Update. Surveillance of healthcare workers exposed to blood/body fluids and bloodborne pathogens: 1 April, 2000 to 31 March, 2001.
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Blood-Borne Pathogens↗
Biomedical subjects
M Nguyen
Publications and source records attributed to M Nguyen.
Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study.
BACKGROUND: Inhibition of leukocyte adhesion can reduce myocardial infarct size in animals. This study was designed to define the safety and efficacy of a recombinant, humanized, monoclonal antibody to the CD18 subunit of the beta2 integrin adhesion receptors (rhuMAb CD18), in reducing infarct size in patients treated with a thrombolytic agent. METHODS AND RESULTS: The Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction Study (LIMIT AMI) was a randomized, double-blind, placebo-controlled, multicenter study conducted in 60 centers in the United States and Canada. A total of 394 subjects who presented within 12 hours of symptom onset with ECG findings (ST-segment elevation) consistent with AMI were treated with recombinant tissue plasminogen activator and were also given an intravenous bolus of 0.5 or 2.0 mg/kg rhuMAb CD18 or placebo. Coronary angiography was performed at 90 minutes, 12-lead ECGs were obtained at baseline, 90, and 180 minutes, and resting sestamibi scans were performed at >/=120 hours. Adjunctive angioplasty and use of glycoprotein IIb/IIIa antiplatelet agents at the time of angiography were discretionary. There were no treatment effects on coronary blood flow, infarct size, or the rate of ECG ST-segment elevation resolution, despite the expected induction of peripheral leukocytosis. A slight trend toward an increase in bacterial infections was observed with rhuMAb CD18 (P=0.33). CONCLUSIONS: RhuMAb CD18 was well tolerated but not effective in modifying cardiac end points.
Antibodies, Monoclonal↗
Clinical presentation of inhalational anthrax following bioterrorism exposure: report of 2 surviving patients.
The use of anthrax as a weapon of biological terrorism has moved from theory to reality in recent weeks. Following processing of a letter containing anthrax spores that had been mailed to a US senator, 5 cases of inhalational anthrax have occurred among postal workers employed at a major postal facility in Washington, DC. This report details the clinical presentation, diagnostic workup, and initial therapy of 2 of these patients. The clinical course is in some ways different from what has been described as the classic pattern for inhalational anthrax. One patient developed low-grade fever, chills, cough, and malaise 3 days prior to admission, and then progressive dyspnea and cough productive of blood-tinged sputum on the day of admission. The other patient developed progressively worsening headache of 3 days' duration, along with nausea, chills, and night sweats, but no respiratory symptoms, on the day of admission. Both patients had abnormal findings on chest radiographs. Non-contrast-enhanced computed tomography of the chest showing mediastinal adenopathy led to a presumptive diagnosis of inhalational anthrax in both cases. The diagnoses were confirmed by blood cultures and polymerase chain reaction testing. Treatment with antibiotics, including intravenous ciprofloxacin, rifampin, and clindamycin, and supportive therapy appears to have slowed the progression of inhalational anthrax and has resulted to date in survival.
Anthrax↗
Role of taurine in regulation of intracellular calcium level and neuroprotective function in cultured neurons.
Glutamate-induced excitotoxicity has been implicated as an important mechanism underlying a variety of brain injuries and neurodegenerative diseases. Previously we have shown that taurine has protective effects against glutamate-induced neuronal injury in cultured neurons. Here we propose that the primary underlying mechanism of the neuroprotective function of taurine is due to its action in preventing or reducing glutamate-induced elevation of intracellular free calcium, [Ca(2+)](i). This hypothesis is supported by the following findings. First, taurine transport inhibitors, e.g., guanidinoethyl sulfonate and beta-alanine, have no effect on taurine's neuroprotective function, suggesting that taurine protects against glutamate-induced neuronal damage through its action on the extracellular membranes. Second, glutamate-induced elevation of [Ca(2+)](i) is reduced to the basal level upon addition of taurine. Third, pretreatment of cultured neurons with taurine prevents or greatly suppresses the elevation of [Ca(2+)](i) induced by glutamate. Furthermore, taurine was found to inhibit the influx but not the efflux of (45)Ca(2+) in cultured neurons. Taurine has little effect on the binding of [(3)H]glutamate to the agonist binding site and of [(3)H]MDL 105,519 to the glycine binding site of the N-methyl-D-aspartic acid receptors, suggesting that taurine inhibits (45)Ca(2+) influx through other mechanisms, including its inhibitory effect on the reverse mode of the Na(+)/Ca(2+) exchangers (Wu et al. [2000] In: Taurine 4: taurine and excitable tissues. New York: Kluwer Academic/Plenum Publishers. p 35-44) rather than serving as an antagonist to the N-methyl-D-aspartic acid receptors.
Animals↗
Human endomucin is an endothelial marker.
The identification of novel endothelial markers is important in the study of angiogenesis, and may have potential uses in cancer diagnosis and treatment. We have isolated potential markers of tumor angiogenesis by screening human umbilical vein endothelial cells (HUVECs) treated with tumor conditioned media. Using suppression subtractive hybridization (SSH), we found endomucin, a potential cell surface marker upregulated in this system. Human endomucin is predicted to encode a 261-aa, 27.5-kDa protein with a transmembrane sequence and multiple glycosylation sites. Northern and in situ hybridization studies show that human endomucin expression is largely, if not uniquely, endothelial cell-specific. Human endomucin is present abundantly in highly vascular tissues such as heart, kidney, and lung. It is seen in human aortic endothelial cells (HAECs) as well as in human microvascular endothelial cells (HMVECs). Furthermore, its expression is increased when endothelial cells are proliferating or are stimulated by tumor-conditioned media or specific angiogenic factors such as bFGF (basic fibroblast growth factor) and TNFalpha (tumor necrosis factor), suggesting that endomucin may have a role in tumor angiogenesis.
Amino Acid Sequence↗
Encapsulation in biodegradable microparticles enhances serum antibody response to parenterally-delivered beta-amyloid in mice.
Poly(lactide-co-glycolide) (PLG) microspheres were tested as a parenteral delivery system for human beta-amyloid (1-42) (Abeta), a potential immunotherapeutic undergoing assessment in Phase 1 studies for Alzheimer's disease (AD). Abeta was successfully encapsulated in PLG microspheres of average sizes of 3 or 15 microm diameter. Swiss Webster (SW) mice were injected by the sub-cutaneous (s.c.) or intra-peritoneal (i.p.) routes with 3-33 microg Abeta. Abeta-PLG microparticles (3 microm) induced dose-dependent antibody responses, which were maximal at 33 microg Abeta, while Abeta in phosphate-buffered saline (PBS) produced weak antibody responses at the same doses by both routes. Significantly increased antibody responses were seen for both small and large particle formulations given by the i.p. route in comparison to the s.c route. It was previously reported that passive immunisation with Abeta-specific antibodies cleared amyloid plaques in a mouse model of AD (Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med 2000;6:916-19), an indication that induction of serum antibody is a prerequisite for efficacy.
Amyloid beta-Peptides↗
Fiberoptic ductoscopy for breast cancer patients with nipple discharge.
BACKGROUND: Breast cancer and precancer are thought to originate in the lining of the milk duct, but until recently, we have not had direct access to this area other than in tissue removed blindly by core biopsy or fine-needle aspiration. Fiberoptic ductoscopy (FDS) is an emerging technique that allows direct visual access of the ductal system of the breast through nipple orifice cannulation and exploration. To date, this technique has been used only in pilot studies. Previously, we have demonstrated that fiberoptic ductoscopy in patients with and without nipple discharge is a safe and effective means of visualizing the intraductal lesion. When combined with cytology, it is a screening technique that has high predictive value. METHODS: We applied ductoscopy to 415 women with nipple discharge with the specific intent of detecting those patients with nipple discharge who had intraductal carcinoma (DCIS) as the basis of their discharge. RESULTS: In this cohort of patients, ductoscopy was successful in visualizing an intraductal lesion in 166 patients (40%). In these cases, ductal lavage following ductoscopy increased the yield of cytologically interpretable ductal epithelial cells 100-fold compared to discharge fluid alone. In the majority of these patients, FDS examination detected lesions that had the appearance of typical papillomas. However, in 10 patients, the intraductal lesion exhibited one of several atypical features, including bleeding, circumferential obstruction, and gross fungating projections. In eight of these patients, the subsequent histopathology turned out to be DCIS. In two of these eight patients, endoscopic biopsy revealed cytologically malignant cells; in two others, ductal lavage (washings) revealed cytologically malignant cells. In three additional patients, although FDS examination uncovered a typical papilloma that was not biopsied, ductal lavage (washings) revealed cytologically malignant cells. On surgical pathology review of the extirpated lesions, all 11 patients were subsequently shown to have DCIS. Of these 11 cases of DCIS that were initially detected with a combination of FDS and ductal lavage cytology, six were completely negative on mammogram and physical exam. CONCLUSION: Although nipple discharge is an unusual presentation for DCIS, in patients with nipple discharge, FDS with ductal lavage cytology is a useful technique for diagnosing DCIS prior to definitive surgery.
Biopsy, Needle↗
Characterization and quality control of recombinant adenovirus vectors for gene therapy.
Highly purified recombinant adenovirus undergoes routine quality controls for identity, potency and purity prior to its use as a gene therapy vector. Quantitative characterization of infectivity is measurable by the expression of the DNA binding protein, an early adenoviral protein, in an immunofluorescence bioassay on permissive cells as a potency determinant. The specific particle count, a key quality indicator, is the total number of intact particles present compared to the number of infectious units. Electron microscopic analysis using negative staining gives a qualitative biophysical analysis of the particles eluted from anion-exchange HPLC. One purity assessment is accomplished via the documented presence and relative ratios of component adenoviral proteins as well as potential contaminants by reversed-phase HPLC of the intact virus followed by protein peak identification using MALDI-TOF mass spectrometry and subsequent data mining. Verification of the viral genome is performed and expression of the transgene is evaluated in in vitro systems for identity. Production lots are also evaluated for replication-competent adenovirus prior to human use. For adenovirus carrying the human IL-2 transgene, quantitative IL-2 expression is demonstrated by ELISA and cytokine potency by cytotoxic T lymphocyte assay following infection of permissive cells. Both quantitative and qualitative analyses show good batch to batch reproducibility under routine test conditions using validated methods.
Adenoviridae↗
Dynamics of subjective contour formation in the early visual cortex.
To elucidate the roles of visual areas V1 and V2 and their interaction in early perceptual processing, we studied the responses of V1 and V2 neurons to statically displayed Kanizsa figures. We found evidence that V1 neurons respond to illusory contours of the Kanizsa figures. The illusory contour signals in V1 are weaker than in V2, but are significant, particularly in the superficial layers. The population averaged response to illusory contours emerged 100 msec after stimulus onset in the superficial layers of V1, and around 120--190 msec in the deep layers. The illusory contour response in V2 began earlier, occurring at 70 msec in the superficial layers and at 95 msec in the deep layers. The temporal sequence of the events suggests that the computation of illusory contours involves intercortical interaction, and that early perceptual organization is likely to be an interactive process.
Animals↗
Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2.
The transition to pulmonary respiration following birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure and remodeling of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. A role for prostaglandins in regulating the closure of this vessel has been supported by pharmacological and genetic studies. The production of prostaglandins is dependent on two cyclooxygenases (COX-1 and COX-2), which are encoded by separate genes. We report here that the absence of either or both COX isoforms in mice does not result in premature closure of the DA in utero. However, 35% of COX-2(-/-) mice die with a patent DA within 48 h of birth. In contrast, the absence of only the COX-1 isoform does not affect closure of the DA. The mortality (35%) and patent DA incidence due to absence of COX-2 is, however, significantly increased (79%) when one copy of the gene encoding COX-1 is also inactivated. Furthermore, 100% of the mice deficient in both isoforms die with a patent DA within 12 h of birth, indicating that in COX-2-deficient mice, the contribution of COX-1 to DA closure is gene dosage-dependent. Together, these data establish roles for COX-1, and especially for COX-2, in the transition of the cardiopulmonary circulation at birth.
Animals↗
Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial. Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip.
OBJECTIVE: To evaluate the ability of diacerein, an interleukin-1beta inhibitor, to slow the progressive decrease in joint space width observed in patients with hip osteoarthritis (OA). METHODS: In this randomized, double-blind, placebo-controlled 3-year study, 507 patients with primary OA of the hip (by the American College of Rheumatology criteria) received diacerein (50 mg twice a day) or placebo. The minimal hip joint space width was measured by a central reader on yearly pelvic radiographs, using a 0.1-mm-graduated magnifying glass. RESULTS: Baseline characteristics were comparable in the 2 treatment groups (255 patients receiving diacerein, 252 receiving placebo); 238 patients (47%) discontinued the study, mainly because of adverse events in the diacerein group (25% versus 12% with placebo) and because of inefficacy in the placebo group (14% versus 7% with diacerein). The percentage of patients with radiographic progression, defined by a joint space loss of at least 0.5 mm, was significantly lower in patients receiving diacerein than in patients receiving placebo, both in the intent-to-treat analysis and in the completer analysis (50.7% versus 60.4% [P = 0.036] and 47.3% versus 62.3% [P = 0.007], respectively). In those patients who completed 3 years of treatment, the rate of joint space narrowing was significantly lower with diacerein (mean +/- SD 0.18 +/- 0.25 mm/year versus 0.23 +/- 0.23 mm/year with placebo; P = 0.042). Diacerein had no evident effect on the symptoms of OA in this study. However, a post hoc covariate analysis that took into account the use of analgesics and antiinflammatory drugs showed an effect of diacerein on the Lequesne functional index. Diacerein was well tolerated during the 3-year study. The most frequent adverse events were transient changes in bowel habits. CONCLUSION: This study confirms previous clinical findings indicating that the demonstration of a structure-modifying effect in hip OA is feasible, and shows, for the first time, that treatment with diacerein for 3 years has a significant structure-modifying effect as compared with placebo, coupled with a good safety profile. The clinical relevance of these findings requires further investigation.
Anthraquinones↗
Selective matrix metalloproteinase (MMP) inhibition in rheumatoid arthritis--targetting gelatinase A activation.
The matrix metalloproteinases (MMP) are a large group of enzymes responsible for matrix degradation. They contribute to joint destruction in rheumatoid arthritis (RA) by directly degrading the cartilage and bone and indirectly promoting angiogenesis (formation of new blood vessels). Inhibition of MMPs is a primary therapeutic target in RA. However, the results of limited clinical trials performed to date are disappointing. Improvements in therapeutic benefit may be achieved by targetting specific MMPs. A subclass of the MMPs, the gelatinases, contribute directly to joint destruction as well as being vital during angiogenesis. Gelatinase A is released as a latent enzyme and must be activated to degrade the matrix. It has a unique mechanism of activation on the cell surface involving membrane-type MMP (MT-MMP). Recently, the serine protease, activated protein C (APC), has been shown to directly activate gelatinase A, without requiring MT-MMP Inhibition of APC represents a selective approach to prevent gelatinase A activation and may prove to be of therapeutic benefit in RA.
Arthritis, Rheumatoid↗
Analysis of nonpenetrating clips versus sutures for arterial venous graft anastomosis.
The use of nonpenetrating clips (NPC) for vascular anastomosis is quickly becoming accepted. Studies attest to decreased anastomotic time, comparable patency rates, and decreased blood loss. Few human studies on the use of NPC have been done to date. The purpose of this study was to evaluate primary patency rates, operative time, and complications associated with NPC compared to those with standard sutures for arterial venous graft (AVG). We retrospectively reviewed the clinical course of 82 patients with a mean age of 45 years (range, 22 to 87) from February 1996 to July 1999. All patients underwent upper extremity AVG construction. The procedures were performed at a single institution, by a single, well-experienced surgeon who has extensive experience with NPC. Primary patency rates, operative time, and complications were analyzed. Overall thrombotic incidence of AVG when NPC were used (27/48, 56%) was similar to that of sutures (17/34, 50%). Thrombotic incidence within the first year was similar as well (23/48, 48% and 13/34, 38%). The mean time to primary thrombosis was similar in both groups (6.9 and 6.8 months). The operative time required to construct an AVG with NPC (83 min) was significantly less than that with sutures (96 min) (p = 0.015). There was no significant difference in incidence of graft infection or pseudoaneurysm formation. NPC for AVG reduced operative time and resulted in primary patency and complication rates similar to those associated with use of sutures. The mean time to primary thrombosis was similar for both groups. Our findings suggest an intimal hyperplastic response of a similar nature resulting in thrombosis of both NPC and sutured AVGs.
Adult↗
Human endothelial gelatinases and angiogenesis.
Endothelial cell invasion is an essential event during angiogenesis (formation of new blood vessels). The process involves the degradation of the basement membrane and the underlying interstitium. The matrix metalloproteinase (MMP) family is considered to be primarily responsible for matrix degradation. Two members of the family, gelatinase A and B play an important role in angiogenesis. This review outlines recent findings on their regulation in human endothelial cells. Latent gelatinase B is secreted from endothelial cells. This enzyme can also accumulate in the cytosol as an active enzyme, free of TIMP-1. In contrast, latent gelatinase A is constitutively secreted from the cells. Unlike other MMPs, gelatinase A activation occurs on the cell membrane and is mediated by MT1-MMP. A number of physiological activators have recently been described. These include thrombin and activated protein C, both of which activate gelatinase A independent of the MT1-MMP pathway. These new findings may lead to therapeutic interventions for the treatment of angiogenic-dependent diseases such as cancer and arthritis.
Cell Membrane↗
Performance characteristics of the COBAS AmpliScreen HIV-1 test, version 1.5, an assay designed for screening plasma mini-pools.
BACKGROUND: The COBAS AmpliScreen HIV-1 test, version 1.5 (v1.5) (Roche Molecular Systems), is designed for screening pools composed of samples from 24 individual units of blood or plasma. A specimen-processing procedure (Multiprep) simultaneously concentrates and extracts HIV-1, HCV, and HBV particles from plasma and incorporates an HIV-1 internal control (IC) RNA. Processed samples are amplified by RT-PCR using HIV-1-specific primers and detected by hybridization of the amplified products to HIV-1- and IC-specific oligonucleotide probes. STUDY DESIGN AND METHODS: Plasma samples containing known quantities of HIV-1 were used to evaluate analytical sensitivity and precision and to validate a pool testing algorithm. Analytical specificity was evaluated by adding various viruses and bacteria to HIV-1-negative plasma. Seroconversion panels were tested to estimate the window-period reduction achieved by RNA testing. RESULTS: The analytical sensitivity of the test (concentration that yields > or = 95% positive results in a set of replicate tests) was 25 copies of HIV-1 RNA per mL of pooled plasma. Representative strains from all HIV-1 group M subtypes were reproducibly detected (> 95% positive results) at concentrations of 20 to 200 viral particles per mL. The test did not cross-react with a set of 31 viral and 5 bacterial isolates, and it yielded negative results on a panel of 500 blood samples from HIV-1-seronegative donors. Plasma samples containing abnormally high levels of Hb, albumin, triglycerides, or bilirubin did not interfere with the test. HIV-1 RNA was detected 2 to 14 days before HIV-1 antibody and 0 to 28 days before p24 antigen. The test specifically detected pools containing a single positive unit with 2400 HIV-1 RNA copies per mL and correctly identified the positive unit. CONCLUSION: The COBAS AmpliScreen HIV-1 test, v1.5, has sufficient sensitivity to detect a single infected unit containing 600 copies of HIV-1 per mL in a pool with 23 uninfected units and should reduce the window period between infection and seroconversion by at least 2 to 14 days.
Acquired Immunodeficiency Syndrome↗
Ingested IFN-alpha preserves residual beta cell function in type 1 diabetes.
Type 1 diabetes mellitus is a chronic disorder that presumably results from an autoimmune destruction of the insulin-producing pancreatic beta cells. The therapeutic potential of interventions aimed at preventing type 1 diabetes can be assessed in newly diagnosed patients. Because there is a historical experience of a low incidence of spontaneous remission in type 1 diabetes mellitus, interventions preserving beta cell function have been used to identify positive therapeutic outcomes. We treated 10 newly diagnosed type 1 diabetes patients with 30,000 IU ingested interferon-alpha (IFN-alpha) within 1 month of diagnosis and examined the difference between baseline and Sustacal-induced (Mead Johnson Nutritionals, Evansville, IN) C-peptide responses, respectively, at 0, 3, 6, 9, and 12 months. Eight of the ten patients showed preserved beta cell function, with at least a 30% increase in stimulated C-peptide levels at 0, 3, 6, 9, and 12 months after initiation of treatment. There was no discernible chemical or clinical toxicity associated with ingested IFN-alpha. Our results support the potential of ingested IFN-alpha to preserve residual beta cell function in recent onset type 1 diabetes mellitus and the testing of IFN-alpha in a placebo-controlled trial.
Administration, Oral↗
The interferon-inducible Stat2:Stat1 heterodimer preferentially binds in vitro to a consensus element found in the promoters of a subset of interferon-stimulated genes.
Regulated expression of type I interferon (IFN)-stimulated genes (ISG) requires the binding of the signal transducer and activator of transcription (Stat) complexes to enhancer elements located in the ISG promoters. These enhancer elements include the IFN-stimulated response element (ISRE) and the palindromic IFN-gamma activation site (GAS) element. Regulated expression of ISRE containing ISG depends on IFN-stimulated gene factor 3 (ISGF3), a heterodimer involving Stat1 and Stat2 in association with a DNA-binding adapter protein, p48/IFN regulatory factor-9 (IRF-9). Several GAS binding Stat complexes involving Stat1, Stat3, Stat4, and Stat5 have been described, but their contribution to GAS-dependent ISG expression remains to be established. We and others previously identified an IFN-alpha-inducible Stat2:1 heterodimer that exhibits binding to the GAS element of the IRF-1 gene. These previous studies raise the possibility that Stat2:1 may participate in the transcriptional activation of the subset of ISG containing GAS elements. To address this question, we performed a PCR-assisted binding site selection procedure to define the Stat2:1 recognition sequence. The data reveal that Stat2:1 preferentially binds to a palindromic sequence similar to the consensus GAS element found in the promoter of several ISG. Our results establish that in addition to the classic complex formation involving Stat2, Stat1, and p48 associations, Stat2:1 heterodimers are formed in response to IFN treatment that may play an important role in the transcriptional regulation of certain ISG.
Base Sequence↗
Olanzapine and hypertriglyceridemia.
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Adolescent↗