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Biomedical subjects

J Ansell

Publications and source records attributed to J Ansell.

At least 37 records · Page 2Linked to original sources

College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of oral anticoagulant therapy.

OBJECTIVE: To review the state of the art of laboratory monitoring of oral anticoagulant therapy, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for improvement in laboratory monitoring of oral anticoagulant therapy. DATA SOURCES: Review of the medical literature, primarily from the last 10 years, and current laboratory practices by a panel of 8 international experts in the field of oral anticoagulant monitoring. DATA EXTRACTION AND SYNTHESIS: After an initial assessment of the literature, key points were identified. Experts were assigned to do an in-depth review of the literature and current practices relevant to each of the key points and to prepare a summary of their findings and recommendations. A draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy prior to the conference. Each of the key points and associated recommendations was then presented for discussion at the Conference. Recommendations were accepted if a consensus of the 26 experts attending the Conference was reached. The results of the discussion were used to revise the manuscript into its final form. CONCLUSIONS: Consensus was reached on 12 recommendations concerning the laboratory monitoring of oral anticoagulant therapy. Detailed discussion of the rationale for each of these recommendations is found in the text of this article. Discussion of points on which consensus was not reached is also included in the text. It is hoped that widespread adoption of these recommendations will further improve the laboratory monitoring of oral anticoagulant therapy.

Administration, Oral↗

A case of Isaacs' syndrome with associated central nervous system findings.

We report a 44-year-old female with Isaacs' syndrome, peripheral motor neuropathy, and features of central pontine myelinolysis (CPM). The patient presented with stiffness and muscle spasms accompanied by profound sweating. She also had bilateral Babinski signs. Electrodiagnostic abnormalities were characteristic of Isaacs' syndrome. Magnetic resonance imaging demonstrated features of CPM. She gained modest relief from baclofen, valproate, and diazepam. She improved dramatically following plasmapheresis and continued to recover on prednisone. She was weaned from steroids without relapse.

Adult↗

N-(5-substituted) thiophene-2-alkylsulfonamides as potent inhibitors of 5-lipoxygenase.

Compound 4k N-[5-(4-fluoro)phenoxythien-2-yl]methanesulfonamide is representative of a new class of potent inhibitors of 5-lipoxygenase (5-LO). These versatile compounds exhibit dose-dependent inhibition of 5-LO with IC50s ranging from 20-100 nM in the rat basophilic leukemia (RBL-1) cell homogenate assay and submicromolar IC50s in both the RBL-1 and human peripheral blood leukocyte (PBL) whole cell assays. Compound 4k also showed significant anti-inflammatory activity in the adjuvant arthritic rat at an oral dose of 3 mg/kg.

Administration, Oral↗

The control of microvascular permeability and blood pressure by neutral endopeptidase.

Plasma extravasation from postcapillary venules is one of the earliest steps of inflammation. Substance P (SP) and bradykinin (BK) mediate extravasation and cause hypotension. The cell-surface enzyme neutral endopeptidase (NEP) inactivates both peptides. Thus, absence of NEP may predispose development of inflammation and hypotension. We examined these possibilities in mice in which the NEP gene was deleted by homologous recombination. There was widespread basal plasma extravasation in postcapillary venular endothelia in NEP-/- mice, which was reversed by recombinant NEP and antagonists of SP (NK1) and BK (B2) receptors. Mean arterial blood pressure was 20% lower in NEP-/- animals, but this was unaffected by reintroduction of recombinant NEP and the kinin receptor antagonists. The hypotension was also independent of nitric oxide (NO), because NEP-/- mice treated with a NO synthase inhibitor remained hypotensive relative to the wild type. Thus, NEP has important roles in regulating basal microvascular permeability by degrading SP and BK, and may regulate blood pressure set point through a mechanism that is independent of SP, BK and NO. The use of NEP antagonists as candidate drugs in cardiovascular disease is suggested by the blood pressure data reported herein.

Animals↗

The reliability of self-reported blood in urine and schistosomiasis as indicators of Schistosoma haematobium infection in school children: a study in Muheza District, Tanzania.

The use of self-reported blood in urine and schistosomiasis by school children was investigated as a tool to estimate the prevalence of infection with Schistosoma haematobium and to identify infected individuals. A general questionnaire about common health problems, including questions about blood in urine and schistosomiasis, was administered by teachers to 25443 children in 137 primary schools in Muheza District, Tanzania. The prevalence of reported schistosomiasis was calculated for each school and used to select 15 schools across a range in prevalence. All children in the 15 schools (n = 2370) were interviewed again by a nurse and gave a urine sample which was subjected to a quantitative microscopical examination for the eggs of S. haematobium by filtration. The prevalence of reported schistosomiasis by the interview in the 15 schools correlated strongly with the prevalence reported during the questionnaire survey. The prevalence of reported schistosomiasis in the interview was strongly correlated with the prevalence of infection determined by microscopy and consistently under-estimated the latter by around 20% across a range in prevalence from 22% to 93%. The sensitivity of diagnosis by an interview increased almost linearly with the prevalence of infection, so that when the prevalence was high, more infected children reported schistosomiasis. The percentage of children who were correct in their self-diagnosis was independent of the prevalence of infection and of the mean concentration of eggs in urine, and averaged 75%. These findings suggest that self-reported schistosomiasis is a useful method to estimate the prevalence of infection in schools and might be used to identify infected individuals.

Adolescent↗

Evaluation of the antiinflammatory activity of a dual cyclooxygenase-2 selective/5-lipoxygenase inhibitor, RWJ 63556, in a canine model of inflammation.

Sterile perforated polyethylene spheres (wiffle golf balls) were implanted s.c. in beagle dogs. A local inflammatory reaction was elicited within the spheres by injecting carrageenan. Changes in leukocyte count, prostaglandin E2, thromboxane B2 and leukotriene B4 levels were monitored in fluid samples collected over a 24-hr period. Blood samples were also collected at various time points and analyzed for prostaglandin E2 and leukotriene B4 production after ex vivo calcium ionophore treatment. Effects of standard antiinflammatory agents (aspirin, indomethacin, dexamethasone, tenidap and zileuton) and newer cyclooxygenase-2 (COX-2) selective agents (nimesulide, nabumetone and SC-58125) were determined after oral administration. Ex vivo inhibition of cyclooxygenase product synthesis (prostaglandin E2, thromboxane B2) in whole blood was used as an indicator of activity for the constitutive COX-1 isoform, although inhibition of the synthesis of these mediators in the chamber exudate during an inflammatory process is believed to represent COX-2 inhibition. Treatment effects on leukotriene B4 production were also determined both ex vivo in whole blood and in the fluid. All of the compounds tested, except aspirin, inhibited leukocyte infiltration into the fluid exudate. Inhibitors that exert their effects on both isozymes of cyclooxygenase attenuate production of cyclooxygenase metabolites in both the inflammatory exudate and in peripheral blood ex vivo, although COX-2 selective inhibitors only demonstrated activity in the exudate. A 5-lipoxygenase inhibitor (zileuton), a corticosteroid (dexamethasone) and a dual COX-2 selective/5-lipoxygenase inhibitor (RWJ 63556) had similar profiles in that they all inhibited cell infiltration and eicosanoid production in the fluid and also attenuated leukotriene B4 production in both the fluid and blood.

Animals↗

Comparison of radiographer/radiologist double film reading with single reading in breast cancer screening.

OBJECTIVES - To assess the efficacy of dual film reading in screening mammography with a suitably trained radiographer as the second reader and to determine a suitable decision model for radiographer/radiologist double reading. SETTING - Three breast screening centres in South Thames (West) region. METHODS - Seven radiographers with prior film reading training double read 17 202 screening mammograms with a radiologist. Screening performance of radiographers and radiologists was assessed taking into account interval cancers. The efficacy of radiographer/radiologist double reading was assessed in terms of changes in sensitivity and specificity compared with radiologist single reading. RESULTS - Radiographers yielded equivalent sensitivity but lower specificity than radiologist film readers. The effect of double reading between radiographer/radiologist pairs was an increase in sensitivity of 6-4%, which was achieved at the cost of a 0-6% decrease in specificity. This was reached by a decision system involving radiologists' review of radiographer queries and recall classifications. If all radiographer queries were recalled a large increase in sensitivity would be counterbalanced by an equally large decrease in specificity. CONCLUSIONS - Radiographer/radiologist double reading resulted in similar increases in sensitivity as those previously reported in radiologist double reading studies. Radiologist review of radiographer reported abnormalities is a suitable means by which to limit excess recall.

Adult↗

Radiographers as film readers in screening mammography: an assessment of competence under test and screening conditions.

The aim of this study was to investigate the potential of radiographers as film readers in screening mammography. Seven radiographers received training in mammogram interpretation at a National Health Service (NHS) Breast Screening Training Centre. Film reading performance was assessed over a period of 1 year after training with test sets of selected screening mammograms. Actual screening performance on contemporary screening mammograms was monitored after training in relation to radiologist decisions and screening outcome. It was found that trained radiographers read mammograms to a standard comparable with that of radiologists. Film reading skills were maintained consistently over the period of this study and transferred to actual screening performance. It was concluded that radiographers could play a useful role as second readers in screening mammography. Training needs have to be assessed in relation to the role the film reading radiographer is to adopt.

Adult↗

Antithrombotic therapy. An abbreviated reference for clinicians.

Antithrombotic therapy is a mainstay in the treatment of patients with thromboembolic diseases of the arterial and venous circulatory systems. Continued work and investigation has provided much-needed information directly applicable to meeting high standards of patient care. The American College of Chest Physicians Consensus Conference on Antithrombotic Therapy has been instrumental in developing guidelines. This article is a synopsis of the proposed guidelines, including recent updates and information that will likely influence future recommendations.

Clinical Trials as Topic↗

Adjuvant intraoperative photodynamic therapy in experimental colorectal cancer.

A reliable animal model for quantitative assessment of local recurrence of colorectal cancer was developed using colo26 tumour in BALB/c mice. The effect of adjuvant intraoperative photodynamic therapy to potentially curative surgery on local recurrence was examined in four study and four control groups. Study groups received 15 mg kg-1 Photofrin (a photosensitizing drug) 24 h before surgery. After 'curative' tumour excision, the tumour beds were illuminated with either 630 nm or 510 nm laser light each at 40 and 70 J/cm-2. Controls received surgery only, surgery and Photofrin only or surgery and either 630 nm or 510 nm light. The local recurrence rates at 70 days were 17-33 per cent in the study groups compared with 83-100 per cent in the control groups (P < 0.001; log rank test). Photodynamic therapy is capable of reducing local recurrence following potentially curative excision of tumour in this model.

Animals↗

Encephalomyeloradiculopathy of infectious or parainfectious etiology--a new entity?

Between 19 March 1990 and 24 December 1992, six persons in Nova Scotia presented with a unique neurological illness. A prodrome of fever and headache was followed by neurogenic bladder, transverse myelitis, and encephalopathy in association with mononuclear pleocytosis of the CSF and nerve-conduction study findings consistent with polyradiculopathy. The spinal cords of three of the patients appeared abnormal on myelograms or magnetic resonance imaging studies. No microbial agent was isolated or demonstrated serologically. All of the patients were treated with antimicrobial agents and corticosteroids. Three recovered completely, but neurogenic bladder persisted in the remaining three. We suggest that this group of patients manifested an encephalomyeloradiculopathy that is likely a new clinical entity of infectious or parainfectious etiology.

Adolescent↗

Synthesis and 5-lipoxygenase inhibitory activities of some novel 2-substituted 5-benzofuran hydroxamic acids.

A series of 2-substituted benzofuran hydroxyamic acids were synthesized as rigid analogs of simple (benzyloxy)phenyl hydroxamates, evaluated for their in vitro and in vivo 5-lipoxygenase activity and found to be potent inhibitors of the enzyme. Substituents which enhanced lipophilicity near the 2-position of the benzofuran nucleus increased inhibitor potency but reduced oral activity. Incorporation of small polar substituents such as methoxymethylene, hydroxymethylene, and amino (urea) on the acyl group led to more consistent oral activity. The most potent inhibitors of this series in vitro were N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)-ethyl]furancarboxamide (12) and methyl 5-[N-hydroxy-N-[1-(2-(3,4,5-trimethoxyphenyl)-5-benzofuranyl]ethyl]-5- oxopentanoate (17), both with IC50 values of 40 nM, and in vivo the most potent compound was N-hydroxy-N-[1-(2-phenyl-5-benzofuranyl)ethyl]urea, 20, with an ED50 = 10.3 mg/kg.

Animals↗

Novel bishydroxamic acids as 5-lipoxygenase inhibitors.

Two series of novel bishydroxamic acids 2 and 3 (types A and B) were synthesized and tested for inhibition of 5-lipoxygenase from rat basophile leukemia (RBL) cells. Both series were potent inhibitors of the isolated enzyme but only the type B reverse hydroxamic acids possessed significant oral activity. The most potent compound, orally, was 3a, [IC50 = 270 nM; ED50 = 1.86 mg/kg], which compares favorably with the clinically useful 5-lipoxygenase inhibitor, zileuton. Unlike known hydroxamic acid inhibitors, the oral activity in this series appears to be associated with the second hydroxamic acid group. The corresponding monohydroxamic acids retained inhibitor potency, in vitro, with reduced oral activity in a mouse zymosan peritonitis model. Compound 4e [IC50 = 7 nM], a monohydroxamic acid derivative related to 3a, is among the most potent inhibitors of the isolated enzyme yet to be reported.

Animals↗

Should cerebral ischemic events in cancer patients be considered a manifestation of hypercoagulability?

BACKGROUND AND PURPOSE: Previous studies, mainly autopsy-based, suggest that the spectrum of stroke in cancer patients differs from that of the general population. These studies also suggest that cerebrovascular events frequently are a manifestation of hypercoagulability. However, no studies that address this question in the adult oncological population from a clinical perspective are available. We therefore assessed the clinical impact of cerebral ischemic events in cancer patients and attempted to determine whether their occurrence represents a manifestation of Trousseau's syndrome. METHODS: A computerized database that records all neurological admissions and consultations at a tertiary medical center was used to retrospectively identify all patients with cerebral ischemic events and cancer. RESULTS: Thirty-three patients representing 3.5% of all stroke consultations and admissions seen at the University of Massachusetts Medical Center were identified during the period 1988 through 1992. Large-vessel atherosclerosis was the most frequent cause of stroke. Furthermore, although 30% were determined to have hypercoagulability as a cause using clinical criteria, in only one of nine patients in whom tests were done was sufficient evidence present to make a presumptive diagnosis of disseminated intravascular coagulation. Irrespective of therapy, recurrent cerebral ischemic events were noted in only 6% of patients during a follow-up period averaging greater than 9 months, a figure that is similar to that for the risk of repeated events in the noncancer population. CONCLUSIONS: Recognizing the limitations of this retrospective study, it appears nonetheless that conventional stroke origins account for the majority of cerebral ischemic events in the adult cancer population. Although hypercoagulability is present to a greater extent than in the nononcological population, recurrent strokes seem to occur no more frequently than in the nononcological population, and antiplatelet agents seem sufficient therapy for most patients.

Adult↗

Aging and the anticoagulant response to warfarin therapy.

OBJECTIVE: To assess the effect of aging on the anticoagulant response to warfarin. DESIGN: Retrospective cohort study. SETTING: A university hospital outpatient anticoagulation clinic. PATIENTS: All patients (n = 530) monitored in the anticoagulation clinic over a 10-year period (1980 to 1990). The 530 study patients had a mean age of 61.5 (+/- 14.7) years (age range, 12 to 90 years). The patients were stratified into four age groups: younger than 50 years (n = 97); 50 to 59 years (n = 107); 60 to 69 years (n = 149); and 70 years or older (n = 177). MEASUREMENTS: For each patient, a dose-adjusted mean prothrombin time ratio was calculated by dividing the mean prothrombin time ratio by the mean daily warfarin dose. RESULTS: Older patients were more likely to be female (P less than 0.001), to have more medical problems (P less than 0.001), to be taking more medications (P less than 0.001), and to weigh less than younger patients (P less than 0.001). Across age groups, there were no significant differences in the use of medications that potentiated or inhibited the anticoagulant effects of warfarin. The prothrombin time ratio, when adjusted for dose, was significantly increased in older patients (P less than 0.001). The increased anticoagulant response to warfarin seen with increasing patient age persisted even after simultaneously controlling for relevant demographic and clinical variables in a multivariate model. Other factors significantly associated with an increased sensitivity to warfarin included use of a medication with a potentiating interactive effect with warfarin, female gender, and overall medication use. Increased body weight and duration of warfarin use exceeding 6 months were found to be inversely related to anticoagulant response. CONCLUSION: The anticoagulant response to warfarin is exaggerated with advancing age. This finding emphasizes the need for close monitoring of older patients treated with warfarin therapy.

Adolescent↗

Does desmopressin acetate prophylaxis reduce blood loss after valvular heart operations? A randomized, double-blind study.

The effectiveness of prophylactic desmopressin acetate in reducing hemorrhage after cardiopulmonary bypass operations is controversial. We conducted a prospective, randomized, placebo-controlled, double-blind trial to determine its effectiveness and safety in such patients. Eighty-three evaluable patients undergoing valvular heart operations were randomized to receive desmopressin (0.3 microgram/kg) (41) or placebo (42) after cardiac bypass. Demographic characteristics were similar in both groups. There was no significant difference in total 24-hour blood loss between groups (desmopressin 1064.8 +/- 647.1 ml versus placebo 844.4 +/- 507.6 ml; p greater than 0.05), or in the requirement for red blood cell, platelet, or fresh frozen plasma transfusion, or for reexploration for control of hemorrhage. Neither was there a difference in the occurrence of thrombotic complications between groups. Analysis of factor VIII activity, von Willebrand factor, or von Willebrand factor multimers failed to show significant correlations with blood loss or differences between groups except for factor VIII activity, which was significantly higher in the desmopressin group 1 hour after operation than in the placebo group. A detailed comparative analysis of similar trials to determine the reasons for different outcomes suggests that desmopressin should not be used routinely as a prophylactic agent to reduce postsurgical hemorrhage, but that it may be beneficial when used in patients who already manifest excessive bleeding postoperatively.

Blood Loss, Surgical↗

Measurement of the activated partial thromboplastin time from a capillary (fingerstick) sample of whole blood. A new method for monitoring heparin therapy.

The monitoring of heparin anticoagulation is fraught with difficulties because of the need for repetitive venipunctures and the vagaries of sample handling and processing. The authors evaluated a new aPTT monitoring system with the potential to eliminate many of these difficulties. The Ciba Corning Diagnostics 512 Coagulation Monitor (CCD monitor) is a hand-held portable instrument that can measure an aPTT from a fingerstick sample of capillary whole blood. Fingerstick aPTTs from 319 subjects (including controls and individuals on heparin and/or warfarin) were compared to venipuncture-derived standard laboratory plasma aPTTs using different aPTT reagents on conventional instruments. The correlation coefficients between fingerstick and standard aPTTs (0.79-0.83) were the same as the correlation coefficient between standard laboratory aPTTs using different reagents (0.79). When venipuncture-derived whole blood was compared to fingerstick samples on the new instrument, the correlation coefficient was excellent (0.93). A high degree of precision, as demonstrated by low coefficients of variations, was shown for within-day and between-day testing using the CCD monitor and normal controls. This capillary whole blood, aPTT system is the first to provide the clinician with a means of rapidly and reliably assessing the anticoagulant response to heparin therapy at the bedside, and its use may ultimately lead to more efficient and effective therapy overall.

Blood Coagulation Tests↗