Children fathered by men treated for testicular cancer conceived before, during and after chemotherapy--examination for evidence of congenital malformations, malignancies and immunological defects. Hundred children of 64 fathers with testicular tumour treated from 1979 on at the National Institute of Oncology, Budapest were studied. Three groups were formed on the basis of the time of conception. 59 children were born before the illness of the fathers, 19 during the 9 pretreatment months and 22 during or after combined chemotherapy. Family anamnesis, perinatal and gestational data were listed, thereafter physical, laboratory, immunological, psychiatric, and, if required, radiological examinations were made. No difference was detectable in the somatic and psychiatric status of the three groups, development was well balanced, corresponding to age. Protocols of the combined chemotherapy applied and incidence of anomalies, malformations, malignancies and other diseases were recorded. Their incidence was similar in all three groups though frequently this was higher than that of the normal population. Often cumulated incidence of severe congenital malformations was found in the group conceived after concluded therapy where twice as many girls were born as boys. The interval between conception and the end of therapy was established in the case of children conceived during and after therapy. This was shortest in the case of healthy children, the number of healthy children conceived during cytostatic treatment was also remarkable. Further compilation of data and individual evaluation of case reports is recommended.


Prognostic data of the second follow-up in childhood wheezy bronchitis. 206 non-selected children who had wheezy bronchitis before two years of age were observed in the first follow-up (1985) about 9 years after their clinical wheezy episode. Among them 31 patients (15%) showed bronchial hyperreactivity (B.H.) after acetylcholine challenge and 9 children became asthmatic. In the second follow-up (1988) 28 children who had B.H. and randomly 17 children who did not have B.H. participated. The prognosis of wheezy bronchitis is good, there was no new asthmatic child at this time. The B.H. was found to diminish only in 7 cases. During the last 3 years wheezy episodes developed only in 5 asthmatic patients. The skin prick test (SPT) positivity did not change (26% versus 29%). The familial atopy in the group B.H. is higher (43%) than in the group non B.H. (23%) but the difference is not significant (X2 = 1.72). No significant correlation was found between the familial atopy and SPT positivity. The familial smoking is higher in the group B.H. (78% versus 64%) but no significant influence on the B.H. (X2 = 1.03) could be detected.


Monitoring the therapy of acute lymphoid leukemia (ALL) in children--changes induced in clinical, cytological and immunological parameters during treatment of high malignancy ALL with ALL-BFM 88. The ALL-BFM 88 RF greater than 1.7 treatment of high malignancy ALL patients in remission was monitored at the 4th week of Protocol I. The qualitative and quantitative processing of parameters indicating cellular transformations by light and electronmicroscopy was performed in lymphocytes separated from peripheral blood drawn at scheduled times of therapy. The immunophenotype of sample lymphocytes was determined by indirect immunofluorescent techniques, by listing the percentual level of CD2, CD3, CD4, CD8, CD19 surface antigens. The incidence of infections, confirmed clinically and bacteriologically, was recorded. The parameters of the patients were compared to those of healthy children. In the group of patients with high malignancy in the intensive period of ALL-BFM 88 RF greater than 1.7 therapy the incidence of cells rich in organelles, dense granules and vacuoles was significantly (p less than 0.05) higher compared to the control cells, poor in structures. During the weeks of induction and after the consolidating combination with VM-26+ARA-C the expression of surface antigens of the lymphocytes was reduced. That means that up to the introduction of maintenance treatment the presence of surface antigens remained below the range of normal deviation. These data obtained during monitoring revealed that the morphological and functional integrity of cells was damaged in patients with high malignancy ALL during intensive therapy, though only temporarily.


Diagnostic value of clinical features and supplementary investigations in tuberous sclerosis in children. The author evaluates the usefulness of clinical features and some supplementary investigations in diagnosis of tuberous sclerosis in children. 52 children ranging in age from 1 month to 14 years took part in the study. Usually depigmented naevi were the first sign of tuberous sclerosis and were seen in 98% of affected children. Epileptic seizures occurred in 96% of patients, mostly during the first year of life. Axial computed tomography of brain seems to be very helpful in diagnosis of tuberous sclerosis in every age. Multiple periventricular calcifications were found in 98% of children. Two-dimensional echocardiography was especially useful in infants and children below 2 years of age. Retinal hamartomas were found in 25% of children with tuberous sclerosis. In some cases these changes were revealed during the first year of age. Abnormal EEGs were found in 90% of recordings. The EEGs tended to improve with increasing age. In 25% of children one of parents was affected by tuberous sclerosis. The careful skin examination of both parents can be especially helpful in children with doubtful diagnosis of tuberous sclerosis.


Insulin, growth factors, and cancer cell energy metabolism: an hypothesis on oncogene action. The hexokinase-mitochondrial acceptor theory provides a model of insulin action which unifies the metabolic effects of this hormone and suggests that these result from insulin's stimulatory effect on mitochondrial ATP synthesis. There are similarities between these changes in cells exposed to insulin and in mitochondria of transformed cell lines and cancer cells, where an increased binding of hexokinase to mitochondria is observed. This phenomenon may play a key role in the high rates of glycolysis sustained by cancer cells under aerobic conditions. Structural and functional evidence support the hypothesis that certain growth factors and oncogenes act through stimulation of oxidative phosphorylation via promoting HK binding to mitochondria.


A sensitive radioisotopic assay of myo-inositol: its application to rat pancreatic islets. A radioisotopic procedure for the assay of myo-inositol is presented. It is based on the generation of NADH from NAD+ in the reaction catalyzed by myo-inositol dehydrogenase and the subsequent NADH-dependent conversion of 2-[U-14C]ketoglutarate to 14C-labeled L-glutamate in the reaction catalyzed by glutamate dehydrogenase. This method was applied to the measurement of myo-inositol in rat pancreatic islets. The myo-inositol islet content was decreased when the animals were fed a diet deprived of myo-inositol. When incubated in the absence of exogenous D-glucose, pancreatic islets, like parotid cells, released myo-inositol in the incubation medium. Over 90 min of incubation, a rise in extracellular D-glucose concentration increased the myo-inositol islet content, which was decreased, however, after incubation in the presence of carbamylcholine. These findings indicate that the myo-inositol content of islets is affected by nutritional and other environmental factors.


Effect of chronic metformin treatment of hepatic and muscle glycogen metabolism in KK mice. Noninsulin-dependent diabetic KK mice, aged 90-100 days, with hyperinsulinemia and insulin resistance were treated with either metformin (N = 13) or water (control, N = 10) orally at a concentration of 50 mg/kg twice daily for 28 weeks. Age-matched nondiabetic Swiss Webster (SW) mice were also similarly treated. Liver and skeletal muscle glycogen synthase and phosphorylase enzymes were determined in all groups of mice. Both enzymes were significantly lower in control KK than in control SW mice. Metformin did not influence either of these enzymes in nondiabetic SW mice. However, it significantly increased the active form of glycogen synthase (a form) in both the liver and muscle of KK mice. Metformin also increased the active form of phosphorylase (a form) in the liver but not in the muscle of these mice. Hepatic glycogen content was similar in both control and metformin-treated KK mice. However, the muscle glycogen content was significantly higher in metformin-treated than in control KK mice. These data suggest that metformin preferentially stimulates glycogen synthesis in skeletal muscle, and this seems to be responsible for the observed improvement in fasting glucose and glucose response to an oral glucose load in KK mice.


The measurement of mitochondrial beta-oxidation by release of 3H2O from [9,10-3H]hexadecanoate: application to skeletal muscle and the use of inhibitors as models of metabolic disease. We describe the use of a simple assay for beta-oxidation which depends on the release of 3H2O from [9,10-3H]hexadecanoate. This was compared with the use of [1-14C]hexadecanoate which gave comparable results when all the products of beta-oxidation were measured. The prediction that 75% of the tritium is released as 3H2O and 25% as [2-3H]acetyl units was confirmed. The assay was used successfully to demonstrate impaired beta-oxidation in tissue preparations from rats treated with etomoxir and methylenecyclopropylpyruvate which are known inhibitors of beta-oxidation. Abnormalities of beta-oxidation were also detected in skeletal muscle from patients with defects of mitochondrial oxidation.


Blood isoprene concentrations in humans and in some animal species. The concentrations of isoprene, the main hydrocarbon of human breath, were measured in the blood of humans and of different animal species (rat, rabbit, dog, ewe, cow). In human blood, the concentrations of isoprene were between 15 and 70 nmol/liter (mean value of 37 +/- 25 (SD) nmol/liter). In the blood of the different animal species tested, traces of isoprene were unambiguously detected by mass spectrometry, but the levels were always lower than 1 nmol/liter.


Abnormal insulin receptor binding in cultured monocytes in myotonic muscular dystrophy. Even though one of the characteristic features of myotonic dystrophy (MyD) is the high level of circulating insulin, 125I-insulin-binding data in MyD have been controversial. In the present study we utilized cultured monocytes to avoid problems of reproducibility and variability in age, and examined the affinity and binding characteristics of 125I-insulin binding in MyD patients and controls. The Bmax and mean affinity constant, Ka, were significantly lower, while the number of receptors per cell had increased in the patient group as compared to the controls. The data confirm our earlier findings that there is no primary defect in insulin receptors in MyD, and the disturbed insulin response may be due to an abnormality in the membrane environment. Since the insulin receptor is an integral membrane protein, abnormal plasma membrane lipid composition may lead to impaired lipid-protein interactions, and hence affect the binding characteristics in MyD.


Ca(2+)-ionophore A23187 and the Ca(2+)-mobilizing hormones serotonin, vasopressin, and bradykinin increase mitochondrially bound hexokinase in muscle. We show that a rise in cytosolic-free Ca2+ in muscle, induced by Ca(2+)-ionophore A23187 or by the Ca(2+)-mobilizing hormones serotonin, vasopressin, and bradykinin, increases the binding of hexokinase to mitochondria in muscle. This increase could be prevented by treatment with the calmodulin antagonists trifluoperazine or CGS 9343B (a novel, potent, and selective inhibitor of calmodulin activity) which strongly suggests that calmodulin is involved in the Ca(2+)-induced binding of the enzyme to muscle mitochondria.


Enzyme-linked immunoassay of haptocorrin: analysis of milk and granulocytes. An enzyme-linked, sandwich-type immunoassay method was described for quantitive assay of haptocorrin. The ranges of haptocorrin concentrations measurable by the method were comparable with those by radioimmunoassay. Using the method, the mean +/- SD of haptocorrin was 4.83 +/- 1.23 micrograms/ml in the colostrum (4th and 5th days after parturition), 3.17 +/- 1.77 micrograms/ml in the mature milk, and 21 ng/10(4) granulocytes (634 ng/mg protein). Haptocorrin from milk showed a homogeneous band at 66 kDa on SDS polyacrylamide electrophoresis followed by immunoblotting, while that from the granulocytes exhibited several closely aligned bands at 80 kDa and one or two bands at around 20 kDa.


Detection of molecular deletions in the Chinese DMD patients using two amplified dystrophin sequences. This Brief Communication reports the detection of molecular deletions in Chinese DMD patients using two new amplified dystrophin DNAs involving the regions of exon 49 and 50. The results show that over 50% of the DMD deletions can be rapidly detected by PCR amplification of these two dystrophin sequences.


[CT in the study of laryngeal carcinoma]. The advances in conservative surgery regarding larynx carcinoma makes necessary nowadays a more precise staging than was required before. In this work we describe our experience with the 54 cases which were studied in our center from March 1988 until October 1990. The radiological findings using CT were correlated with those by clinical exploration and checked by pathology in all cases.


[Contribution of clinical and diagnostic aspects of vocal cord nodules, polyps, and Reinke's edemas]. We have made a retrospective study about 100 cases of vocal cords nodules, polyps and polypoid degeneration: we study the clinic and diagnostic aspects for this pathology that has been considered of functional cause. We also have made a review of literature.


[Prognostic value of lymph node histologic pattern in epidermoid carcinoma of the larynx]. Histologic specimens from 48 patients with squamous cell carcinoma of the larynx treated exclusively by surgery were studied with special attention paid to the reactivity of regional lymph nodes. The lymph nodes were classified into four microscopic patterns of immune response: lymphocytic predominance, sinus histiocytosis, germinal center predominance and unstimulated or lymphocytic depletion. As a result no correlation were then made between the patterns and survival rate at 5 year follow-up.


[Diminution of epidermal growth factor in saliva of patients with carcinoma of the oropharynx]. EGF, the Epidermal Growth Factor which is found ubiquitous in the human body can also be detected in saliva and increases in general proliferation and differentiation of epithelial cells which enables mucosa regeneration to maintain their protective function. In this study concentrations of EGF in saliva of smokers and patients with carcinoma of the oropharynx were examined. Both groups showed a decreased concentration compared to non smokers. We studied also secretion of EGF in saliva after smoking. Only the group of non smokers showed a transient elevation of EGF.


[Value of myotomy of the lower constrictor in surgery of tracheo-esophageal puncture]. The importance of the inferior myotomy for speech restoration in total laryngectomized patients following not only primary techniques (speech restoration by tracheo-esophageal puncture during total laryngectomy) but also secondary punctures, is well documented. In this paper, the results obtained by manometric studies applied to 25 patients divided into two groups are shown (the first group) (15 patients) following primary techniques, and the second one (10 patients) following secondary punctures. We observe a sphincter pressure decreasing after secondary myotomy in those patients which previously presented dysphagia, prostheses breaking or intermittent speech, therefore considering the inferior constrictor myotomy as of great value in speech rehabilitation.


[Post-surgical results of 48 septal perforations]. We have studied the post-surgical results of 48 perforations of the nasal septum, regarding their etiology, location and size, which must be taken into account when deciding which closure technique to use.


[Acute external otitis: retrospective study of 170 cases]. 170 external otitis have been diagnosed and treated for one year (1989) in our ENT department. The etiology of the otitis was both bacterial and mycotic. The purpose of this paper is to study the clinical, therapeutic, epidemiologic and microbiologic aspects of this type of otitis.


[Calcium phosphates in otologic surgery. III. The role of fibrin glue in the integration of calcium phosphate implants. Experimental study]. Obliteration of the mastoid cavity has been realized with calcium phosphates associated to heterologous fibrin glue in otologic surgery. 22 artificially created epitympanic and 65 femoral defects in 22 rabbits were closed by means of dense or porous granulates of hydroxyapatite with homologous fibrin glue. Follow-up was for three weeks to 6 months. Osteo-integration of the implants was significantly delayed in the first weeks, comparing the integration of the same phosphates without fibrin glue.


[Audiometric value of workers exposed to different levels of occupational noise]. We have obtained the information collected in routine clinical examinations of 806 healthy workers. We have studied the threshold hearing levels (audiometries) of our sample. Workers have been classified under three groups of noise exposure--low, medium and high--according with their job and with the activity of the company where they work. We have take into account the influence of factors such as age, use of ototoxic substances (certain antibiotics, tabac, alcohol) or presence of otoscopic irregularities which can affect the hearing levels. In general, hearing losses increase with noise exposure in all the explored frequencies; in the other hand, in the three groups of noise exposure the highest loss is for the 4000 Hz frequency. Losses in left hear are systematically higher than in right hear.


Race and ethnicity in health research.

Race and ethnicity in health research. 'Race' and 'ethnicity' are increasingly being used as variables in health research. However, studies have been mainly descriptive and have not been used to develop and evaluate strategies to improve health care. In part this reflects the poor analytical standards. The status of the concepts of 'race' and 'ethnicity' as research tools are rarely considered and there is poor consistency in terminology. This paper gives an overview of the research literature and raises questions about the validity of 'race' and 'ethnicity' as epidemiological variables. The tendency to collect routine ethnic data and include ethnic variables in an ad hoc and uncritical way in the United Kingdom and other countries may help transform minorities into mere statistical categories and produce data and findings which reinforce stereotypes. Multiculturalist ethnic health explanations also tend to displace more material explanations of health outcomes. It is concluded that more thought and care is needed before data are routinely categorized by ethnicity, or race or ethnicity are included as variables in research.


[Influence of acoustic stimulation in the maturation of the auditory pathway]. The aim of this study is to analyze the relationship between age and the maturational changes occurring in the peripherical auditory system and the influence of the acoustic stimulation. With this purpose Auditory Brainstem Responses (ABR) were recorded at the 35 and 39 weeks gestational age, in 56 ears of 28 premature infants. The ABR were analyzed the changes in latency values of the I, V waves and I-V intervals. In order to know the influence of the acoustic stimulation on the development of auditory pathway, we made 2 groups with the 28 premature children, one of them control group and the other stimulated with maternal voice from 35 till 39 weeks. The stimulated group had one maturate auditory evoked responses at 39 weeks gestational age. Showing a latency decrease wave V and I-V interval, compared to control group.


Selective medical examination at school entry: should we do it, and if so how? A prospective study was conducted on 82 consecutive 5+ examinations performed by four school doctors over a period of two months. The aim was to assess the impact of applying selection criteria for examination. Information gathered included immunization status, history of previous developmental assessments and previous detection of problems, and the result of the examination for each child. Forty-three per cent of children were up to date with their immunizations, 66 per cent had had a six-week check and 38 per cent and 17 per cent had been assessed at 15 months and 2 1/2 years respectively. Forty-eight problems were detected in 37 children (45 per cent), of which 27 had not been previously detected. Of these, 19 were detected by the school nurse before the examination as a result of hearing (nine) and vision (10) testing and measurement of height and weight (one). Of the remaining problems, four were presented by the parent, one by the teacher and two were detected by the school doctor. If a policy of selective examination had been in place in which children were called for examination only if they had never been assessed before, or where there were no records of a previous assessment, or if their immunizations were incomplete, or they had previous problems, or the school nurse or teacher or parent had expressed concern, all but four children would have been examined. It was concluded that this particular method of selection would be unproductive and that a system whereby the school nurse was responsible for screening and selection for examination would be preferable.(ABSTRACT TRUNCATED AT 250 WORDS)


[Surgical treatment of Eagle syndrome by way of the oropharynx. A case report]. The authors present one case of elongated Styloid process which surgeons was undertaken due to intense symptomatology. Oropharyngeal approach was used and showed to be the election way for resection.


[Adverse reactions to medications in patients in ambulatory otorhinolaryngology]. A 12 months prospective study to detect adverse drug reactions (ADR) was carried out in an ORL outpatients clinic. 52 patients (1.8%) out of 2891 examined suffered one or more ADRs. The incidence was higher in women and in older patients. 94% of the ADRs were mild to moderate and 3 patients suffered irreversible lesions. Reactions were most commonly located in the nervous system (50%) and gastrointestinal tract (21%). The most common drugs involved were cardiovascular (40%) and central nervous system (25%) active drugs. Papers concerning ADRs published from 1976 to 1985 in spanish otorhinolaringologic journals have also been analyzed. 0.88% of 1357 published papers described ADRs. The incidence of ADRs observed in our study is higher than expected from the low number of papers published on this subject.


Rationality and the use of formulae in the allocation of resources to health care. The paper describes how the apparent move towards rationality in allocating resources in the National Health Service using statistically based formulae is illusory. This is not just a technical problem of poor application of statistical techniques. The basic problem is to find a combination of factors reflecting dimensions of need and then appropriate weights with which to combine them within the context of the guiding principles of equity and efficiency. The paper explains how there has been little consistency in measuring need and how statistical methods have often masked the lack of appropriate data and models. Alternative approaches to measuring need within a policy context are discussed and a research agenda is outlined which, rather than concentrating on evermore complex statistical techniques, focuses on the necessity for more validly operationalizing 'needs' and their resource implications.


[Infraorbital bone hemangioma].

[Infraorbital bone hemangioma]. Osseus hemangioma is a rare tumor. Its concept and a etiology are not well established. We preset a review and a case of this tumor located in the upper maxilla. Clinical, of this exploration and pathology are studied in this paper. Antigen in factor VIII has been observed. Considerations on different diagnosis are made.


Non-consulters and high consulters in general practice: cardio-respiratory health and risk factors. The 1990 General Practitioner contract requires that health promotion and illness prevention services should be provided to all patients aged 16-74 years. Consultation rates over a period of three years were examined in 7010 middle-aged men in Great Britain to compare the cardio-respiratory health and risk factor status of non-consulters (men who did not consult in three years) with those of average consulters (men who consulted 3-5 times in three years) and high consulters (men who consulted 24 or more times in three years) to assess their relative need for health promotion and illness prevention services. The non-consulters (n = 1025) were remarkably similar to the average consulters (n = 1585) in health and lifestyle characteristics. The high consulters (n = 306) had a greater burden of ill-health and a less healthy lifestyle. Chest pain on exertion, chronic bronchitis, breathlessness or wheeze were present in 23 per cent of non-consulters, 27 per cent of average consulters and over 50 per cent of high consulters. Similarly, 48 per cent of the non-consulters smoked, drank heavily or were obese compared with 47 per cent of the average consulters and 61 per cent of the high consulters. The prevalence of recall of high blood pressure which had been diagnosed by a doctor rose from 6 per cent in non-consulters and 10 per cent in average consulters to 29 per cent in high consulters.(ABSTRACT TRUNCATED AT 250 WORDS)


Unexpected high mortality rates found in a review of district statistics: what action is appropriate? The regular review of statistical and other data is now a routine public health activity in district health authorities. The interpretation of findings indicative of high or otherwise unexpected rates of mortality or disease may be complicated by small numbers, and also by questions concerning the reliability with which the available data describe the problems. Judgement about whether to undertake further investigation of these problems is subject to uncertainty about the likely effectiveness and efficiency of the investigation, and of any remedial action that would be expected to follow. Examples of these problems are explored in relation to the finding of a high rate of infant and late neonatal mortality in a district population, and a high rate of female suicide. The late neonatal death rate showed a rising trend over a period of four years and was significantly elevated above national and regional rates. The perinatal death rate was not correspondingly low, nor had there been an excess of multiple births over the period. A review of neonatal death certificates did not demonstrate any identifiable problems relating to either the cause or place of death, and the high rate subsequently reverted to the expected level without further intervention. In the case of female suicide, analyses including deaths by misadventure and open verdicts were carried out to allow for possible differences between men and women in the certification of suicide. However, this did not alter the conclusions, and further investigation of the circumstances of death is planned to assess the potential for preventive action in the locality.(ABSTRACT TRUNCATED AT 250 WORDS)


Criteria for audit of annual reports on the public health: do they exist? Production of an annual report is a statutory duty of the Director of Public Health; its production uses significant resources. Audit of reports may help in the effective use of these resources. For audit to be performed criteria need to be agreed upon which to set standards. The present study investigated whether Directors of Public Health agree on suitable criteria for the audit of annual health reports. Districts within North East Thames Regional Health Authority were paired; Directors of Public Health, who had produced the most recent report, interviewed each other using a semi-structured questionnaire. Reports were examined for the presence of the 'key indicators' from the common data set. The results show that there was little agreement on what were suitable criteria to evaluate reports. The criteria in the Toolbox produced by the Faculty of Public Health Medicine were thought to be unsuitable because of the diversity of Districts. Effective audit requires agreed criteria and standards but these were not identified. The Faculty criteria were not considered suitable. Directors of Public Health may develop criteria that they consider suitable for audit of their annual report in discussion, focusing upon their objectives in producing an annual report. This should be the first step in the audit process and an integral part of producing an annual report.


Inappropriate reattendances in out-patient departments. In an attempt to identify the number and characteristics of inappropriate reattendances at out-patient clinics, clinic doctors and patients in two specialties throughout a health district were given a questionnaire to complete on every patient attendance over one week. Four hundred and fifty-two patients were seen, and 293 were asked to reattend: in some 80 of the latter cases the clinic doctor felt that the GP could nevertheless manage the problem. These 'inappropriate' invitations to reattend were more likely to be given by junior hospital staff to long-standing patients of the clinic attending for monitoring purposes. The patients involved in these 'inappropriate' requests to reattend also tended to think that their GP could manage the problem. It is concluded that discharge policy needs to be made more explicit and training for juniors organized if out-patient resources are to be used most efficiently.


A study of 'inappropriate' attendances to a paediatric Accident and Emergency Department. 'Inappropriate' attendance to Accident and Emergency Departments (AEDs) has been shown in many studies to be a sizeable problem. However, only one previous study has investigated inappropriate attendance to these departments amongst children. In this paper we report an investigation of 'inappropriate' usage of a children's AED in Nottingham. Information was collected relating to a representative sample of children who attended this department during September and October 1989 by interviewing the adults accompanying them to the AED and by examining the children's AED medical records. Using defined criteria, the doctors treating each child within the AED assessed whether their attendance was 'appropriate' to the department. Nearly a third (30.1 per cent) of the patients studied were subsequently considered to be inappropriate attenders to this department. This proportion was highest amongst younger children, those from families of lower social class and those living closest to the hospital. 'Inappropriate' attendance was not found to relate to the availability of general practitioners. The reasons stated for choosing to attend the AED suggested that these attendances resulted from perceptions of the adult(s) accompanying the children to the department. In view of this finding, action is required to correct these perceptions, although it is recognized that this may be difficult to achieve.


Improving obstetric outcomes in ethnic minorities: an evaluation of health advocacy in Hackney. Ethnic differences in birthweight, perinatal mortality and other obstetric outcomes are now well known. In some districts with a significant ethnic minority population, services are provided for non-English-speaking women using maternity units. Various models have developed, including translators, interpreters, Linkworkers, the Department of Health funded Asian Mother and Baby Campaign and health advocates. This paper describes the evaluation of a health advocacy programme in Hackney, East London. The advocates do more than simply interpret language. Anecdotal examples of how this approach changes clinical practice encouraged the project steering group to commission a study to test the hypothesis that health advocacy could improve obstetric outcomes in non-English-speaking women. A retrospective study was carried out comparing 1000 non-English-speaking women delivering at the Mothers' Hospital, Hackney, in 1986 who had been accompanied by an advocate with women delivering at the same hospital in 1979 and at a reference hospital, Whipps Cross. The study found significant differences between the groups in three outcomes: antenatal length of stay, induction and mode of delivery. The changes in Caesarean section were of particular note. The rates rose from 11 to 17 per cent at the reference hospital, whereas they fell from 10.8 to 8.5 per cent at the Mothers' Hospital. This is highly statistically significant. Although these changes cannot be directly attributed to health advocacy, it was considered reasonable to deduce that improved communication could have influenced clinical practice. These findings suggest that health advocacy may offer a mechanism to address some of the adverse obstetric outcomes observed in ethnic minorities.


Surgeons' views of day surgery: is there a consensus among providers? Managers and purchasers of health services are being encouraged to expand day surgery as a means of providing high-quality care and reducing costs per case and waiting times. This study examined general surgeons' views of day surgery with particular reference to day case inguinal hernia repair. A postal questionnaire was completed by 240 consultants (85 per cent) in four Regional Health Authorities. Only 11 per cent were regularly undertaking day case inguinal hernia repair, a further 44 per cent held positive attitudes towards this form of treatment and 45 per cent were not interested, with attitudes varying by age and region. Major constraints perceived by those with positive attitudes were the lack of facilities at a hospital level and problems of community services. Negative attitudes were associated with concerns about post-operative complications and pain, and assumptions about patients' preferences. This demonstrates a considerable range in surgeons' attitudes to day surgery despite its formal endorsement by professional bodies, and identifies what are perceived as the organizational and clinical barriers to its wider introduction. It is suggested that eliciting provider views and concerns forms an important requirement for the successful implementation of organizational change.


Assessing the effects of a health promotion programme for elderly people. Physical exercise is an increasingly popular health promotion activity for elderly people, although evidence of its effectiveness is limited. We aimed to evaluate the impact of the exercise component of the Look After Yourself (LAY) package promoted by the Health Education Authority in two groups of elderly people attending the 10 weekly sessions which make up the LAY course. Classes 1 and 2 comprised 13 and 18 subjects, aged from 65 to 89 years, and from 58 to 87 years respectively. Class 1 subjects were white with the exception of one Jamaican man, and Class 2 subjects were all Afro-Caribbean. Subjects had measurements of shoulder joint flexibility, grip strength, blood pressure, weight and a self-perceived health questionnaire, the Nottingham Health Profile (NHP) completed at baseline, 10 weeks and at six months. Class 1 showed reductions in grip strength and a deterioration in pain and mobility dimensions of the NHP, whereas Class 2 showed large improvements in shoulder joint flexibility and a small and non-significant trend towards improved self-perceived health. Class 2 subjects felt that they had benefited, and just over half had continued with an exercise programme. These findings suggest that the effect of mild exercise on objective indicators and self-perceived health may depend on the context in which it is done, the type of exercise promoted, and that continued exercise is aided by the provision of further group classes. There is a need for evaluation of the impact of different types of exercise programmes, covering a wider range of indicators of fitness, in larger groups of elderly people.


In vivo derived HIV-1 nef gene products are heterogeneous and lack detectable nucleotide binding activity. Multiple HIV-1 nef genes were cloned from lymphocyte DNA of asymptomatic seropositive individuals by polymerase chain reaction (PCR). Sequence analysis of these clones revealed a unique set of nef variants with premature terminations (PCRnef 1 and 6), mutations at sites of potential posttranslational modification (PCRnef 2 and 3) and deletions. In common with laboratory isolates of nef, strong sequence conservation was observed in the central domain of nef and in the myristylation target sequence, with variable domains toward the N- and C-termini of the molecule. The biochemical function of nef remains elusive however, as the products of these genes cloned into a bacterial expression system failed to reveal any nucleotide binding activity.


Study of the interaction of HIV-1 and HIV-2 envelope glycoproteins with the CD4 receptor and role of N-glycans. In order to further characterize the interaction of human immunodeficiency viruses (HIV) with the CD4 receptor at the molecular level, a binding test was performed using iodine-labeled glycoproteins, 125I-gp160 from HIV-1 and 125I-gp140 from HIV-2, to bind to lymphoid cells expressing the CD4 receptor. The inhibition of binding of the radiolabeled glycoproteins to CD4+ cells by increasing concentrations of nonradiolabeled gp160 or gp140 was used to determine the affinity of the interaction between the glycoproteins and CD4. The gp-CD4 association occurs with a high affinity: K0.5 gpHIV-1 = 9 x 10(-9) M and K0.5 gpHIV-2 = 7 x 10(-8) M, indicating that the affinity of the interaction between HIV-2 gp140 and CD4 is 10 times lower than that observed with HIV-1 gp160. The N-linked glycans of the HIV-1 and HIV-2 glycoproteins account for a high proportion of their molecular mass (about 50%). Total deglycosylation of gp160 and gp140 by enzymatic treatment with Endo F-N glycanase occurred under nondenaturing conditions, indicating the high accessibility of the N-linked glycan chains in the three-dimensional structure of the molecule. Moreover, the deglycosylated proteins retained a significant binding capacity to CD4. These results show that the carbohydrate chains of HIV-2 gp140, as those of HIV-1 gp160, do not play a major role in the gp-CD4 interaction.


A randomized, double-blind, phase I/II trial of tumor necrosis factor and interferon-gamma for treatment of AIDS-related complex (Protocol 025 from the AIDS Clinical Trials Group). To determine safety and efficacy of tumor necrosis factor (TNF) and interferon-gamma (IFN gamma) in the treatment of patients with acquired immunodeficiency syndrome (AIDS)-related complex, a randomized, double-blind study was conducted. Twenty-five patients with AIDS-related complex and CD4 lymphocytes less than or equal to 500 x 10(6)/L attended an AIDS Clinical Trials Unit of a tertiary referral center. Patients were administered tumor necrosis factor (TNF) (10 micrograms/m2) or IFN gamma (10 micrograms/m2), or both intramuscularly three times weekly for 16 weeks. Side effects from all three preparations included fever, constitutional symptoms, and local reactions. No significant hematologic, hepatic, renal, or coagulation abnormalities were observed. CD4 lymphocyte counts, beta 2-microglobulin, p24 antigen levels, and anti-p24 antibody did not change significantly during therapy. Similarly, no significant change was noted in rates of HIV isolation from peripheral blood mononuclear cells or plasma. TNF and IFN gamma were tolerable after premedication with acetaminophen; however, no significant change in markers of human immunodeficiency virus infection was demonstrated. These cytokines alone do not appear to be of benefit, nor do they appear to hasten the progression of HIV infection.


Three-drug synergistic inhibition of HIV-1 replication in vitro by 3'-fluoro-3'-deoxythymidine, recombinant soluble CD4, and recombinant interferon-alpha. 3'-Fluoro-3'deoxythymidine (FLT), recombinant soluble CD4 (CD4), and recombinant interferon-alpha (IFN alpha) were evaluated in two- and three-drug regimens against HIV-1 replication in vitro. Peripheral blood mononuclear cells were studied using p24 antigen production as the virologic endpoints. FLT showed 2.5-fold higher efficacy and a similar selectivity index to zidovudine. Drug interactions were evaluated by the median effect principle and the isobologram technique. FLT, CD4, and interferon alpha at noncytotoxic concentrations inhibited HIV-1 synergistically in two- and three-drug combinations with a combination index smaller than one and dose reduction index greater than one. The three-drug regimen provided greater virus suppression than the two-drug regimen. These results suggest that FLT is an alternative agent to AZT for the treatment of HIV infection either as a single agent or in combination with CD4 and/or interferon-alpha.


Curdlan sulfate and HIV-1: II. In vitro long-term treatment of HIV-1 infection with curdlan sulfate. Short-term (1 h) treatment with a newly synthesized sulfated polysaccharide, curdlan sulfate (CRDS), showed relatively weak blocking effects on the binding of human immunodeficiency virus type 1 (HIV-1) to the surface of H9 cells. To investigate whether long-term treatment with CRDS could strengthen this effect, CRDS in various doses (0.1, 1, 10, and 100 micrograms/ml) was used in 2-week treatment periods in four separate protocols or "Procedures." SF titers and p24 antigen levels were partially suppressed during long-term CRDS treatment but returned to control levels after the treatment was terminated. In addition, no direct cytotoxicity of CRDS to H9 cells or H9/HIV-1 cells was observed in vitro in the course of continuous exposure to 100 micrograms/ml CRDS for 2 weeks. These results demonstrate the effectiveness of long-term treatment of cells infected with HIV-1 in inhibiting virus expression. The most dramatic inhibition results were obtained when the compound was present both at the time of exposure of cells to virus and during a long-term follow-up treatment. These results show that CRDS inhibits both the cell-free and cell-associated transmission of HIV-1 to host cells and interferes with early events in virus infection. In contrast, CRDS exhibits no significant virucidal activity and has little effect on already infected cells.


Treatment of the murine, retrovirus-induced lymphoproliferative immunodeficiency disease (LP-BM5) in C57BL/10 mice with the immunomodulator Imexon. Imexon (4-imino-1, 3-diazabicyclo-(3.1.0)-hexan-2-one) a cyanoaziridine compound was studied in the treatment of the murine retrovirus-induced immunodeficiency disease model of AIDS (LP-BM5, MAIDS). Imexon, in dose-dependent fashion, partially prevented the development of hypergammaglobulinemia and splenomegaly, and partially prevented the decline in the phytohemagglutinin-induced proliferative response of spleen lymphocytes when started 1 or 15 days after virus inoculation. There was a statistically significant reduction in these disease-associated manifestations. When animals were treated starting 78 or 92 days after virus inoculation, lymphadenopathy was completely abrogated and survival was significantly prolonged in a dose-responsive manner. Since Imexon and other cyanoaziridine compounds have been safely administered to humans, we suggest that this class of compounds be further investigated in both large animal models of HIV infection and in patients with HIV-induced disease.


The effects of AZT and DDI on pre- and postimplantation mammalian embryos: an in vivo and in vitro study. This study reports the effects of the nucleoside analogs dideoxyinosine (DDI) and 3'-azido-3'-deoxythymidine (AZT) on mammalian embryonic development. When administered to pregnant mice (at concentrations ranging from 10 to 300 mg/kg/day), through all or part of gestation, AZT and DDI did not result in any visible effect on mouse embryos nor did they cause any obvious malformation or defect at birth or during postnatal growth. Similarly, when embryonic or fetal mouse or human cells (from brain, limb buds, or different organ rudiments) were exposed to AZT or DDI in vitro, cytotoxicity was observed only in the mM range, with AZT showing slightly higher cytotoxicity and brain cells appearing slightly more sensitive to both nucleosides. However, even in cultures treated with very high concentrations of AZT or DDI, the reduction in the number of terminally differentiated skeletal myotubes, cardiocytes, neurons, and chondrocytes was similar to the reduction in the total number of cells, indicating that AZT and DDI did not selectively inhibit differentiation of any of the above-mentioned cell types. Finally, preimplantation mouse embryos (at the 2-cell or 4-cell stage), treated in vitro with micromolar concentrations of AZT, were arrested at the 4-cell stage. DDI or other nucleoside analogs tested did not have this effect.


Seroprevalence and cofactors of HTLV-I infection in Tumaco, Colombia. This study presents an analysis of the factors associated with HTLV-I seroprevalence in the endemic area of Tumaco, Colombia. During June to August 1988, 1,077 individuals were selected at random from a population of 45,594. The overall prevalence rate of HTLV-I antibodies was 2.8%. Among females prevalence was significantly higher (p less than 0.02) than among males. Rates increased substantially with age. HTLV-I prevalence among individuals with history of use of intravenous medications was significantly higher (p less than 0.001) than in those without such history. Logistic regression analysis included age in years, indicators for male gender, and for i.v. injections, and their interactions. Age was very strongly associated to HTLV-I infection among females. At early ages prevalence was not different between sexes, but females presented a significantly higher rate than males after age 42. History of i.v. administered medications was very strongly associated in the univariate analysis and, although significance was borderline in the multivariate analysis, it had the effect of doubling the odds of HTLV-I infection.


Frontiers in HIV-1 Therapy: fourth conference of the NIAID National Cooperative Drug Discovery Groups-HIV. This summary describes current studies in antiviral targeting as reported at the Frontiers in HIV Therapy conference, November 3-7, 1991, in San Diego, California. In parallel with the progressive steps in HIV-1 replication, the meeting covered potential antiviral targets starting from the time HIV-1 docks with the CD4 receptor to virus release. The summary concludes with current research trends to block HIV-1 growth.


Abnormal regional hypermethylation in cancer cells. Let me summarize by reviewing a model which is meant to raise as many questions as it answers (Fig. 2). What I have discussed today are data suggesting that during progression of solid tumors, like colon cancer, an increased cellular DNA methylating capacity characterizes the initial stages of multi-clonal hyperplasia. Despite this increase, the altered pattern of DNA methylation which subsequently emerges is largely manifest by a widespread hypomethylation of DNA. However, on a more regional basis, areas of hypermethylation appear which can affect strategic areas such as normally unmethylated CpG islands. These shifted DNA methylation patterns have the capacity to both follow, or cause, chromatin changes that can both directly silence genes critical for normal cell maturation--and/or participate in the structural chromosome changes which constitute genetic instability during tumor progression (Fig. 2). I suggest that one must view these changes as an interchangeable cycle of events during tumor progression. The chromatin changes and abnormal methylation patterns can drive one another with increasingly deleterious effects as the malignant phenotype emerges (reviewed in Baylin, 1991). What are the molecular events that would initiate the above dynamics? A working construct model is shown in Fig. 3. As discussed for the normal adult cell, there is a delicate balance between the strategic location of DNA MTase, regulation of this enzyme, and rate of DNA synthesis at replication forks (top panel, Fig. 3). In pre-neoplastic and cancer cells, perhaps failure of cells to exit the cell cycle and halt DNA replication, facilitates some sort of pressure to increase cellular DNA methyltransferase activity (bottom panel, Fig. 3). This increase may involve loss of feedback inhibition of the enzyme during the post DNA replication phase. There are also probable structural alterations in the nucleus which may alter the geographic relationship between the DNA replication fork and DNA MTase. In consequence, many DNA areas that should be getting methylated do not, and novel areas of methylation also arise. This cycle of events leads to the imbalance of DNA methylation that I have talked about. Future investigations of these possibilities, and of their specific consequences for alterations of gene expression and chromosome structure, may reveal a key molecular step underlying virtually all stages of tumor progression.


The activity of single-agent carboplatin in advanced seminoma. Between 1982 and 1990, 70 patients with advanced metastatic seminoma were treated with 4-6 courses of single-agent carboplatin (SAC) administered at 400 mg/m2 every 3-4 weeks. Treatment was of low toxicity and no patients suffered neurotoxicity, ototoxicity or significant renal damage. There was only one episode of neutropenic sepsis and no thrombocytopenic bleeding. The median follow-up of surviving patients was 3 years. 16 patients have relapsed and 4 of these 16 have died, thus the actuarial 3-year relapse-free survival was 77% (95% CI 65-86%), cause-specific survival was 94% (95% CI 82-99%) and overall survival was 91% (95% CI 80-96%). The risk of relapse was reduced by post-chemotherapy irradiation (PCRT) to involved nodes, occurring in 1/20 patients treated with PCRT compared with 11/31 who could have been treated but were not (P = 0.04). Of the 16 patients who relapsed, 12(75%) have been salvaged with combination chemotherapy and remain free from further relapse with a median follow-up of 18 months. Though this level of survival is equivalent to that obtained with initial cisplatin-based combination chemotherapy, the recurrence rate indicates that SAC remains an investigative treatment, except for unfit patients.


Pharmacokinetically guided dosing for intravenous melphalan: a pilot study in patients with advanced ovarian adenocarcinoma. Pharmacokinetically guided administration of melphalan was investigated during a pilot study in patients with advanced ovarian adenocarcinoma. The schedule involved a fixed dose on day 1 (7.9 mg) followed by a second dose on day 2, calculated on the basis of pharmacokinetic data to achieve a target area under the concentration-time curve (AUC). 20 courses of intravenous melphalan were administered to 7 patients. AUC, standardised to 1 mg/m2, ranged between 4.3 and 8.9 (mg/l) min. In 12 fully evaluable courses, less than 15% deviation from the target AUC was found, showing that AUC monitoring was possible by means of the test dose. Pharmacodynamic effects showed a positive correlation with melphalan AUC. Myelosuppression appeared at 47 (mg/l) min and grade 3 or 4 haematological toxicities were observed in 4 cycles, associated with AUC values ranging between 86 and 112 (mg/l) min. Relative leucocyte decreases were well correlated with AUC values.


Prognostic relevance of pS2 status in association with steroid receptor status and proliferative activity in node-negative breast cancer. Expression of the oestrogen-regulated pS2 protein was investigated on paraffin-embedded sections of primary breast tumours from 200 node-negative patients. Immunoreactivity was observed in 56% of the cases. pS2 expression was inversely correlated with tumour size and proliferative activity, whereas a direct correlation was observed with steroid receptor. 5-year relapse free survival was influenced by tumour size (P = 0.02), oestrogen receptor status (P less than 0.05), and proliferative activity (P less than 0.01). No difference in relapse-free survival was observed between patients subdivided according to pS2 expression alone. However, among patients with oestrogen-receptor-negative tumors, pS2 expression predicted a shorter relapse-free survival.


Toxicity of single-day high-dose vincristine, melphalan, etoposide and carboplatin consolidation with autologous bone marrow rescue in advanced neuroblastoma. 16 unselected patients with advanced neuroblastoma were given high-dose consolidation chemotherapy with vincristine, melphalan, etoposide and carboplatin over 5 h followed by autologous bone marrow rescue. 3 patients died from treatment-related toxicity, 2 from disease, 1 is alive with disease and 10 are alive and disease-free a median of 12.5 months (range 2-38 months) after bone marrow rescue. All had bone marrow toxicity, most mucositis and 6 had seizures. Renal failure was unexpectedly severe. In the last 3 patients, administration of carboplatin was delayed by 18 h in an attempt to reduce renal damage. The results show that this regimen produces significant morbidity and has a high mortality. Although the overall outcome is encouraging, too few patients have been studied to gauge its efficacy. Whether such aggressive consolidation is necessary in heavily pretreated children with neuroblastoma remains unknown.


Pilot study of high-dose vincristine, etoposide, carboplatin and melphalan with autologous bone marrow rescue in advanced neuroblastoma. The efficacy and toxicity of a high-dose multiagent consolidation regimen, OMEC (vincristine, melphalan, etoposide and carboplatin), with autologous bone marrow rescue was studied in patients with poor-prognosis neuroblastoma, 20 patients were treated with OMEC, 18 after induction chemotherapy and 2 following relapse. All patients received, per m2, vincristine 4 mg, etoposide 1 g, carboplatin 1.0-1.75 g and melphalan 180 mg followed by bone marrow rescue. 4 patients (20%) died of treatment-related complications. Severe gastrointestinal toxicity occurred in all of these patients, and in 75% of patients overall. 1 of 5 patients with evaluable disease achieved complete remission. 13 patients (65%) have relapsed a median of 10 months (range 3-26) after receiving OMEC. Thus, OMEC was not more effective, yet more toxic, than high-dose melphalan given alone, and the use of similar multiagent regimens with overlapping toxicities in advanced neuroblastoma appears inadvisable.


Can Karnofsky performance status be transformed to the Eastern Cooperative Oncology Group scoring scale and vice versa? There is no consensus regarding the equivalence of performance status between the Karnofsky (KPS) and the Eastern Cooperative Oncology Group (ECOG) scales. In the present study KPS and ECOG scores were compared in 150 consecutive cancer patients. An empirical relation was established through regression analysis in a subsample of 75 patients and the results tested in the second subsample. Transformation tables including 95 and 66% confidence intervals were calculated. Both performance scales are highly correlated, but inferences about individual patients were subject to a high level of error. These results stress the difficulty of translating one score to another, especially in the range of lower performance status where a wide spread is observed.


Psychological effects of participation in a prevention programme for individuals with increased risk for malignant melanoma. The Swedish Melanoma Study Group runs a programme aimed at prevention and early detection of premalignant and malignant melanoma in families with two or more members having malignant melanoma. Psychological consequences of participation in this programme were studied. A questionnaire containing items concerning cognitive and emotional responses to the programme was completed by 115 consecutive individuals at their first visit to the clinic. The same questionnaire was administered by mail 7 months later. The levels of psychological and psychosomatic problems were relatively low at both points of assessment. No negative psychological effects were found, neither in the group with dysplastic naevus syndrome (DNS) with increased risk for malignant melanoma, nor in the group without dysplastic naevi. Only one variable, "emotional responses to the visit" differentiated between the groups, with higher scores in the group without DNS. A majority of the individuals expressed positive attitudes to the clinic.


Mastectomy or conservation for early breast cancer: psychological morbidity. A consecutive series of 197 women under 70 years of age with operable breast cancer, randomised to treatment by a conservation technique in comparison to mastectomy, were assessed using structured interviews. The prevalence of cases of anxiety and depression was high before treatment commenced, there were fewer cases in the conservation group but no significant difference at 3 or 12 months in the number of new cases, social adjustment, or capacity to return to work. Attitudes to treatment showed significant differences between the groups, more women in the conservation group were able to wear their usual clothes and most women rated the cosmetic result highly. Patients were more likely to stop sexual intercourse completely after mastectomy. An effective conservation technique should be an attractive treatment choice available to selected women with early breast cancer.


Comparison of three protracted antiemetic regimens for the control of delayed emesis in cisplatin-treated patients. Antiemetic activity of three protracted regimens for the control of cisplatin-evoked delayed emesis was explored. 63 patients were randomly assigned to receive one of three protracted antiemetic schedules over 4 days. Group C patients received dexamethasone 8 mg twice daily on days 2 and 3, then 4 mg twice daily on days 4 and 5; in group B, alizapride 2.5 mg/kg four times daily on days 2-5 plus dexamethasone as in group C was administered; and in group A, metoclopramide 0.5 mg/kg four times daily on days 2-5 plus dexamethasone was given at the same dose-schedule as in groups C and B. Complete protection from delayed vomiting was achieved in 44% of group C, 30% of B and 70% of group A (P = 0.02). Mild side-effects were noted in all three groups. A higher complete protection for delayed emesis was obtained in metoclopramide-dexamethasone-treated patients. Neither of the regimens used in the protection of delayed emesis controlled late nausea.


Drug-sensitivity testing in patients with human oesophageal squamous cell carcinoma. To evaluate the response to chemotherapeutic agents against human oesophageal cancer, 19 samples were tested by the human tumour clonogenic assay (HTCA), 21 samples by subrenal capsule assay (SRCA) and 33 samples by SRCA with immunosuppressant (IS-SRCA). The evaluability rate of was 21% for HTCA, 95% for SRCA and 91% for IS-SRCA. No active agent was detected by HTCA, however, 29% of the drugs tested by SRCA and 22% by IS-SRCA were considered to be active. Histological analysis revealed substantial inflammatory infiltrates and poor tumour cell preservation with SRCA; however, infiltrates were minimal and there was a high degree of tumour cell preservation with IS-SRCA. The response rates of IS-SRCA were comparable with those of prior clinical tests for each drug. These results suggested that IS-SRCA is the most useful drug sensitivity test for human oesophageal cancer.


CA72-4 compared with carcinoembryonic antigen as a tumour marker for gastric cancer. Serum levels of a newly identified, tumour-associated antigen, CA72-4, were measured in 86 patients with histologically proven gastric carcinoma. Preoperative levels of CA72-4 in serum tended to be higher with increased dissemination of the cancer. Elevated levels of CA72-4 (above 5.0 U/ml) were significantly more frequent than those of carcinoembryonic antigen (CEA) (above 5.6 ng/ml) in patients with stage III or IV (P less than 0.01) carcinoma, in patients with Borrmann type 4 (P less than 0.01), and in patients with peritoneal metastasis (P less than 0.01). No correlation was seen between serum levels of CA72-4 and those of CEA. Serum levels of CA72-4 were lower 1 month after gastrectomy in 25 of 39 patients with resected cancers. In each of 4 patients with recurrence, lower levels of CA72-4 after gastrectomy were replaced by elevated levels on detection of the recurrence of cancer. These results indicate that CA72-4 is highly specific to gastric cancer and may be more reliable as a tumour marker than CEA for gastric cancer.


Feasibility of measuring oxygen tension in uterine cervix carcinoma. Cellular hypoxia is a cause of radioresistance. The oxygen tension (pO2) in normal tissues and in tumours can be measured by polarography. In this feasibility study we have measured the tissue pO2 of 10 patients suffering from uterine cervix carcinoma, using the Eppendorf histograph. The measurements were performed at the time of the brachytherapy after external radiotherapy. The machine was found to be reliable and no adverse effect was noted. The mean pO2 values in tumours were lower than those of normal tissues.


The long-term retention of platinum in human tissues following the administration of cisplatin or carboplatin for cancer chemotherapy. Mass spectrometry has been used to study the distribution and retention of platinum in the tissues of patients following the administration of cisplatin or carboplatin. Blood platinum was measured up to 2 years and renal excretion up to 5 years after treatment. Platinum concentrations in plasma and red cells fell according to a power function, approximately as the inverse square of the time after administration. The concentration in the urine fell more slowly. Necropsy samples were used to examine the distribution of platinum in various human organs up to 17 months after treatment. The highest concentrations were found in the liver, which retained approximately 2% of the dose. Although the results were scattered between patients, there was little loss of platinum after about 1 month. The prolonged retention of platinum may be relevant to long-term toxicity.


Phase I study of intravenous 4-hydroxyanisole. 4-Hydroxyanisole is a depigmenting agent which has been shown to have activity against malignant melanoma when given intra-arterially in man. An intravenous dose escalation study has been carried out with the aim of obtaining maximum plasma concentrations in a 5 day schedule. 8 patients entered this study which was stopped because of drug toxicity after 3 patients had been treated at the third dose escalation of 15 g/m2. 2 patients had WHO grade 4 liver and one also grade 4 renal toxicity and another had grade 4 haemoglobin toxicity. Extrapolated plateau plasma levels between 112 and 860 mumol/l were obtained, which in vitro studies suggested would be cytotoxic. Hopefully, newer analogues will have a greater specificity for the melanin pathway with less toxicity.


Curative non-surgical combined treatment of squamous cell carcinoma of the oesophagus. Between April 1982 and June 1989, 65 patients (15 T1, 13 T2, 32 T3, 5 T4) with squamous cell carcinoma of the oesophagus were treated with a curative intent with multimodality combined treatment. A first course of 5-fluorouracil and cisplatin was given during work up, especially if NdYAG laser therapy was used. Irradiation was started 3-4 weeks after induction and two courses of concomitant chemotherapy were given during the radio therapy (aiming at 64 Gy over 7 weeks). Actuarial survival was 79.6% at 1, 36.7% at 3 and 26.7% at 5 years. 5 year survival rates were 56.3% for T1, 29.8% for T2 and 12.9% for T3. All T4 cases died within 16 months. Complete initial disease response was achieved in 76%. Tolerance was good. Thus patients with squamous cell carcinoma of the oesophagus can have long survival and may be cured with combined modality therapy. This treatment may be an alternative to radical surgery when there is a high risk of operative mortality.


Prospective randomised study of double hemi-body irradiation with and without subsequent maintenance recombinant alpha 2b interferon on survival in patients with relapsed multiple myeloma. Immediately before first hemi-body irradiation, 59 patients with relapsed multiple myeloma were randomised to receive or not to receive subsequent alpha-2b interferon maintenance. 13 patients (22%) [8 of 31 (26%) controls, 5 of 28 (18%) in the interferon arm] received single hemi-body irradiation alone due to progressive disease and/or persistent cytopoenias following the initial procedure. Mean time between upper and lower hemi-body irradiation was 69 days (range 35-294). Of 23 patients randomised to receive interferon and completing double hemi-body irradiation, 15 (65%) achieved peripheral blood counts adequate to allow interferon administration as per study criteria commencing at a mean 116 days (61-241) from time of study entry. The mean period of interferon therapy, starting at a mean 65 days (26-160) post second hemi-body irradiation, is 16.4 months (2-33.5). There was no significant difference in median survival durations (10 months) from time of initial radiotherapy between control and interferon patients.


High-dose chemotherapy and autologous bone marrow transplantation for relapsed and refractory Hodgkin's disease. The results of high-dose chemotherapy with melphalan or melphalan (carmustine) etoposide for 66 consecutive patients with relapsed or resistant Hodgkin's disease are described. 55 patients were evaluable for response and 22% of these achieved complete remission and 59% partial remission. The actuarial survival at 2 years was 45% and the principal factors determining survival were the sensitivity of the disease to therapy given before high-dose chemotherapy and the type of treatment received. Intensive chemotherapy with autologous bone marrow transplantation can produce long-term survivors among patients for whom long-term survival would otherwise be improbable. However, this treatment remains toxic with an uncertain place in management.


Adrenal masses in lung cancer: sonographic diagnosis and follow-up. Ultrasound has become an important diagnostic modality in the staging of patients with lung cancer. Between 1980 and 1990, 410 patients with histologically proved lung cancer were evaluated. In 44 patients (11%) an adrenal mass was discovered on ultrasound; in 13 patients it was isolated, and in 31 further evidence of abdominal disease was shown. Sonographic follow-up examinations of adrenal masses showed changes of size in all but 2 patients, and were therefore found to be adrenal metastases. In the 2 patients with isolated and stable adrenal disease, fine-needle biopsy revealed adenomas. Adrenal masses in patients with lung cancer are more likely to be metastatic than benign. The existence of neoplastic adrenal disease can be retrospectively confirmed by changes of size during sonographic follow-up examinations in almost all patients. Histologically verification would only appear necessary in stable adrenal disease and in cases with isolated adrenal disease in which prompt diagnosis affects treatment decision.


Droloxifene, a new anti-oestrogen in postmenopausal advanced breast cancer: preliminary results of a double-blind dose-finding phase II trial. Droloxifene (3-OH-tamoxifen citrate) is a novel anti-oestrogen with a higher affinity for oestrogen receptors (ER), a lower oestrogenic to anti-oestrogenic activity ratio and faster pharmacokinetics compared with tamoxifen. From May 1988 to April 1991, 369 postmenopausal women with metastatic or locally unresectable breast cancer of which the ER or progesterone receptor status was positive or unknown, were randomised to receive an oral dose of 20, 40 or 100 mg droloxifene once daily. 43 Brazilian, Canadian and European centres took part in this double-blind phase II trial. 60 women were ineligible for violation of entry criteria; 20 were inevaluable and 15 still await definitive response evaluation. 234 patients have been evaluated for response. The over-all objective response rate (complete plus partial) was 92/234 (39.3%): 23/74 (31.1%) for 20 mg, 33/74 (44.6%) for 40 mg and 36/86 (41.9%) for 100 mg (not significantly different within this dose range). There was no significant difference in time to tumour progression between the three doses. Toxicity was minimal at all doses. These preliminary results show that droloxifene is active against advanced breast cancer. Because of its outstanding preclinical characteristics, the drug warrants large-scale clinical investigation.


Expression of cathepsin D in head and neck cancer. To determine overexpression of cathepsin D in head and neck tumours we examined cytosols from 53 primary tumours, nine cytosols of lymph node metastases and 12 cytosols from adjacent normal tissue. We found a significantly lower concentration in normal tissue compared with tumour cytosol as well as with metastases, even when we compared tumours and corresponding metastases pairwise. In addition, we found a significantly higher concentration of cathepsin D in five lymph node metastases than in the corresponding tumours. We conclude that the reported role of cathepsin D is not restricted to breast cancer but could also be important in head and neck cancer.


Axillary dissection of level I and II lymph nodes is important in breast cancer classification. The Danish Breast Cancer Cooperative Group (DBCG). In order to define the term "a node-negative patient", the axillary nodal status at the primary operation for breast cancer was evaluated in 13,851 patients registered by the Danish Breast Cancer Cooperative Group (DBCG). The determinants for node negativity in primary breast cancer were the number of lymph nodes removed and the tumour size. The number of lymph nodes removed should be at least 10 to exclude misclassification of node-positive patients as node negative. There was a strong relationship between tumour size and the percentage of node-negative patients. Another observation was that high rate of node negativity was associated with low histological grade. The age of the patients had no influence on node negativity. Where 10 or more negative lymph nodes were removed, significantly better axillary recurrence-free survival (P less than 0.0001), over-all recurrence-free survival (P less than 0.0001) and survival (P less than 0.005) were found.


A rapid anticancer drug screening assay by [14C] thymidine uptake in cultured human cancer cells. A rapid screening test by suppression of DNA synthesis in cancer cells was developed with [methyl-14C]-thymidine (14C-TdR), a microculture filtration plate and a radiochromatoscanner. Mitomycin, tamoxifen and 5-fluorouracil (5-FU) were tested against four human gastric cancer cell lines and HeLa cells. The tetrazolium-based colorimetric (MTT) assay underestimated cell inactivation by mitomycin in three cell lines compared with the cell count and the 14C-TdR assays. Inactivation by 5-FU in one cell line by 14C-TdR uptake was considerably lower than that by other methods. Thus neither the radio-labelled DNA precursor uptake nor the MTT assay is suitable for every anticancer drug but they are complementary.


Relationship of cell cycle parameters to in vitro and in vivo chemosensitivity for a series of Lewis lung carcinoma lines. The sensitivity of three Lewis lung carcinoma sublines, which grow in culture and in vivo, and vary in in vivo drug sensitivity, have been compared using topoisomerase II poisons amsacrine, amsacrine analogue CI-921, doxorubicin and etoposide. D10 (drug concentration for 10% clonogenic survival) values were determined in vitro for low and high density cultures, and ex vivo for cells from subcutaneous tumours. The cytokinetic parameters of these populations were obtained by flow cytometric analysis of bromodeoxyuridine-labelled cells. Regression analysis showed that logarithmic D10 values were significantly correlated (r greater than 0.95) with G1- and S-phase proportions and highly correlated (r = 0.99) with calculated G1 transit times. The slopes of the regression lines were similar for all topoisomerase II poisons tested and it is suggested that this slope reflects the disappearance of topoisomerase II during G1 phase.


Epidermal growth factor receptor and transforming growth factor alpha expression in human ovarian carcinomas. The varying tumorbiological behaviour of ovarian carcinomas probably influences operability, response to chemotherapy, being one of the most relevant prognostic factors. Because it is believed that an activation of the epidermal growth factor/transforming growth factor alpha (EGF/TGF alpha) signal pathway could be involved, we analysed the expression of epidermal growth factor receptor (EGFR) and TGF alpha with molecular-chemical, biochemical and immunohistochemical methods in 42 ovarian carcinomas, 4 ovarian metastasis, 2 other malignant ovarian tumours, and in 25 nonmalignant tissues (ovary, myometrium). No major rearrangements or amplification of the EGFR or TGF alpha genes were found. In non-malignant tissues no strong EGFR or TGF alpha signals were detected. TGF alpha is mainly produced by the tumour cells as shown by immunohistochemistry. Four different high molecular weight forms (20-48 kD) were detected in malignant tissues by western blot analysis.


Comparison of intra-arterial versus intravenous 5-fluorouracil administration on epidermal squamous cell carcinoma in sheep. Clinical evidence that intra-arterial chemotherapy is more effective in regressing head and neck cancers than equivalent intravenous doses is lacking. Intra-arterial versus intravenous 5-fluorouracil infusion was compared in a naturally occurring, auricular epidermal squamous cell cancer in sheep. Of 18 lesions infused intra-arterially and of 18 infused intravenously with the same dose, 39 and 11%, respectively responded objectively (over 50% regression); mean (S.E.) tumour volume reduction was 37(23) and 18(22)%, respectively. There was a statistically significant difference in the mean tumour response and in numbers of tumours regressing by at least 40% of tumour volume (50% of intra-arterial treated tumours compared with 11% of intravenous treated lesions) after the 16 day total infusion time in favour of intra-arterial treatment. Technically, the intra-arterial route in this model was an improvement on previous small animal models. These findings lend support to the need for continuing clinical study of intra-arterial infusion.


Expression of glutathione-S-transferase-pi in human tumours. Expression of glutathione-S-transferase-pi (GST-pi) gene was quantitatively analysed on various human tumours (renal cell, colorectal, head and neck, ovarian carcinomas, soft tissue sarcomas; non-Hodgkin lymphomas) and on the corresponding normal tissues when available (kidney, colorectum and head and neck). GST-pi mRNA expression level was found to be significantly higher in tumours (P less than 0.01) than in the normal counterparts (mainly 7.3, 3.5- and 3.0-fold in colorectal, head and neck, and renal carcinomas, respectively). Most tumours displayed a significant relationship between higher GST-pi expression level and poor differentiation grade of tumour cells, thus suggesting a relationship between GST-pi activity, neoplastic transformation and cellular differentiation grade. The high requirement of GST-pi activity neoplastic cells displayed was not singularly related to cellular replication rate. Finally, GST-pi gene expression levels were not affected by chemotherapeutic treatments.


Methotrexate alters the fatty acid composition of NC adenocarcinoma cells in culture. The effects of methotrexate and indomethacin alone and in combination have been examined on the fatty acid (FA) composition of total cellular lipids in cultured NC adenocarcinoma cells. These studies show that methotrexate can alter the lipid content of cancer cells. Methotrexate 16 ng/ml incubated with NC cells for 2 days increased the content of various FAs. When used alone, indomethacin 1 microgram/ml or methotrexate 8 ng/ml had no significant effect, but in combination caused FA increases, usually to about the same extent as with the higher concentration of methotrexate alone. No FA changes were seen up to 3 h with these drug concentrations or with methotrexate up to 10 micrograms/ml alone or with INDO 1 microgram/ml. These effects may explain previous findings that indomethacin potentiates methotrexate, an interaction which may be important in cancer therapy.


Lack of therapeutic gain when low dose rate interstitial radiotherapy is combined with cisplatin in an animal tumour model. The interaction of cisplatin with low dose rate interstitial radiotherapy was studied in an animal tumour model with a range of dose rats commonly used in clinical low dose rate brachytherapy. Small pieces of R1-rhabdomyosarcoma were implanted subcutaneously in the flanks of female Wag/Rij rats. When the tumour had grown to the desired treatment volume, four afterloading catheters were inserted in the tumour in a square geometry, and a fixed spacing was attained by means of a template. Subsequently, four 2 cm Ir192 wires were inserted. A range of tumour doses of 20-120 Gy at a mean dose rate of 48 cGy/h was applied; 15 mins before the implant an intraperitoneal bolus injection of 3 mg/kg cisplatin was given. For growth delay and cure rate, no modification of the effects of low dose rate brachytherapy by the addition of cisplatin was observed. The observed effects of the combination of cisplatin with low dose rate interstitial radiation in relation to the animal tumour are discussed.


The influence of age on treatment choice and survival of elderly breast cancer patients in south-eastern Netherlands: a population-based study. The influence of age on treatment choice and survival was studied in 2268 breast cancer patients of 55 years and older reported to the Eindhoven Cancer Registry from 1975 to 1987. Among patients of 75 years and older, stage I and II tumours occurred less often, whereas stage IIIb and undefined tumours occurred more often than among younger patients. Physicians were found to be less likely to treat women of 75 years and older with adjuvant radiotherapy after a mastectomy. Instead, these women received either surgery alone or surgery followed by hormonal therapy. Surgical procedures in the oldest age group were also less extensive. The 10-year relative survival for women over 74 years (32%) was significantly worse than that for younger patients (57%). Multivariate analyses showed that this poor outcome for the oldest age group was largely related to their unfavourable stage distribution: stage-specific survival appeared to be similar in all age groups. Age-related differences in treatment did not have an effect on survival.


Coffee consumption and bladder cancer risk. The relation between consumption of regular and decaffeinated coffee and other methylxanthine-containing beverages and bladder cancer was analysed in a case-control study in two different areas of northern Italy (555 cases and 855 controls). The multivariate relative risk (RR) adjusted for smoking, occupation and sociodemographic variables for coffee drinkers versus non-drinkers was 1.3 (95% CI 1.0-1.8). The RR was 1.2 for one cup of coffee per day, 1.4 for two, 1.5 for three and 1.4 for four or more (P = 0.05). RRs for current drinkers were 1.5 (0.9-2.4) for decaffeinated coffee, 0.9 (0.6-1.2) for tea, and 0.6 (0.3-1.4) for cola. With reference to duration of consumption of coffee, RRs were 1.2 for less than 30 years or 1.4 for 30 years or more. Coffee-related RRs were higher in the older age group and in ex-smokers. Among 105 cases and 338 controls who had never smoked, RRs were 1.9 for one or two cups per day, 1.8 for three and 1.5 for four or more (trend not significant). A higher prevalence of coffee drinking among bladder cancer cases than controls was confirmed, with no clear dose-risk relation.


The effect of family history of cancer, religion, parity and migrant status on survival in colorectal cancer. The Melbourne Colorectal Cancer Study. The association between 5-year survival and several risk factors was investigated in 705 histologically confirmed, new cases of colorectal adenocarcinoma as one aspect of a comprehensive population-based study of large bowel cancer incidence, aetiology and survival--the Melbourne Colorectal Cancer Study. 5-year survival was not influenced by the previously determined risk of a family history of colorectal cancer in near-relatives. Similarly, other previously determined risk factors of religion, number of children, age at birth of first child and migrant status did not influence survival.


Linkage of death certification of AIDS and cancer registration in Vaud, Switzerland. 58 death certifications (40 males and 18 females) of residents of the Canton of Vaud (Switzerland) which reported AIDS as the cause of death in 1986-1989 were matched with the list of incident cancers available since 1974 from the Vaud Cancer Registry. Such linkage was successful for 20 individuals (age range 25-63, median 37), mostly males (18/20), homosexual or bisexual (11/18) and affected by Kaposi's sarcoma (14 males and 1 female). Other identified neoplasms included one Burkitt's lymphoma, one prostate adenocarcinoma and one multiple myeloma (whose histological picture included, however, lymphocytosis in addition to plasmocytosis). Three additional malignancies (one undifferentiated skin cancer, one carcinoma of the salivary glands and one in situ cervical carcinoma), and one myelodysplastic syndrome had also been diagnosed from 1 to 2 years before AIDS death. Cancer was mentioned on the death certificate, in addition to AIDS, in only 2 cases. Albeit of limited size, the present report confirms that a systematic integration of AIDS and cancer registration statistics provides additional information, of particular interest for histological classification, on the AIDS-cancer relationship.


Trends in cancer survival in Vaud, Switzerland. Survival rates from the Vaud Cancer Registry were compared for incident cases registered in 1974-1978 and 1979-1983. No appreciable difference was evident for most major cancer sites: 5-year relative survival rates were 0.21 in 1974-1978 and 0.23 in 1979-1983 for stomach, 0.49 and 0.46 for colon, 0.45 and 0.47 for rectum, 0.04 and 0.03 for pancreas, 0.08 and 0.10 for lung, 0.41 and 0.42 for kidney, 0.21 and 0.13 for brain, and 0.32 and 0.30 for multiple myeloma, respectively. A modest advancement in 5-year relative survival rates was, however, registered for total cancer mortality (non-melanomatous tumours excluded, from 0.41 to 0.43) while, with regard to specific sites, a significant improvement was seen only for cancer of the testis (from 0.73 to 0.88). More than 10% non-significant improvements in survival were recorded for melanomatous skin cancer (from 0.67 to 0.78), thyroid cancer (from 0.73 to 0.85), particularly in females, non-Hodgkin lymphomas (from 0.37 to 0.45), Hodgkin's disease (from 0.61 to 0.78), cancer of the ovary (from 0.28 to 0.32) and the prostate (from 0.44 to 0.52). However, significant declines in survival rates were seen for cancer of the larynx, gallbladder and biliary tract, and for connective tissue neoplasms. A few differences in the modification of relative survival rates according to age (less than 60 versus greater than or equal to 60 years) were noted for a few cancer sites. Changes were larger in older patients with respect to cancer of the prostate and thyroid and non-Hodgkin lymphomas (increases) and connective neoplasms (decreases). Conversely, changes in survival were greater or restricted to younger individuals for testis, bladder and leukaemias (improvements) and cancer of the mouth or pharynx (decline), thus suggesting the different play of age-specific biological characteristics of some tumours, in addition to diagnostic improvements and gradual spread of effective cancer treatments to more advanced age groups.


PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design. The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.


Tobacco chemistry. 73. 4,6,8-trihydroxy-11-capnosene-2,10-dione, a new cembrane-derived bicyclic diterpenoid from tobacco. A new diterpenoid containing a rare carbobicyclic cembrane-derived skeleton, the capnosane skeleton, has been isolated from flowers of Greek tobacco. It has been identified as (1S*,3R*,4S*,6R*,7R*,8R*,11Z)-4,6,8-trihydroxy-11-capnosene- 2,10-dione by spectral methods and X-ray analysis of the corresponding benzoate. A full account of the X-ray work is given.


Left ventricular filling characteristics in pulmonary hypertension: a new mode of ventricular interaction. To examine the effects of pulmonary hypertension on left ventricular diastolic function and to relate the findings to possible mechanisms of interdependence between the right and left sides of the heart in ventricular disease. A retrospective and prospective analysis of echocardiographic and Doppler studies. A tertiary referral centre for both cardiac and pulmonary disease. 29 patients with pulmonary hypertension (12 primary pulmonary hypertension, 10 pulmonary fibrosis, five atrial septal defect (ASD), and two scleroderma) were compared with a control group of 10 patients with an enlarged right ventricle but normal pulmonary artery pressure (six ASD, one after ASD closure, one ASD and pulmonary valvotomy, one tricuspid valve endocarditis and repair, and one pulmonary fibrosis). None had clinical or echocardiographic evidence of intrinsic left ventricular disease. M mode echocardiographic measurements were made of septal thickness, and left and right ventricular internal cavity dimensions. Doppler derived right ventricular to right atrial pressure drop, and time intervals were measured, as were isovolumic relaxation time, and Doppler left ventricular filling characteristics. The peak right ventricular to right atrial pressure gradient was (mean (SD)) 60 (16) mm Hg in pulmonary hypertensive patients, and 18 (5) mm Hg in controls. The time intervals P2 to the end of the tricuspid regurgitation, and P2 to the start of tricuspid flow were both prolonged in patients with pulmonary hypertension compared with controls (115 (60) and 120 (40) v 40 (15) and 45 (10) ms, p values less than 0.001). Pulmonary hypertensive patients commonly had a dominant A wave on the transmitral Doppler (23/29); however, all the controls had a dominant E wave. Isovolumic relaxation time of the left ventricle was prolonged in pulmonary hypertensive patients compared with controls, measured as both A2 to mitral valve opening (80 (25) v 50 (15) ms) and as A2 to the start of mitral flow (105 (30) v 60 (15) ms, p values less than 0.001). The delay from mitral valve opening to the start of transmitral flow was longer in patients with pulmonary hypertension (30 (15) ms) compared with controls (10 (10) ms, p less than 0.001). At the time of mitral opening there was a right ventricular to right atrial gradient of 12 (10) mm Hg in pulmonary hypertensive patients, but this was negligible in controls (0.4 (0.3) mm Hg, p less than 0.001). Prolonged decline of right ventricular tension, the direct result of severe pulmonary hypertension, may appear as prolonged tricuspid regurgitation. It persists until after mitral valve opening on the left side of the heart, where events during isovolumic relaxation are disorganised, and subsequent filling is impaired. These effects are likely to be mediated through the interventricular septum, and this right-left ventricular asynchrony may represent a hitherto unrecognised mode of ventricular interaction.


Vasodilator myocardial perfusion imaging: demonstration of local electrophysiological changes of ischaemia. To examine the incidence and severity of myocardial ischaemia provoked in the course of perfusion scintigraphy by coronary vasodilators using endocardial recordings of steady state monophasic action potentials as an independent marker of early localised myocardial ischaemia. 31 men undergoing routine cardiac catheterisation for investigation of chest pain were studied. A tertiary cardiac referral centre. Single site monophasic action potentials were recorded from the left or right ventricle or both (50 recording sites) during intravenous infusion of dipyridamole (0.015 mg/kg/min) for four minutes. Heart rate was held constant with atrial pacing at 20% above the patient's resting rate. Technetium-99m hexakis-2-methoxy-2-methylpropyl-isonitrile (MIBI) was administered four minutes after dipyridamole, and single photon emission tomographic imaging was performed an hour later. Rest images were obtained the next day (two day, two dose protocol). Recordings were divided into three groups based on the scintigraphic perfusion characteristics and coronary anatomical data for the action potential recording site: group 1--recordings from areas with a normal perfusion pattern (n = 30), group 2--recordings from areas with a perfusion defect and subtended by significantly narrowed coronary arteries without obvious angiographic collateral supply (n = 10), and group 3--recordings from areas with a perfusion defect and subtended by occluded arteries with angiographically evident collaterals from adjacent vessels (n = 10). There were changes in the duration of the monophasic action potential indicative of ischaemia--that is, shortening of duration of steady state action potential--in 18 of the 20 recordings from areas of abnormal perfusion. Peak changes were apparent eight minutes from the start of the dipyridamole infusion. Mean (SEM) values for duration of the action potential between control and peak effect at eight minutes were 276.5 (5.3) ms v 276.6 (5.4) for group 1 (NS), 289.6 (4.7) ms v 278.4 (4.9) ms for group 2 (p less than 0.001), and 269.6 (5.7) ms v 242.0 (4.4) for group 3 (p less than 0.0001). These changes were significantly different between the three groups (p less than 0.01). ST segment changes on the surface electrocardiogram were seen in only eight patients, all with areas of viable myocardium supplied by collateral vessels. These data provide strong evidence for the presence of myocardial ischaemia in regions of reversible perfusion defects induced by dipyridamole. This study also shows that such ischaemia is more intense and more likely to be seen when myocardial viability is dependent on collateral circulation.


Characteristics of presystolic flow in the superior vena cava: new thoughts on a forgotten sound. Cross sectional, M mode, and Doppler echocardiography, apexcardiography, and phonocardiography were used to characterise presystolic cardiovascular sounds in three patients with ventricular disease. Although the aetiology was different (dilated cardiomyopathy, primary pulmonary hypertension, and chronic pulmonary thromboembolic disease), in each case the presystolic sound was associated with a rapid change in acceleration of blood and with flow reversal in the superior vena cava, and could only be recorded at the right sternal edge or over the jugular veins. Such flow characteristics may be explained by a raised ventricular end diastolic pressure with reduced compliance. Use of these techniques helps to understand the cause of a previously described but little recognised heart sound, and adds weight to the interpretation of its presence in disease.


Remnant of the common pulmonary vein mistaken for a left atrial mass: clarification by transoesophageal echocardiography. Faulty incorporation of the common pulmonary vein leaves it as a distinct structure posteriorly, into which the pulmonary veins empty. This "chamber" is separated from the anterior "fetal" left atrium (containing the left atrial appendage and communicating with the mitral valve) by a diaphragm, and is known as cor triatriatum, one of the rarest of cardiac malformations. Less pronounced but still incomplete regression of this vein would result in the persistence of a portion of the common pulmonary vein appearing as a mass along the lateral wall of the left atrium at the junction of the left atrial appendage and left upper pulmonary vein. In two patients, both referred for evaluation of a left atrial mass, transoesophageal echocardiography identified the "mass" as a remnant of the common pulmonary vein. Cardiologists need to be aware of this structural remnant and its possible variants so as to avoid misdiagnosis of this prominence as an atrial tumour or mass.


Coronary venous lipid peroxide concentrations after coronary angioplasty: correlation with biochemical and electrocardiographic evidence of myocardial ischaemia. Raised lipid peroxide concentrations in coronary venous plasma have been reported after coronary angioplasty in humans. This may reflect increased free radical activity after myocardial ischaemia and reperfusion. If so, it may be possible to correlate lipid peroxide concentrations with the degree of myocardial ischaemia produced during angioplasty. 15 patients (age range 42-70; 12 men) with stable angina pectoris undergoing angioplasty of a proximal left anterior descending coronary artery stenosis were studied. Plasma lipid peroxide and lactate concentrations were measured in sequential blood samples taken from the great cardiac vein before and immediately after one to five serial 60 second balloon inflations. The maximum ST segment shift during each balloon inflation was also measured. Lipid peroxide concentrations in coronary venous plasma were raised from pre-angioplasty values by more than 2 SDs of the relevant measurement error after 27 out of 46 (59%) balloon inflations. Lactate concentrations were raised after 43 out of 46 (93%) balloon inflations. No significant difference was found between the peak percentage change of either lipid peroxide or lactate concentrations after any of the first three serial inflations. The maximum ST segment shift after each of the first three serial inflations was also similar. Coronary venous lactate concentrations after balloon inflation correlated positively with the maximum ST segment shift, but did not correlate with lipid peroxide concentrations. Raised lipid peroxide concentrations in coronary venous plasma can be detected in humans after balloon angioplasty. There is no positive correlation between lipid peroxide concentrations in coronary venous plasma after angioplasty and the degree of preceding myocardial ischaemia as assessed by either ST segment shift or lactate production. These indices showed that one to three serial 60 second balloon inflations each produce a similar degree of myocardial ischaemia. The origin of the raised lipid peroxide concentrations in coronary venous plasma after angioplasty remains unknown.


Thallium scans in syndrome X.

Thallium scans in syndrome X. To review thallium scans in patients with angina and normal coronary arteriograms. Retrospective review of data. Regional cardiac centre in Glasgow. 100 patients selected from those undergoing diagnostic angiography for typical angina who had normal arteriograms (around 10%), no other cardiovascular abnormality, and available thallium scans (performed routinely before angiography). Coronary arteriography, exercise tests, and gated thallium scans at peak exercise. The exercise test was positive in 30 and negative in 70 patients. Thallium defects were found in 98 patients, but no consistent pattern and no significant correlation existed between the extent of thallium defect and positive exercise test or exercise tolerance. Thallium defects described in 98 of 100 patients with angina and normal coronary arteriograms suggest that microvascular angina may be commoner than is generally appreciated.


Use of an autoperfusion catheter in the treatment of acute refractory vessel closure after coronary balloon angioplasty: immediate and six month follow up results. To determine the usefulness of the Stack autopersion dilatation catheter in patients with acute recurrent vessel closure during coronary angioplasty. Prospective data collection. University hospital. In 37 of 1003 consecutive patients undergoing angioplasty between November 1989 and December 1990 acute vessel closure developed that could not be redilated by a conventional balloon catheter. 13 (35%) of these 37 patients were sent immediately for emergency bypass surgery. In the remaining 24 patients an attempt was made to reopen the vessel with a Stack catheter. Successful reopening of the vessel. All successfully treated patients were followed for at least six months to detect recurrent ischaemia. In 16 patients (67%) the Stack procedure was successful. Of the eight patients in whom reopening of the occluded vessel was not achieved, seven were sent for bypass surgery and one was successfully treated by emergency stent implantation. The 16 patients successfully treated with the Stack autoperfusion system were followed up for a mean (SD) of 6.7 (2.6) (range 2 to 11) months. Ten patients remained symptom free but early clinical restenosis developed in four (25%). Overall, only three (19%) of 16 patients experienced recurrence of severe (class III-IV) symptoms and required further mechanical revascularisation. These data support the use of the Stack autoperfusion catheter system in selected patients with acute vessel closure not responsive to attempted redilatation with conventional balloon catheters. The short-term outcome seen in this series of patients who were successfully treated with this coronary autoperfusion system is encouraging.


Giant right atrial diverticulum: an unusual cause of Wolff-Parkinson-White syndrome. A case of a giant right atrial diverticulum associated with neonatal supraventricular tachycardia is reported. The electrocardiogram in sinus rhythm showed pre-excitation that may have been caused by the right atrial diverticulum adhering to the right ventricle.