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Biomedical subjects

D Day

Publications and source records attributed to D Day.

At least 19 recordsLinked to original sources
PubMed2003

Hypoxia-mediated tumour targeting.

Hypoxia is a common physiological feature of tumours. It activates a signalling cascade that culminates in the stabilization of the HIF-1 transcription factor and activation of genes that possess a hypoxia response element (HRE). We have used an optimized hypoxia responsive promoter (OBHRE) to investigate hypoxia-targeted gene expression in vivo in the context of an adenovirus vector. The OBHRE promoter showed limited activity in the liver or spleen such that expression was 1000-fold lower than that driven by the strong CMV/IE promoter. However, in the context of the tumour microenvironment, the OBHRE promoter achieved expression levels comparable to that of the CMV/IE promoter. Next, we showed that an adenovirus expressing the human cytochrome P450 (CYP2B6) regulated by the OBHRE promoter delays tumour growth in response to the prodrug cyclophosphamide (CPA). Finally, we exploited the hepatotropism of adenovirus to investigate whether the OBHRE promoter could mitigate the hepatotoxicity of a recombinant adenovirus expressing thymidine kinase (TK) in the context of the prodrug ganciclovir (GCV). High-dose Ad.CMVTK/GCV treatment caused significant liver necrosis whereas the same dose of Ad.HRETK was well tolerated. These in vivo data demonstrate that hypoxia-targeted gene expression via the OBHRE promoter can be used to increase the therapeutic window of cytotoxic cancer gene therapy.

Adenoviridae↗
PubMed2001

Resolution of Michaelis complex, acylation, and conformational change steps in the reactions of the serpin, plasminogen activator inhibitor-1, with tissue plasminogen activator and trypsin.

Michaelis complex, acylation, and conformational change steps were resolved in the reactions of the serpin, plasminogen activator inhibitor-1 (PAI-1), with tissue plasminogen activator (tPA) and trypsin by comparing the reactions of active and Ser 195-inactivated enzymes with site-specific fluorescent-labeled PAI-1 derivatives that report these events. Anhydrotrypsin or S195A tPA-induced fluorescence changes in P1'-Cys and P9-Cys PAI-1 variants labeled with the fluorophore, NBD, indicative of a substrate-like interaction of the serpin reactive loop with the proteinase active-site, with the P1' label but not the P9 label perturbing the interactions by 10-60-fold. Rapid kinetic analyses of the labeled PAI-1-inactive enzyme interactions were consistent with a single-step reversible binding process involving no conformational change. Blocking of PAI-1 reactive loop-beta-sheet A interactions through mutation of the P14 Thr --> Arg or annealing a reactive center loop peptide into sheet A did not weaken the binding of the inactive enzymes, suggesting that loop-sheet interactions were unlikely to be induced by the binding. Only active trypsin and tPA induced the characteristic fluorescence changes in the labeled PAI-1 variants previously shown to report acylation and reactive loop-sheet A interactions during the PAI-1-proteinase reaction. Rapid kinetic analyses showed saturation of the reaction rate constant and, in the case of the P1'-labeled PAI-1 reaction, biphasic changes in fluorescence indicative of an intermediate resembling the noncovalent complex on the path to the covalent complex. Indistinguishable K(M) and k(lim) values of approximately 20 microM and 80-90 s(-1) for reaction of the two labeled PAI-1s with trypsin suggested that a diffusion-limited association of PAI-1 and trypsin and rate-limiting acylation step, insensitive to the effects of labeling, controlled covalent complex formation. By contrast, differing values of K(M) of 1.7 and 0.1 microM and of k(lim) of 17 and 2.6 s(-1) for tPA reactions with P1' and P9-labeled PAI-1s, respectively, suggested that tPA-PAI-1 exosite interactions, sensitive to the effects of labeling, promoted a rapid association of PAI-1 and tPA and reversible formation of an acyl-enzyme complex but impeded a rate-limiting burial of the reactive loop leading to trapping of the acyl-enzyme complex. Together, the results suggest a kinetic pathway for formation of the covalent complex between PAI-1 and proteinases involving the initial formation of a Michaelis-type noncovalent complex without significant conformational change, followed by reversible acylation and irreversible reactive loop conformational change steps that trap the proteinase in a covalent complex.

Acylation↗
PubMed2001

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Acetamides↗
PubMed2001

The ep -->e'p eta reaction at and above the S11(1535) baryon resonance.

New cross sections for the reaction e p-->e p eta are reported for total center of mass energy W = 1.5--1.86 GeV and invariant momentum transfer Q2 = 0.25--1.5 (GeV/c)(2). This large kinematic range allows extraction of important new information about response functions, photocouplings, and eta N coupling strengths of baryon resonances. Newly observed structure at W approximately 1.65 GeV is shown to come from interference between S and P waves and can be interpreted with known resonances. Improved values are derived for the photon coupling amplitude for the S11(1535) resonance.

Journal Article↗
PubMed2001

Elution characteristics of tobramycin from polycaprolactone in a rabbit model.

This study investigated the elution characteristics of tobramycin from polycaprolactone, a bioabsorbable polymer, in a rabbit model. Sixty rabbits were divided into two groups. Group 1 had polycaprolactone rods impregnated with 6% tobramycin surgically implanted into the proximal femoral intramedullary canal. Group 2 received polymethylmethacrylate rods of like size, shape, and antibiotic concentration. Serum and urine samples were obtained, and tobramycin levels were determined via fluorescent immunosorbent assay. Rabbits were sacrificed as long as 56 days after surgery. Local bone tobramycin concentration was determined using the agar diffusion method. Polycaprolactone delivered a significantly higher peak bone concentration of tobramycin (22.4 microg/mL) than did polymethylmethacrylate (13.59 microg/mL). Polycaprolactone also had a more gradual decrease in local tobramycin concentration than did polymethylmethacrylate. Neither polycaprolactone nor polymethylmethacrylate yielded consistently detectable (> 0.1 microg/mL) serum tobramycin levels. Urine concentrations mirrored those seen in bone, with polycaprolactone achieving significantly higher tobramycin concentrations than did polymethylmethacrylate. Polycaprolactone had superior elution characteristics compared with polymethylmethacrylate in this lapine model, suggesting that polycaprolactone might be a promising local antibiotic delivery vehicle for the treatment of osteomyelitis.

Animals↗
PubMed2001

In vitro elution of tobramycin from bioabsorbable polycaprolactone beads.

OBJECTIVES: To compare the in vitro elution characteristics of tobramycin impregnated beads made of polycaprolactone (PCL) and polymethylmethacrylate (PMMA). DESIGN: Six-millimeter PCL and PMMA beads with 6% tobramycin were formed and placed in phosphate-buffered saline or newborn calf serum and incubated at room temperature or 37 degrees C. Aliquots were taken at intervals for eight weeks. Tobramycin levels were determined by fluorescent assay and antibacterial efficacy was assessed by measuring the zones of inhibition against Staphylococcus aureus and Pseudomonas aeruginosa on agar diffusion plates. RESULTS: Tobramycin elution rates at room temperature were similar up to three weeks. At three weeks, elution rates from PCL beads were twice those from PMMA beads, and at eight weeks, elution from PCL was quadruple that from PMMA. At 37 degrees C, tobramycin elution rates from PCL were eight times greater than those from PMMA by eight weeks. Total tobramycin eluted from PCL beads was 38.9% and 20% in PMMA beads. All samples showed bacteriostatic activity against S. aureus and P. aeruginosa at eight weeks. CONCLUSIONS: These in vitro results show that PCL has superior antibiotic elution characteristics compared with PMMA, and this may translate into a more effective antibiotic delivery vehicle. In addition, PCL is a bioabsorbable polymer, which may decrease the need for a second surgical procedure to remove retained beads.

Analysis of Variance↗
PubMed2001

Three-dimensional coherent transfer function for reflection confocal microscopy in the presence of refractive-index mismatch.

The three-dimensional (3-D) coherent transfer function for reflection confocal microscopy of high-numerical-aperture objectives is derived and calculated in the presence of refractive-index mismatch when a laser beam is focused into a medium of refractive index different from its immersion medium. This aberrated coherent transfer function is then used to estimate the readout efficiency of 3-D data bits recorded in a thick medium. It is shown that the readout efficiency of confocal microscopy for 3-D bit data storage is decreased with the focal depth of an objective in a recording medium. However, a high readout efficiency can be maintained if the tube length of a reading objective is linearly altered to compensate for the spherical aberration caused by the refractive-index mismatch.

Microscopy, Confocal↗
PubMed2000

Defective hMSH2/hMLH1 protein expression is seen infrequently in ulcerative colitis associated colorectal cancers.

BACKGROUND: Ulcerative colitis is associated with an increased risk of colorectal cancer above that of the normal population. The relative risk correlates with the extent and duration of the disease but the genetic basis of ulcerative colitis associated cancer risk is not known. AIMS: To assess the prevalence of microsatellite instability and mismatch repair gene abnormalities in ulcerative colitis associated colorectal cancer. PATIENTS: Forty six patients with colorectal cancer, with a previous histological diagnosis of ulcerative colitis. METHODS: The frequency of microsatellite instability and/or immunohistochemical expression of hMSH2 and hMLH1 was assessed. Thirty three cases were investigated using both approaches. RESULTS: Although 6/41 (14.6%) cases showed microsatellite instability at one or more markers, only one case (2. 4%) exhibited high level instability (at least two markers affected). Of 38 cases which were assessed using antibodies against hMSH2 and hMLH1, only one case (2.6%) showed loss of expression. This case, which showed loss of hMSH2 expression, was the same case which exhibited high level microsatellite instability. The 33 cases which were investigated using both approaches showed that loss of expression of either hMSH2 or hMLH1 was not seen in any case which exhibited microsatellite instability in no more than one marker. CONCLUSIONS: This study suggests that both high level microsatellite instability and loss of expression of hMSH2/hMLH1 are infrequent events in ulcerative colitis associated colorectal cancers. Low level microsatellite instability was not associated with loss of expression of either hMSH2 or hMLH1.

Biomarkers↗
PubMed1999

Metal and sediment ingestion by dabbling ducks.

The chemical analysis of intestinal digesta from hunter-killed carcasses or of wildlife scat is a promising means of estimating the exposure of wildlife to those environmental contaminants that, like lead, are poorly absorbed in the digestive tract. When evaluating contaminants at a site, biologists may find the results of this non-destructive approach more straightforward to interpret in terms of exposure to wildlife than would be analyses of soils, sediments, water, or wildlife tissues. To illustrate the approach, we collected digesta from 47 waterfowl shot by hunters at Prime Hook National Wildlife Refuge, in Delaware, USA. The waterfowl digesta contained an average of approximately 2.4% sediment, estimated from the Al concentrations in the digesta, a marker for sediment. Al concentrations were significantly correlated with concentrations of Cr (Spearman's rank correlation coefficient, r = 0.57), V (r = 0.70), Ni (r = 0.31), and Pb (r = 0.55), and we concluded that these metals were ingested mainly with sediment. American widgeon (Anas americana) ingested sediment at a rate of about four times that of three other species of dabbling ducks (Anas crecca, A. acuta, A. rubripes) and had several times the exposure to the sediment-associated metals. The digesta of one American black duck contained a high concentration of lead (70 mg/kg, dry wt.), presumably from lead shot, but none of the other samples had notably elevated metal concentrations. We suggest that scat and digesta be analyzed more widely by biologists and resource managers seeking a simple, inexpensive assessment of contaminants in local wildlife habitat.

Aluminum↗
PubMed1999

Accelerated conversion of human plasminogen activator inhibitor-1 to its latent form by antibody binding.

The serpin plasminogen activator inhibitor-1 (PAI-1) slowly converts to an inactive latent form by inserting a major part of its reactive center loop (RCL) into its beta-sheet A. A murine monoclonal antibody (MA-33B8), raised against the human plasminogen activator (tPA).PAI-1 complex, rapidly inactivates PAI-1. Results presented here indicate that MA-33B8 induces acceleration of the active-to-latent conversion. The antibody-induced inactivation of PAI-1 labeled with the fluorescent probe N, N'-dimethyl-N-(acetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) ethylene diamine (NBD) at P9 in the RCL caused a fluorescence enhancement and shift identical to those accompanying the spontaneous conversion of the P9.NBD PAI-1 to the latent form. Like latent PAI-1, antibody-inactivated PAI-1 was protected from cleavage by elastase. The rate constants for MA-33B8 binding, measured by NBD fluorescence or inactivation, were similar (1.3-1.8 x 10(4) M-1 s-1), resulting in a 4000-fold faster inactivation at 4.2 microM antibody binding sites. The apparent antibody binding rate constant, at least 1000 times slower than one limited by diffusion, indicates that exposure of its epitope depends on an unfavorable equilibrium of PAI-1. Our observations are consistent with this idea and suggest that the equilibrium involves partial insertion of the RCL into sheet A: latent, RCL-cleaved, and tPA-complexed PAI-1, which are inactive loop-inserted forms, bound much faster than active PAI-1 to MA-33B8, whereas two loop-extracted forms of PAI-1, modified to prevent loop insertion, did not bind or bound much more weakly to the antibody.

Antibodies, Monoclonal↗
PubMed1999

Acute toxicity and sublethal effects of white phosphorus in mute swans, Cygnus olor.

Among the waterfowl affected by white phosphorus (P4) at a military base in Alaska are tundra (Cygnus columbianus) and trumpeter (C. buccinator) swans. To estimate the toxicity of P4 to swans and compare the toxic effects to those of mallards (Anas platyrhynchos), we dosed 30 juvenile mute swans (C. olor) with 0 to 5.28 mg P4/kg body weight. The calculated LD50 was 3.65 mg/kg (95% CI: 1.40 to 4. 68 mg/kg). However, many of the swans still had P4 in their gizzards after dying, as determined by "smoking gizzards" and characteristic odor, and a lower LD50 might be calculated if all of the P4 had passed into the small intestines. We attribute the retention of P4 in swans to the possibility that P4 pellets were mistaken for the similarly sized grit in their gizzards. Most swans took 1 to 4.5 days to die in contrast to the few hours normally required in mallards and death appeared to be related more to liver dysfunction than to hemolysis. White phosphorus affected several plasma constituents, most notably elevated aspartate aminotransferase, blood urea nitrogen, lactate dehydrogenase, and alanine aminotransferase.

Analysis of Variance↗
PubMed1999

Computer-assisted evaluation of antibiotic regimen coverage and cost.

Evaluation of the cost-effectiveness of antibiotic regimens has become an essential part of drug selection for pharmacists and physicians. However, these evaluations can be complicated, time-consuming, and, if the data used are not based on local conditions, misleading. The computer program Dare to Compare 98 was developed to provide an analysis of empiric antibiotic regimens. The Infectious Disease Challenge portion of the program lists the commonly identified pathogens in specific infectious diseases. The Antibiogram Susceptibility Reports section generates susceptibility reports based on local antibiogram data or data from institutions nationwide that have similar demographic profiles. Susceptibility information is combined with cost data in the Quality/Cost Index section. Comparison of the quality and cost index values allows the user to determine which regimens provide the optimal microbiologic activity and cost values for treatment of a particular infectious disease based on local data. Thus Dare to Compare 98 can help pharmacists and physicians evaluate antibiotic regimens and their suitability for inclusion in formularies and disease-management algorithms.

Anti-Bacterial Agents↗
PubMed1998

Therapy cost 2000: an electronic tool for evaluating the cost-effectiveness of therapeutic regimens.

Providing quality care to patients at the lowest cost is of primary concern to hospitals, clinics, managed care organizations, integrated health systems, and other health care providers operating in a prospective payment environment. Therapy Cost 2000 can help health care providers and decision-makers in a variety of settings reach the goal of cost-effective, high-quality patient care.

Cost-Benefit Analysis↗
PubMed1997

Auto-faxing imaging reports to referring physicians.

One of the major service issues within Medical Imaging is delivering reports quickly to referring physicians. As an effort to improve service, Mount Sinai Hospital's Department of Medical Imaging implemented Auto-Fax to distribute imaging reports to physicians instead of the postal service. When a report is transcribed and then verified by the dictating radiologist, the radiology information system will automatically fax the result report to the referring physicians if subscribed to the Auto-Fax service. If not, the report will be printed and mailed out manually. A transmission log is kept recording the requisition number, time, date, fax number, number of pages, and transmission status of all reports faxed. The system will try three times to fax the report. If unsuccessful at all attempts, the report will be printed and sent out by mail. Referring physicians are required to sign an agreement that the receiving parties are responsible to ensure transmitted reports are kept confidential. Over 150 referring physicians have signed on for the service. Initial problems with missing cover pages, missing report pages, and reports not being received by physicians have been resolved. A recent survey of physicians receiving reports by Auto-Fax indicate that the service is very popular and has increased the speed with which transcribed report are received. Suggestions for improvement included faxing reports in batches, at specific times of the day, and directly to personal computers. Challenges reported included photocopying thermal paper faxes and sorting reports (for those offices with shared fax machines).

Diagnostic Imaging↗
PubMed1997

High-risk obstetric patients. Maternal morbidity after cesareans.

OBJECTIVE: To assess maternal morbidity associated with cesarean delivery among high-risk obstetric patients in a private practice setting. STUDY DESIGN: Maternal outcome parameters were prospectively studied in 1,000 consecutively delivered patients over a one-year period. RESULTS: Three hundred forty-one patients (34%) delivered by cesarean; 194 of the procedures were performed without labor. The incidence of febrile morbidity and wound infection in patients undergoing cesarean delivery without labor, 0.5%, was no greater than that of patients who delivered vaginally (P = 1.0). There was a higher incidence of transfusion in patients delivered by cesarean without labor, but these patients were more likely to have preoperative anemia (P = .036). Patients undergoing cesarean with labor or ruptured membranes had an increased incidence of both febrile morbidity (P = .023) and wound seroma (P = .008). CONCLUSION: Maternal morbidity following cesarean delivery in high-risk obstetric patients in a private practice setting is low.

Cesarean Section↗
PubMed1997

Pressure ulcer prevention: review of literature.

Much has been written about the causes, prevention, and nursing management of pressure ulcers. A review of current literature on the subject reveals that, in spite of the enormity of information available, the problem continues to consume a large percentage of nursing time and energy. Studies of aggressive prevention and ongoing continuing education programs have demonstrated significant reduction of incidence and time of treatment, as well as dramatic cost savings. The Agency for Health Care Policy and Research (AHCPR) has recommended that all patients at risk for pressure ulcer development be placed on some form of pressure-reducing support surface. There is a wide variety of these products available, but a surprisingly limited quantity of published articles specifically compare the efficacy of one product to another.

Adolescent↗