, evaluation of this segment may prevent a substantial number of thrombi from being missed.
Acute Disease↗
Pains, strains, and fasciculations: lower extremity muscle disorders.
Muscle injuries that were suspected only on the basis of clinical examination are now readily demonstrated and characterized using MR imaging. Imaging is used not only for assessment of location, type, and severity of muscle injuries; it plays an important role in treatment planning, and the detection of complications. MR imaging also is useful in nontraumatic muscle disorders including congenital, inflammatory, and infectious myositis, and in cases of denervation, MR imaging is valuable for diagnosis, staging, and prognostication. In cases where the origin of myopathy is unknown, MR imaging can direct biopsy to increase diagnostic yield.
Compartment Syndromes↗
Pyrrolidine-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ET(B) selectivity.
When the dialkylacetamide side chain of the ET(A)-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ET(B) over ET(A). By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ET(B) and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ET(B) receptor in modulating blood pressure; the observed hypertensive response to persistent ET(B) blockade is consistent with previous postulates and indicates that ET(B)-selective antagonists may not be suitable as agents for long-term systemic therapy.
Acetanilides↗
Design, synthesis, and activity of a series of pyrrolidine-3-carboxylic acid-based, highly specific, orally active ET(B) antagonists containing a diphenylmethylamine acetamide side chain.
The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstriction. On the basis of the pharmacophore of the previously reported ET(A)-specific antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ET(B) receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of the phenyl rings could further increase ET(B) affinity and also boost the ET(A)/ET(B) activity ratio of the resulting antagonists. A similar antagonism selectivity profile could also be achieved when one of the phenyl rings of the acetamide side chain was replaced with an alkyl group, preferably a tert-butyl group (10h). Combining these features with modification of the 2-aryl group of the pyrrolidine core, we have identified a potent antagonist (9k, A-308165) with over 27 000-fold selectivity favoring the ET(B) receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.
Acetamides↗
Sensory feedback can coordinate the swimming activity of the leech.
Previous studies showed that sensory feedback from the body wall is important and sometimes critical for generating normal, robust swimming activity in leeches. In this paper, we evaluate the role of sensory feedback in intersegmental coordination using both behavioral and physiological measurements. We severed the ventral nerve cord of leeches in midbody and then made video and in situ extracellular recordings from swimming animals. Our electrophysiological recordings unequivocally demonstrate that active intersegmental coordination occurs in leeches with severed nerve cords, refuting earlier conclusions that sensory feedback cannot coordinate swimming activity. Intersegmental coordination can in fact be achieved by sensory feedback alone, without the intersegmental interactions conveyed by the nerve cord.
Animals↗
A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy.
BACKGROUND: Hemolytic uremic syndrome (HUS) is a rare condition that occasionally is reported in cancer patients. Recently it has been observed that gemcitabine rarely may be associated with this condition. METHODS: The manufacturer's safety database and literature were reviewed for any report regarding gemcitabine associated with renal and hematologic abnormalities. Descriptive analysis was used to examine each case for an association between gemcitabine therapy and HUS and to identify its incidence and risk factors. RESULTS: Through December 31, 1997, 12 cases were identified that fit either the clinical (uremia, microangiopathic hemolytic anemia, and thrombocytopenia) or pathologic (renal biopsy) criteria for HUS. There were 7 males (58%) and 5 females (42%) with a median age of 55.5 years (range, 37-73 years). The median duration of gemcitabine therapy was 5.8 months (range, 3.8-13.1 months). Six patients died, five improved, and one patient's outcome was unknown. Among the six deaths, three patients died of cancer progression, one patient died of an unrelated myocardial infarction, and two patients died of HUS or HUS-related complications. For the five patients who improved, treatment was comprised of dialysis, plasmapheresis, splenectomy, or a combination. Attempts to correlate patient demographics, primary malignancy, and cumulative gemcitabine dose failed to identify consistent risk factors in predisposing patients to HUS. Confounding factors were common, including mitomycin-C and/or 5-fluorouracil exposure, advanced stage tumors, or preexisting renal dysfunction. CONCLUSIONS: Based on a patient exposure of 78,800, a crude overall incidence rate of 0.015% (range, 0.008-0.078%) was determined, showing that HUS associated with gemcitabine treatment appears to be rare. Nonetheless, as with other cancer treatments, clinicians should weigh the appropriate risk/benefit ratio in using gemcitabine to treat their patients.
Adult↗
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↗
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↗
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↗