Observer error: are medical students good observers?

Observer error affects virtually all aspects of medicine. Our objective was to find a way to reduce it among clinical students. A minority need to be shown how to observe. A classroom exercise, repeated 6 times on separate days, using different simple objects, more than doubled the mean score on observation of visible properties of objects by a class of students in their first clinical year. Their corrected answer-slips were returned to the students at the next lecture 2 or 3 days later. Errors of omission and commission both decreased. Omission errors showed greater improvement but commission errors persisted in the class. The increment in observation seemed to be retained 5 months after tuition. Attempts were made to make a universal proforma suitable for any observation. It increased mean class score by 33% in 1994. Reducing observer error may have an educational strand. strand.

Finding, confirming, and managing gonorrhoea in a population screened for chlamydia using the Gen-Probe Aptima Combo2 assay.

OBJECTIVES: To identify the prevalence of Neisseria gonorrhoeae (NG) within a population screened for Chlamydia trachomatis (CT). To monitor confirmatory microscopy, culture, and partner findings following reactive Aptima Combo2 assay (AC2) gonorrhoea screening tests. METHODS: Between June and December 2004, all gonorrhoea screening tests performed using AC2 for clients taking part in the Liverpool Chlamydia Screening Programme were monitored. Clients with AC2 NG reactive results were referred to a local genitourinary medicine (GUM) department for confirmatory microscopy, culture, treatment, and partner follow up. RESULTS: 47 (1%) of 4680 women and eight (1.7%) of 473 men had AC2 reactive gonorrhoea screening tests. Of those clients who agreed to follow up and were tested before any treatment, supportive evidence for a gonorrhoea diagnosis was found in 37 (97%) of 38 women and all five men. In the population opportunistically screened for chlamydia, CT prevalence rates were 12% for women and 15.7% for men. Although both women and men showed a higher relative risk for NG if chlamydia positive, of the 47 women who were reactive for NG by AC2, 55% (26) were negative for chlamydia. CONCLUSIONS: Sexually transmitted infections are rising in England and reduction of gonorrhoea rates is an objective of the Department of Health Sexual Health and HIV Strategy. AC2 tests provide an acceptable and accurate means of testing for gonorrhoea in an asymptomatic population in the community. AC2 had a higher positive predictive value than might be suggested by previous clinical trials in this low prevalence population. Although antibiotic sensitivity must be monitored, AC2 testing may offer a more acceptable alternative to microscopy and culture for NG in some populations.

Effect of irradiation, asbestos and chemical cocarcinogens on incidence of sarcoma on implants.

An implant can act as a physical carcinogen. Chemicals applied to its surface can augment that. To explore if cocarcinogenesis would affect the incidence of tumour on implants, we tested several physical (asbestos, beta irradiation) and chemical (acridine orange, phorbol methyl ester, cigarette smoke tar, extract of Agaricus bisporus mushroom) carcinogens on 25 mm diameter nitrocellulose filters implanted in groups of BALB/c mice in 9 experiments. Saline was applied in 287 concurrent controls. Irradiation by 540 kBq I-125 fibrinogen on foreign bodies of surface area 20sq cm induced tumour in 6/6 pilot animals (expected 2/6) and in 25/36 animals (controls 13/29; p < 0.04). The mean dose (beta and gamma) to cells within 20 microm of the filter surface was estimated to be 782 mGy. Exposures to 270kBq or less were not significantly cocarcinogenic with single implants. Radiation from the paired implants was detectible up to 80 weeks. Asbestos, however, 2.3 or 4.6 mgm on implants did not in 3 trials increase sarcoma yield significantly, but did induce mesothelial-type growths in the peritoneum. Asbestos (2.3 mg) injected without an implant provoked no tumour at the site. The chemical carcinogen acridine orange gave ambiguous results, and the others reduced tumour incidence insignificantly. The irradiation history may be germane in the human cases that arise.

Inhibition of foreign-body sarcoma by mammalian RNA?

Long-implanted foreign bodies can provoke sarcoma in several species, although rarely in man. In neoplasia, RNA metabolism is highly active. Several kinds of RNA from 5 species were tested for prevention of foreign-body sarcoma in 8 experiments. Nitrocellulose filters or dialysis bags were the implants used. RNA, usually 1 g/dl, was applied to saturate the filters. They were implanted in groups of 30--50 mice, while concomitant controls received saline-saturated implants. The filters surfaces were 9.8 or 19.6 sq cm with pore diameters (roughness) of 0.05, 0.1 and 0.22 mu. The dialysis bags had 6.3 sq cm surface area and RNA content. Tumour yield was logged weekly. It was compared to that of the controls in each experiment and in the series of trials. Mammalian RNA decreased tumour yield in 9 of 11 trials (1 only at p<0.05), ribosomal RNA (85% reduction) being best. Yeast RNA was inactive. RNA from E.Coli increased tumour yield. Two of three samples of bovine RNase also increased tumour yield, an effect counteracted by admixed RNA. The results would indicate an antitumour effect of mammalian RNA, or a species or concomitant of it, which was irregularly present in the fractions tested, perhaps of ribosomal origin and dialysable.

MMPI-2 fake-bad scales: an attempted cross-validation of proposed cutting scores for outpatients.

Minnesota Multiphasic Personality Inventory-2 (MMPI-2) results were compared in 118 psychiatric outpatients given standard instructions, instructions to exaggerate their problems, instructions to feign a disorder they did not have, or instructions to feign global psychological disturbance. The groups were comparable on demographic, occupational and diagnostic characteristics as well as intake MMPI-2 results. Experimental MMPI-2 results showed that clinical scales were generally elevated in the feigning groups, with only modest differences across dissimulating instruction sets. The feigning groups had reliably higher scores than controls on all overreporting indexes examined, although no significant differences between feigning groups were present for overreporting indexes. Classification rates using previously proposed cutting scores for outpatients on individual feigning indexes showed near perfect specificity, but low to at best moderate sensitivity. Multiple regression analyses indicated that Gough's (1954) Dissimulation Scale (Ds2) was most strongly related to feigning status, and no other feigning scale contributed a significant increment in predictive power once Ds2 was entered.

Objective assessment of the contribution of each diagnostic test and of the ordering sequence in jaundice caused by pancreatobiliary carcinoma.

BACKGROUND: Computer-assisted diagnostic systems are not substantially more accurate than the clinician in the differential diagnosis of jaundice but may help in optimal selection and sequencing of tests. The present study aimed to assess with an electronic diagnostic tool the pattern of ordering tests and the diagnostic contribution and related financial cost of each test in jaundiced patients with pancreatobiliary carcinoma, in an effort to make the clinician's diagnostic behaviour more efficient and economical. METHODS: Clinical and diagnostic test data were prospectively gathered from 356 jaundiced patients with pancreatobiliary carcinoma and entered in a Bayesian diagnostic programme. The test results were added to the existing diagnostic evidence, and the programme calculated the diagnostic contribution of each test. RESULTS: A total of 1804 diagnostic tests were ordered. Quantitative assessment of the diagnostic contribution of each test showed that percutaneous transhepatic cholangiography and computed tomography were associated with the highest provision of information. The most cost-effective tests were ultrasonography and liver function tests. CONCLUSIONS: It is possible to determine objectively the diagnostic contribution of each test in establishing the diagnosis of pancreatobiliary carcinoma. The observed physician behaviour in ordering the various diagnostic tests might be improved with regard to its efficacy and its cost-effectiveness profile.

Validation of ICTERUS, a knowledge-based expert system for Jaundice diagnosis.

The study aimed to describe an example of the assessment and validation of knowledge-based clinical expert systems. The paper focuses on ICTERUS, an expert system for jaundice diagnosis. It describes system design, the methodology applied for upgrading and validating the program, and the most important outcomes of the validation procedure. The clinical validation of the system on a very large European database (Euricterus Project) shows that diagnostic conclusions are reliable in about 70% of eligible cases. This figure appears acceptable for a system which provides decision support only on the basis of clinical data, assuming that the final decision is achieved under user responsibility. Expected biases, limitations and inconsistencies in the practical application of the system are discussed.

Foreign body sarcoma: effects of foreign DNA, beta-carotene and paprika applied to the implant surface.

Sarcoma arises extremely rarely on foreign bodies in man, but is aggressive and often lethal. A coating for implants which would further reduce the risk in man is desirable. The incidence in mice is much greater, and responds to chemical treatment of the implant surface. Coating with histones increases tumour yield. Accordingly, related substances, foreign DNA, DNase and a mixture of the two, were tested for anticancer activity by application to 25 mm nitrocellulose filters in groups of 30-45 BALB/c mice, in comparison with untreated filters. Other substances reported to influence neoplasia, paprika, beta-carotene, rhodamine and tuftsin; and substances expected to be neutral, oxyprenolol, liquid paraffin, iodine, and adenosine diphosphate were similarly tested against concurrent untreated controls for comparison. Bovine DNA (p = 0.01) and DNA/DNase mixture (p = 0.04) and DNase fomented tumour growth by 55, 45 and 59% respectively. Paprika and beta-carotene did so by 70% (p = 0.05). The other substances were inert. None were candidates for an anti-sarcoma coating.

Effect of 3 growth control substances on foreign body sarcomagenesis: IFN, IUdR, MGBG.

The purpose was to observe the effect on sarcomagenesis of 3 substances reported to inhibit neoplastic growth--interferon alpha-2/alpha-1 hybrid (IFN), 5-iodo-2-deoxyuridine (IUdR) and methylglyoxal bis(guanylhydrazone) (MGBG). Inhibitory effect might help diminish the sarcoma risk of human implants. The substances were applied respectively to groups of 25mm cellulose filters which were implanted subcutaneously 1 per animal in randomly assigned respective groups of 50 female BALB/c mice. The implant sites were palpated weekly. On detection of a tumour the animal was sacrificed. The number of tumours arising and the accumulated weeks of exposure to the implants were recorded per group and compared to those of controls with untreated filters. Tumour incidence in the 2 IFN groups was 33/45 and 35/48 mice--160 per cent that of the controls, 22/48 (chi-square p < 0.05). In the IUdR group tumour incidence was 24/44 mice--194 per cent that of controls (p < 0.05), and in the MGBG group 15/43--122 per cent that of controls (p < 0.75). Although the substances inhibit tumour growth in man, they did not inhibit but increased film sarcomagenesis, not significant for MGBG. Observation of the effects of such substances with dual neoplastic activity may furnish clues to the control processes of neoplasia.

Some effects of prophylactic aspirins and heparins on concurrent arterial and venous thrombosis in the same animal.

The antithrombotic effect of unfractionated heparin, a low-molecular weight heparin, oral acetylsalicylic acid, intravenous lysine-aspirin and oral soluble aspirin was measured on platinum wire simultaneously in artery and vein, in groups of 12-20 rats with concurrent untreated controls. Subcutaneous low molecular weight heparin reduced mean thrombus weight by 26% in the artery only. Venous thrombosis was reduced 56% by oral soluble acetylsalicylic acid and 27% by oral aspirin. Other reductions did not reach statistical significance. While thrombus deposition was induced by both 2-cm (upper site) and 1-cm (lower site) wires, the results obtained on the 2-cm wires in the upper vein and artery were more reliable [corrected].

Bleeding times and the antithrombotic effects of high-dose aspirin, hirudin and heparins in the rat.

Bleeding can occur unexpectedly during antithrombotic therapy. Impaired haemostasis is commonly measured by the bleeding time. We measured it by 3 methods in controls and in anticoagulated animals and related it to their antithrombotic status. In 42 control rats template, tail-tip transection and needle occlusion bleeding times correlated poorly (r = 0.05-0.34). The template method had the best range (mean 126.97 +/- SEM secs) and consistency. In 10 control animals it correlated mildly (r = 0.55) with venous thrombus in the same animal. Thrombus was measured by its weight deposited on platinum wires (2 cm long, 0.4 mm diameter) set in vein and in artery for 1 h. In respective groups of 10 rats, a decrease of mean thrombogenesis was obtained using aspirin, heparin and low molecular weight heparin in 2 dosages and hirudin in 1 dosage. The drugs reduced mean venous thrombus by 13-86 per cent of the mean control thrombus, and prolonged the mean template bleeding time by 29-199 per cent. The ranking of the drugs according to their increase of template bleeding time was virtually the same as the ranking given by their reduction of thrombus weight (Spearman rank coefficient 0.81, sig 0.007). The transection test produced a similar ranking and similar correlation with thrombus (0.71, sig 0.049). Low molecular weight heparin induced the greatest thrombus reduction (39 per cent) for least prolongation of bleeding time (24 per cent). Arterial thrombus was more variable. The bleeding times and thrombus weight were measured in each animal of 2 groups given aspirin, the template method correlating mildly with venous thrombus reduction (r = 0.23, 0.58 respectively), the transection method with arterial (0.74, 0.45) and the occlusion test poorly with either (0.13, 0.22). Bleeding time lengthens with increasing antithrombotic effect of drugs, but not in direct proportion, nor similarly with each drug.

Assessment of liver cirrhosis severity in 1015 patients of the Euricterus database with Campbell-Child, Pugh-Child and with ascites and ascites-nutritional state (ANS) related classifications. Euricterus Project Management Group.

BACKGROUND/AIMS: The assessment of disease stage in cirrhosis is important for the individual patient (prognosis, timing and risk for requiring surgical intervention) and also for population comparisons and trials. There are several established methods, and we have aimed at comparison of the methods within a large cirrhosis population. METHODOLOGY: In the European Union Euricterus database, there are 1015 patients with a "certain" diagnosis of cirrhosis, each of whom in one session had a protocol work-up of history, physical examination and all laboratory investigations needed for this study. The Child-Turcotte (CT), Campbell-Child (C) and Pugh-Child (P) classifications, as well as ascites/no ascites, ascites 1, 2, 3 (no, therapy responsive, nonresponsive) and ascites/nutritional state (ANS, 1-9) scores were used. CT and C have the same 5 variables, P has prothrombin time instead of nutritional state. CT, C and P variables score 1-3 each. C and P furthermore have variable range scores of 5-15. CT, C and P have classes A-C. The variables used were ascites, nutritional state, encephalopathy, bilirubin, albumin and prothrombin time. RESULTS: Only 53 patients (5%) fit within the CT criteria. C and P variable range scores (5-15) correlated strongly (r = 0.84). Cross-over calculation showed slightly different results in the P and C choice of variables, while the variable ranges (1-3) did not matter. Different selection of score ranges for the A-C classes in C and P resulted in 69% class C in P (35% in C) and 3% A in P (19% in C). The patients with ascites (70%) had worse bilirubin, albumin, nutritional states and C and P 5-15 scores (p < 0.0001). Patients with ascites 3 had all variables and also C, P 5-15 scores worse than those with ascites 2 (p < 0.02). ANS scoring showed wasting in 33% of the patients without ascites (ANS 3), 50% of the patients with ascites 2 (ANS 6) and 60% with ascites 3 (ANS 9) (p < 0.0003), and C and P scores were higher in the 3 ANS scores with wasting. CONCLUSIONS: Campbell and Pugh 5-15 scores correlated closely and can be used interachangeably. As C does not contain the more elaborate prothrombin time determination, it probably can be used anywhere in the world. Ascites (degree) and Ascites/Nutritional State (ANS) scoring only use history and physical examination and are, or remain, although less refined, clinically relevant.

Physician's working diagnosis compared to the Euricterus Real Life Data Diagnostic Tool Trial in three jaundice databases: Euricterus Dutch, independent prospective and independent retrospective.

BACKGROUND/AIMS: In the European Union Euricterus Project on (sub)Icterus proforma, the history and physical examination items were to be used for the physician's working diagnosis (PWD) and 'among others, for the development of the real life data electronic diagnostic tool, Trial. Trial delivers diagnosis probabilities based on Bayes' Theorem (B), completed by Trial Algorithm (TA). We wanted to compare the diagnostic accuracies (PWD and Trial probabilities as a percentage of the final diagnosis (FD) in a patient population) in 3 Dutch databases. METHODOLOGY: The inclusion criteria for both Euricterus and Trial were age > or = 16 and bilirubin > or = 20 mmol/l. Euricterus data gathering took place at the bedside on a proforma with (among other questions) 79 questions on history and physical examination as well as the diagnosis levels for the PWD (1 alternative possible) and FD (17 disease categories, dc). Trial was developed on the data of 7,104 Euricterus patients and its data-entry Demo has the same questions. It calculates the probability of each diagnosis of the 17 dc as a percentage, as each significant finding is encountered (BO, Bayesian Overall). It can simultaneously calculate the resemblance of the patient's signs and symptoms to each disease concomitantly (BV, Bayesian Vertical), and to any subset of a disease. Any probability is further tested for compatibility using TA, a subset of BV, delivering TA-PWD, TA-BO and TA-BV. The Trial test patients came from 3 databases: a Euricterus Dutch Patients Random Sample EDRS (n = 184, internal database) and 2 independent databases: prospective P (n = 80) and retrospective R (n = 152), totalling 416 patients. RESULTS: The accuracies of PWD and Trial showed no differences between the databases, and the results are therefore pooled (n = 416). With testing on the highest probability found, the PWD accuracy was 78%, TA-PWD 81%, TA-BO 74% and TA-BV 72%. The true FD's were mentioned (at any probability) in the PWD in 86%, TA-PWD in 92%, TA-BO in 94% and TA-BV in 91% of the patients. Testing only patients whose FD was "certain" or whose data were without omissions did not improve accuracy. Testing on probability > 95% improved BO and BV accuracy, but not TA-BO or TA-BV. CONCLUSIONS: The Physician's Working Diagnosis accuracy was approximately 80% and did not greatly improve after TA. The Trial TA-BO and TA-BV accuracies were only slightly less than the PWD. For well-trained physicians, Trial strengthens the physician's judgment, and for those less trained (or those to be trained), it delivers a (sub)icterus diagnostic disease probability at nearly consultant level.

The reliability of thrombotic tendency measured by intravascular wires in the rat.

The objective was to determine if the amount of thrombus on two adjacent wires in an artery or in a vein was similar, and whether an upstream wire affected thrombosis on the downstream wire. Two 2 cm platinum wires were placed at adjoining sites in the abdominal vena cava and a further 2 in the abdominal aorta in 26 male and 24 female rats. In the artery, mean thrombus weight on the aortic downstream wire, set where the vessel is narrow, was significantly (p < 0.001) less than on the upstream wire, but the two correlated fairly well correlation coefficient (r = 0.608). In the vein, mean thrombus weight deposited in 1 hour was comparable on the pairs of wires both in males (r = 0.819) and females (r = 0.805). The mean downstream thrombus was slightly (10%) heavier than the upstream one both in males and females, a possible effect of vessel diameter, or of an activation by the upstream wire of thrombosis on the downstream one. An experiment to clarify that issue showed mean downstream venous thrombus to be again heavier than mean up-stream in both sexes (22 males, 30 females), and heavier than in controls in which no upstream wire was inserted. The platinum wire venous model seems to measure individual thrombotic response in a reasonably reproducible way in the rat. Upstream venous wire appears to activate thrombosis downstream from it by some 10%.

Quantitation of the thrombotic effects in artery and vein of the increase in coagulation factors during normal pregnancy in the rat.

Coagulation factors increase and fibrinolysin activity decreases in pregnant women. While the nett change in thrombotic tendency is unmeasured, venous thromboembolism increases five-fold in this group. We measured thrombus formation in vein and artery on standard platinum wires in 45 near-term pregnant rats, 19 pregnant for the first time and 26 for the second time, and in 33 never-pregnant controls. No significant increase in arterial thrombus occurred in the pregnant rats. Venous thrombus, however, increased by 65% in rats pregnant for the first time and 176% in those pregnant for the second time, compared to never-pregnant animals. Their mean increase in coagulation factors VIII, X, V, VII and II varied from 165 to 268%. Factor VIII level (r = 0.59, p < 0.05) correlated with venous thrombosis level, but the rarity of spontaneous thrombosis did not permit the limits of risk to be determined. Factors VII, X and V showed little correlation with thrombus weight (r = < 0.16) and Factor II an insignificant one. Monitoring factor VIII levels in pregnant women might help identify a group at risk of thromboembolism and establish a threshold for prophylactic intervention.

Survival probabilities of Pugh-Child-PBC classified patients in the euricterus primary biliary cirrhosis population, based on the Mayo clinic prognostic model. Euricterus Project Management Group.

BACKGROUND/AIMS: Estimation of prognosis becomes increasingly important in primary biliary cirrhosis (PBC) with advancing disease and also with regard to patient management. The ubiquitous used Pugh scoring for severity of disease is simple while the Mayo model which has been validated for survival estimates is more sophisticated. We wanted to investigate whether Pugh and Mayo scores correlate (they have 3 of 5 variables in common) and if so whether a survival probability based on Mayo data could be affixed on Pugh classes and scores obtained in the same patients. METHODOLOGY: All variables used for Mayo Clinic Prognostic Model (Mayo) scoring and Pugh-Child-PBC (Pugh) scoring were available in 143 PBC patients of the Pan European database Euricterus. Pugh scores P5-P15 and has classes A (P5-6), B (P7-9) and C (P10-15). We subdivided P5 in P5A (patients with albumin > 40 g/l plus prothrombin time < or = 12 secs) and P5B (the other patients in P5). We designed a category Pugh Early (PE) for patients with P5A characteristics and bilirubin < 17 mmol/l. Mayo scores R0-R15-with 1-7 years survival probabilities S-and has risk classes Low (L), Intermediate (Int), High (H) and Very High (VH). RESULTS: The estimated survival probabilities of the 143 patients ranged from 88% at 7 years to 0% at 1 year, median 14% at 5 years. The Pugh and Mayo scores correlated r = 0.87 (p < 0.0001) and except age with P, all Mayo and Pugh variables correlated with both R and P at p < 0.0001. Survival in Pugh class A was median 43% at 7 years and was not different from survival in Mayo L+Int (p 0.58). In Pugh class B 7 years survival was 2%, not different from Mayo H (p 0.25). Survival in Pugh C was median 24% at 1 years and better than Mayo VH (p 0.02). Between P5A (survival 78% at 7 yr) and R 3-4; P5B-6 (40% at 7 yr) and R5; P7 (22% at 7 yr) and R6; P8-11 (12% at 5 yr) and R7-8; and P12-14 (5% at 1 yr) and R9-10 no significant differences were found. From P8 upward there was a steep increase in death rate. PE has a 7 year survival of at least 89%. Charts of projected survival estimates for Pugh scores and classes are presented. CONCLUSION: It was possible (affixing Mayo to Pugh) to define 1-7 years survival probabilities to Pugh classes and scores for the last 7 years of the disease, i.e. the most important period for therapeutic decisions. These results need to be validated in other PBC populations.

Primary biliary cirrhosis: an electronic diagnostic tool trial based on symptoms, (past) history and signs only, using the European database euricterus. The Euricterus PMG.

BACKGROUND/AIMS: Primary Biliary Cirrhosis (PBC) is a relatively rare chronic progressive disease in which a working diagnosis of PBC easily leads to a final diagnosis by testing for anti-mitochondrial antibodies. Liver transplantation is the only effective treatment. The aim of this study was to test an electronic diagnostic tool (tool) for it's ability to include PBC in the working differential diagnosis. METHODOLOGY: In the European Union Euricterus project a large number of (sub)icteric patients in 17 discrete disease categories, PBC being one of them, were gathered prospectively. A tool was developed-using Bayes (B) and Trial Algorithm (TA) pattern-recognition and based on items related to the history, symptoms and signs of all Euricterus patients. We have tested the diagnostic tool on 143 PBC Euricterus patients. RESULTS: PBC was mentioned by the tool in 86% (B) and 91% (TA) of the 143 patients. These figures were higher for patients under 60 and (TA only) females. Females under 60 (n = 89) scored 92% B and 96% TA. A sole diagnosis of PBC was made in 31% (B) and 66% (TA). In the other patients with a PBC probability, 7 other (first) diagnoses were presented by the tool of which non-alcoholic active liver disease and pancreatic or biliary carcinoma were the leaders. These 7 diseases appeared evenly distributed along the percentual probabilities of PBC given by the tool (B) and also along Pugh and Mayo scores (B and TA). PBC was mentioned by the tool in all patients with a Pugh score 10 or higher (advanced disease, class C). In the patients in whom the tool did not mention PBC, the primary diagnoses came from 9 other disease categories. CONCLUSION: This electronic tool has been able to identify PBC as one of the differential diagnostic modalities in the large majority of a present population of PBC patients.

Effect of film size on production of foreign body sarcoma by perforated film implants.

Sarcoma may arise on unabsorbable foreign bodies in rodents and more rarely in man. Perforations of the implant reduce its carcinogenicity so that nitrocellulose filters of pore size 0.45 micron have failed to induce tumour. We examined whether increase of surface area would restore carcinogenesis to film with such pore size. Nitrocellulose filters of 25 mm diameter and pore size 0.45 micron were implanted singly, in pairs and in trios subcutaneously in 3 respective groups of BALB/c mice (total 97) and observed for sarcomagenesis for 100 weeks. No tumour arose on the singles (surface area 0.98 mm2), while 7 arose on the paired (1.96 mm2) at a mean of 54 weeks and 16 on the trios (2.95 mm2) at a mean of 46 weeks (differences significant at p > 0.01). A sufficiency of surface area restores carcinogenicity to perforated foreign surfaces in mice. Surface area is dominant over film perforation size in film sarcomagenesis.

The quantitative reduction by acute-dose warfarin of venous thrombosis in normal and hyperthrombotic rats.

Warfarin was tested for its relative ability to reduce thrombosis in two series of rats. In one series both the warfarin and control animals were made hyperthrombotic by an infusion of ellagic acid just before thrombosis was measured. In the second series (termed normothrombotic) no thrombotic stimulant was given. In all, 179 test and 109 control animals were used. Warfarin was given in varying doses to the test animals. Ellagic acid was administered as a single standard dose. At operation, two test animals and one control of similar weight were operated on concurrently. Thrombosis was measured by the weight of thrombus occurring on a standard 2 cm intravenous platinum wire in one hour. In optimum dose, warfarin reduced thrombus formation by 74% in the unstimulated series and by 83% in the hyperthrombotic one, when the mean factor II levels were 18% and 19% respectively. The residual thrombus under warfarin treatment was, however, greater in the hyperthrombotic than in the unstimulated animals at all levels of factor II. Best correlation of thrombus weight was with factor II in unstimulated animals.