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Biomedical subjects

W R Wilson

Publications and source records attributed to W R Wilson.

At least 145 records · Page 8Linked to original sources
PubMed1992

Nitric oxide: its production in host-cell-infiltrated EMT6 spheroids and its role in tumour cell killing by flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid.

Flavone-8-acetic acid (FAA) and its more dose-potent analogue 5,6-dimethylxanthenone-4-acetic acid (5,6-MeXAA), appear to exert their antitumor effects through vascular and other host-mediated mechanisms and are known to induce the synthesis of nitric oxide by murine macrophages. We investigated the role of nitric oxide in the cytotoxic effects of these drugs in host-cell-infiltrated spheroids. EMT6 murine mammary adenocarcinoma cells were grown in culture to produce multicellular spheroids in vitro spheroids), which were then inoculated i.p. into mice. After 6 days the spheroids were removed ex vivo spheroids). Exposure to FAA (890 microM) and 5,6-MeXAA (80 microM) in vitro for 20 h increased nitrite concentrations to 6.7 and 9.7 nmol/spheroid, respectively, as compared with 0.7 nmol/spheroid in the absence of drug. FAA and 5,6-MeXAA did not increase nitrite production in in vitro spheroids in cells obtained by peritoneal lavage. However, mixed cultures of in vitro spheroids and peritoneal cells treated with 5,6-MeXAA produced nitrite (2.4 nmol/spheroid), indicating that interactions between host cells and tumour cells were important for induction. The effects of these drugs on ex vivo spheroids were prevented by co-incubation with NG-monomethyl-L-arginine, indicating that nitrite originated from the oxidation of L-arginine to nitric oxide. Cell sorting of disaggregated spheroids into EMT6 cells and Mac-1-positive macrophage populations indicated that both of these cell populations could be induced to synthesise nitric oxide by subsequent incubation with 5,6-MeXAA. Incubation of ex vivo spheroids with FAA and 5,6-MeXAA decreased the clonogenicity of EMT6 cells, and this effect was wholly (FAA) or partially (5,6-MeXAA) reversed by the presence of NG-monomethylarginine (250 microM). FAA and 5,6-MeXAA may therefore exert some of their cytotoxic effects on tumour cells through the production of nitric oxide.

Adenocarcinoma↗
PubMed1992

Partial median sternotomy for repair of heart defects: a cosmetic approach.

A modified median sternotomy incision that results in a cosmetically appealing scar is described. It includes the use of a low-lying short skin incision and partial transection of the sternum. The outcome in 182 infants and children indicates that this approach is safe, provides adequate exposure, and has excellent cosmetic results.

Adolescent↗
PubMed1992

Bis-bioreductive agents as hypoxia-selective cytotoxins: nitracrine N-oxide.

Drugs with two reducible centers, both of which must be metabolized by oxygen-inhibitable processes for full activation ("bis-bioreductive agents"), offer potential for the development of hypoxia-selective cytotoxins with improved oxygen sensitivity. The sidechain N-oxide (1-NCO) of the (mono)bioreductive agent nitracrine (1-NC) has been synthesized and evaluated as a potential example of such an approach. The association constant for reversible DNA binding of 1-NCO was 15-fold lower than that of 1-NC, as measured by equilibrium dialysis in a low ionic strength buffer, indicating that the N-oxide has the potential to act as a less toxic pro-drug of 1-NC. Cell uptake and aerobic cytotoxicity of 1-NCO were much lower than for 1-NC whereas its hypoxic selectivity as a cytotoxin was greatly increased. In stirred suspension cultures of AA8 cells, pure (less than 0.02% 1-NC) 1-NCO was 1000-1500 times more potent under hypoxia than in 20% O2. For 1-NC the corresponding ratio was 10 +/- 1. 1-NCO had greater hypoxic selectivity in this system than misonidazole (ratio 11), RSU 1069 (ratio 25), 8Me-5NQ (ratio 60), or SR 4233 (ratio 80). Studies of 1-NCO metabolism indicate rapid, O2-inhibited reduction to 1-NC. The data are consistent with a two-step bioactivation mechanism, with reduction of the N-oxide generating a DNA intercalator of increased binding affinity, followed by reduction of the nitro group of this DNA-targeted cytotoxin to form reactive cytotoxic metabolites.

Animals↗
PubMed1992

Correlation of the radiosensitization potency afforded by nitroacridine intercalators with their electron scavenging efficiency in DNA.

Nitracrine (1-NC) and its nitro-positional analogues are electron-affinic DNA intercalating compounds that act as hypoxic cell radiosensitizers in cell culture, but are too rapidly metabolized to provide radiosensitization in vivo. We have explored the electron-trapping efficiencies of nitroacridines to see if such compounds can scavenge radicals formed in irradiated DNA and if the efficiency of such trapping is related to their radiosensitization properties. We have shown that a correlation does indeed exist as 1-NC, the most potent radiosensitizer, scavenges approximately 45% of the migrating electrons (formed by attachment of eaq- to the DNA) compared with approximately 4% for 4-NC, the least efficient radiosensitizer. The quenching of the delayed fluorescence from acridine orange bound to DNA was also used to probe intracellular uptake and association with DNA. The results are in accord with earlier measurements of average uptake and a suggestion that intercalators which form DNA complexes with short residence times will be preferable to highly bound agents as radiosensitizers. Since 1-NC possesses the smallest association constant with DNA of the four compounds, it is suggested that its high radiosensitization potency may well be related to it being able to interact with more radical sites on the DNA than the other analogues, in addition to its capture of migrating electrons in DNA.

Animals↗
PubMed1992

NLA-1: a 2-nitroimidazole radiosensitizer targeted to DNA by intercalation.

Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DNA-targeted acridine-linked 2-nitroimidazole (NLA-1) as an example of such a compound. NLA-1 binds reversibly to DNA with an affinity similar to 9-aminoacridine, and is approximately 1000 times more potent than MISO as a cytotoxin, despite a similar reduction potential. It shows less enhancement of cytotoxicity under hypoxia (5- to 6-fold) than does MISO (approximately 11-fold), but is a potent hypoxia-selective radiosensitizer in AA8 cells with a concentration for an enhancement ratio of 1.6 (C1.6) of 9 microM. The mean intracellular concentration at the C1.6 is 400 microM, on which basis its potency is about twice that of MISO. The in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C1.6) of NLA-1 is approximately 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors in vivo at the maximum tolerated dose (MTD) of 100 mumol.kg-1.

Aminoacridines↗
PubMed1992

Ciprofloxacin versus trimethoprim-sulfamethoxazole: treatment of community-acquired urinary tract infections in a prospective, controlled, double-blind comparison.

In this study, we determined the safety and efficacy of the treatment of adults with urinary tract infection with ciprofloxacin hydrochloride (250 mg twice daily for 10 days) in comparison with trimethoprim-sulfamethoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole twice daily for 10 days). Patients with signs and symptoms of urinary tract infection were randomized to receive ciprofloxacin (98 women and 5 men) or trimethoprim-sulfamethoxazole (92 women and 8 men). The success rate of therapy was 91% for both treatment arms of the study. Among seven failures after ciprofloxacin therapy, three were due to relapse of infection and two to side effects that necessitated a change in medication; in addition, two patients had persistent symptoms and required hospitalization. Among the six failures associated with trimethoprim-sulfamethoxazole therapy, four were due to relapse, one to persistence of infection, and one to a side effect that necessitated a change in medication. Among the patients treated with trimethoprim-sulfamethoxazole, 32% had mild or moderate adverse reactions; in comparison, 17% of the ciprofloxacin-treated patients had adverse reactions (P = 0.026). For the treatment of urinary tract infection in adult patients in this study, ciprofloxacin and trimethoprim-sulfamethoxazole were equally effective, but ciprofloxacin was associated with fewer adverse reactions.

Adult↗
PubMed1992

Prophylaxis and treatment of infections complicating abdominal surgery.

The suitability of commonly used antimicrobial regimens for prophylaxis in abdominal surgery and treatment of intra-abdominal sepsis is discussed. These various therapies are often limited in their usefulness by the range of microorganisms against which they are effective and thus, to extend the antimicrobial cover, agents may be combined. Some forms of therapy may produce adverse effects in susceptible patients, thus limiting their use to certain groups, or there may be cost constraints. Beta-lactamase-inhibiting compounds appear to offer an optimal combination of a broad spectrum of activity against aerobic and anaerobic microorganisms, minimal toxicity and reasonable cost.

Abdomen↗
PubMed1992

Evaluation of new anti-infective drugs for the treatment of infective endocarditis. Infectious Diseases Society of America and the Food and Drug Administration.

These guidelines describe the design and implementation of clinical trials to assess the safety and efficacy of anti-infective drugs for the treatment of infective endocarditis. Identification and enrollment of patients in clinical trials is based on a modification of traditional criteria. To accrue a sufficient number of patients, only those with streptococcal or staphylococcal endocarditis should be included in studies. Results of treatment with approved drugs allow for projection of expected bacteriologic cure rates and survival rates. Prospective randomized, double-blind studies are recommended. These guidelines are based on the premise that future protocols may include shorter courses of therapy, combinations of drugs, or progression from parenteral to oral therapy. Clinical response is judged as cure, failure, or indeterminate; there is no "improved" category. Microbiologic response is categorized as eradication, persistence, or relapse. When a patient has shown no clinical evidence of active disease for a protracted period, there may be no need to perform a posttreatment blood culture; for such patients, the microbiologic response is termed presumptive eradication. Several months of follow-up may be necessary to detect late relapses.

Anti-Infective Agents↗
PubMed1992

Animal models as predictors of outcome of therapy with broad spectrum cephalosporins.

Broad spectrum cephalosporins have been studied extensively in animal models of experimental infections. There is generally good correlation between the results of therapy of experimental infections and clinical trials in humans. However, the results of animal model studies are better predictors of the failure than of the success of a chemotherapeutic regimen. Cefotaxime and the new 'fourth' generation agent, cefpirome, were comparable in the treatment of experimental meningitis caused by Streptococcus pneumoniae. Cefpirome was the most effective cephalosporin as therapy for methicillin-susceptible Staphylococcus aureus experimental endocarditis. The most effective broad spectrum cephalosporins for the treatment of Gram-negative experimental pneumonia were cefpirome, cefotaxime and cefodizime. Cefpirome was equivalent to ceftazidime or cefazolin as treatment for Pseudomonas aeruginosa or methicillin-susceptible S. aureus experimental osteomyelitis. Because of its potent activity in vitro and in animal models of experimental infections caused by methicillin-susceptible S. aureus and Gram-negative bacilli, cefpirome may offer a therapeutic advantage over currently available broad spectrum cephalosporins.

Animals↗
PubMed1992

Efficacy of cilofungin therapy administered by continuous intravenous infusion for experimental disseminated candidiasis in rabbits.

Cilofungin has potent in vitro activity against Candida albicans, but previous in vivo models using twice daily intermittent dosing regimens have not consistently demonstrated in vivo efficacy. Because of the pharmacokinetics of cilofungin in rabbits, it has been suggested that administration by continuous intravenous infusion might be more effective. We compared the in vivo efficacy of continuous intravenous infusion of cilofungin with that of amphotericin B in a rabbit model of disseminated candidiasis. Cilofungin prepared as previously described in phosphate-buffered 33% polyethylene glycol was lethal to infected rabbits in this model, as was phosphate-buffered 33% polyethylene glycol alone. In contrast, cilofungin in 26% polyethylene glycol and sterile water administered by continuous intravenous infusion was tolerated by rabbits, was significantly more effective than amphotericin therapy in reducing candida colony counts in kidney tissue, and was as effective as amphotericin therapy in lung and spleen tissue and in cardiac valvular vegetations. The dosage regimen and diluent used in some previous studies may have adversely affected outcome of treatment with cilofungin.

Amphotericin B↗
PubMed1992

Continuous intravenous versus intermittent ampicillin therapy of experimental endocarditis caused by aminoglycoside-resistant enterococci.

We studied the efficacy of continuous intravenous infusion of ampicillin compared with that of intermittent administration of ampicillin alone or in combination with gentamicin for the therapy of highly aminoglycoside-resistant enterococcal experimental endocarditis. Rabbits were infected with a gentamicin-susceptible (MIC, 256 micrograms/ml) strain of Enterococcus faecalis or a strain of E. faecalis which was highly resistant to gentamicin in vitro (MIC, greater than 2,000 micrograms/ml). Administration of ampicillin by continuous intravenous infusion did not significantly enhance the killing of enterococci in vivo compared with that by intermittent administration of ampicillin for either the aminoglycoside-susceptible or the aminoglycoside-resistant strain. In combination with gentamicin, there were no significant differences in efficacies obtained with intermittent versus continuous intravenous infusion of ampicillin therapy for experimental endocarditis caused by either strain of E. faecalis.

Ampicillin↗
PubMed1992

5-Nitro-4-(N,N-dimethylaminopropylamino)quinoline (5-nitraquine), a new DNA-affinic hypoxic cell radiosensitizer and bioreductive agent: comparison with nitracrine.

Targeting of electron-affinic radiosensitizers to DNA via noncovalent binding (e.g., intercalation) may offer the potential for increasing sensitizing efficiency. However, it has been suggested that high-affinity DNA binding may compromise sensitization by restricting the mobility of sensitizers along the DNA, and by decreasing rates of extravascular diffusion in tumors. The weak DNA intercalator nitracrine (1-NC) is a more efficient radiosensitizer than related nitroacridines with higher DNA-binding affinities (Roberts et al., Radiat. Res. 123, 153-164, 1990). The present study investigates whether electron-affinic agents of even lower DNA-binding affinity may be superior to nitroacridines. The quinoline analog of 1-NC, 5-nitraquine (5-NO), was shown to have an intrinsic association constant for calf thymus DNA in 20 mM phosphate buffer which was 12-fold lower than that of 1-NC. 5-Nitraquine was not accumulated as efficiently as 1-NC by AA8 cells, but, despite a similar one-electron reduction potential, was 2- to 3-fold more potent than 1-NC as a hypoxia-selective radiosensitizer in vitro when compared on the basis of average intracellular concentration. Thus the radiosensitizing potency of 5-NQ appears not to be compromised by its low DNA-binding affinity. The cytotoxic mechanisms of 5-NQ and 1-NC appear to be similar (hypoxia-selective formation of DNA monoadducts), but 5-NQ is 1200-fold less potent than 1-NC as a cytotoxin. Despite this advantage, 5-NQ was not active in vivo as a radiosensitizer in SCCVII tumors. This lack of activity appears to be due to its relatively high toxicity in vivo (intraperitoneal LD50 of 105 mumol kg-1 in C3H/HeN mice), high one-electron reduction potential (-286 mV), and rapid metabolism to the corresponding amine in mice. The in vitro therapeutic index (hypoxic radiosensitizing potency/aerobic cytotoxic potency) of this weak DNA binder was lower than that of the non-DNA targeted radiosensitizer misonidazole, suggesting that DNA targeting enhances cytotoxicity more than radiosensitization. Development of useful DNA-targeted radiosensitizers may require the exploitation of DNA binding modes different from those of the nitroacridines and nitroquinolines.

Aminoquinolines↗
PubMed1992

Facial and trigeminal neural dysfunction by a primary cutaneous squamous cell carcinoma: MRI and clinicopathologic correlates.

Carcinomatous neural infiltration and subsequent neural dysfunction are phenomena associated with the facial nerve and parotid gland tumors, particularly adenoid cystic carcinoma. The association of primary cutaneous squamous cell carcinoma (PCSCC) with these phenomena is not as well recognized, especially with respect to the involvement of the trigeminal nerve. By presenting the case history of a man who successively developed facial and trigeminal neural dysfunction after Mohs chemosurgery of a PCSCC, this paper documents histologically the occurrence of such neural invasion, and illustrates the utility of gadolinium-enhanced magnetic resonance scanning in patient management.

Carcinoma, Squamous Cell↗
PubMed1992

The role of immune effector cells in flavone acetic acid-induced injury to tumor cells in EMT6 spheroids.

Inhibition of tumor blood flow appears to a major antitumor mechanism of flavone acetic acid (FAA), although non-ischemic processes may also be a significant role. To distinguish between direct and immune effector cell-mediated cytotoxicity as the basis for non-ischemic killing, effects of FAA were compared in EMT6 spheroids grown entirely in vitro and spheroids recovered from the peritoneal cavities of mice after six days of in vivo growth (ex vivo spheroids). Approximately 50% of the cells in the latter case were of host origin (macrophages and lymphocytes). Ex vivo spheroids showed specific histological changes when exposed to FAA, including tumor cell rounding, apoptosis, depression of mitotic activity and dissolution of necrotic debris in the spheroid core. Quantitation of histological changes indicated these effects to be significantly greater in ex vivo than in vitro spheroids. The histological changes in FAA treated ex vivo spheroids were partially inhibited by dexamethasone. Oxygen tension did not influence the response of spheroids to FAA. The results suggest that immune effector cells, probably macrophages, mediate blood flow-independent antitumor effects of FAA.

Animals↗
PubMed1992

Technical modifications for improved results in total anomalous pulmonary venous drainage.

To delineate factors that contribute to improved surgical outcome in patients with total anomalous pulmonary venous drainage, we reviewed the records of 52 consecutive patients. Venous drainage was supracardiac in 25 (48%), cardiac in 12 (23%), infracardiac in 10 (19%), and mixed in five (10%). Preoperative pulmonary venous obstruction was present in 18 patients (35%). Median age at the time of repair was 35 days and weight, 3.7 kg. Repair was performed with deep hypothermia, low-flow cardiopulmonary bypass, and occasional short periods of circulatory arrest. In patients with coronary sinus drainage, the veins were tunneled to the left atrium through an enlarged atrial septal defect, with a mortality of 8% (1/12) and no postoperative stenosis. The approach in patients with supracardiac, infracardiac, and mixed drainage varied with time. In 16 patients, the condition was managed by apical or right-sided exposure of the common vein, anastomosis of the common vein to the left atrium with continuous sutures, and primary closure of the atrial septal defect (type I repair). In the other 24 patients the common vein was approached from the right side through the right atrium and the interatrial septum. Common vein-left atrium anastomosis was performed with interrupted sutures and a piece of pericardium used to augment the anastomosis, prevent common vein distortion, and close the atrial septal defect (type II repair). Mortality in type I repair was 25% (4/16) and in type II repair, 4% (1/24). Follow-up was 7.86 +/- 4.0 years with no late deaths. Postoperative stenosis occurred in five of 14 (36%) patients who had type I repair versus two of 23 (9%) who had type II repair. Multivariate analysis showed that type I repair was a positive risk factor for hospital mortality (p = 0.05) and restenosis (p = 0.04). The technique of transatrial exposure of the common venous chamber, interrupted suturing of the common vein to the left atrium, and pericardial patch augmentation significantly improves survival and decreases risk of restenosis.

Anastomosis, Surgical↗
PubMed1991

Emboli in infective endocarditis: the prognostic value of echocardiography.

OBJECTIVE: To determine whether vegetations visualized on two-dimensional echocardiography are an independent risk factor for the development of subsequent emboli in patients with infective endocarditis and to assess the timing of emboli relative to the initiation of antimicrobial therapy. DESIGN: Investigator-blinded, retrospective incidence cohort study. SETTING: Tertiary referral center. PATIENTS: Patients with left-sided native valve infective endocarditis who had two-dimensional echocardiography within 72 hours of beginning antimicrobial therapy. MEASUREMENTS AND MAIN RESULTS: The crude incidence rate of first embolic events in patients receiving antimicrobial therapy was 6.2 per 1000 patient-days (95% CI, 4.2 to 9.2). The rates in patients with and without vegetations were 7.1 and 4.9 per 1000 patient-days, respectively (incidence rate ratio, 1.4; 95% CI, 0.6 to 3.3). The relation between vegetations and risk for emboli was microorganism-dependent: Stratified incidence rate ratios were 6.9 (95% CI, 1.1 to 42.5; P less than 0.05) and 1.0 (95% CI, 0.2 to 3.9) for viridans streptococcal and Staphylococcus aureus endocarditis, respectively. The rate of first embolic events diminished over time (P less than 0.001), falling from 13 per 1000 patient-days during the first week of therapy to less than 1.2 per 1000 patient-days after completion of the second week of therapy. CONCLUSIONS: Overall, the presence of vegetations on echocardiography was not associated with a significantly higher risk for embolus in patients with left-sided native valve infective endocarditis. The relative risk for embolic events associated with echocardiographically visualized vegetations may be microorganism-dependent, with a significantly increased risk seen only in patients with viridans streptococcal infection. The rate of embolic events declines with time after initiation of antimicrobial treatment.

Adolescent↗
PubMed1991

Prevalence of Helicobacter pylori in specific forms of gastritis. Further evidence supporting a pathogenic role for H. pylori in chronic nonspecific gastritis.

Helicobacter pylori colonization of the gastric mucosa is strongly associated with chronic nonspecific gastritis; moreover, there is evidence to suggest that H. pylori may cause this form of gastritis. However, there is little or no information on the prevalence of H. pylori in specific forms of gastritis. Our hypothesis was that if H. pylori was pathogenic in chronic nonspecific gastritis, organisms would be found frequently in this type of gastritis but infrequently in specific forms of gastritis. Prevalence rates of H. pylori were determined independently in patients with eosinophilic and Crohn's gastritis, Menetrier's disease, and chronic nonspecific gastritis. The prevalence of H. pylori in patients with chronic nonspecific gastritis was 71%, whereas the organism was not identified in patients with any form of specific gastritis. This finding further supports the accumulating evidence that H. pylori is a primary pathogenic factor in chronic nonspecific gastritis.

Adolescent↗