Cement thickness and microleakage under metal-ceramic restorations with a facial butted margin: an in vivo investigation. Ten metal-ceramic restorations with buccal porcelain butt margins and palatal metal beveled margins were fabricated for periodontally hopeless teeth. After cementation, the experimental crowns remained in the oral environment for 3 to 6 months; the teeth were then extracted and used for microscopic and microleakage evaluation. All ten crowns showed at least a small amount of microleakage, but adaptation of beveled margins proved to be superior to that of shoulder porcelain margins.


Spinal patterns as predictors of personality profiles: a pilot study. The present pilot study is part of an ongoing effort to further the investigation of the relationship between spinal patterns and personality. The present pilot study seeks to identify likely spinal patterns of certain personality profiles and asks whether changing posture can affect personality, and/or can emotional states alter posture? Forty patients of a private chiropractic practice participated in the study. Four radiographs (x-rays) of each subject were taken and each subject completed the Minnesota Multiphasic Personality Inventory (MMPI). Measurements obtained from the radiographs and the MMPI data were used to derive general linear models of the predictability of the MMPI in terms of the spinal/postural measures. Several models were highly significant and preliminary support for the authors' hypothesis that spinal patterns are likely to be predictive of personality profiles is suggested. Support for previous research is offered and directions for future research are discussed.


Surface EMG topography and pain distribution in pre-chronic back pain patients. The relationship between surface EMG recordings from paraspinalis recording sites and subjective pain ratings were examined in a group of pre-chronic back pain patients. thirty-eight back pain patients without major orthopedic diagnosis and a pain duration between 2 to 6 months participated in a three week long subjective pain rating. Following the completion of their pain diary, the paraspinal sites were assessed under the "static" postural conditions of sitting and standing using an EMG scanning procedure. Results of the correlational analysis revealed significant and positive relationships between pain and muscle activity in the upper back (Trapezius, T1 paraspinalis sites) and significant but negative relationships between erector spinae activity (L3 paraspinalis site) and pain. When considering etiological factors of pre-chronic back pain, the results support both the organicity model for upper back, as well as the biomechanical model for the lower back.


Self-regulation and assessment approaches for vaso-occlusive pain management for pediatric sickle cell anemia patients. An interdisciplinary program with the goal of teaching self-regulation and minimizing excessive narcotic use in the management of vaso-occlusive pain (V-O) in pediatric sickle cell anemia patients is described. A small group of patients do not respond well to any of our outpatients or inpatients medical regimens, leading us to suspect that psychological factors are influencing pain reports. We outline our multi-faceted assessment approach to evaluating such psychological factors, which includes a pain flow sheet, symptom check list, and a psychophysiologic profile. Published reports of self-regulation training including biofeedback, relaxation/imagery, and hypnosis have been associated with decreased pain symptoms, reduced number of emergency room and hospital visits for pain, decreased narcotic use, and increased school attendance. A case study of a nine-year-old patient with sickle cell disease is described before and after self-regulation training. Finally, other alternative approaches that avoid excessive narcotic use are discussed with some case reports.


Anorexia nervosa as manifested in Russia. The authors describe current theoretical and clinical conceptualizations and treatment of anorexia nervosa in Russia, based on their experience in the follow-up of 800 patients. Three-quarters of the patients exhibited anorexia nervosa linked with a border-line state, and one-quarter associated with schizophrenia. Different relationships to dysmorphophobic fears were observed in the different anorexic groups. In the border-line group, follow-up study indicated that the clinical symptoms of anorexia nervosa were significantly reduced. However, the disorder preserved its connection with dysmorphophobic fears even in the remote stages of the disease, and in later stages there was an occurrence of pathological personality changes. In the second group, from the very beginning, anorexia nervosa in schizophrenia was closely connected with affective disorders, pathological body sensations, hypochondriacal complaints, and a gradual personality deterioration. As the schizophrenic defect increased, anorexia nervosa was reduced to an exhausted form of vomiting behaviour, and lost its connection with dysmorphophobic experiences.


Relaxation as an altered state of consciousness: a rationale for a general theory of relaxation. A general theory of relaxation is presented. It is based on an integrated model of the main states of consciousness, which enables one to differentiate "techniques for relaxing" leading to the "relaxing states" and "meditative techniques" leading to the differentiated waking states of consciousness. These latter include specific "only the relaxation response states" and the "ultraconsciousness states". Each state is described along the following dimensions: of biological rhythms, i.e., Sleep-Wakefulness and the Basic Rest-Activity Cycle; brain hemispheric activity; the threshold of the extero- and interoceptive stimuli reception; perceptual dominance of stimuli from external or internal sources; spontaneous versus goal-oriented imagination activity, i.e., passive or active state of mind; feed-back relation with the surroundings.


Clarification of the concept of psychological stress ("psystress"). The concept of "stress" in the current academic literature is unstandardized, and therefore confusing. The theoretical approach of regarding stress as an intervening variable seems most generally agreed on by researchers; the unambiguous term "Psystress" proposal to denote the mental state involved. Aspects of vocabulary concerning psystress production and response are also discussed.


Hassles, life events, and health status among Chinese college students in Hong Kong. Major life events and daily hassles were examined in a sample of 102 university undergraduates. While the major clusters of events were related to personal loss, life-style changes, family conflict, and personal insecurity, those of hassles were related to drudgery and uncontrollable environmental irritants, personal concerns, time and work management, minor routine expenses, and the dilemma of emigration. Using life events and hassles, and hassle clusters added significantly to the sensitivity of the concurrent prediction of undifferentiated and differentiated physical and psychological symptom criteria, and consistently showed better performance as predictors. However, the independent contributions of events and event clusters could hardly be discounted. The combined effects of major discrete and minor chronic stress on health status and the limitations of the present retrospective study were discussed.


Pavlovian conditioning of phobic fear: effects on skin and salivary pH. This experimental work was designed to investigate the relationships between pH and conditioned fear. The levels of pH were measured in skin and saliva, and were studied in connection with conditioned electrodermal and heart rate (HR) responses (extinction versus resistance to extinction or enhancement). The results of this investigation show that the changes in skin and salivary pH have a tendency to occur in an inverse pattern to the changes in skin conductance and HR. The data are interpreted in terms of skin and salivary pH as new psychophysiological variables and as new tools for psychopathological and psychosomatic research.


Adverse effects of meditation: a preliminary investigation of long-term meditators. Adverse effects of meditation were assessed in twenty-seven long term meditators (average 4.27 years) both retrospectively (time one) and prospectively at one month (time two) and six months (time three) following a meditation retreat. At both time one and time three subjects reported significantly more positive effects than negative from meditation. However, of the twenty-seven subjects, seventeen (62.9%) reported at least one adverse effect, and two (7.4%) suffered profound adverse effects. When subjects at time one were divided into three groups based on length of practice (16.7 months; 47.1 months; 105 months) there were no significant differences in adverse effects. How the data should be interpreted, and their implications both for the clinical and psychotherapeutic use of meditation as a relaxation/self-control strategy, and as a technique for facilitating personal and spiritual growth, are discussed. Limitations of the study and suggestions for future research are also offered.


Psychophysiological effects of stimulation with pictures of works of art in old age. The present article reports on a controlled intervention study concerning the effects of non-directed use of pictures of works of art as a way of stimulating institutionalized elderly women. After the stimulation period differences in ratings between the groups indicated improved well-being in the intervention group. Such improvement was not seen in the C-group. The quantitative analyses of the results reveal a significant change of the parameters happiness, peacefulness, creativeness, social activities and systolic blood pressure. The qualitative analysis shows that the conversations about pictures of works of art in the intervention group give the person free rein to her own imagination and are merely characterized by happiness. In the control group the conversations are to a great extent characterized by downheartedness, despair and complaining.


Referral patterns of dentists: analysis and implications of a questionnaire. The interpersonal and psychodynamic aspects of the referral process, that is, the reciprocal relationship between the specialist and his referral source are investigated. A questionnaire designed by the author, with anonymity guaranteed, was given to the members of 2 dental societies. There were more similarities than differences in the answers of the respondents in both groups. Several conscious patterns of referral emerged or were evident. A number of unconscious, psychodynamic motivations were explored.


Prolactin and weeping.

Prolactin and weeping. Fourteen women with functional hyperprolactinemia and an equal number of matched healthy controls completed a questionnaire on weeping behavior. Contrary to expectations the patient group were not more prone to weeping than the controls. In addition, their appraisal of weeping behavior (as a way to tension release and relief) did not differ from the controls. It is concluded that moderately elevated prolactin levels, although causing somatic disturbances such as amennorrhea and galactorrhea, do not affect the weeping threshold.


Creative psychotherapy and the facilitation of insight. The following case studies provide insight into the effectiveness and methodology of the facilitation of insight technique in psychotherapy. This technique has been successful in reducing the incubation process, which is the second of four stages in Wallas's Stage Model of Creativity, i.e., Preparation, Incubation, Illumination and Verification. The application of this technique in other areas of human endeavor are discussed.


Alcohol and narcotics. Epidemiology and pregnancy risks. Among alcohol and narcotics, alcohol is most comprehensively documented as a teratogen. However, for all other narcotics, data are continuously accumulating, convincingly displaying the teratogenic effects. The proportions between "somatic" teratogenicity and "behavioral" teratogenicity vary between the different agents. Preventive work in prenatal clinics and among social workers, as well as objective mass media attention to the problem, seems to have lowered the incidence of severe fetal alcohol syndrome where the above-mentioned activities have been practiced. The female alcohol consumption in Sweden decreased from 1976 to 1985; thereafter, a slow continuous increase is underway again. In Sweden the number of recruits to narcotic abuse peaked in the 1970s and early 1980s. Thereafter, the number of recruits among females decreased, but abuse has continued among the members of the older age groups.


Diagnostic and preventive possibilities of excessive drinking in antenatal care. Alcoholism among women has increased during the last decades. Thus it is likely that an increasing number of pregnancies will involve risk of alcohol damage to the fetus. In this article, two antenatal programs are presented to identify pregnancies at risk. Adequate alcohol information seems to be sufficient for socially drinking women, whereas alcoholic women need extensive support to abstain from alcohol. The psychosocial support was not experienced as intrusive.


Perspectives of users of the services.

Perspectives of users of the services. This article draws on social science evidence concerning the views and experiences of those using the antenatal services. It identifies several important themes in this evidence, including the need to consider pregnancy a normal process, to provide care that is sensitive to individual circumstances and that offers continuity of care throughout the antenatal period, and the obligation on providers to assess scientifically the effectiveness of the care they give.


Prevalence and significance of social and psychological risk factors during pregnancy. Moderate psychosocial problems identified during early pregnancy in 78 women were found to predispose for various "complications" during gestation, but not for prematurity or obstetrical complications during delivery. However, from a normal postnatal status the children of these mothers demonstrated a significantly unfavorable somatic, as well as psychomotoric development, until the age of 4. Pregnant women with certain psychosocial problems must be early identified and property attended to in order to preclude an adverse child development.


Measuring the effectiveness of psychosocial interventions in pregnancy. Questions about the effectiveness of psychosocial interventions in pregnancy are important in any overall evaluation of antenatal care. This article reviews the evidence as to the positive benefit on a range of pregnancy outcomes provided by 35 published and unpublished randomized controlled trials of psychosocial interventions.


Norwegian experiences. Competence of the providers and compliance to the treatment program for antenatal care in Norway. Antenatal care was established in Norway during the 1930s. Unlike the other Nordic countries, care is provided by general practitioners, not be midwives. Guidelines were first issued in 1984 after a debate about the quality of the care. This article reports providers' compliance to important parts of the guidelines.


Small-for-gestational-age (SGA) definitions and associated risks. Samples and methods vary in constructing birthweight charts. Introduction of ultrasound dating affects the distribution of gestation, increases the proportion of preterm births, and reduces postterm and small-for-gestational-age (SGA) births. The need for standardized charts is emphasized. Preferably such charts ought to be sex- and parity-specific, also taking into account the mother's previous pregnancy outcome in terms of birthweight. The risks associated with being born SGA involve various morbidity as well as short- and long-term survival.


Antenatal screening and risk factors for intrauterine growth retardation. Antenatal risk factors in combination with symphysis-fundus distance can identify pregnancies with small infants, who can be divided in genetically small, malformed, and malnourished infants. Only the last category benefit from fetal surveillance. Maternal diseases, pregnancy complications (hypertension), and environmental factors (smoking) are connected to malnourished small infants.


Prediction of fetal growth deviations by use of symphysis-fundus height measurements. The development of various symphysis fundus (SF) growth charts and the use of SF height measurements in the diagnosis of small-for-gestational-age (SGA) births and the prediction of newborn complications are reviewed. Measurement precision and accuracy are also discussed. It is concluded that further research of this simple, low cost, harmless, and widespread technology to detect fetal growth disturbances in routine prenatal care is warranted.


Antenatal diagnosis of intrauterine growth retardation by ultrasound. Ultrasound estimation of fetal weight or ultrasound measurement of fetal abdomen alone enables identification of small-for-gestational-age fetuses. A prerequisite for this is a reliable dating of pregnancy, which is provided by a routine ultrasound screening in the first half of gestation. The fetal growth can be followed by serial fetometric measurements. As a standard, charts of intrauterine growth based on the ultrasonic measurement can be used. As a secondary diagnostic test for monitoring fetal health in pregnancies suspected of intrauterine growth retardation, Doppler ultrasound evaluation of fetal and uteroplacental hemodynamics provided useful for early detection of imminent fetal distress.


Detection of intrauterine growth deviation. A comparison between symphysis-fundus height and ultrasonic measurements. Efficacy of ultrasonography to detect fetal growth retardation is reviewed. Ultrasound dating is held as a prerequisite. Abdominal anthropometry is reported to reflect fetal growth best. Efficacy of symphysis-fundus (SF) height measurements is reviewed similarly. Proposed protocols that include ultrasound and SF height measurements and other maternal characteristics with known prognostic properties are reported. Preferably, both kinds of measurements should be analyzed longitudinally.


The prognostic significance of antenatal diagnosis of fetal growth retardation. Intrauterine growth retardation is associated with high risk of perinatal asphyxia. The neonatal mortality rate of small-for-gestational-age (SGA) infants (birthweight < or = 2 SD) in Sweden decreased from 5.6% in 1973 to 2.0% in 1987. During the same period, the number SGA infants with postnatal asphyxia (5 min Apgar score < 7) decreased from 10% to 5%. Based on antenatal diagnosis of fetal growth retardation, an optimal time of delivery reduces the risk of major neurological and developmental sequelae of the individual infant.


Assessing the scientific basis of antenatal care. The case of Sweden. The Swedish routine program for antenatal care is based on a number of scheduled visits for the detection of symptomless complications, as well as psychosocial support and health education. The scientific evidence to support the present timing and contents of routine visits is unsatisfactory, and there is a great need for evaluation both of single diagnostic procedures and interventions and of programs of antenatal care.


Competence and compliance in antenatal care. Experience from Sweden. Swedish antenatal care is staffed by midwives working within the primary health care system, but with close collaboration with the hospital. The compliance to the program both from staff and mothers is very high, with 13.2 visits on average. There is a regional variation both in the number of visits and in the use of routine tests.


Antenatal care in Denmark. Assessments of program, staff competence, compliance, and outcome. Antenatal care in Denmark is shared between general practitioners, midwives, and hospital departments. A minimum of 9 visits is officially recommended for all pregnant women. In 1987, 80% made 10 or more visits. An inadequate number of visits in relation to recommendations was most frequent in the lowest social group. Risk of stillbirth and neonatal death varied substantially between social groups even after taking account of number of visits made.


Methodological problems and possible endpoints in the evaluation of antenatal care. Antenatal care is evaluated based on observational trend studies, geographical comparisons, medical audits, and randomized trials. The last method is preferable and should be applied whenever feasible. Most components of antenatal care have not been properly evaluated. In order to evaluate an antenatal care program, a randomized study is suggested using geographical areas as units of randomization.


Randomized controlled trials in the evaluation of antenatal care. Many of the practices carried out during antenatal care improve the well-being of mother or baby and reduce the burden of adverse perinatal outcome. Other practices have either not been evaluated or have been shown to be ineffective. Evidence from randomized clinical trials provides the best evidence about the effectiveness of these practices.


Register studies and clinical studies in the evaluation of antenatal care. The advantages and limitations of national registers containing individual identification numbers in clinical epidemiological research are reviewed. The author concludes that such registers are very valuable for epidemiological research and for formulation of research questions of public health importance.


Problems and prospects in the economic evaluation of antenatal care. Economic evaluations can be used to compare alternative antenatal care programs in terms of cost and outcome. The cost of routine antenatal care is small compared to the total cost associated with pregnancy and childbirth. The main problem in economic evaluations is related to outcome measurement.


Epidemiology of hypertension during pregnancy. Hypertension during pregnancy, defined as a diastolic blood pressure of at least 90 mm Hg, occurs in about 7% of Western countries. Primiparity and familial factors are the most important risk factors. Fifty percent of women experienced blood pressure elevation as late as the last month of pregnancy.


Screening for hypertension in pregnancy. The literature dealing with screening for hypertension in pregnancy was reviewed. No level of blood pressure or any other factor provides a guarantee of no risk for the development of preeclampsia. However, higher blood pressure in early pregnancy and a failure to decrease blood pressure in mid-pregnancy are both associated with the development of preeclampsia. The development of proteinuria, rather than the level of blood pressure, is the best predictor of poor pregnancy outcome. Multiparas, especially those with severe chronic hypertension who develop preeclampsia, are at greatest risk of poor pregnancy outcome.


Diagnostic methods for pregnancy hypertension. Significance of standardized conditions. Standardized conditions for blood pressure measurements and strict definitions of systolic and diastolic blood pressure are essential for a consequent management of hypertension during pregnancy. In Sweden, it has been agreed to measure blood pressure with the pregnant women sitting in upright position. Home-monitoring of blood pressure is recommended in women at risk of preeclampsia.


Cost-effectiveness of present programs for detection of asymptomatic hypertension in relation to the severity of hypertension and proteinuric hypertension. Proteinuric hypertension is an important cause of maternal and perinatal mortality. Eclampsia cannot always be prevented. The likelihood of identifying a new case of proteinuric hypertension at any particular visit is very low using traditional antenatal care schedules, and care could be focused on women at higher risk.


Blood pressure, growth retardation, and preterm delivery. The effect of various levels of both diastolic and systolic blood pressure at various times during pregnancy on the rates of intrauterine growth retardation (IUGR) and preterm delivery (PTD) were determined. Low systolic and diastolic pressures were associated with both IUGR and PTD, as were high pressures. Low pressures tended to be associated with spontaneous preterm deliveries, whereas high pressures were associated with more indicated preterm deliveries.


Smoking during pregnancy. Pregnancy risks and socio-demographic characteristics among pregnant smokers. Maternal smoking during pregnancy is causally related to fetal growth retardation. Smoking more than doubles the risk for the birth of a small-for-gestational-age infant. About 30% of the Swedish pregnant population smoke in early pregnancy. Despite that practically all pregnant women in Sweden today are aware of the hazards of smoking, about 70% of the smokers continue to smoke during pregnancy. Women who continue to smoke during pregnancy differ in terms of socio-demographic characteristics from those who stop smoking during pregnancy.


Smoking during pregnancy. Possibilities of prevention in antenatal care. Prevention of smoking in pregnancy is a mission of utmost importance since the fetal outcome is improved when the mother quits smoking. Methods to prevent smoking have to consider maternal attitudes and characteristics and be based on pedagogical and behavioral principles. A well-motivated staff, a self-help manual accepted by most women, and special support to those who want it are minimal requirements.


Community and culture: a Chinese model of community care for the mentally ill. Although psychiatric hospitals are thought to be the main focus of care for the mentally ill, China has not inherited the large asylums that were, and are, such a feature in the West. China has developed her own model of community care for the mentally ill, which is coherent with what are seen to be the available resources and fits into existing structures of social organisation. The elements in this model include small neighbourhood workstations, factory clinic liaison work, 'home beds' and neighbourhood care units. So far alternative accommodation schemes appear to have no part to play in the model. The reasons for this are discussed. However, while the Chinese model of community care for the mentally ill is quite well articulated, there appear to be major problems in ensuring its implementation.


The community meeting: a review.

The community meeting: a review. Community meetings are conducted in many psychiatric units and institutions. The formats, methods and theoretical backgrounds of the meetings however are very diversified. Most of the claims for beneficial effects are based on clinical impressions or indirect observations. The few structured studies that have been performed show that community meetings have the effect of reducing unfavorable ward incidents, especially aggressive ones. Much research remains to be done to confirm these findings and to elucidate the basic ingredients of the community meeting in providing beneficial effects.


Nurses respond to substance abuse.

Nurses respond to substance abuse. Because of their close contact with the community, nurses are vital in caring for substance abusers and in preventing addiction. And their roles in community and national programmes in this area are increasing. Below, an overview of the problems associated with substance abuse and how nurses are needed to provide effective care, prevention and education.


The 1983 Mental Health Act in five local authorities: a study of the practice of approved social workers. This paper represents the first report of an ongoing collaborative project and charts the activities of social workers undertaking their duties within the framework of the 1983 Mental Health Act in five English Local Authorities for one year. Social workers are involved in a range of duties under the Act, but most commonly they are involved in assessments with a view to compulsory detention. The characteristics of people assessed are examined, and a profile emerges of vulnerable subgroups, typically younger men, older women, and people living in socially impoverished situations. Considerable variation between Authorities is found in terms of numbers of assessments, and in numbers of detentions. Low levels of 'diversion' into alternative care are identified. Comparisons are made with a major national study which took place four years earlier. Higher rates of detention are found on average, but lower rates of use of emergency provision (Section 4). An examination of the organisational context within which Approved Social Workers (ASWs) practice reveals a great deal of variation between authorities in terms of the ongoing experience of assessments available to ASWs. Social workers based in Emergency Duty Teams and Hospital Teams are compared, and a distinctive profile of their work emerges, the hospital-based ASWs being more likely to be assessing 'known' people, often already in hospital, and referred for assessment by consultants. The implications of these findings for the management and deployment of Approved Social Workers are briefly discussed. The emphasis is upon the role of the ASW in terms of balancing the rights and needs of people assessed under the Act.


Counselor training as a treatment for alcoholism: the helper therapy principle in action. Extensive harmful drinking of alcohol is a major problem for many groups of Australian Aborigines and western treatment approaches have had limited effect. In order to stress cultural factors in treatment, a program to train indigenous Aborigines as alcoholism counselors for their communities was developed. In its more than 10 years of existence 145 counselors have been graduated. Of those initially entering the two year program 60% have graduated. Most of those have found employment as alcohol counselors for their people, and the numbers of Aborigines treated has increased. About 90% of those who entered the training had severe repeated substance abuse disorders in their recent history. The training and the alcohol counseling employment appears to be highly associated with continuing sobriety. For those who graduated the program only 4.8% returned to drinking. Those who completed only the first phase, 8.4% returned to drinking. Of those who were terminated from the program, 74% returned to drinking. Training alcoholics as alcohol counselors appears to be associated with vocational success and maintenance of sobriety as predicted by Riessman's "helper-therapy principle."


Assessment of life stress events: the etiology and measurement of traumatic stress disorder. The impact of stressful life events on health has been of considerable interest from a cross-cultural perspective. Examined herein is the etiology and onset of post-traumatic stress disorder with careful review of the diagnostic criteria, current measures used and clinical dimensions of PTSD. Also examined from a cross-cultural perspective is how psychological trauma may be processed by victims of trauma and subsequent approaches both pharmacological and psychotherapeutic to the treatment of post-traumatic stress disorder.


The Arab nurse and the Jewish psychotic patient in the closed psychiatric ward. The ongoing Israeli-Arab conflict has its impact on the mental health system. This issue is investigated from the point of view of the interactional process in the locked unit mainly between the Arab nurse and the Jewish psychotic patient. The unique experience of being treated by the formal enemy during one of the most vulnerable periods seems to be sometimes even therapeutic for the patient. Aspects concerning psychopathology, psychodynamics and social interaction are evaluated through observation and interviews with patients and staff members. Ways of dealing with the complicated issues are discussed.


The detection of psychiatric cases by Greek physicians: report on a study carried out in a Greek primary care setting. The detection of psychiatric disorder by primary care physicians in Greece was investigated using four non-psychiatric physicians. The General Health Questionnaire indicated a high probable prevalence of psychiatric disorder (77.8%), but the physicians rated only 9.3% of the sample as cases. Eighty eight per cent of the probable cases were undetected by the doctors. The doctors' reporting of cases was not affected by the demographic characteristics of the sample and only weakly affected by the patients' total GHQ score. The high probable prevalence and low detection rate is a cause for concern and requires further investigation.


Development of a PHC nursing information system in Korea. WHO has established collaborating centres at educational institutions throughout the world to assist with WHO research. In 1988 a WHO Collaborating Centre was inaugurated at Yonsei University College of Nursing in Korea. Since then two important research projects have been completed for establishing a data bank of human resources of nursing for primary health care (PHC) in Korea. Both projects strengthen the PHC nursing information systems in Korea and, as such, are beginning to develop PHC networks throughout Korea, passing on information to an international network system. Below, the rationale behind the two projects, the methodology and the results.


Changing the image of nursing in Jordan through effective role negotiation. As with other nurses worldwide, image, status and role definition are prominent issues in Jordan. Here nursing is considered menial work and the roles and responsibilities of the nurse have not yet been formally defined by royal decree, Jordanian courts or the nursing profession. Moreover, while nursing curricula ordinarily influence scope of practice, nurse educators have long noted an incongruity between nurses training and their roles in practice. Although Jordanian nurses are educated to be change agents, patient advocates, health educators and critical thinkers they function more like medical assistants and housekeepers.


Higher education via satellite.

Higher education via satellite. With the rapid advances in health, medical and technological fields, there is a pressing need for more nurses to obtain higher university degrees and continuing education in order to deliver quality care. Advanced education is necessary for not only nurse teachers but also clinical nurses. Yet access and familial duties often impede further study. Below, how Norwegian educational bodies solved the problem of reaching and teaching nurses throughout the country.


Radial keratotomy. 1. The wound healing process and measurement of incisional gape in two animal models using in vivo confocal microscopy. Using in vivo confocal microscopy, corneal wound healing was evaluated in both rabbit and cat eyes after radial keratotomy. A total of six rabbit and six cat eyes were evaluated sequentially over time for 1 mo after surgery by in vivo confocal microscopy, and quantitative measurements of changes in incisional wound gape were determined. In vivo histopathologic changes were correlated with conventional histopathologic findings in 18 rabbit and 4 cat eyes; the animals were killed at various intervals from 0-30 days after surgery. In the rabbit, in vivo corneal wound healing was characterized by the initial ingrowth of corneal epithelium followed by persistence within the wound without a marked fibrotic response. Measurement of incisional wound gape showed increasing gape from 144 +/- 32 microns on day 0 to 976 +/- 155 microns on day 26 at a distance of 2.4 mm from the optical zone. These in vivo measurements were not significantly different (P = 0.996) from those obtained using conventional histopathologic techniques which showed an incisional wound gape of 252 +/- 112 microns on day 0 and 917 +/- 216 microns on day 26 at 2.5 mm from the optical zone. In the cat eyes, healing of radial keratotomy wounds showed an initial increase in incisional wound gape from 135 +/- 56 microns on day 0 to 245 +/- 88 microns on day 7 at a distance of 2.4 mm from the optical zone. Starting at day 14 and continuing to day 30, there was a progressive decrease in incisional wound gape from 198 +/- 41 microns to 92 +/- 35 microns. Sequential, in vivo histopathologic analyses indicated that increasing incisional wound gape correlated with the retention of corneal epithelium in the wound. Initiation of decreasing incisional wound gape was associated with replacement of the incisional epithelial plug with fibroblastic tissue. These changes in the incisional wound gape observed in the cat suggest that healing of radial keratotomy wounds involves contraction of the wound in response to the ingrowth of fibroblastic cells. Furthermore, the contractile response appears to be biphasic involving a precontractile and contractile phase. Overall these data indicated that in vivo confocal microscopy provides quantitative histopathologic data on living tissue comparable with that obtained with conventional techniques on dead, fixed, and sectioned tissue. Additionally, the absence of wound fibrosis in the rabbit radial keratotomy model raises important questions as to the appropriateness of this experimental model for human radial keratotomy.


Radial keratotomy. II. Role of the myofibroblast in corneal wound contraction. The cellular mechanism of corneal wound contraction after radial keratotomy (RK) was studied in a feline eye model. A total of 10 cat eyes were evaluated at various times from 0-30 days after surgery. Changes in the distribution of intracellular filamentous actin, nonmuscle myosin, alpha-actinin, surface membrane alpha 5 beta 1 integrin, and extracellular fibronectin were studied using immunofluorescence and laser confocal and electron microscopy. From day 3-7, staining for fibronectin increased along the wound margin. By day 7, keratocytes adjacent to the wound margin showed increased f-actin staining with intense staining for fibronectin compared with normal keratocytes. Myosin and alpha 5 beta 1 integrin expression was very weak at this time; alpha-actinin was not found. By day 14, fibroblasts within the wound formed f-actin microfilament bundles (stress fibers) which colocalized with fibronectin. Wound-healing fibroblasts also stained positively for alpha 5 beta 1 integrin, myosin, and alpha-actinin (the latter two were colocalized). The presence of myosin and alpha-actinin in the wound fibroblasts and the re-organization of f-actin into stress fibers by day 14 correlated with the development of wound contraction. A comparison of the cellular distribution of actin, myosin, and alpha-actinin with alpha 5 beta 1 integrin 14 days after injury suggested that integrin was localized along stress fiber bundles during wound contraction. The data from this study suggest that modulation of wound gape during healing of RK wounds may involve transformation of the corneal keratocyte to a myofibroblast-like cell and the subsequent formation of intracellular stress fibers composed of f-actin, nonmuscle myosin, and alpha-actinin. Based on the colocalization of fibronectin filaments and f-actin filaments and the unique distribution of alpha 5 beta 1 integrin, these findings support the hypothesis that the tension within the wound is generated by the formation of intracellular stress fibers and the interactions between stress fibers and the extracellular matrix, mediated by specific membrane receptor molecules.


Radial keratotomy. III. Relationship between wound gape and corneal curvature in primate eyes. The relationship between changes in wound gape and corneal curvature after radial keratotomy (RK) was evaluated in five primates. Four-incision RK was performed using a diamond knife set to 100% of central corneal thickness with a 3-mm optical zone. In vivo measurements of wound gape were obtained using tandem scanning confocal microscopy at 3, 7, 14, and 45 days after surgery. The changes in corneal contour were measured at the same time points using a corneal modeling system with a specially designed primate cone. Wounds progressively increased in width to a maximum of 38 +/- 1 microns (n = 5) at day 7. After day 7, wounds showed increasing fibrosis which correlated with decreasing wound gape to 20 +/- 1 microns at day 45. A similar temporal change was detected in central corneal curvature (K), with maximum flattening occurring at day 7 (delta K = -3.17 +/- 0.90 diopters, n = 5), and progressive regression of effect to -1.32 +/- 0.61 diopters (n = 5) at day 45. Although there was interanimal variation, the mean temporal changes in corneal curvature significantly paralleled the changes in wound gape (r = -0.96, n = 4, P < 0.05). Based upon these findings, a simple geometric model was proposed which provides a hypothetic foundation for the relationship between corneal curvature and wound gape after RK. Calculations of wound gape made from this analytic model (using the measured topographic data) showed significant correlation with the actual wound gape measurements (r = 0.96, n = 4, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of epidermal growth factor, fibroblast growth factor, and transforming growth factor-beta on corneal cell chemotaxis. The effects of recombinant basic fibroblast growth factor (FGF), epidermal growth factor (EGF), and transforming growth factor-beta (TGF-beta) on migration of human and bovine corneal cells were determined using checkerboard analysis in Boyden chambers. EGF, FGF, and TGF-beta each stimulated high levels of chemotactic migration. Each growth factor, however, induced a different dose-response pattern. Migration stimulated by FGF reached a plateau at a concentration between 100 and 200 ng/ml for endothelial, epithelial, and stromal fibroblasts. By contrast, chemotactic responses to EGF peaked between 10 and 50 ng/ml, then decreased at higher concentrations. TGF-beta also stimulated a peak in migration in all three corneal cells, but the peak of migration occurred at an approximately 1000-fold lower concentration (1 pg/ml) than for EGF. Checkerboard analysis demonstrated that FGF and EGF, but not TGF-beta, stimulated chemokinesis of bovine, stromal, and endothelial cells. These results demonstrate that FGF, EGF, and TGF-beta induce migration in pure populations of bovine and human corneal cells and support the concept that these growth factors may play key roles in corneal wound healing by regulating migration of corneal cells.


Detection of transforming growth factor-alpha messenger RNA and protein in human corneal epithelial cells. Human corneal epithelial cells are normally shed from the apical surface and replaced primarily by mitosis of basal cells. Growth factors may regulate this process, but the sources for the growth factors have not been fully established. One potential source for growth factors is tear fluid, and epidermal growth factor (EGF) has been detected in the lacrimal gland and in tears. However, the hydrophilic structure and size of growth factors such as EGF may limit penetration to basal layers of intact epithelium. It is possible that turnover of basal human corneal epithelial cells might be regulated by growth factors acting by an autocrine mechanism. To determine if human corneal epithelial cells synthesize a potential autocrine growth factor, the authors analyzed human corneal epithelial cells for transforming growth factor-alpha (TGF-alpha) messenger RNA and protein, a growth factor that is structurally related to EGF and binds to the EGF receptor. Radioimmunoassay of human corneal epithelial cell cultures detected substantial levels of immunoreactive TGF-alpha (3 ng/10(6) cells). Immunohistochemical staining of human corneas also revealed the presence of immunoreactive TGF-alpha in the corneal epithelium. Northern hybridization with a 32P-labeled complementary DNA probe for TGF-alpha generated a single intense band at 4.4 kilobases, indicating the presence of TGF-alpha messenger RNA in cultured human corneal epithelial cells. These results support the hypothesis that normal turnover of corneal epithelium is controlled by the autocrine production of growth factors, such as TGF-alpha. Growth factors present in tears may function primarily as exocrine factors to stimulate healing of epithelial injuries after the epithelial barrier has been damaged.


Fos expression and growth regulation in bovine corneal endothelial cells. The authors evaluated the effects of stimulation (by serum, wounding, and three peptide growth factors: fibroblast growth factor [FGF], insulin, and transforming growth factor-beta [TGF-beta 1]) on the expression of the protein product of the immediate early gene, c-fos in bovine corneal endothelial (BCE) cells. These results were compared with those of cells which were made quiescent by serum starvation. They also examined the effect of these same growth factors or wounding on DNA synthesis. Quiescent cells expressed low levels of c-fos protein. Serum was the most potent stimulator, whereas FGF and insulin were modest stimulators. TGF-beta 1 did not significantly stimulate c-fos protein production. The results from DNA synthesis were different. Serum and FGF were still the most potent stimulators; insulin and TGF-beta 1 were weak stimulators. These data suggest that growth factors induce c-fos protein in BCE cells and that this may in part regulate the downstream event, cellular proliferation. Further investigation into the regulation of this and other protooncogene products may provide insight into the mechanisms which modulate corneal endothelial cell growth in humans.


Metabolic and morphologic changes in the corneal endothelium. The effects of potassium cyanide, iodoacetamide, and ouabain. The metabolic pathways of glycolysis and mitochondrial respiration in the corneal endothelial cell are the primary sources of the adenosine triphosphate (ATP) necessary to maintain endothelial structure and pump fluid to maintain the corneal stroma in its normally dehydrated and transparent state. The correlation between endothelial metabolism and morphology in rabbits was studied for 7 days after the application of three different agents: (1) iodoacetamide, used to inhibit ATP synthesis from both glycolysis and respiration; (2) potassium cyanide (KCN), used to inhibit ATP synthesis from respiration only; and (3) ouabain, used to inhibit fluid pumping but not ATP synthesis. After application of each of these three drugs to the corneal endothelium, changes in endothelial morphology were measured. The greatest change resulted from the use of iodoacetamide. Specular microscopic examination of the endothelium after the application of iodoacetamide showed progressive degradation of the integrity of the cellular structure; after 6 hr, there were no discernible cell borders. In those corneas treated with either KCN or ouabain, only minor changes in the endothelium were seen during the full 7 days of the investigation. Computer-assisted morphometric analysis showed an increase in the coefficient of variation of both cell area and perimeter in all cases. This increase was greater in the corneas treated with ouabain than those treated with either iodoacetamide or KCN. Redox fluorometry showed that the metabolic ratio (autofluorescence of reduced pyridine nucleotides divided by that of oxidized flavoproteins) decreased significantly in the iodoacetamide-treated corneas, increased significantly in the KCN group, and showed no significant change in the corneas in the ouabain group, all compared with a control group. The results showed that (1) when ATP produced by both glycolysis and respiration was inhibited by 0.1 mmol/l iodoacetamide, the endothelial cells could not survive, but (2) when ATP synthesis produced by respiration alone was inhibited by 1.0 mmol/l KCN, the cells could survive for at least 1 wk on the ATP produced by anaerobic glycolysis. Furthermore, the polymegathism seen after application of ouabain, a drug that is not believed to affect ATP synthesis but inhibits the endothelial pump function, is greater than that seen as a result of reduced pump function caused by inhibited respiration produced by 1.0 mmol/l KCN. Combining specular microscopy, computer-assisted morphometric analysis, redox fluorometry, and corneal pachymetry allowed correlations between corneal endothelial metabolism, pump function, and morphology to be studied.


Comparison of external and internal approaches for transplantation of autologous retinal pigment epithelium. The feasibility of autologous transplantation of retinal pigment epithelial (RPE) cells from just posterior to the ora serrata to the posterior pole was demonstrated in the rabbit model. Two techniques for introducing the transplanted cells were compared: an internal (anterior transvitreal) and an external (posterior transscleral) penetration to the subretinal space. In both approaches, RPE cells were obtained by biopsy from the peripheral retina of a rabbit eye, cultured, labeled with a fluorescent dye and 3H-thymidine, and transplanted to the posterior pole of the same or contralateral eye. The external approach consistently resulted in a greater number of transplanted cells on Bruch's membrane. The internal technique was more precise because it permitted direct visualization of the placement of the transplanted RPE. Transplantation of autologous RPE is a possibility that should be further pursued.


Morphologic comparisons between rhodopsin-mediated and short-wavelength classes of retinal light damage. The histologic manifestations of rhodopsin-mediated versus short-wavelength classes of retinal phototoxicity were compared after spectral exposures of the albino rat retina. Animals were exposed to wave-bands of light centered at the peak of rhodopsin absorbance (green, 500 nm) or in the ultraviolet A (UVA; 360 nm). Intensity-damage curves generated for each wave-band indicated that UVA light was 50-80 times more effective than green light at causing photoreceptor cell losses. Examination of early ultrastructural changes in rod inner segments, outer segments, and retinal pigment epithelium revealed a remarkable degree of similarity between UVA and green light-induced damage. Furthermore, the two classes of damage were indistinguishable in terms of post-exposure recovery from threshold damage and regional distribution of photoreceptor cell loss along the vertical meridian. The finding of essentially identical histologic manifestations for the two classes of damage raises the possibility that they share a common biochemical etiology or pathway of cell destruction.


Dissociation between prostaglandin levels and blood flow to the retina and choroid in the newborn pig after nonsteroidal antiinflammatory drugs. To assess whether prostaglandins contribute to the control of basal retinal and choroidal hemodynamics, retinal (RBF) and choroidal blood flow (ChBF) were measured by a microsphere technique in 1- to 4-day-old pigs before and after (at 20 and 60 min) administration of indomethacin (0.3 mg/kg, n = 6 or 10 mg/kg, n = 5), ibuprofen (40 mg/kg, n = 7), naproxen (20 mg/kg, n = 5) or vehicle (n = 8). In 40 other animals, PGF2 alpha, PGE2, and 6-keto-PGF1 alpha were measured in the retina and choroid at times corresponding to blood flow measurements. Mean arterial blood pressure and blood gases and pH were not altered by any of the agents. Except for the lower dose of indomethacin (0.3 mg/kg), which did not change retinal and choroidal prostaglandin concentrations, the prostaglandin levels were decreased similarly (P < 0.01) by the three drugs. However, RBF and ChBF were not changed by ibuprofen and naproxen, but decreased to the same extent after low and high doses of indomethacin. The data suggest that the effects of indomethacin on RBF and ChBF cannot be simply attributed to prostaglandin synthesis inhibition, and that prostaglandins may not play a significant role in controlling basal blood flow to the retina and choroid.


Blood-retinal barrier dysfunction at the pigment epithelium induced by blue light. Exposure to low-intensity white light can induce dysfunction of the blood-retinal barrier (BRB) at the retinal pigment epithelium (RPE). To determine whether the shorter wavelengths white light are responsible for this dysfunction, rabbit retinas were exposed to blue light (400-520 nm) or yellow light (510-740 nm). The permeability of the BRB, a parameter for the integrity of the barrier, was quantified with vitreous fluorophotometry. Morphologically, the barrier at the RPE was visualized on light and electron microscopy using horseradish peroxidase (HRP) as a tracer. Seventeen pigmented rabbits were exposed to blue light and 11 were exposed to yellow light. Vitreous fluorescein leakage increased with the exposure energy according to a power function (correlation coefficient > 0.79). The threshold energy for an increase in BRB permeability was 50 J/cm2 (0.014 W/cm2 for 1 hr) after blue and 1600 J/cm2 after yellow light. HRP tracing demonstrated that after blue light exposure, a significant fluorescein leakage on fluorophotometry corresponded to the presence of HRP in the RPE cells and in the subretinal space. After yellow light exposures of < 3700 J/cm2 and in rabbits with no significant fluorescein leakage, the HRP was limited to the choroidal capillaries and Bruch's membrane. These results demonstrate that the blue component of white light causes dysfunction of the BRB at the RPE 30 times more effectively than the longer wavelength fraction of white light. As a result, a blue light blocking filter should be used in ocular surgery on humans when an operating microscope is being used (light power 0.1-0.9 W/cm2).


Retinal pigment epithelium-stromal interactions modulate hyaluronic acid deposition. Hyaluronic acid (HA) is a major component of the extracellular matrix (ECM) and is particularly prominent in various structures of the eye. Choroidal mesenchymal fibroblasts (CHM) and fetal retinal pigment epithelial (fRPE) cells were cultured individually and in cocultivation, as a paradigm for ocular stromal-epithelial interactions. Such interactions are thought to be a key mechanism for the modulation of the ECM and of HA deposition in the region of Bruch's membrane and related structures. In cocultivation, increased levels of HA production were observed, more than the sum of the two cell types grown individually. Conditioned medium from fRPE cultures placed over CHM cells was able to enhance production in such cells several-fold, demonstrating that cell-cell contact was not needed for this enhanced production. On the other hand, when conditioned medium from CHM fibroblasts was added to the fetal RPE cells, no increase in HA production was observed. A soluble HA-stimulating factor apparently released by fRPE cells in a paracrine manner enhanced HA production in CHM cells. The fRPE cell-conditioned media was unable to exert this effect on the fRPE cells themselves. The fRPE cells may lack the appropriate receptor. Alternatively, they may not have the biosynthetic machinery for augmented HA production.


Grating, vernier, and letter acuity in retinitis pigmentosa. Grating, vernier, and letter acuities were compared in 25 patients with retinitis pigmentosa (RP), whose Snellen visual acuities were better than 20/40, to address the mechanism of visual acuity loss. For these patients with RP, all three types of visual acuity were reduced to an equivalent degree from those of a control group of 10 age-similar, visually normal subjects. The findings indicate that the visual acuity losses of these subjects with RP did not result from cone spatial undersampling (due, for example, to a random loss of foveal cones), from cone sampling irregularities (due to random alterations in foveal cone position), or from a selective loss of sensitivity to high spatial frequencies (as might result from changes in media transmission characteristics or a gain reduction in high spatial frequency mechanisms). In addition, previous studies have indicated that acuity losses in such patients with RP do not result from reductions in the quantum-catching ability of foveal cones. The most likely explanation for the equivalent losses in all three acuity types in these patients with RP appears to be an alteration in foveal spatial scale, consistent with a generalized increase in foveal intercone spacing.


In vitro studies of the contractility of cell types involved in proliferative vitreoretinopathy. The contractile activity of cells in epiretinal membranes leads to retinal detachment and proliferative vitreoretinopathy, but it is unknown which cell type contributes most to this process. In this study, the relative contractility of three cell types thought to be involved in epiretinal membrane formation was measured. Bovine scleral fibroblasts (BSF), retinal pigment epithelium (BRPE) and retinal glia (BRG) were suspended in a rapidly polymerizing floating type I collagen matrix. Matrix contraction was assessed and morphologic studies were performed using light microscopy and scanning electron microscopy. BSF reached 50% contraction within 4 days and BRPE needed 7-10 days, whereas BRG showed no matrix contraction. Cell proliferation, as shown by bromodeoxyuridine labeling, did not occur in the matrix. During the period of greatest contraction, cells had formed processes but were isolated from each other. Over the 7 day period, an increasing number of cells was found on the surface of the matrix, resulting (with BSF) in an encapsulating monolayer. This monolayer developed only after most of the contraction was over. These findings suggest that BSF and BRPE reorganize the collagen matrix through a combination of individual cellular mobility and attachment to the collagen fibers. BRG's inability to attach to the collagen and reorganize its arrangement resulted in its lack of matrix contraction.


Proteins of the vitreous humor during experimentally induced myopia. Significant myopia was evident within 14 days after a translucent goggle was placed over the eye of a newly hatched chick. This myopia was characterized by large negative refractive error, increased axial and equatorial eye lengths, and increased wet eye weight. The volume of the vitreous humor increased in the myopic eye, because of a signficant accumulation of liquid vitreous humor. The protein concentration of the vitreous humor of the myopic and nonmyopic eyes was greater at day 14 than at day 0 (ie, first day after hatching). Moreover, over this time, the protein concentration in the liquid component decreased, whereas the protein concentration in the gel component increased in both myopic and nonmyopic eyes. No difference was found in the protein concentrations between the myopic and nonmyopic eye at day 14. Polyacrylamide gel electrophoresis revealed changes in band position and intensity of individual protein compoents between days 0 and 14. No major differences were found in the gel or the liquid vitreous humor between the myopic and the nonmyopic eyes. Comparison of vitreous humor proteins with proteins from the plasma showed that some but not all of the proteins in the vitreous had the same apparent molecular masses as proteins from these sources.


Subconjunctival sustained release 5-fluorouracil. The authors have developed a sustained release device for 5-fluorouracil (5-FU) made up of a 12 mg pellet of drug coated in a mixture of permeable and impermeable polymers. When implanted subconjunctivally in rabbits, these devices released 5-FU at approximately 1 mg/d for over 10 days. Devices were implanted into four cynomolgus monkey eyes after posterior lip sclerotomy. One eye (treatment) received a device that contained 12 mg 5-FU and the other eye (control) received a placebo device that contained no drug. In control eyes, intraocular pressures returned to normal within 1 wk. In treatment eyes, pressures remained significantly lower throughout the experimental period (3 mo). There was no indication of impaired wound healing, corneal toxicity, inflammation, or damage to the ciliary body in rabbits or monkeys.


Injectable microspheres with controlled drug release for glaucoma filtering surgery. The authors evaluated the effects of biodegradable poly (lactic acid) microspheres that provided the controlled release of the antimetabolic agent adriamycin (ADR) to prevent post surgical fibrosis after glaucoma filtering surgery. Fifty six eyes of 28 rabbits underwent posterior lip sclerotomy and received a 0.2 ml subconjunctival injection that contained microspheres 90 degrees from the filtering site immediately after surgery. Microspheres containing ADR (100 or 200 micrograms) were randomly administered to one eye. The fellow eyes served as controls and received microspheres without the drug. Intraocular pressure in the eyes treated with the microspheres that contained the drug was significantly lower than that in the control eyes from days 7-12 in the 100 micrograms group and from days 6-16 in the 200 micrograms group (P < .05). Eyes that received ADR had a significantly longer patent filtering bleb compared with the control eyes (P < .05). No corneal complications were observed in the eyes treated with 100 micrograms of ADR and the control eyes. Peripheral corneal opacities (25%) and epithelial erosion (17%) were observed in the eyes that received the 200 micrograms dose, but the cornea returned to normal after 4 wk. These results suggest that controlled-drug-release microspheres with an antimetabolic agent may be promising for preventing fibrosis after surgery.


Basal tear turnover and topical timolol in glaucoma patients and healthy controls by fluorophotometry. To assess the effect of glaucoma and timolol on tear secretion, basal tear turnover was measured with fluorophotometry in 13 open-angle glaucoma patients not using any ophthalmic medication, 24 patients using timolol medication daily, and 41 healthy control subjects. Basal tear turnover is defined as the tear turnover at the lowest level of reflex lacrimation possible under physiologic conditions. Tear turnover was calculated from the decay of the tear fluorescence after instillation of fluorescein. Minimal influence of reflex lacrimation was obtained by instilling 1 microliter of 2% fluorescein without touching the eye and by discarding measurements performed in the first 5 min. Minimization was confirmed by a monophasic decay of tear fluorescence. The values of patients who used timolol and those who did not use timolol were significantly lower than those of healthy control subjects (mean values in percent/minute +/- standard deviation: 10.1 +/- 3.2, 12.3 +/- 4.1, and 15.6 +/- 5.4, respectively; Student's t-test: P < 0.02). The values of patients who used timolol were significantly lower compared to those of patients who did not use timolol (P = 0.03). The tear film break up time values of patients who used timolol were significantly shorter than those of patients who did not use timolol and healthy control subjects (Fisher exact test: P < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)


Identification and quantification of transferrin receptors on trabecular cells. The authors identified and quantified the receptor for transferrin on trabecular meshwork (TM) cells cultured from porcine eyes by using two receptor assays. Flow-cytometric analysis of TM cells that were incubated with a monoclonal antibody to the transferrin receptor revealed such receptors, which decreased in number as the cells passed from the pre- to the post-confluent phase. Quantitative characterization by radioligand binding of 125I-transferrin to trabecular cells followed by Scatchard analysis showed that pre-confluent cultures expressed 23,839 +/- 6746 high-affinity receptors/cell and post-confluent cultures expressed 5104 +/- 3639 receptors/cell. The expression of the receptor for transferrin reflects the index of mitotic activity and can be correlated with the proliferative state of the trabecular cells. Further characterization of the receptors for transferrin in the TM may open up the possibility of a pharmacologic approach that enhances the TM cell population, which is known to decrease with age and in glaucomatous states of the eye.


Reducing intraocular pressure by intubation elicits precocious development and innervation of the embryonic chick cornea. Growth of the embryonic chick cornea was directly related to, and coordinated with, overall eye growth. During normal development, the size of the embryonic chick cornea increased in three linear phases of diametric growth. Corneal diameter increased at a rate of 216 microns per day between embryonic day 4 (E4) and E7, 511 microns per day between E7 and E10, and 144 microns per day from E10 until after hatching. After the sustained release of intraocular pressure by intubation on E4, corneal diametric growth was reduced to a single phase of 122 microns per day. After intubation on E4, the mesenchyme surrounding the developing cornea was substantially thicker and the neural crest-derived corneal endothelium was established earlier. The primary corneal stroma of the intubated eye swelled and was precociously populated by neural crest-derived corneal fibroblasts. Thus, the timing of arrival of neural crest cells in the anterior segment and their contribution to the cornea were determined by the growth rate of the eye. Although the diameter of the cornea was substantially reduced after intubation, it was more densely populated by fibroblasts, resulting in a cornea that was substantially thicker than the control by E14. Prospective corneal nerves normally extend into the cornea proper on E11, concomitant with a decrease in its diametric growth rate. After intubation on E4, the perilimbal nerve ring was virtually complete by E5 and numerous nerves had extended throughout the E8 cornea. By E16, the cornea from the intubated eye contained a very high density of nerve fibers, possibly reflecting its reduced size. These data suggest that the primary corneal stroma does not permit nerve fiber extension and demonstrate that the timing of nerve fiber extension into the secondary corneal stroma is specified by the rate of oppositional diametric growth of the cornea.


In vitro and in vivo circumvention of multidrug resistance by Servier 9788, a novel triazinoaminopiperidine derivative. S 9788 is a novel triazinoaminopiperidine derivative which does not belong to any of the classes of compounds known to reverse multidrug resistance (MDR). S 9788 was far more potent than verapamil (VRP) in reversing resistance to adriamycin (ADR) in the ADR-selected murine leukaemia cell lines P388/ADR-1 and P388/ADR-10, and the human chronic myelogenous leukaemia K562/R. Fold reversion with S 9788 (5 microM) was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5 microM). S 9788 was also a more potent reversant of ADR resistance in the intrinsically resistant human colon adenocarcinoma COLO 320DM (2.3 fold), and of vincristine (VCR) resistance in the human MDR1 gene-transfected squamous lung carcinoma line S1/tMDR1 (5.6 fold). The activity of S 9788 depended on both the MDR cell line and the cytotoxic agent. S 9788 (50-100 mg/kg/d) administered IP once a day on days 1-4 resulted in a dose-dependent increase in the chemotherapeutic effect of VCR (0.25 mg/kg/d) in P388/VCR - bearing mice and ADR (4 mg/kg/d) in P388/ADR - bearing mice. Increases in antitumor activity were (% T/C) of +20-34% in the P388/ADR model and + 50-78% in the P388/VCR model with respect to cytotoxic agent treatment alone. S 9788 appeared to be devoid of toxicity at its effective doses. The mechanism of action of S 9788 is unknown but S 9788 (0.5-10 microM) induced a dose-dependent increase in ADR accumulation in KB-Al cells and compared to verapamil its effect was twice as active and approximately seven times more potent. We conclude that S 9788 is a novel agent capable of reversing MDR in vitro and in vivo, and whose pharmacological profile warrants its selection as a candidate drug for eventual assessment in the clinic.


Pharmacokinetics and cytotoxicity of B.3839, a molecular combination of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea, in a mouse model. B.3839 is the prototype compound in a series of novel molecular combinations of chloroethylnitrosoureas and 5-fluorouracil(5-FU) and has been tested against MAC tumours in mice. Previous studies have shown it is moderately active against MAC15A and highly active against MAC13 though this activity is dependent on route of administration. The aim of this study was to determine whether bioavailability could explain this difference in anti-tumour activity. Plasma levels of B.3839 and 5-FU after i.p. and oral administration were measured using HPLC. Non tumour-bearing and MAC26 bearing mice gave almost identical plasma profiles after i.p. administration with the Cmax being 29.8 and 30.4 micrograms ml-1 and t1/2 16 and 15 min. The AUCs were 15.3 and 13.9 micrograms h ml-1 suggesting tumour load had no influence over plasma levels. Oral administration gave a much lower Cmax of 8.0 micrograms ml-1 but an AUC of 15.2 micrograms h ml-1 due to a longer terminal t1/2 (94 min) giving 99% bioavailability. Levels of 5-FU release from B.3839 by either route were considered too small to influence anti-tumour activity. Cytotoxicity assays in vitro against the MAC lines gave IC70 values of 5.3, 13.8 and 8.6 micrograms ml-1 for MAC 26, 13 and 15A respectively after a one hour exposure. Bone marrow toxicity was shown to be less severe than that of TCNU which is currently in clinical trials. The results show bioavailability alone is not enough to explain tumour response. There appears to be a need for a threshold concentration (C) to be maintained for a period of time (t).


Comparison of N-acetylcysteine and mesna as uroprotectors with ifosfamide combination chemotherapy in refractory germ cell tumors. From January 1983 through August 1988, 318 consecutive patients with refractory germ cell neoplasms were treated with ifosfamide-containing combination chemotherapy. The patients received ifosfamide at 1.2 gm/m2/day with cis-platin 20 mg/m2/day for 5 days and etoposide 75 mg/m2/day for 5 days or vinblastine 0.11 mg/kg on days 1 and 2 for each cycle. Of 277 evaluable patients, NAC was used as an uroprotector in the initial 86 patients while the latter 191 consecutive patients received mesna to reduce urothelial toxicity. Dosages of NAC was 2.0 gm po q 6 hr and for mesna 120 mg/m2 IV push prior to ifosfamide and then 1200 mg/m2/day as continuous infusion of 5 consecutive days. All patients received 3.0 liters of normal saline per day. The number of courses of chemotherapy given in the two groups were similar. Twenty-four of the 86 patients (27.9%) receiving NAC developed hematuria (13 patients - grade 1, 4 patients - grade 2, and 7 patients - grade 3 toxicity). While 8 out of 191 (4.2%) mesna patients developed hematuria (6 - grade 1 and 2 - grade 3) (p < 0.0001). The incidence of severity of renal toxicity was similar in the two groups. Ifosfamide dosage was reduced solely for urothelial toxicity in 11 patients receiving NAC compared with none of the patients receiving mesna (p < 0.0001). Chemotherapy response was similar in the two groups. In conclusion, mesna provides better urothelial protection from ifosfamide-induced toxicity than NAC and allows better maintenance of the drug dosage.


Difluorodeoxycytidine (dFdC)--gemcitabine: a phase I study. Difluorodeoxycytidine (dFdC) demonstrated broad spectrum activity in preclinical models. A phase 1 study utilizing twice weekly injections was conducted in 50 eligible and evaluable patients. Twenty-nine patients received drug by 30 minute infusion at doses of 5-90 mg/m2 and 22, by 5 minute bolus at 30-150 mg/m2. The primary dose limiting toxicities were marrow suppression and flu-like symptomatology. Thrombocytopenia was dose limiting at 75 mg/m2 on the infusion schedule and 150 mg/m2 on the 5 minute schedule. Flu-like symptoms with fever, rigors and malaise occurred the day of injection in many patients. One patient with renal cell carcinoma attained a partial response. Evaluation of the drug's efficacy and schedule dependency continue.


Phase I study of mitonafide in solid tumors. Mitonafide was the first synthetized compound of a new series of 3-nitronaphthalimides with intercalative properties. A phase I study with a conventional escalation scheme was developed. The schedule of drug administration was a daily x 5 days by short (1 h) intravenous (i.v.) infusion, every 21 days. Thirty evaluable patients were treated at doses from 15.4 mg/m2/d x 5 days to 138.6 mg/m2/d x 5 days. The study was interrupted due to appearance of central nervous system toxicity in 5 patients treated at doses above 118 mg/m2 x 5 days. This toxicity consisted firstly of loss of memory in all patients. It was irreversible and progressed in 3 patients to disorientation and confusion, leading to dementia in one of them. This was considered to be dose-limiting toxicity, and since it appeared to be related to the administration schedule, no further studies with short i.v. infusions of mitonafide are recommended. A phase I study utilizing a more desirable administration schedule over longer periods of time is ongoing in other centers.


A phase I pharmacokinetic study of recombinant human tumor necrosis factor administered by a 5-day continuous infusion. Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokine in vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40 micrograms/m2 and was ultimately escalated to 200 micrograms/m2. A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160 micrograms/m2 was defined as the MTD. At 160 micrograms/m2 peak serum levels occurred within 5-20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80 micrograms/m2. This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule.


Phase I clinical trial and pharmacokinetic evaluation of doxorubicin carried by polyisohexylcyanoacrylate nanoparticles. Doxorubicin (DXR) incorporated into biodegradable acrylate nanoparticles such as polyisohexylcyanoacrylate (PIHCA) has been shown to increase DXR cytotoxicity and reduce cardiotoxicity by modifying tissue distribution in preclinical studies. We have conducted a phase I clinical trial of DXR-PIHCA in 21 patients with refractory solid tumors (10 male, 11 female, median age: 53 years, median PS: 1, prior free-DXR therapy: 7 patients). A total of 32 courses at 28 day intervals were administered at 6 dose levels (15, 30, 45, 60, 75 and 90 mg/m2). The drug was given as a 10 minute IV infusion on day 1 to the first 5 patients: 2 of them presented a grade 2 allergic reaction (W.H.O. criteria) during infusion, which was rapidly reversible once drug administration was discontinued. Subsequently, in the other 16 patients, the administration was modified to a 60 minute i.v. perfusion diluted in 250 cc of Dextrose 5%: only 1 patient presented the same allergic reaction. Grade 2 fever and vomiting occurred in 9 patients and 7 patients respectively during the first 24 h after treatment. There was no cardiac toxicity among the 18 evaluable patients. Grade 3 or 4 hematologic toxicity occurred at the 75 and 90 mg/m2 dose level. The dose limiting toxicity was neutropenia. The maximum tolerated dose was 90 mg/m2 and the recommended phase II dose was 75 mg/m2. A pharmacokinetic evaluation of DXR-PIHCA was conducted in 3 patients each at a different dose level (60, 60 and 75 mg/m2) and was compared with free DXR given to the same patients in the same conditions.


Phase II study of didemnin B in advanced colorectal cancer. Didemnin B is a depsipeptide derived from a Caribbean tunicate (sea squirt) that has demonstrated antineoplastic activity against a variety of murine tumor models, including the L1210 and P388 leukemia, the B16 melanoma, and M5076 sarcoma cell lines. Based on these data, we designed a phase II trial in which 15 patients with measurable, unresectable colorectal cancer were treated with Didemnin B at an initial dosage of 3.47 mg/m2 over 30 minutes administered by intravenous infusion every 28 days; the dosage was altered in accordance with the toxicity observed, with only one patient requiring a dosage reduction for pronounced nausea and vomiting. No hematologic or nonhematologic toxicity developed. No complete or partial responses were observed. These results do not compare favorably with results of treatments using other single agents or combinations that are currently available for the treatment of advanced colorectal cancers. However, because of the tolerable levels of toxicity experienced by in our patients, it is possible that an insufficient dose of the medication was delivered. We concluded that Didemnin B is not active against of colorectal cancers at the dosage and schedule at which it was administered in this study.


A phase II study of interleukin-2 and interferon-alpha in head and neck cancer. The capacity to modulate host response against metastatic head and neck cancer may eventually lead to improved survival. This phase II study in patients with advanced head and neck cancer evaluated the efficacy of combination systemic recombinant interleukin-2 (IL-2) and interferon-alpha (INF-a) and evaluated laboratory correlates between tumor response and a) tumor differentiation and b) NK cell activation. Five of fourteen patients responded; two had partial responses and three had transient responses (one complete and two partial, each lasting less than four weeks). Patients that responded had relatively lesser tumor burden and poorly-differentiated metastases. No response was observed in those few individuals in whom natural immune function was only minimally enhanced by therapy. Major toxicity, including but not limited to fever, fatigue and pulmonary compromise, allowed only 3 of 14 patients to complete three cycles of therapy. This preliminary phase II study shows that combination IL-2/INF-a therapy has clinical anti-tumor activity and that the level of NK cell activation and the degree of tumor differentiation may correlate with response.


A phase II trial of interferon alpha-2A plus fluorouracil in advanced renal cell carcinoma. A Hoosier Oncology Group study. In vitro studies have documented the synergistic activity of interferon (IFN) and fluorouracil (5-FU) in human cancer cell lines, and recent clinical trials have demonstrated the efficacy of this combination in metastatic colon cancer. The current study was undertaken to evaluate the combination of IFN alpha-2a plus 5-FU in previously untreated patients with metastatic renal cell carcinoma. From May 1990 through August 1990, 14 patients with metastatic renal cell carcinoma were treated with 5-FU 750 mg/m2/day continuous infusion IV days 1-5, followed by weekly IV infusions of 5-FU 750 mg/m2 beginning on day 12. Patients concurrently received IFN alpha-2a 9 x 10(6) IU subcutaneously 3 times per week beginning on day 1. The median age of patients treated was 57 (range 38-80) with a median Karnofsky performance status of 90 (range 60-100). Sites of metastases included lung only in 6 patients, liver only in 1 patient, 1 patient had bilateral disease at presentation, and the remaining patients had multiple sites of metastases. The median duration of therapy was 2 months. The predominant toxicities seen were stomatitis, nausea, flu-like symptoms and neurotoxicity. The only grade IV toxicity observed was severe vomiting in 1 patient, though 5 patients discontinued therapy within 2 months because of poor subjective response. With a minimum follow-up of 13 months no objective responses were seen. Thirteen of the 14 patients have had progressive disease and 11 have died. The median time to progression was 2 months (range 0.5-6 months) and the median survival was 5 months (range 2-14.5 + months).(ABSTRACT TRUNCATED AT 250 WORDS)


A study of toxicity and comparative therapeutic efficacy of vindesine-prednisone vs. vincristine-prednisone in children with acute lymphoblastic leukemia in relapse. A Pediatric Oncology Group study. Vindesine (des-acetyl Vinblastine) is a synthetic derivative of vinblastine, and was produced with the hope that it would have less neurotoxicity and hematopoietic toxicity than other vinca alkaloids. Phase I and II studies also demonstrated significant activity in lymphoid malignancies, especially Acute Lymphoblastic Leukemia (ALL). The present study was designed to compare therapeutic effectiveness of twice weekly vindesine (2 mg/M2/dose) plus Prednisone (60 mg/M2/dose) (Treatment 1) to weekly Vincristine (2 mg/M2/dose) plus Prednisone (60 mg/M2/day) (Treatment 2). All patients were less than 21 years of age, and had documented bone marrow relapse (blast count > 25%). In 39 patients presumed sensitive to vincristine, there were 11 complete responses out of 20 patients (55%) randomized to receive vindesine/prednisone and 7 complete responses out of 19 patients (37%) treated with Vincristine/Prednisone. In 37 patients resistant to vincristine, there were 7 complete responses (19%). Vindesine was more toxic than Vincristine. Major toxicities of vindesine included paraesthesias, peripheral neuropathy and ileus. Vindesine hematological toxicity appeared greater, but such toxicity is hard to assess in patients with bone marrow disease. In this study, vindesine and vincristine had similar efficacy, but vindesine use was associated with more toxicity.


Post-ligation dilatation of the fallopian tube. Dilatation of fallopian tube remnants after ligation has been described but never systematically studied in post-ligation hysterosalpingograms (HSGs). This study describes the frequency and appearance of proximal tubal remnant dilatation as seen on HSGs in women with a history of bilateral tubal ligation (BTL). A retrospective review of medical records and a subjective and objective evaluation of dilatation seen on HSGs included 68 consecutive women seen for pre-reanastomosis HSG. Among the 68 women, 44 (67%) had objectively measured dilatation on one or both tubes. Dilatation was present in both short and long tubal remnants. There were no measurable differences between women with and without presence of dilatation. Neither length nor dilatation of tubal remnant was associated with pregnancy outcome. Dilatation of the tubal remnant after bilateral tubal ligation is a common finding on HSG and can be accurately identified from the HSG by radiologists. Dilatation is not strictly related to length, and in our small sample with follow-up, was not associated with pregnancy outcome.


Meteorologic influences on the frequency of pulmonary embolism. Reports published earlier this century suggested that meteorologic factors influence the incidence of pulmonary embolism. These observations were based on few patients and often lacked rigorous standards of evidence. In the current study, the authors evaluate the association between barometric pressure changes and pulmonary embolism using radionuclide ventilation-perfusion (V/Q) scan data. Daily interpretation data for V/Q lung scans were correlated retrospectively with daily local barometric pressure changes over a 7-year period. The incidence of pulmonary embolic disease was significantly related to a decrease in barometric pressure during the 3 days preceding clinical presentation. Meteorologic factors are less important than better-known risk factors for pulmonary embolism; however, their effect is demonstrable in a large data sample. This work confirms previously published associations between barometric pressure changes and the incidence of pulmonary embolism.


Image feature analysis of false-positive diagnoses produced by automated detection of lung nodules. To reduce the number of false-negative diagnoses by radiologists, the authors are developing a computer-aided diagnosis scheme for detection of lung nodules in digital chest images. In this study, the authors attempted to reduce the number of false-positive diagnoses obtained with a previous computer scheme by incorporating additional knowledge from experienced chest radiologists into the computer scheme. The authors applied their previous computer scheme, using less-strict criteria, to 60 clinical chest radiographs; this yielded 735 candidate nodules (23 true nodules and 712 false-positive diagnoses). These candidates were analyzed using region-growing, trend-correction, and edge-gradient techniques to determine measures by which to quantify image features of candidate nodules. The 712 false-positive diagnoses represented various anatomic structures that were located throughout the chest image. From this analysis, we were able to decrease the number of false-positive errors from an average of 12 to approximately 5 per image without eliminating any true nodules. Our results show that incorporating knowledge from experienced chest radiologists into the computer algorithm will play an important role in the development of computerized schemes for the detection of pulmonary nodules.


Visual increment and decrement threshold curves as a function of luminance range and noise in simulated computed tomographic scans. The effect of luminance range compression on the visual threshold of a target in a computed tomographic (CT) scan was investigated in eight experiments. Both visual increment thresholds of a hot target and visual decrement thresholds of a cold target were obtained. Realistic noisy CT images simulating a scan reconstruction and partial volume blurring were tested as representative of complex medical images. Negative versions, high luminance versions, and noise-free versions of these CT images also were tested. In all the noisy images, as the luminance range of the image was compressed, proportionately smaller physical luminance differences between the target and its local background were needed to reach visual threshold. However, the thresholds were the same in terms of the difference in CT numbers between target and background. Noise in terms of CT numbers sets the threshold for a wide range of display conditions. In the noise-free CTs, as the luminance range was compressed, the luminance differences between the target and background needed to reach threshold also decreased, but only marginally. However, in terms of CT numbers, the thresholds were increased.


Effects of vasoconstrictors on isolated rabbit coronary arteries exposed to isotonic iohexol. Potassium chloride-, histamine-, endothelin-, and prostaglandin-F2 alpha-induced contractions on arteries exposed to iohexol without and with osmotic additions (sodium chloride or glucose). A major effect of contrast media (CM) on coronary vessels is vasodilatation, but occasionally, both ionic and nonionic media may cause coronary artery spasm. The influence of CM on the actions of vasoactive substances is not well known. To investigate the effects on rabbit coronary arteries of an iso-osmolar nonionic CM, iohexol (140 mg I/mL) the vasoconstrictors potassium chloride (KCl), histamine, endothelin, and prostaglandin-F2 alpha (PGF2 alpha) were used. The effects of iohexol with 30 to 150 mM sodium chloride (NaCl) or with 25-50 g/L glucose also were investigated. Coronary artery segments were mounted between two L-shaped prongs in tissue baths with buffer solution. Before each investigation, buffer was exchanged with iohexol solution. Increasing concentrations of a vasoconstrictor were added, and the constriction of the vessels was recorded. Iohexol caused a comparatively small inhibition of the contractile effects of histamine and endothelin. This meant little reduction in maximal contraction (Emax), and the concentration of constrictory substance resulting in half maximal contraction (EC50) compared with buffer solution. Iohexol also caused a small reduction in Emax of KCl, but EC50 was significantly lower. Adding NaCl or glucose to iohexol decreased Emax and increased EC50. Iohexol inhibited most of the contractile effect of PGF2 alpha, but adding NaCl increased Emax slightly. The effects caused by a nonionic CM on coronary arteries cannot be attributed to osmolality alone. The CM influenced the effects of vasoconstrictors to differing degrees, but the inhibition of the CM per se was usually small.


Gadolinium-ethoxybenzyl-DTPA, a new liver-specific magnetic resonance contrast agent. Kinetic and enhancement patterns in normal and cholestatic rats. Gadolinium-ethoxybenzyl-DTPA (Gd-EOB-DTPA) is a new hepatobiliary magnetic resonance imaging (MRI) contrast agent with a dual elimination: 70% via the liver and bile and 30% via the kidney in normal rats. The abdominal enhancement patterns of this new compound and the uptake mechanism by the liver were studied in rats using tissue relaxometry and MRI. Twelve normal rats, 33 rats treated with agents designed to inhibit biliary excretion of the agent, and 6 rats with surgically ligated common bile ducts received Gd-EOB-DTPA intravenously. Distribution and excretion were measured by MR relaxometry. MR signal intensity was measured over time for liver, kidney, and bowel. In normal animals, 0.1 mmol/kg Gd-EOB-DTPA induced a significantly greater (200%) and more prolonged liver signal enhancement (100% at 30 minutes) than Gd-DTPA at the same dose. Either hyperbilirubinemia, induced by common bile duct ligation, or bromosulfophtalein (BSP) infusion inhibited liver uptake of Gd-EOB-DTPA, resulting in a preferential elimination via the kidney. Taurocholate (TC), an inhibitor of the bile acid transporter, was unable to block the liver uptake of Gd-EOB-DTPA. Blood half-lives of Gd-EOB-DTPA in rats were 2.4 minutes for the first component and 8.2 minutes for the second. Data indicate that transport of Gd-EOB-DTPA through the liver into bile is driven by the organic anion transporter. The relation between enhancement of liver and kidney may be diagnostically useful to indirectly evaluate liver excretory function. Yet, persistent enhancement of liver, even in the presence of severe hyperbilirubinemia, should be sufficient to identify focal mass lesions.


Fluorinated blood substitute retention in the rat measured by fluorine-19 magnetic resonance imaging. Emulsions of perfluorocarbons (PFCs) have been tested as blood substitutes. However, evidence exists that there is long-term retention of some PFCs by the organs of the reticuloendothelial system (RES). The authors investigate organ retention of the blood substitute component, perfluorotripropylamine (FTPA), using fluorine-19 (19F) magnetic resonance imaging (MRI). Various dosages of an emulsion of FTPA were administered to five rats. At intervals up to 86 weeks after infusion, 19F MRI was used to measure the amount of FTPA in liver and spleen. The data were fit to both linear and exponential elimination models, and organ retention half-lives were calculated. The exponential half-lives for combined liver and spleen FTPA ranged from 110 to 190 days. Linear half-lives ranged from 175 to 300 days. FTPA retained by the liver and spleen may be quantified by 19F MRI: The half-lives that were measured are longer than those reported previously for FTPA.


Changes in serum magnesium during excretory urography. A comparison of ionic and nonionic contrast media. It is known that ionic contrast media (CM) bind magnesium and that patients with asthma often benefit from magnesium injections. Similarly, asthmatics have a higher incidence of CM reactions. This work tests the hypothesis that ionic CM alter serum magnesium more than nonionic CM. Ten patients were divided into two groups; one group received iothalamate and the other received iohexol. The total magnesium level changed significantly from baseline in the iothalamate-treated group (P less than .01). Iothalamate produced a significant decrease in protein-bound magnesium (P less than .01) with a significant increase in filterable magnesium (P less than .01). Iohexol did not produce significant changes for any of the magnesium fractions. The patient with the most clinically significant adverse reaction (though minor) had the lowest baseline magnesium level. Further studies with larger groups including patients with asthma are needed.


Emergency radiology services at medical schools in the United States. Little has been published on the delivery of emergency radiologic services in academic radiology training programs. The author surveyed 127 medical schools in the United States concerning aspects of radiology services for their emergency rooms, including who interprets images, what training in emergency radiology is provided, and problems with film retrieval. Emergency department radiographs most often are initially interpreted by a radiology resident and subsequently reviewed by a faculty radiologist who does not have a major interest in or time commitment to emergency radiology. Most schools describe problems such as disappearance of emergency department films and a paucity of provided clinical information. Only one third of schools provide formal instruction in emergency radiology for their radiology residents.


Computer-aided radiopharmaceutical design. The ultimate goal of a QSAR analysis is prediction, which depends on the elaboration of the most appropriate set of molecular descriptors. As such, molecular description is the nucleus of QSAR and in the absence of exhaustive molecular description, rational drug design may be greatly impeded. As previously discussed, computational methods such as quantum mechanics and molecular mechanics provide molecular description at a fundamental level which then enhances the descriptive capability and predictive power of a QSAR analysis. In recognition of these capabilities, semi-empirical molecular orbital methods and molecular mechanics now have been incorporated into or interphased with QSAR programs. Such integrated packages are being successfully used in computer-aided molecular modeling. Computer-aided molecular modeling can provide the three-dimensional structure of a molecule, its chemical and physical characteristics, comparisons of structures of different molecules, and visualization of complexes formed between them. From the foregoing, predictions may be made about how related new molecules may function. Thus, the combination of quantum and/or molecular mechanics and QSAR provides a formidable weapon in the chemist's armamentarium. The molecular modeling approaches are certainly more practical to use than physicochemical methods. They also provide electronic and thermodynamic data that are not available from x-ray crystallographic data. Of course, these techniques are not confined to radiopharmaceutical development and they also could aid in the development of contrast agents for radiography or magnetic resonance imaging. We believe that as computational resources and capabilities increase over the next decade, computer-aided drug design will become a standard procedure in all drug development laboratories.


Opiate addiction in Iowa.

Opiate addiction in Iowa. Where do opiate addicts obtain drugs? Interviews with patients in an Iowa methadone clinic reveal some surprising responses with definite implications for physicians who prescribe.


Expression of cauliflower mosaic virus ORF II in a baculovirus system. The cauliflower mosaic virus ORF II encoding the aphid transmission factor (ATF) was mutagenized to introduce a BamHI restriction site upstream from the initiation codon and then cloned into an eukaryotic viral expression vector (Autographa californica nuclear polyhedrosis virus). All recombinant viruses tested in Spodoptera frugiperda (SF21) cells expressed a protein of about 18 kD which comigrated in PAGE with ATF from infected plants. Western blotting using an oligopeptide antiserum to ATF confirmed the identity of the 18-kD protein from infected cells as the product of the ORF II sequences (P18). Subcellular fractionation of cells infected with the recombinant AcMNPV demonstrated that the expressed P18 accumulated intracellularly in an insoluble form. Antiserum was produced in rabbit against the partially purified P18 expressed in SF21 cells. When used to immunogold label ultrathin sections of cauliflower mosaic virus (CaMV)-infected turnip tissue, this antiserum was shown to be highly specific, labelling only the electronlucent inclusion bodies (containing P18) and not other plant cellular components.


Differentiation of biologically distinct cucumber mosaic virus isolates by PAGE of double-stranded RNA. Electrophoresis on 5% polyacrylamide was used to analyze dsRNAs of 26 cucumber mosaic virus isolates propagated in Nicotiana tabacum. There was variation between isolates in the migration of each of the dsRNAs 1, 2, and 3. Comparison of the dsRNA profiles enabled each isolate to be allocated to 1 of 7 distinct dsRNA profile types. Two distinct and readily distinguishable isolates were mixed in planta and dsRNA from these infected plants compared with in vitro mixtures of them. All bands from both types were present, indicating that the differences were real and reproducible. This method is of value as a means of classifying cucumber mosaic virus isolates, as it more closely reflects a range of biological characteristics than do other methods currently used.


Common identity of grapevine viroids from USA and Australia revealed by PCR analysis. Pairs of viroid-specific oligonucleotide primers were selected and used in separate reverse transcription reactions coupled with the polymerase chain reaction to obtain DNA products of predetermined sizes characteristic of each viroid. The reaction conditions allowed efficient incorporation of small amounts of 32P-dATP which enabled rapid detection of the products in polyacrylamide gels. Using this method as well as probe hybridization, the presence of grapevine yellow speckle viroids 1 and 2 (previously known as GV1B) in grapevine samples from California was demonstrated, and it was established that the Australian grapevine viroid occurs in California. These comparisons provide the basis for uniform nomenclature of grapevine viroids found in different geographical regions.