Lowell T. Coggeshall and American Medical Education: 1901-1987. This essay analyzes Lowell T. Coggeshall's impact on American medical education by focusing on Coggeshall's 1965 report to the Association of American Medical Colleges (AAMC), Planning for Medical Progress through Education. Coggeshall graduated from medical school in 1928 and became an expert on tropical diseases. During his military experience in World War II, Coggeshall shifted his focus to administration. He was a skilled executive and became well acquainted with the ways of both the federal government and academic medicine. The AAMC, founded in 1876, was a kind of informal "deans' club" for many years. The many social and medical changes of the 1950s and 1960s prompted the AAMC to form a committee, headed by Coggeshall, whose chief task was to provide guidance for the AAMC. The 1965 report recommended that the AAMC move its headquarters to Washington, D.C., and take a more active role in shaping national health policy. However, many of the report's suggestions were not implemented, such as having the AAMC change its name and represent not only medical schools but all health-related academic units. While the report was widely praised, it was also strongly opposed by some powerful groups. This essay reviews the impact of Coggeshall's report and examines the nature of such reports in general. Coggeshall's greatest contribution to American medical education was his role in reshaping the AAMC into an effective voice for academic medicine.


The "health of the public" approach to medical education. The author examines the growing discontinuity between medical education and the general health needs of society. He explains and illustrates this failure of the academic medical center in several ways: by a parable; by reporting the results of his informal survey of faculty and residents; by presenting the findings of an international conference on medical education; and by giving a detailed description of the design and impact of the "Health of the Public" program, launched by the Pew Charitable Trusts and the Rockefeller Foundation in 1986. He maintains that there is an imbalance in the training of physicians and other health professionals because academic medical centers are dominated by supply-side thinking--which is driven by new knowledge and technology and the resulting need to find patients to fit the interests and technical capabilities of specialists and the equipment and services of hospitals--and have under-emphasized demand-side thinking, which concerns the patient and the health expectations, needs, and trends in the community. The author maintains that academic medical centers can continue to achieve the recognition they seek, but can do so by making the changes needed to better balance the driving forces of supply and demand. Only by doing this will they fulfill their fundamental mission of fostering the health of the public.


Modulation by monovalent anions of calcium and caffeine induced calcium release from heavy sarcoplasmic reticulum vesicles. Both calcium and caffeine induced calcium release from actively loaded heavy sarcoplasmic reticulum vesicles were studied to analyze the dependence of both activities on the composition of the release medium with respect to monovalent anions. Calcium is unable to induce net calcium release while caffeine remains effective as releasing agent when the experimental media contain neither chloride nor nitrate ions. Caffeine induced calcium release is not suppressed by chelating residual medium calcium (approximately 0.5-1 microM) with 2 mM EGTA added 15 s prior to 10 mM caffeine. Calcium release from vesicles loaded in media containing 0.2 M gluconate as monovalent anion is induced when the medium is supplemented with chloride or nitrate. The release amplitude increases linearly when K-gluconate is replaced by KCl. At constant ionic strength the release amplitude becomes maximal at a chloride concentration of 0.2 M. The chloride effect completely disappears when 2 mM EGTA are added simultaneously. When chloride is replaced by nitrate, as releasing agent, maximal release is achieved already by addition of 0.1 M K-nitrate. The releasing effect of nitrate can only partially be suppressed by EGTA. The different effectiveness of gluconate, chloride and nitrate as calcium release supporting ions corresponds to their activating effect on the binding of ryanodine to the calcium release channel in the vesicular membranes.


The coming influence of a social sciences perspective on medical education. Medical education will change from within in response to continued advances in biological sciences and technology, but changes that are occurring outside the natural sciences can have greater impact, especially (1) the reconceptualization of the meaning of health, (2) the increase in the number and range of different health improvement strategies, (3) the growing awareness of the paradox of the relatively low health status of the U.S. population and high per-capita and national health care expenditures, and (4) shifts in the causes of illness and death. These changes make it necessary for medical students to be given a foundation in both the natural and the social sciences, for most ill health has causal roots in both the social and physical environment, even though it is not understood how some of these outside influences are translated into disease or biologic derangements that lead to disease. Consideration should be given to changes in medical education that include (1) interpreting the sociology as well as the biology of health, (2) expanding the horizons of medicine to incorporate health improvement as well as disease cure, (3) training for population-based health care at the community level, and (4) learning to assess medical outcomes with more than biometric measures to include measurements of functioning and well-being. The author presents in detail a health input-output model to show the complex interrelationships of socio-ecologic (i.e., outside) factors and the individual's genetic-biologic makeup (inside factors) that determine the individual's state of health.


Maturation and responsiveness to extracts of corpora allata from male Locusta migratoria containing allatotropic factors. Corpora allata (CA) from male Locusta migratoria were tested for their ability to synthesize juvenile hormone (JH) and to respond to stimulating brain/corpora cardiaca (CC)-extracts under in vitro conditions. We found that a preincubation of the CA of both sexes at 4 degrees C for 24 h lowers their basal rate of synthesis and retains their responsiveness to allatotropic factors. Male CA can be stimulated by brain/CC extracts as well as female CA. JH biosynthesis stimulating factors are also present in male brain/CC extracts. Thus such extracts from male locusts can be used for the isolation of locust allatotropin. Furthermore male locust CA are appropriate for bioassaying such allatotropic factors.


Evidence for a pathway of distal screening pigment granules across the basement membrane of the crayfish photoreceptor. The distal pigment cells of Orconectes limosus contain two layers of large electron lucent vacuoles that are separated by layers of small right-angled platelets adjacent to the crystalline cones. The crystalline cones of the dioptric apparatus of this species have evaginations into the distal pigment cell cytoplasm. In photoreceptors of Orconectes limosus and Procambarus clarkii a dark pigment accumulation site was detected just distal to the basement membrane at the edges of each retina. These pigment accumulations occurred independent of the state of light adaptation. Ultrastructurally the pigment granules at this accumulation site resemble distal screening pigment granules according to their size (up to 1.2 microns in diameter) and fibrous structure. Distal screening pigment granules were also found in tube-like cell processes or extracellularly within and proximal to the retinal basement membrane, indicating pigment transport to and across the basement membrane. Proximal to the basement membrane screening pigment granules were also observed disintegrated to a gravel-like electron dense material in widely branched cells. Evidence was found that an electron dense material, probably resulting from disintegrating screening pigment granules, was incorporated in the integument of the eyestalk. Four hours after injection of gold particles into the eye stalk distal to the retina they were detected inside and proximal to the retinal basement membrane.


Preventing the decline of academic medicine. Academic medicine in North America has been highly successful in many ways in the last 50 years, including being able to resist change while unprecedented and fundamental changes are taking place in the practice, technology, and financing of medicine. This stance places academic medicine at risk of being bypassed by events. To prevent this, what balance between rigidity and flexibility should be sought? The author addresses this question by first reviewing the history of academic medicine and then defining in detail three current problems in medical education and two in biomedical research, two of academic medicine's domains. All these problems have in common some form of harmful dissociation of endeavors: for example, in education, there is a dissociation between both the teaching and academic clinical practice of medicine and the health care needs of the public. The author then proposes solutions to the problems, based on his examination of three major principles that motivate academic medicine. For example, he maintains that the teaching of all the medical sciences should be part of, and equal in quality to, the overall program of sciences in a university, and that the interdependence of medical schools and universities should be nurtured. He also maintains that the narrow conceptual framework of medicine that focuses on mechanisms of disease must be expanded to include rigorous attention to such areas as prevention, technology assessment, and organization of care.(ABSTRACT TRUNCATED AT 250 WORDS)


Fluorescence of chromatin DNA by an oxazolium scintillator. Aqueous solutions of a yellow and highly fluorescent derivative from dimethyl-POPOP, obtained by treating a chloroform solution of this oxazole scintillator with dimethylsulfate, induce a strong blue-green or yellow-green fluorescence in chromatin DNA under ultraviolet (365 nm) or violet-blue (436 nm) excitation, respectively. It is suggested that this new and selective fluorescence reaction could originate from binding of the oxazolium derivative into the minor groove of DNA.


O6-alkylguanine-DNA alkyltransferase in the chick embryo during development. In the whole embryo, O6-alkylguanine-DNA alkyltransferase (AT) activity increased until day 9 of development and declined sharply after day 13. AT activity of the liver was greatest between day 12 and day 20 and decreased fast after hatching. In the brain, AT activities reached a maximum at day 17 and 18 and declined sharply after hatching. At two developmental stages with different AT activities (day 10 and day 17) DNA alkylation in the brains was estimated 6, 12, 24 and 48 h after administration of N-methyl-N-nitrosourea in ovo by viscometric measurement of DNA fragmentation. The high AT activities of the chicken embryo brain at the 17th day of development correlated with minor DNA fragmentation following a repair period of 12-24 h. It is suggested that the high basal level of AT in the chick embryo might have a protective function against the persistence of the genotoxic lesion O6-methylguanine during development.


Flexner's model and the future of medical education. Less attention has been paid to Flexner's educational philosophy as compared with the recommendations he made to reform American medical education in Bulletin No. 4 of the Carnegie Foundation, the so-called "Flexner Report." His philosophy begins with the education of the child, having much in common with the educational theories of John Dewey, and is based on learning by observing and doing. Flexner believed that all education should be utilitarian and should prepare the individual for the responsibilities of citizenship and for an occupation or a profession. He also believed that general education lasted too long in this country. Based on Flexner's educational philosophy rather than the four-year medical school model that bears his name, the education of the physician is reexamined. Recommendations are made concerning the interface between the last two years of college and the first two years of medical school that would better equip the future physician to face the complexities of medical practice in the next century. Further, if medical schools were given responsibility for graduate medical education, as has been recommended by prestigious committees in the past, it would be possible to integrate the medical school clinical years with those of residency training and thereby improve the educational experience. A consideration of the education of the physician as a continuum, beginning in the third year of college and ending with the conclusion of residency training, also would be entirely consistent with Flexner's educational views.(ABSTRACT TRUNCATED AT 250 WORDS)


Academic achievement and acceptance rates of underrepresented-minority applicants to medical school. While the participation of minority groups underrepresented in medicine has increased from 3% of first-year enrollment in 1968-69 to 11% in 1992, many have been concerned that the percentage of underrepresented-minority applicants accepted is smaller than that of other applicants. To investigate the relationship of acceptance rates and measures of academic achievement, historical data from 1978-79 through 1991-92 on applicant characteristics maintained by the Association of American Medical Colleges were used to develop statistics on acceptance rates for underrepresented minorities and for other applicants, by each applicant's mean score on the MCAT (Medical College Admission Test) and undergraduate science grade point average. Those statistics were then related to trends in applicant numbers. Results show that acceptance rates for both underrepresented minorities and others increased as the numbers of applications from both groups declined, then decreased as applications again rose. When underrepresented-minority applicants were compared with other applicants within the same ranges of grades and MCAT scores, underrepresented-minority applicants were accepted at substantially higher rates in every stratum. Thus, medical schools generally are acting affirmatively in selecting applicants from underrepresented-minority groups.


A pilot study of biomedical trainees' perceptions concerning research ethics. The authors surveyed 2,010 biomedical trainees in the fall of 1990 at the University of California, San Diego, regarding their perceptions about unethical practices in research and the extent of their training exposure to the ethics of scientific investigation; 549 responded, representing both clinical and basic science departments and including graduate students and postdoctoral fellows in addition to medical students, residents, and fellows. Of the 549 trainees, 129 (23%) responded that they had received no training in research ethics; 195 (36%), that they had observed some kind of scientific misconduct (although not necessarily in the sense of research fraud defined in federal regulations); and 81 (15%), that they would be willing to select, omit, or fabricate data to win a grant or publish a paper. The trainees planning an academic career were more likely to report having been aware of others' scientific misconduct. Reported exposure to ethics training was not associated with a difference in past or potential unethical behavior. The authors conclude that while the apparent ineffectiveness of past ethics instruction does not preclude the possibility that more systematic training may be useful, it does underscore the need to assess the efficacy of training activities.


Physicians, preventive care, and applied nutrition: selected literature. The authors review a core of 25 articles (dating from 1982 through 1991) regarding medical school curricula and physicians' knowledge, attitudes, and practices related to nutritional care, with a focus on prevention of coronary heart disease through cholesterol control. They supplement this review by discussing the relation of the core articles' results to those of additional articles, which focus more generally on physicians' health promotion and patient counseling. While there appear to be modest increases in attention to nutrition at various levels of medical training and some improvement in physicians' attitudes about dietary intervention, the authors conclude that both educational opportunities and physicians' practices warrant increased and more effective attention to nutrition. Finally, in light of recent trends and growing efforts to better prepare physicians to play a leading role in preventive care, the authors identify gaps in physicians' training and in research on physicians, preventive care, and applied nutrition.


Combined-degree programs: a valuable alternative for motivated students who choose medicine early. The author reviews the history and philosophy of combined-degree programs and summarizes research on the performances of students in these programs. He notes that about one-fifth of U.S. medical schools offer programs that integrate premedical and medical school studies and lead to the award of both an undergraduate and an M.D. degree in six to eight years. The students in these programs perform as well as students electing traditional programs, if not better. The author concludes that university-affiliated medical schools might well consider establishing combined-degree programs as a means of (1) achieving better integration of the premedical and medical curricula and (2) allowing greater access to combined-degree programs for students mature enough early on to select careers in medicine.


Curricular variations in combined baccalaureate-M.D. programs. The authors review curricular characteristics of combined baccalaureate-M.D. programs at 28 U.S. medical schools from 1961, when the first programs started, until 1991-92. Initially, in the 1960s, these programs were created (1) to offer talented high school graduates an accelerated track leading to the baccalaureate and M.D. degrees, (2) to reduce educational expenses, (3) to improve education in the humanities, and (4) to attract outstanding students into careers in medicine. In the 1970s these objectives were modified to address national health care needs, particularly the need to graduate more physicians more quickly, especially primary care physicians for underserved areas. In the 1980s the objectives were broadened to achieve more diverse goals, including emphases on the humanities, community medicine, and biotechnology, in addition to the continued stress on the education of primary care physicians.


The Jefferson-Penn State B.S.-M.D. program: a 26-year experience. Since the 1960s a number of physicians have completed both their baccalaureate and their M.D. degrees in six or fewer years. In this longitudinal study the authors track the academic performances, clinical ratings, and career follow-up data of 659 students in one of these accelerated programs, the Jefferson Medical College-Pennsylvania State University B.S.-M.D. program, from entering years 1964 through 1989. The medical school performances, clinical performances in residencies, and rates of board certification and faculty appointment of the accelerated students compared favorably with those of a control group of medical students with similar high school credentials who had followed a four-year baccalaureate program. The authors conclude that a carefully chosen group of students can achieve high academic standards in an accelerated medical school program, graduate as younger physicians able to perform well in postgraduate training, and go on to highly productive careers in medicine.


Expert systems in histopathology. V. DS theory, certainty factors and possibility theory. Uncertainty management for the evaluation of evidence based on linguistic and conceptual data is taking advantage of developments in the Dempster-Shafer (DS) theory of evidence, possibility theory and fuzzy logic. The DS theory offers the capability to assess the uncertainty of different subsets of assertions in a domain and the way in which uncertainty is affected by accumulating evidence. The DS theory goes beyond probability theory in its ability to represent ignorance about certain aspects of a situation. However, the theory is very sensitive to the numerical assessments provided by users and can lead to intuitively unexpected and even undesirable results. Certainty factors are widely used in various expert systems. Their definition and updating may follow either a probabilistic model or fuzzy set theoretic concept.


Nucleoli and AgNOR proteins in 32 cases of primary breast carcinoma. Spatial pattern of interactions between 50 clinical and histometric criteria. The purpose of this paper is to analyze a method allowing selection of the best morphometric criterion for quantifying AgNOR proteins under conventional observation conditions by light microscopy. We determined 50 parameters for 32 cases of primary breast carcinoma. For each case, three 100-nucleus samples (tumor center and periphery on a Giemsa-stained, 3-microns tumor section, periphery on a silver-stained section) were quantified. Distribution-free multidimensional data analysis was used to explore the geometric significance of the coefficient of correlation. This analysis revealed a clinical message linked with the largest "nucleolar structure" (nucleolus or AgNOR clump) per nucleus on the tumor periphery. Tumor recurrence or death correlated only with the coefficient of variation of the "nucleolar/nuclear" ratio of the greatest clump of AgNORs per nucleus periphery (CVRSa). The prognostic value of CVRSa is independent of that of conventional criteria, such as age, tumor size, Scarff-Bloom-Richardson grading and lymph node status. The largest AgNOR clump per nucleus may prove to be a further practical prognostic predictor.


Quantitative precision of an automated, fluorescence-based image cytometer. Digital image-based cytometry of clinical specimens labeled with fluorescent, disease-specific markers holds promise for becoming an important diagnostic and prognostic technique because the technique can make a diverse range of quantitative biochemical, morphologic, densitometric and contextual measurements on intact specimens. It has been previously shown by us, using an image cytometer (IC) consisting entirely of commercially available components, that the nuclei of individual cells in slide-supported specimens can be detected automatically using a fluorescent DNA stain and image analysis software. The purpose of this study was to determine the precision of the IC for quantifying the integrated fluorescence intensity and area of fluorescent standard beads and nuclei. Integrated intensities could be quantified to between 2.3% and 3.5% precision using a 40x objective lens and between 1.6% and 2.3% using a 20x objective. The main contribution to this uncertainty was 2% inaccuracy in determining the variations in sensitivity over the imaging area. Areas could be quantified to between 0.91% and 2.1% using a 40x objective and between 2.8% and 3.2% using a 20x objective. Significant quantification errors were introduced if the objects were not in focus or were touching each other. Overall, however, these results demonstrated that image cytometry of fluorescence-stained specimens can yield quantitative results with sufficient precision for determining DNA ploidy distributions and for making other measurements on clinical specimens.


Effect of storage time of pleural effusions on immunocytochemical cell surface analysis of tumor cells. To determine how long tumor cells can be stored without losing their immunocytochemical reactivity, five malignant pleural effusions in EDTA-coated tubes were analyzed after different storage times at either 4 degrees C or room temperature. Only minor differences were observed between the cells from the two storage conditions. Though there was a considerable decrease in the number of tumor cells attached to the slides from day 0 to 1, the number of tumor cells was still sufficient to allow their clear detection with the monoclonal antibody HEA-125 even on day 4 of storage in all cases. Therefore, for routine purposes, pleural fluids in EDTA-coated tubes can be stored for at least one day prior to immunocytochemical staining if the cells are gently handled during preparation. Pleural fluid is a richly nutritious medium not only for keeping cells alive but also for preserving their immunoreactivity.


Morphometry of nuclei of the normal and malignant prostate in relation to DNA ploidy. Fine needle biopsies from 70 patients with prostate carcinoma and 10 patients with benign hyperplasia were used to study area, variation in size and form factors of the nuclei by image analysis. The results were related to DNA ploidy of the cell populations as measured by flow cytometry, cytologic grade and patients' survival. Nuclear area differed significantly between benign lesions and tumors. It increased in diploid low-grade tumors from a normal value of 54.2 +/- 3.1 microns2 to 75.6 +/- 5.3 microns2. In aneuploid tumors with an increase in the chromosome number, the nuclear size further increased to about twice that of benign nuclei. Variation in size also differed between benign and malignant epithelium, with a further increase between diploid and gross aneuploid tumors. While nuclear size and variation in nuclear size made it possible to discriminate malignant from benign lesions, form factor did not differ between benign and malignant lesions. In follow-up, however, none of these factors reached significance for predicting survival.


Prognostic importance of the DNA ploidy pattern in malignant mesothelioma of the pleura. Malignant mesotheliomas often raise a difficult diagnostic problem: once the diagnosis is made, the possibilities of predicting the biologic activity and prognosis of the tumor are limited. DNA ploidy patterns have been used as a prognostic instrument for other tumors, and this pattern was therefore studied in 37 cases of verified mesothelioma. The measurements were made on Feulgen-stained smears from pleural effusions using a Leica Miamed computer microscope. When a highly aneuploid tumor was defined as a condition with greater than 5% of the cells within defined intervals outside the ranges of the stem-line and the peaks representing polyploidization thereof, a near-diploid/polyploid pattern was obtained in 41% of the cases, while the remaining 59% were classified as highly aneuploid. The prognosis was significantly better among the near-diploid/polyploid cases. This estimate of the outcome could not be improved by using alternative algorithms for high-grade aneuploidy.


DNA analysis of malignant effusions. Comparison with cytologic diagnosis and carcinoembryonic antigen content. Twenty-three consecutive malignant effusions from 19 patients submitted for cytologic examination were analyzed for carcinoembryonic antigen (CEA) content and for DNA analysis by flow cytometry. The study was undertaken to determine if the addition of DNA analysis would improve the sensitivity of cytologic diagnosis and CEA assay. CEA examination was performed on Papanicolaou-stained smears and hematoxylin-and-eosin-stained cell blocks. Final diagnoses were correlated with histologic examination (four patients), clinical and radiologic studies, and follow-up. The malignant effusions in 19 patients were secondary to carcinoma of the breast (5), lung (5), ovary (1), endometrium (1), mucinous carcinoma of the colon (1), unknown primary (1), extraovarian papillary carcinoma (1), mesothelioma (2) and large cell lymphoma (2). The sensitivity of cytologic diagnosis was 100% and specificity 100%. DNA aneuploidy, defined as the presence of two separate peaks in the histogram, was present in 7 of 23 fluids (sensitivity, 30%). Four fluids had insufficient cells for analysis, and one histogram showed debris (following chemotherapy). DNA aneuploidy was detected in effusions secondary to carcinoma of the breast (4), lung (1) and lymphoma (2). Using 5 ng/mL as the cutoff, the sensitivity of CEA was 68%. DNA analysis of cells in malignant effusions is less sensitive than cytologic diagnosis, and CEA assay and is not recommended for routine use in the diagnosis of malignant effusions.


The three-group metaphase as a morphologic indicator of high-ploidy cells in cervical intraepithelial neoplasia. There is a need for additional morphologic criteria to improve the value of histologic classification for the prediction of the biologic behavior of cervical intraepithelial neoplasia (CIN). Representative slides from 72 cone specimens containing CIN were examined to study the correlation between the presence of three group metaphases (TGMs), a morphologically well defined and light microscopically readily recognizable atypical mitotic figure, and the incidence of aneuploid cells with a nuclear DNA content greater than 5C. The numbers of cells greater than 5C (minus the polyploid cells 8C +/- 1C) were counted, using LEYTAS image cytometry on Cytospin preparations from the 72 blocks corresponding to the slides searched for TGMs and used for histologic classification of the lesions in classes CIN 1-3. It appeared that large numbers of aneuploid cells greater than 5C were more closely related to the presence of TGM than to a higher CIN class per se, particularly in women older than 35. Since aneuploid CIN has a higher progression rate than euploid CIN, the presence of TGMs will indicate a biologically unfavorable lesion. Thus, TGM deserves further investigation as an additional morphologic parameter for predicting the biologic behavior of CIN.


Information, discrimination and divergence in cytology. V. General symmetry of total discrimination and total divergence. Total discrimination and divergence are derived from Baye's theorem and based on backward (a posteriori) probabilities. Total forward (a priori) discrimination and divergence can be computed from a test matrix from which total backward discrimination and divergence were calculated for optimization of the classifications of gynecologic cytology (Papanicolaou smears) and quality control in a laboratory. The total forward discrimination and divergence appears to behave in parallel with the total backward discrimination and divergence, and the discrepancies in the backward and forward discrimination/divergence were the smallest near the optimum classification scheme. Conversely, the discrepancies between backward and forward discrimination and divergence may be helpful in finding the best classification scheme for gynecologic cytology. The general symmetries of the total backward and forward discrimination/divergence may be related to the human cognitive process of preferring symmetry and to the historic process in which cytologic classification followed histologic classification and continuously checked for matches in two directions--i.e., from histology to cytology and vice versa--thus resulting in the preservation of symmetry.


Information, discrimination and divergence in cytology. VI. Biases and errors of measurement in small samples. Total discrimination and total divergence have been shown to be useful measures of performance in diagnostic cytology. The sample size, Ns (observed number of cytology-histology pairs, essential components of a confusion matrix), may be small for the comparison of two or more laboratories or periodic quality control using observed values. From actual data from previous reports in this series, the best estimation of the confusion matrix of a population was obtained by fitting a Gaussian-type curve after pseudoscalar transform of ranks (row and column numbers). Small sample confusion matrices were generated by Monte Carlo simulation to 2.5 x 10(-7) resolution. To keep measurement biases within +/- 0.5 decits, we found that 100-200 samples of cytology-histology pairs were required in the best classifications of three, four and five category-states. At these sample sizes, measurement errors (standard errors) were also contained within +/- 0.5 decits. This study also confirmed that previously reported overestimated propagated errors in small samples were in fact overestimation and that their use for testing a null hypothesis was valid. The number of samples with indefinable statistics due to a zero denominator can be as high as 30% when the sample sizes are 500 for three, four and five category-state classifications. Biases due to small samples were positive for most category-states except for the optimum three category-states, in which bias changed to negative ("bias inversion"), and observed errors of discrimination and divergence paradoxically decreased as Ns decreased ("error-sample paradox") for a small sample size (Ns less than 700).(ABSTRACT TRUNCATED AT 250 WORDS)


[Atropine versus glycopyrrolate in eye surgery. A comparison of rhythm disorders and heart frequency using Holter-ECG]. Anticholinergics are indicated in ophthalmic surgery to inhibit oculocardiac reflexes (OCR). Although all anticholinergics exert an arrhythmic effect, comparative data on occurrence and severity of arrhythmias are not available. The aim of this investigation was to compare atropine (A) and glycopyrrolate (G) in adults undergoing ophthalmic surgery. One hundred patients (ASA class I and II, age range 20-60 yrs.) were given equipotent doses of either A (10 micrograms.kg-1) or G (5 micrograms.kg-1) in a randomized, double-blind fashion, before induction of anaesthesia. Continuous Holter monitoring was performed. The procedure was divided into the following phases: O (5 min before drug), I (5 min after drug), II (up to induction), III (induction until intubation), IV (intubation until operation), V (operation). Supraventricular, junctional, and ventricular arrhythmias were analyzed. Severe arrhythmia was judged to be greater than 5 events per min, or ventricular beats Lown classes III-V. The beat to beat analog signal was digitalized. The heart rate (HR) and the occurrence rate of OCR (greater than 20% decrease in heart rate, arrhythmias) was calculated by a computerized program. Analysed were: 1. the frequency of OCR, 2. the mean HR for each phase, 3. the frequency of all the various arrhythmias during the whole period, 4. as well as for each phase. The number of patients with severe arrhythmias 5. either for all the time or 6. for the individual phase were registered separately. There were no differences 1. in the frequency of OCR and 2. in mean HR during all phases between A and G.(ABSTRACT TRUNCATED AT 250 WORDS)


[The effect of etomidate on the upper airway reflexes]. Clinical observations during anaesthesia and intubation of emergency patients are presented showing a differentiated impact of etomidate (Hypnomidate) on upper airway reflexes: a blockade of pharyngeal reflexes with sustained but possibly delayed laryngeal reflexes and a certain protection against laryngospasm and vomiting. In addition etomidate enables, preferably in combination, difficult intubation with sustained spontaneous breathing due to its low respiratory depressant effect. These features were confirmed in a small foreshortened clinical study using thiopentone (Trapanal) or etomidate without muscle relaxants, whereby the difference in high risk patients became obvious. The impact of anaesthetics on airway reflexes is generally concealed by muscular relaxants, and observations on this matter are difficult to make subject to quantifiable parameters and controlled studies; accordingly such observations are scarcely found in newer anaesthetic literature. In the development of new techniques for intubation and anaesthesia without muscle relaxation, these methodical problems deserve attention.


[Propofol for sedation during postoperative mechanical ventilation. A comparative study with Lytic Mixture]. Propofol infusion was found to provide excellent sedation and rapid recovery in intensive care. The present study compared Propofol with lytic solution (lytic solution = mixture of 100 mg Pethidine, 50 mg Promethazine and 0.6 mg Dihydroergotamine) during 6 hours of postoperative artificial ventilation. 60 patients after major abdominal surgical procedures were studied with ethical committee approval and informed consent. Patients were randomly allocated to receive either Propofol or lytic solution. We aimed at a sedation level of stage 5 according to the Ramsey score. The mean drug dosages were 3.9 mg/kg/h of Propofol and 4.2 ml/h of lytic solution. Hemodynamic values, blood gases as well as various biochemical measures did not show any difference between the groups. At the end of the sedation period triglyceride concentrations were significantly higher in patients receiving Propofol (166 + 79 mg/dl) compared to the control group (97 + 60 mg/dl). Significant and relevant differences were found for the times of recovery after discontinuation of the sedative. These times were very short in the Propofol group. Furthermore, in view of a longer recovery time after lytic solution in this group the respiratory rate was significantly slower up to the end of the observation period. We conclude that a major advantage of Propofol in the present study was the rapid recovery after 6 hour sedation. Patients gain vigilance rapidly and sufficient spontaneous respiration within minutes. Not at least thanks to these facts patient's safety can be improved in the recovery period.


[Death and assisted death--current medical, ethical and legal questions]. Taking care of dying people is one of the most difficult obligations of the physician, perhaps the most difficult one. In this field, a lot of ethical problems arise which have to be coped with. In German the term "Sterbehilfe" ("helping to die") has more and more replaced the medical term "euthanasia". At present there are doubts whether this new term "helping to die" is useful because it might reflect liberal attitudes towards human life. Due to this terminological uncertainty many physicians are in two minds about the way of taking care of dying patients. Using an exact and unequivocal term for dying without pain and torture is an important demand for modern medicine in order to increase people's confidence in the last stage of their lives.


[The treatment of status asthmaticus using ketamine--experimental results and clinical experience]. Intensive therapy of a patient with status asthmaticus must lead to a reduction of vital threat by improving respiratory and cardiac functions. Because of the bronchodilating effect of ketamine, analgesic sedation with ketamine and benzodiazepines is extremely useful for prolonged ventilation. At the beginning of this treatment it can be necessary to supplement the continuous intravenous infusion of ketamine and diazepam or ketamine and midazolam with small bolus doses of up to 3.5 mg/kg/h of ketamine. Experience has shown that the combination of ketamine and midazolam has better controllability. In some of our patients the bronchodilating effect of ketamine was not sufficient and therefore ventilation with halothane was necessary at least intermittently. In contrast to halothane, ketamine can be combined with vasodilators and sympathomimetics as our own experience has shown. The combined application of ketamine with glycerol trinitrate or sodium nitroprusside is indicated in the event of pulmonary or general hypertension. The use of sympathomimetics--mainly beta-sympathomimetics--antagonizes the negative inotropic effect of ketamine, improves the circulatory system and leads to a direct bronchodilating effect. Progress in treatment was mainly achieved by continuous intravenous infusions of terbutaline (Bricanyl). Aminophylline is very compatible with ketamine, but because of its stimulating effect the use of aminophylline seems to be reasonable only during weaning from the ventilator. Control of the usually deep analgesic sedation and an accompanying optimum drug therapy are only possible with complete cardiorespiratory monitoring including invasive blood pressure measurement and catheterization of the pulmonary artery. In our clinic 24 patients with status asthmaticus were treated. Sixteen asthmatic patients were treated with analgesic sedation using ketamine and benzodiazepines, three of them without intubation and ventilation. In spite of the life-threatening situation and reanimation before admission to the intensive care unit, only one patient died. Our experience has shown that intensive therapy including analgesic sedation with ketamine and benzodiazepines, optimized by application of sympathomimetics and vasodilators, is suitable for overcoming the life-threatening situation of patients with status asthmaticus.


[The humidification of anesthetic gases during anesthesia using heat and moisture exchangers]. This study looks at the question of whether anaesthetic gases are sufficiently moistened in a semi-closed system by the partial recycling of expired air with simultaneous absorption of CO2. During the inspiration phase only a maximum of 42% relative humidity at a temperature of 24.8 degrees C was reached. These values lie far below the demands of the American National Standard Institute (ANSI) of 70% relative humidity at 30 degrees C. When various heat and moisture exchangers were used, the relative humidity improved to 99% at a maximum temperature of 30.3 degrees C (HME Edith; Engström Corporation). The maximum values of the BB 12-15, Pall Corporation, and SH 150 from Siemens were slightly lower. A marked fall was noticed when using the Humid Vent I of the Medimex Corporation, especially in the initial phase. An improved version, the Humid Vent II, has been produced. Physiological values (37 degrees C, 100% relative humidity) are not achieved by any heat and moisture exchangers. This problem could possibly be solved by using infra-red light when warming the gases.


[The HELLP syndrome--a challenge to the obstetrician and the intensive care therapist]. The HELLP-syndrome is a severe complication in late pregnancy. The etiology is still largely unknown. It is defined as a separate disease but also as a severe course of EHP-gestosis. It is mainly characterised by increased liver enzymes, a low platelet count, increased haemolysis and hypertension. According to primary organ affection, neurological symptoms and acute respiratory distress syndrome, acute renal insufficiency and/or upper abdominal complaints may occur. The only causal therapy is immediate caesarean section. Postoperative intensive care must be guaranteed. As a gentle anaesthetic method neuroleptanalgesia is recommended. Based on 7 of our own case reports, pathophysiology and therapy are discussed.


Product notebook: occlusive skin paste.

Product notebook: occlusive skin paste. When selecting products for the prevention or treatment of skin breakdown due to fecal incontinence and diarrhea, the health care professional should consider the following: The premixed skin paste we tested, Critic-Aid, is an important part of our treatment plan, but it is not a cure for the etiology of loose stools. Use premixed products, or ingredients in an institutional mixture, only in ways approved by the FDA. Convenience: The staffing situation has made the use of time-savers imperative. Quality Control: The product you use or mix should perform consistently. Cost: Choose the most cost-effective product that meets your patients' needs. Conventional treatments and preparations failed to prevent or heal skin breakdown in our patients with fecal incontinence and diarrhea. In response to this problem, we concocted our own institutional mixture, using only ingredients approved by the FDA for use in wounds and consulting the hospital pharmacist at every turn. However, the procedural and potency problems resulting from our institutional mixture prompted us to test a premixed skin paste, Critic-Aid, which exceeded our expectations.


Antibodies to mycobacterial 65 kDa heat shock protein in systemic sclerosis (scleroderma). It has been reported that immunity to the 65 kDa heat shock protein of Mycobacterium tuberculosis (MT-hsp65) not only accompanies rheumatoid arthritis (RA), but may also be characteristic of chronic inflammation. We now report serum antibodies to MT-hsp65 in 47% of systemic sclerosis (SSc), 38% of primary Raynaud's phenomenon (PRP) and 5% of systemic lupus erythematosus (SLE). Antibody levels were higher in patients with active or progressive SSc and correlated with the degree of skin fibrosis. Thus, immunity to MT-hsp65 appears in SSc and is not limited to RA. However, it does show some degree of specificity beyond chronic inflammation: PRP patients have a higher reactivity than do SLE patients.


Secretory granule autoantigen in insulin-dependent diabetes mellitus is related to 62 kDa heat-shock protein (hsp60). Recent studies in NOD mice suggest that cellular and humoral responses against beta cell protein(s) cross-reactive with mycobacterial heat-shock protein, hsp60, are implicated in the development of autoimmune diabetes. However, this putative, hsp60-related autoantigen has not yet been identified nor have the preceding events triggering the autoimmunity against it. Our recent studies show that antibodies to the mammalian hsp60 bind specifically to the 62 kDa protein located to insulin secretory granules and mitochondria of pancreatic beta cells of healthy mice [1]. In islets of prediabetic NOD mice affected by insulitis, the cellular distribution of this hsp60-related antigen was found to be altered. In the present report, we have examined whether this endogenous hsp60-related protein of secretory granules serves as an autoantigen in type I diabetes. The results of Western blot analysis indicate that diabetic mice sera show reactivity to a 62 kDa islet cell antigen. The NOD mice sera that were positive in detection of the 62 kDa islet cell antigen were also able to recognize the recombinant human hsp60. Immunogold electron microscopy revealed that diabetic NOD mouse sera, cross-reactive to human recombinant hsp60, recognize the antigen located in secretory granules of beta cells. Double-immunogold labelling demonstrated that antigens recognized by both diabetic NOD mice sera and monoclonal hsp60 antibodies co-localized in the same secretory granules of beta cells. Preincubation of islet cell sections with one type of antibody blocks subsequent binding of the other, indicating that epitopes recognized by both antisera on these proteins are shared. Moreover, preadsorption of diabetic sera with the recombinant human hsp60 abolished labelling of secretory granules. These results indicate that the hsp60-related protein of beta cell secretory granules is an autoantigen in type I diabetes in NOD mice.


Induction of experimental anti-phospholipid syndrome associated with SLE following immunization with human monoclonal pathogenic anti-DNA idiotype. MIV-7 is a human monoclonal antibody that binds to DNA and carries a pathogenic anti-DNA idiotype 16/6. The antibody was generated by fusing peripheral blood lymphocytes of a healthy donor which were stimulated with an anti-idiotypic antibody to B11 (a human mAb anti-mouse mammary tumor virus-MMTV). The MIV-7, in addition to being an anti-DNA antibody, also binds to MMTV glycoproteins. Following immunization into the footpad of naive BALB/c mice with MIV-7, the mice developed anti-phospholipid syndrome (APLS) and SLE. The APLS was characterized by thrombocytopenia, the presence of anticardiolipin antibodies, lupus anticoagulant (prolonged APTT), high resorption rate of fetuses and lower mean weights of the placentae and fetuses. The SLE was characterized by serological markers (e.g. anti-DNA), laboratory (increased sedimentation rate and proteinuria) and histological findings (deposition of immune complexes in the glomeruli). Active immunization of mice with mouse monoclonal anti-cardiolipin antibodies led to the induction of primary APLS without SLE. The results add to our previous passive transfer model in which mouse monoclonal anti-cardiolipin antibody generated from immunized mice (CAM) was infused into the tail vein and also resulted in induction of pure APLS [11]. Our results demonstrate the ability to induce secondary APLS to SLE following immunization with a pathogenic idiotype of anti-DNA antibodies and to induce primary APLS with anti-cardiolipin mAb. The existence of these experimental models may permit controlled studies of novel therapeutic models.


Production and characterization of human hybridoma monoclonal anti-Sm and anti-U1RNP antibodies spontaneously produced from normal human lymphocytes. A panel of human:human hybridomas secreting monoclonal anti-Sm/RNP antibodies was established by the fusion of normal human tonsillar lymphocytes to the lymphoblastoid B cell line GM4672. The specificity of these antibodies was studied by direct binding and competitive inhibition in enzyme linked immunosorbent assays (ELISAs), and by immunoblotting. The stable subclones of these hybridoma monoclonal anti-Sm/RNP antibodies could be classified into four groups according to ELISA. Group I bound Sm/RNP only, group II bound Sm-RNP, Ro/SS-A and La/SS-B, group III bound Sm/RNP and ssDNA, and group IV bound Sm/RNP, Ro/SS-A, La/SS-B and ssDNA. When antibodies from each of the groups were tested by immunoblotting, the following pattern of reactivity emerged. Group II and IV antibodies reacted with U1RNP-A, Sm-B'/B, Sm-D and Sm-E proteins, as well as the Ro/SS-A and La/SS-B proteins. In contrast, group I and III antibodies did not bind to any individual protein components of Sm/RNP,Ro/SS-A or La/SS-B antigens, but recognized their conformational epitopes. These results, therefore, directly demonstrate for the first time that normal-derived B cells have the genetic potential, revealed here by somatic cell hybridization, to produce anti-Sm/RNP antibody responses which are ordinarily only associated with systemic lupus erythematosus (SLE) and related connective tissue diseases.


Thymulin and its role in immunomodulation. Even though thymulin was isolated, sequenced and characterised some 20 years ago and later identified as a thymic hormone involved in immunomodulation, much more work is still required to further understanding of the mechanisms of action(s) of this peptide. Since the observation, by a semiquantitative bioassay, of diminished levels of thymulin in immunodeficiency and autoimmune disease, new data obtained by radioimmunoassay have not only confirmed previous observations but also demonstrated that thymulin plays a role in the interaction between the immune system and the neuro-endocrine system. In this paper we give an up to date account of recent developments in research into the role of thymulin in immunomodulation.


Analysis of anti-idiotypic antibodies against anti-microsomal antibodies in patients with thyroid autoimmunity. Anti-microsomal antibody (AMA) activity was inhibited in 14 of 16 sera and in all 12 IgG preparations from patients with postpartum thyroiditis following incubation with F(ab')2 fragments from normal polyspecific immunoglobulin for therapeutic use (ivIg). Similar results were observed with sera from seven of seven patients with Graves' disease and five of six patients with autoimmune hypothyroidism. Results of these competitive binding assays and affinity chromatography of AMA IgG on Sepharose-bound F(ab'), fragments from ivIg indicated that AMA antibodies reacted with ivIg through idiotypic-anti-idiotypic interactions. Eight out of 10 IgG preparations from patients with autoimmune thyroid disease also showed inhibition of AMA activity when coincubated with autologous IgM at various IgG:IgM molar ratios. These observations suggest that ivIg can inhibit anti-microsomal antibodies through idiotype-anti-idiotype interactions and that such interactions occur with IgM anti-idiotype antibodies in vivo, providing evidence of a role for idiotypic network regulation in the control of thyroid autoimmunity.


Involvement of dendritic cells in early insulitis of BB rats. In this study, subsets of mononuclear infiltrates in pancreatic islets of BB rats at different stages of insulitis were determined by various monoclonal antibodies against rat lymphoid cells, including a mouse monoclonal IgM antibody that distinguishes between macrophages and dendritic cells (mAb 1F119). 1F119+ dendritic cells were absent in and around islets of Wistar control rats. In BB rats, the first alteration of islets detectable by immunohistochemistry when compared with normal islets was the enhanced expression of 1F119 antigen around and in the islets (17% 1F119+ islets). At disease stage 1 (i.e. no leukocyte infiltration after HE staining), lymphocytes and macrophages were almost absent. At disease stage 2 (leukocyte infiltration < 20 cells), a more intense form of dendritic cell infiltration was seen (stage 1 versus stage 2, P < 0.0001). In addition, ED2+ and ED3+ cells were present around the islets (50% of islets were infiltrated with 1F119+ cells versus 16% with ED2+, 19% with ED3+, 11% with W3/25+ cells, and 11% with OX8+ cells, P < 0.0001). At disease stage 3 (> 20 cells), a clear increase of ED2+ and ED3+ macrophages and of W3/25+ and OX8+ T-lymphocytes in the infiltrates was observed. These observations suggest a role for antigen presenting dendritic cells in the initiation of immune reaction in type 1 diabetes of BB rats.


Incidence and phenotype restriction of lymphoid BLT-serine protease granules in spontaneously diabetes prone BB rats compared with a normal rat strain. In diabetes prone BB rats a relative increase of serine protease (SP)-positive lymphocytes (39.8 +/- 10%) was observed in peripheral blood at the time of diabetes manifestation (DM) compared with non-diabetic healthy Sprague Dawley control rats (Co: 10.3 +/- 4%), with BB rats at age of premanifestation (PM: 14.7 +/- 4%) and beyond age of expected manifestation (non-diabetic animals, ND: 25.2 +/- 4%). Similar absolute numbers were found in diabetic BB rats in comparison with Sprague Dawley rats. In PM, absolute numbers were lower in comparison with diabetic BB rats. SP granular positivity was found restricted to OX8+ lymphocytes. SP granule-bearing OX8+ lymphocytes were more frequently seen in the BB rat strain (PM: 74.3 +/- 8%; DM: 79.4 +/- 8%; ND: 78 +/- 10%) compared with normal rats (Co: 32.5 +/- 8%). Absolute numbers were lower in PM animals in comparison with DM rats. OX8+ cells were found in a higher relative number in DM animals (49.1 +/- 7%) compared with controls (28.2 +/- 3%), PM (26.3 +/- 5%) and ND (34 +/- 2%) animals. T lymphocytes expressing the W3/25+ marker, invariably negative for SP granules, were present in a higher relative number in ND (49.8 +/- 7%) and the control group (52.3 +/- 10%) compared with PM (31 +/- 8%) and DM (38 +/- 11%) animals. Absolute numbers of the OX39+ lymphocyte subpopulation were decreased in PM and DM-BB rats in comparison with the control group.


Acquired allo-tolerance to major or minor histocompatibility antigens indifferently contributes to preventing diabetes development in non-obese diabetic (NOD) mice. Diabetes in NOD mice represents the end stage of a genetically-programmed autoimmune process mediated by T lymphocytes and directed against insulin-producing beta cells. We have shown in a previous study that the course of the disease is significantly inhibited in NOD mice which have been made tolerant at birth to foreign histocompatibility antigens. This early T cell manipulation results in a significant delay of disease onset, reduced overall incidence and less severe alterations of islet cells. In order to characterize better the nature of the foreign tolerogenic determinants responsible for this protection, we have now examined separately the contribution of MHC and non-MHC antigens. Two lines of congenic mice were used as donors of tolerogenic cells, NOD.H-2b, which differ from NOD by the MHC-encoded antigens only, and B10.H-2g7, which differ by all the minor histocompatibility antigens encoded by the B10 background, but which share with NOD mice the same MHC haplotype. Our results show that NOD recipients of F1 semi-compatible cells become specifically tolerant to the set of alloantigens to which they were neonatally exposed. Unresponsiveness, assessed by lack of CTL generation, is profound and specific. Yet, despite the fact that distinct sets of alloreactive T cell precursors are silenced, mice made tolerant indifferently to major or minor histocompatibility antigens are significantly protected against overt diabetes. These results could mean that each set of MHC and non-MHC encoded determinants can independently cross-tolerize a sufficient proportion of the autoreactive repertoire to slow the natural course of the disease. Alternatively, neonatally-acquired tolerance might induce polyclonal activation of the immune system resulting in the suppression or the immunodeviation of potentially harmful, autoreactive T cell clones.


Cultured fibroblasts in avian scleroderma, an autoimmune fibrotic disease, display an activated phenotype. University of California, Davis, line 200 and 206 chickens spontaneously develop an autoimmune syndrome that has many features analogous to human scleroderma, including dermal fibrosis, antinuclear antibodies and antibodies to type II collagen. These birds also have thymic subcapsular epithelial defects and an abnormality in T cell calcium influx and proliferation in response to both T cell receptor-dependent and -independent activators. To determine whether fibroblast activation is a contributing factor to development of skin fibrosis in line 200/206 chickens, as it is in human scleroderma, we studied the collagen, non-collagenous protein and glycosaminoglycan (GAG) production of 34 separate fibroblast lines derived from the normal and fibrotic skin of line 200 and 206 chickens and from the skin of control chicken lines 058 and 254. The mean +/- SEM 24-h incorporation of 3H-proline or 3H-glucosamine into extracellular collagen, non-collagenous protein or GAG by first passage fibroblast lines derived from the fibrotic skin of diseased birds was 1,526 +/- 136, 859 +/- 82 and 25.7 +/- 1.3 dpm/10(3) cells, respectively, while fibroblast lines derived from the skin of control birds produced only 341 +/- 36, 343 +/- 42 and 15.2 +/- 1.4 dpm/10(3) cells. Similar differences in results were recorded for cell-associated production, and when collagen and non-collagenous protein production were assessed using non-radioactive electrophoretic methods. The activated phenotype of the fibroblast lines derived from the fibrotic skin of diseased birds persisted through 10 cell doublings in tissue culture. However, the ratio of type I:III collagen and the profile of GAG types produced were similar in all fibroblast lines studied. These results suggest that fibroblast activation is responsible for the skin fibrosis observed in this avian model of scleroderma.


Autoimmune thyroiditis (EAT) in genetically resistant mice mediated by a T cell line. Experimental autoimmune thyroiditis (EAT) can be induced in genetically susceptible strains of mice by immunization to mouse thyroglobulin (Tg). EAT also can be produced by administration of anti-mouse Tg T cell lines and clones. Previously we were able to raise virulent anti-Tg T cell lines from mice genetically susceptible to EAT. These virulent lines, upon attenuation, were able to vaccinate the susceptible mice against EAT. We now report the isolation of a virulent T cell line from C57BL/6 mice genetically resistant to EAT. The T cell line and its clones recognize a Tg epitope cross-reactive between mouse and bovine Tg. Unexpectedly, the virulent anti-Tg line attenuated in various ways failed to vaccinate C57BL/6 mice against EAT mediated by the line itself. These results shed some light on the regulation of autoimmunity.


Susceptibility and resistance to autoimmunity following neonatal injection of semi-allogeneic spleen cells in rats. A model of neonatal allotolerance was developed in rats. Brown-Norway (BN) neonates injected with semi-allogeneic (BN x Lewis) F1 hybrid spleen cells express a long-lasting chimerism and exhibit polyclonal B cell activation demonstrated by hyperimmunoglobulinemia affecting mainly IgE and IgG1, anti-laminin and anti-DNA autoantibodies as well as glomerulonephritis and anti-hapten antibodies. These abnormalities are autoregulated although the chimerism persists. In contrast, Lewis (LEW) neonates injected with semi-allogeneic (BN x LEW) F1 hybrid spleen cells exhibit a very short-lasting chimerism and transient activation of B cells, as reflected by increased allo-class II antigen expression, but do not develop an autoimmune disease. The autoimmune syndrome observed in BN rats is similar to that reported in mice during host-versus-graft reaction. Similarities between the drug-induced models of autoimmunity and allogeneic reactions in BN rats are also striking. The susceptibility of BN rats and the resistance of LEW rats to these autoimmune diseases might respectively reflect the involvement of TH2-like or of TH1-like subsets.


Acquisition of autoimmunity genes by New Zealand mice is associated with natural resistance to infection by mycobacteria. New Zealand (NZ) mouse strains comprise both autoimmune and non-autoimmune animals: NZ black (NZB) mice and the F1 hybrid (NZB/W) of NZB and NZ white (NZW) mice show spontaneous autoimmune disease by 6 months of age and die before the first year of age from renal disease, while NZW mice do not show autoimmune disorders. We investigated whether the autoimmunity-prone NZ animals (NZB and NZB/W) differ from the non-autoimmune NZW mice in susceptibility/resistance to mycobacterial infection. The three groups of NZ mice were infected by intraperitoneal inoculation of 10(8) colony forming units (cfu) of Mycobacterium avium. The M. avium infection was induced in 3-month-old mice (i.e., before NZB and NZB/W mice develop autoimmune disease) and studied for 4 months. Infected NZB and NZB/W mice showed evidence of renal disease at 2 and 4 months of infection (but not at 1 month). The non-autoimmune NZW mice were found to be susceptible to M. avium since they allowed massive proliferation (4-5 log growth) of the bacilli in liver and spleen. In contrast, both groups of autoimmunity-prone mice (NZB and NZB/W) were resistant to M. avium since their mycobacterial loads remained below the value of the initial inoculum. We conclude that in NZ mice the acquisition of autoimmunity genes is associated with expression of natural resistance to mycobacterial infection. This is consistent with the view that autoimmunity genes may have been evolutionarily selected because of their association with increased resistance of the host to infections by intracellular parasites.


Induction of anti-DNA IgG and IgE antibodies in BALB/c mice. Immunization of BALB/c mice with denatured DNA (dnDNA)-methylated bovine serum albumin (MBSA) complex along with aluminium hydroxide gel as adjuvant, resulted in the induction of anti-DNA antibodies of both IgG and IgE isotypes demonstrable by avidin-biotin micro enzyme-linked immunosorbent assay (ELISA) and solid phase radioimmunoassay (SPRIA), respectively. In contrast to the high levels of IgG2a and IgG2b anti-DNA antibodies observed in SLE-prone autoimmune mice, more than 90% of the anti-DNA antibodies of IgG isotype were found to be of IgG1 subclass. Specificity of both IgG and IgE antibodies which recognized activated DNA, dnDNA and double-stranded DNA but not RNA was established by competitive ELISA and SPRIA inhibition assays. These antibodies cross-reacted with cibacron blue and chondroitin sulfate but not with various other proteoglycans, nucleosides and nucleotides. Passive cutaneous anaphylaxis reaction in rats showed that these antibodies are capable of inducing in vivo degranulation of mast cells in a dose-dependent manner. These studies lend support to the concept that IgE antibodies directed against DNA may mediate mast cell degranulation and thus contribute to immediate-type hypersensitivity phenomena including hives seen in patients with systemic lupus erythematosus and to the localization of IgE-nucleic acid complexes.


Forebrain norepinephrine: role in controlled information processing in the rat. A series of experiments examined the effects of 6-hydroxydopamine (6-OHDA)-induced depletion of forebrain norepinephrine (NE) on the performance of a visual detection (spatial localization) task. The behavioral paradigm used was an analogue of Leonard's 5-choice serial reaction time task for humans. The 6-OHDA lesion of the dorsal noradrenergic bundle (DNAB) produced a 98% depletion of the NE content in the neocortex, and a much smaller depletion (32%) of the NE content in the hypothalamus. As reported previously, performance of visual discrimination was unaffected by DNAB lesions, even when the discrimination was made more difficult by decreasing the intensity of the visual stimuli. However, the lesion produced a significant decrease in accuracy and a significant increase in omissions when a burst of loud white noise was presented just prior to the onset of the visual discriminanda. Similarly, a significant decrease in discriminative accuracy was produced in the rats with forebrain NE depletion by systemic administration of the psychomotor stimulant, d-amphetamine (0.2 to 0.8 mg/kg). In both of these experiments, the lesion-induced discrimination impairment was not magnified by reducing the brightness of the visual discriminanda, suggesting that the behavioral impairment was not caused by a decreased ability to detect the visual stimuli. In addition, the lesion impaired discriminative accuracy when the visual discriminanda were presented at an unpredictable rate. The implications of these behavioral impairments produced by forebrain NE depletion for theories of catecholamine involvement in attentional processes and arousal are discussed in terms of a possible role for the DNAB in controlled or "effortful" processing.


Continuous cocaine induces persisting changes in behavioral responsivity to both scopolamine and diazepam. Forty-eight male rats were administered continuous cocaine, daily cocaine injections (intermittent), continuous amphetamine, or no drug for 5 days. Beginning 45 days after the administration all groups were tested for their responsivity, as measured by automated activity cages, to a low dose of the cholinergic agonist scopolamine. The continuous cocaine group showed decreased sensitivity to this challenge as compared to the other groups. When tested with a low dose of diazepam, the continuous cocaine group showed the greatest response. However, when observed following an injection of cocaine HCl, the intermittent cocaine group showed the greatest behavioral response. These findings support those of previous studies that indicated that the mode of initial cocaine administration is a key factor in the production of persisting changes in behavior and biochemistry.


Circadian changes in psychologic effects of ethanol. Six healthy human males (aged 22 to 26 years) synchronized with diurnal activity from 0700 hours to midnight and nocturnal rest, volunteered to document changes in psychologic variables resulting from ethylalcohol ingestion (ethanol 0.67 g/kg of body weight). For each subject four separate tests were performed at least 1 week apart at 0700, 1100, 1900, and 2300 hours in randomized order, with measurements taken before and 15, 30, 60, 90, 120, 140 minutes postingestion and thereafter at 4-hour intervals during a 24- to 36-hour period. Subjects fasted for 12 hours preceding ethanol ingestion time and for 8 hours thereafter. Self-rated inebreity (visual analogue scale) was greatest after ingestion at 2300 hours and lowest after ingestion at 1100 hours. Both speed to perform random number addition and eye-hand skill tests were slowest after ingestion at 2300 hours. However, changes observed for self-rated physical vigor, tempo, hand-grip strength, and systolic blood pressure did not appear to be ethanol ingestion time dependent. Validated ethanol ingestion time-dependent effects including those of oral temperature were not related to changes in the drug pharmacokinetics.


Pharmacologic evaluation of SCH-39166, A-69024, NO-0756, and SCH-23390 in neonatal-6-OHDA-lesioned rats. Further evidence that self-mutilatory behavior induced by L-dopa is related to D1 dopamine receptors. The purpose of the present investigation was to explore further the hypothesis that the self-injurious behavior induced by L-dihydroxyphenylalanine (L-DOPA) in neonatal-6-hydroxydopamine (OHDA)-lesioned rats is associated with an action on D1 dopamine receptors. This was accomplished by examining the behavioral responses induced by SKF-38393, quinpirole, and L-DOPA after treatment with the D1 antagonist SCH-23390 and three new pharmacologic agents, SCH-39166, NO-0756, and A-69024, reported to be D1 antagonists. All putative D1 antagonists were found to antagonize the action of SKF-38393 without reducing the increased locomotion and behavioral responses induced by quinpirole, consistent with an in vivo action on D1 receptors. The potency hierarchy of the compounds against the action of SKF-38393 on activity, from strongest to weakest, was: SCH-39166 equaled SCH-23390 and these were greater than NO-0756, which was greater than A-69024. All compounds were found to antagonize L-DOPA-induced self-mutilatory behavior (SMB) in neonatal-6-OHDA-lesioned rats in a dose-related manner. The potency hierarchy against this behavior, from strongest to weakest, was: SCH-23390, SCH-39166, NO-0756, and A-69024. The correlation between the ED50 for the ability of these drugs to antagonize SKF-38393-induced activity and their ability to reduce SMB by L-DOPA was greater than 0.99. In conclusion, the present findings provide additional evidence in vivo that NO-0756, SCH-39166, and A-69024 are selective D1 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)


Rejection associated with early appearance of donor-reactive antibodies after kidney transplantation treated with plasmapheresis and administration of 15-deoxyspergualin. A report of two cases. In two kidney transplant patients, one of whom had panel-reactive antibodies (PRA) before transplantation, a pretransplant negative donor-recipient crossmatch became positive within the 1st week after transplantation. Simultaneously, good graft function deteriorated to a state of anuria. One patient graft biopsy showed a vascular rejection, whilst the other patient biopsy was unrevealing. Both patients were treated with plasmapheresis and a new immunosuppressive drug, 15-deoxyspergualin (DSG). Plasmapheresis was performed for 6 and 9 days, respectively, and DSG was given for 5 days in a dosage of 6 mg/kg body weight per day. One of the patients received methylprednisolone i.v. in addition. During treatment the cross-match became negative and has since remained that way. In both patients the graft function was restored. No adverse effects were seen from the treatment, except for a slight leukocytopenia and thrombocytopenia.


Protective effect of a prostaglandin oligomer on liver mitochondria in situ: time-shared measurements of fluorescence and reflectance in the cold-preserved rat liver. The protective effect of a new oligomeric derivative of prostaglandin B2, known as OC-5186, was evaluated using time-sharing spectrofluorometry in the cold-preserved rat liver. Experiments were divided into three groups: in group A, a 5000 ng dose of OC-5186 was administered via the peripheral vein, 1000 ng via the portal vein, and 200 ng/ml in University of Wisconsin (UW) solution; in group B, the OC-5186 dosage was ten times greater than that in group A; in group C (control group), liver procurement and storage were performed without OC-5186. At 0, 12, and 24 h after cold preservation at 4 degrees C, the liver was perfused for 30 min at 12 degrees C with oxygenized Krebs-Henseleit solution, after which the perfusate was switched to deoxygenized Krebs-Henseleit solution. Time sharing spectrofluorometry was used to follow NADH fluorescence at 450 nm with a 360-nm excitation wavelength, as well as the reflectance of cytochrome aa3 with 605 minus 620 nm from oxidation to reduction. Rate constants of NADH fluorescence and cytochrome aa3 reflectance were used as indices of integrity of the mitochondrial respiratory chain. In group C, the rate constant of NADH fluorescence decreased significantly (P < 0.05) from the control value of 8.31 +/- 0.21 x 10(-3) (sec-1) to 4.97 +/- 0.15 x 10(-3) and 5.58 +/- 0.16 x 10(-3) (mean +/- SEM) at 12 and 24 h after cold preservation, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Efficacy of pyrimethamine for the prevention of donor-acquired Toxoplasma gondii infection in heart and heart-lung transplant patients. Seven (11%) of the first 65 patients who received heart transplants at Papworth Hospital were mismatched for Toxoplasma gondii. Of these, four (57%) experienced T. gondii infection and two died. The remaining two had severe symptoms and received anti-T-gondii chemotherapy for a year after transplantation. In an attempt to reduce the impact of donor-acquired T. gondii in our heart transplant recipients, we decided in April 1984 to give prophylactic pyrimethamine to all T. gondii-mismatched patients. In this study, 7 years later, we review the efficacy of this policy. Five of 37 (14%) patients given prophylactic pyrimethamine acquired T. gondii infection; only one was symptomatic, and none died. This compares with 100% symptomatic infection in the pre-1984 patients, who did not receive prophylactic pyrimethamine. We believe that our experience has shown that pyrimethamine is effective in reducing the incidence and severity of primary donor-acquired T. gondii infection in mismatched heart and heart-lung transplant recipients.


Octreotide administration in the treatment of pancreatic fistulae after pancreas transplantation. Among the surgical complications of pancreas transplantation are pancreatic fistulae, which arise rather frequently. Suppression of exocrine secretion with polymers has succeeded in reducing the rate of this complication. Nevertheless, in some instances, pancreatic fistulas may occur. Thirty pancreas transplantations were performed in 27 diabetic patients. In 5 cases a pancreatic fistula occurred and was drained after the insertion of a catheter for the collection of secretions. A serous liquid was collected with a high concentration of amylases (61604 +/- 19562 IU/24 h). Fistula output was 280 +/- 87 ml/24 h. Patients were treated with octreotide, administered subcutaneously in a dose of 300-750 micrograms/day. In all patients a progressive reduction in fistula output was observed after a mean of 16 + 2 days. Fistula flow rate dropped to 24 +/- 10 ml/24 h--a reduction of 95% +/- 5% and drainage was subsequently stopped. Sonographic follow-up did not show recurrence of peripancreatic collections in these patients. All patients were insulin-independent up to 12-44 months after surgery.


Pediatric liver transplantation from neonatal donors. Sixteen recipients of neonatal liver grafts were compared with 114 contemporaneous pediatric recipients of grafts from older donors. Graft and patient survival were worse in the neonatal group although the differences were not statistically significant. Patients with neonatal livers who had no technical complications required a longer time postoperatively to correct jaundice and a prolonged prothrombin time. These functional differences were limited to the 1st postoperative month and the end result was the same as with liver transplantation from older donors.


Transplantation of allogeneic fetal pancreases combined from MHC-different donor strains does not change rejection of the graft. A number of 17.5- to 18.5-day-old fetal pancreases were grafted under the kidney capsule of streptozotocin-diabetic rats. Eight syngeneically grafted glands were sufficient to reverse the diabetes of the recipients within 4 weeks when the recipient rats were treated with insulin for 18 days after transplantation. Eight allogeneic fetal pancreases obtained from one donor strain were rejected after transplantation and the recipients relapsed into hyperglycemia immediately after insulin withdrawal. Eight allogeneic fetal pancreases obtained from eight MHC-different donor strains were also rejected and the recipients relapsed into hyperglycemia after insulin withdrawal. Using fetal pancreases as tissue sources, the combination of the allogeneic graft from different donor strains was not sufficient to prolong the survival time of the grafted tissue.


15-deoxyspergualin treatment of graft rejection in man: effect on mononuclear cells. We studied the effects of 15-deoxyspergualin (DSG) on human mononuclear cells in blood when DSG was administered as anti-rejection treatment to kidney-transplant patients in combination with methylprednisolone (MP) in a safety study. The numbers of leucocytes, lymphocytes and monocytes, the percentages of T and B cells and the expression of the interleukin 2 receptor and the human leucocyte antigen DR locus (HLA-DR) were determined in blood from these patients and from patients treated with MP only. We found that the number of lymphocytes and monocytes decreased in all groups, as also did the CD4/CD8 ratio and the HLA-DR expression on monocytes. DSG counteracted the increase in the number of leucocytes observed in patients treated with MP only. Different effects of DSG and MP were also observed on B cells. While the percentage of CD20+ cells increased in the MP group, it remained unaltered in patients given low-dose DSG and/or was decreased in those given higher doses. Since available evidence suggests an effect of DSG on B-cell reactivity, this drug may become an important addition to the arsenal of immunosuppressive drugs in clinical transplantation.


Analysis of prognostic factors affecting renal allograft survival. A total of 201 consecutive cadaveric kidney transplantations were performed in 188 patients at the Chinese Great Wall Hospital, Beijing, from October 1977 to May 1990. The overall 1-, 2-, 5-, and 10-year graft survival rates were 75.5%, 64.5%, 37.0%, and 32.9%, respectively. In the last 5 years, these figures have risen to 83.7% at 1 year, 69.5% at 2 years, and 40.8% at 5 years, respectively. The 14 variables correlating to graft survival in the present study were analyzed using the log rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis. The results show that immunosuppressive drug therapy, cold ischemia time, acute tubular necrosis, and infection were significant factors affecting the survival of cadaveric kidney grafts. Triple therapy with low-dose cyclosporin, as compared to conventional immunosuppressive drug therapy, significantly increased the 1-year graft survival rate (90.3% vs 31.3%) but did not influence the long-term graft survival rate after 3 years. The incidence of acute tubular necrosis significantly correlated to the cold ischemia time and influenced the 1-year graft survival. Analysis showed that the lymphocytotoxic crossmatch affected graft survival after 3 years and that most late graft losses were due to chronic rejection, suggesting that histocompatibility is the strongest factor affecting long-term graft survival. A beneficial effect of pretransplant blood transfusions on long-term graft survival was seen in patients treated with conventional immunosuppressive drugs but not in cyclosporin-treated patients.


Endoscopic treatment of vesicoureteral reflux prior to renal transplantation. Endoscopic subureteral injection of Teflon was done in 34 potential renal transplant recipients to correct vesicoureteral reflux. Follow-up ranged from 6 to 24 months. After one injection reflux was corrected in 53.7% of the patients; this increased to 64.8% after a second injection. The procedure is simple, effective, without major morbidity, and avoids the risk of nephroureterectomy. However, efforts must be made to find an ideal substance with a higher biocompatibility and without risk of migration.


Monoclonal antibodies in renal transplantation: a review. OKT3 is the first anti-CD3 monoclonal antibody available for treatment in humans. Over the last few years it has proven to be a very powerful immunosuppressive agent in renal transplantation. Clinical studies have shown that OKT3 is superior to high-dose steroids as first-line treatment for acute renal allograft rejection. Furthermore, it is comparable to antithymocyte globulin (ATG) in treating steroid-resistant rejection and is also effective as rescue treatment in ATG- and antilymphocyte globulin-(ALG-) resistant rejection. Despite its excellent rejection-reversal rate, OKT3 treatment is followed by a substantial percentage of re-rejections, most of which respond well to steroids. In the early post-transplantation period, a prophylactic course of OKT3 is very effective in preventing acute rejections, and in this respect it is probably equivalent to ATG. Indirect evidence exists that a prophylactic course of OKT3 may be beneficial in immunologically high-risk patients and in patients with delayed graft function. However, more clinical studies are required to answer the question whether OKT3 should be given as induction treatment, as first-line treatment, or as rescue treatment. To answer this question, the side effects of OKT3 should also be taken into account. First-dose-related side effects, although frequent and disturbing, are usually transient and seldom life-threatening, provided overhydration has been corrected and steroids have been given before the first administration. These side effects are attributed to the release of cytokines as a result of T-cell activation or lysis. After exposure of patients to OKT3 an increased incidence of infections and malignancies has been reported. However, it is not yet clear whether this is due to OKT3 as such, or whether it merely reflects the total burden of immunosuppression. Xeno-sensitization represents an important limitation to OKT3 treatment, although a second or third course can still be effective in patients with low antibody titers. The precise immunosuppressive mechanism of anti-CD3 monoclonal antibodies is yet unknown. Monitoring of patients treated with OKT3 revealed CD3 and/or T-cell antigen receptor depletion and immunological incompetence of remaining T cells. More clinical data are required to establish the correct dose and duration of OKT3 treatment. In conclusion, OKT3 is a powerful immunosuppressive agent but its real value in renal transplantation remains to be determined. A practical approach may be to reserve it for the treatment of steroid-resistant rejections.(ABSTRACT TRUNCATED AT 400 WORDS)


VIP restores natural killer cell activity depressed by hepatitis B surface antigen. Vasoactive intestinal peptide (VIP) has recently been shown to bind to human lymphocytes and modulate immune functions. The ability of VIP in restoring natural killer (NK) cell activity depressed by hepatitis B surface antigen (HBsAg) has been investigated in the present research. Human lymphocytes were incubated with HBsAg and, after washing, a 4-hr cytotoxicity assay was performed. VIP was coincubated with lymphocytes during the preincubation with HBsAg or, alternatively, throughout the cytotoxicity assay. The study revealed that VIP, either preincubated or coincubated in the 4-hr assay, strongly restores NK cell activity depressed by viral antigen. This is noteworthy considering that a number of lymphocyte modulators such as interferons fail in restoring viral-dependent NK cell activity depression. In contrast with previous reports, even when coincubated in the 4-hr assay, VIP is a strong activator of NK cell activity. Further studies will be required to understand which mechanisms are involved in the interrelation between VIP and NK cells during viral infections.


Altered macrophage antigen-presenting cell function following Friend leukemia virus infection. To investigate the mechanism by which Friend leukemia virus (FV) causes immunosuppression, the ability of peritoneal macrophages to mediate antigen-specific T-cell activation following FV infection was examined. Decreased IL-2 production was observed when antigen-primed T cells were cultured with antigen-pulsed macrophages from mice infected with FV, compared to T cells cultured with macrophages from control mice. Macrophages from FV-infected mice demonstrated decreased phagocytic and pinocytic activity, suggesting that antigen uptake may be impaired in these cells. In addition, FV-infected mice had decreased numbers of MHC class II positive macrophages compared to uninfected controls, as measured by immunofluorescence. The alterations in antigen uptake and class II expression observed in macrophages from FV-infected mice may be the result of infection of these cells by FV, which was demonstrated by in situ hybridization using a FV-specific probe. The ability of FV to infect and modulate the functions of macrophages may account, at least in part, for the immunosuppression observed in FV-infected mice.


Conformation-dependent accessibility of the linear epitopes located on the rabies virus glycoprotein. Seven monoclonal antibodies (MAbs) were derived from mice immunized with the rabies virus glycoprotein of the Pitman-Moore (PM) strain. These antibodies recognized at least five partially overlapping sites located in one immunodominant region. A panel of MAbs was then used to characterize antigenic relationship between PM strain and SAD-Vnukovo strain of these rabies viruses. In immunoblot, all tested antibodies bound to the glycoprotein of both rabies strains, indicating shared antigenic determinants located on the corresponding immunodominant regions. The pattern of reactivity in immunoblot suggested the specificity of antibodies against linear epitopes. However, the supposed close antigenic relation between PM and SAD-Vnukovo strains (evidenced by immunoblot) was not fully confirmed by immunoenzymatic assay. Data provided by ELISA demonstrated two distinct patterns of MAbs reactivity with both antigens. Four antibodies showed specificity for PM strain glycoprotein only, while three MAbs bound with both PM and SAD-Vnukovo strain antigens. We supposed the strain-specific conformation of the native glycoprotein to be responsible for selective access of single MAbs to the respective common linear epitopes.


Antibodies against p24 of HIV-1 in patients with systemic lupus erythematosus? The involvement of retroviruses in the etiopathogenesis of autoimmunity is discussed. Recently antibodies against p24 of HIV-1 were described in patients from Texas with SLE. Therefore we investigated the presence of these antibodies in our SLE collective (German caucasians and blacks from Michigan) employing ELISA and Western blot. No anti-p24 reactivity was observed in our SLE patients in Western blots, suggesting that there may be ethnological or regional differences between our patients those from Texas.


Monoclonal antibody characterization of Jamestown Canyon (California serogroup) virus topotypes isolated in Canada. Jamestown Canyon (JC) virus of the California (CAL) serogroup has been isolated in 12 American states and 6 Canadian provinces. A study was undertaken to produce monoclonal antibodies (MAbs) to JC virus and to use these MAbs to assay for possible heterogeneity among naturally occurring JC topotypes in Canada. MAbs were produced to the prototype strain of JC virus using BALB/c mice. Twenty-seven secreting MAbs were obtained and three of these MAbs were propagated and studied. All three MAbs, M1 (IgG1), M2 (IgG2b), and M3 (IgG2a), were reactive by immunofluorescent antibody assay against JC-infected vero cells and by ELISA against JC antigen. MAb M2 reacted with all members of the Melao complex, MAb M1 reacted only with Keystone virus, while MAb M3 exhibited no reactivity with other CAL serogroup viruses. Only MAb M3 possessed neutralization and hemagglutination inhibition activities against JC virus. The MAbs were also tested by ELISA and for neutralizing activity against 13 JC topotypes isolated in 5 provinces from Newfoundland to Saskatchewan. ELISA confirmed closer identity of the Canadian topotypes to JC as opposed to the closely related South River virus. The MAbs verified all Canadian topotypes to be JC virus but revealed different patterns of reactivity between these topotypes and prototype JC virus.


Coping with substance abuse: a many-sided task. Steady progress is being made towards understanding the use of drugs for non-therapeutic purposes. The associated problems are increasingly regarded as having psychological, biological and social dimensions. There is a growing acceptance that the hazardous consumption of alcohol and other drugs can both result from and exacerbate poor socioeconomic conditions. Sustained action to combat drug-related problems is needed on a broad front; there is no panacea.


Myiasis: the battle continues against screwworm infestation. The New World screwworm fly (Cochliomyia hominivorax) caused myiasis extensively among livestock in Mexico and the southern third of the USA until eradication was achieved by repeatedly releasing sterile males of the species on a massive scale. The pest appeared in Libya in 1988, the first time it had become established outside the western hemisphere. Because of the threat of myiasis in animals and people, not only in Libya but also elsewhere in Africa and beyond, a concerted campaign of sterile male releases was mounted with strong international support, and the outbreak has been eliminated. Action is continuing against the pest in Central America.


Evaluation of maternal and child health services in Latin America. A methodology has been devised for evaluating the efficiencies of maternal and child health care services in 18 countries of Latin America. The results point towards ways of developing local health systems, strengthening coordination between programmes and services, and utilizing resources more rationally.


Health in space--and on Earth.

Health in space--and on Earth. Because astronauts confront unprecedented hazards, manned space exploration has to proceed gradually and cautiously, each new step being taken with the benefit of what has been learned during earlier stages about bodily requirements. As well as helping to protect the lives of astronauts, however, space medicine is proving to have valuable applications in global health care.


Rational education for rational therapy. A sound knowledge of pharmacology and clinical therapeutics could help future prescribers in India to master the principles and practice of rational therapy. The teaching of pharmacology in medical schools should be restructured accordingly, and greater attention should be given to the applied aspects of the subject. Practicals in experimental pharmacology and dispensing pharmacy should be discontinued and useful exercises should be introduced. Methods of evaluation should be modified.


Action to reduce road casualties.

Action to reduce road casualties. Progress in road safety is reviewed with particular reference to radical measures that have proved beneficial in Australia. Community involvement in decision-making is vital if gains are to be made and sustained in this field.


Finance for health care: part of a broad canvas. The economic crisis of the 1980s led to cuts in both government and household expenditure on health in the Third World. In order to address these issues it is necessary to adopt a macroeconomic approach to the analysis of the health sector; this allows its relationship to the whole economy to be understood. The efficient and equitable utilization of resources is particularly important in times of severe financial constraint.


Community participation in the control of filariasis. A programme was launched in 1986 for the control of brugian filariasis in an area of high endemicity in southern India. Sustained community involvement was achieved by integrating economic measures to improve the lot of the people with the creation of widespread awareness about the cause of the disease and about the possibilities of combating it.


Traditional healers and community health. A review of projects in various countries suggests that traditional healers, if properly trained, can contribute significantly to the work of primary care teams. Recommendations are offered with a view to making the best possible use of this valuable resource.


Health systems research--a key to progress. Papua New Guinea has made significant strides towards establishing a capacity in health systems research. This can be expected to strengthen the country's overall health development programme.


Food and drugs: the perils of plenty.

Food and drugs: the perils of plenty. The abundance of both food and pharmaceuticals in much of Europe has brought serious health problems as well as benefits. It is no longer possible to assess the quality of most products on the basis of physical examination, and labels often carry information that is incomprehensible to lay persons. Governments should ensure that consumers can understand both the broad principles of healthy living and the nature of the foodstuffs and medicines on offer. It is also important that prescribers be kept abreast of developments in the pharmaceutical field.


Challenges and opportunities--one vitamin, two minerals. Millions of people suffer and many die from lack of minute traces of nutrients. Methods of prevention are cheap and simple. Their universal application could yield health and economic benefits comparable to those achieved by smallpox eradication.


A better prospect for city life.

A better prospect for city life. The WHO "healthy cities" concept is discussed with particular reference to initiatives taken in Rennes, France. An outline is given of the collaboration between cities, both nationally and internationally, in efforts to achieve the health-for-all goals.


Which way for housing and human settlements? In order to clarify the housing and settlements component of the European health-for-all programme and to identify perceived priorities with a view to the preparation of training materials, members of WHO's Rural and Urban Development and Housing Network were invited to complete a questionnaire. The results are reported below. The questionnaire can be used in identifying local development priorities, comparing attitudes, and studying perceived needs. Intended as a tool for policy-makers, course organizers and public health professionals, it is available from the authors of the present article.


Promotion of heart health in schools.

Promotion of heart health in schools. The Netherlands Heart Foundation is making a significant contribution to the education of primary and secondary school children on the prevention of cardiovascular disease, within a broad context of encouragement for healthy life-styles. Efforts are also being made to ensure that both schoolteachers and pupils enjoy a healthy working environment.


Alzheimer's patients should be included in phase I clinical trials to evaluate compounds for Alzheimer's disease. Dosage and tolerance are critical issues in successful drug therapy for patients with Alzheimer's disease (AD). A clear distinction among patient populations and AD patient subpopulations is necessary to ensure a thorough assessment of new central nervous system-active compounds. Phase I inpatient trials, in which tolerance and safety are evaluated under double-blind conditions in the target population, provide valuable information for use in planning multicenter outpatient trials. In similar studies, even those involving the elderly, tolerance and safety outcomes in healthy volunteers are not always predictable. An early trial of the effects of velnacrine in healthy, elderly, male volunteers was followed by a trial in the target population. A group of volunteers, aged 60 to 74 years who did not have AD, received 300 mg of velnacrine each day. This dosage was well tolerated for 28 days. Diarrhea, generally of moderate severity, was the only reported adverse effect. No subjects were required to discontinue taking velnacrine. In contrast, a similar trial showed a dosage of 300 mg of velnacrine each day intolerable among patients with AD. Adverse reactions to dosages greater than 225 mg/day included dizziness, fainting, nausea and/or vomiting, headache, and severe diarrhea. A velnacrine dosage of 225 mg/day appeared to be safe and well tolerated in a small population of healthy patients with AD. Based on the inpatient experience with AD subjects, a maximum dose of 225 mg/day was adopted for outpatient studies. Although factors that may contribute to drug sensitivity in patients with AD vary beyond conclusive parameters, the observed sensitivity within the target AD group may indicate a safety/tolerance study as a worthwhile antecedent to multicenter efficacy trials.


Antidepressant treatment of pathologic laughing or crying in elderly stroke patients. Pathologic laughing or crying (PLC), a complication of many neurologic disorders, involves behavior that is either inappropriate to the context or to the patient's subjective feeling state. It is due to a dysregulation of the motoric components of emotional experience. PLC is distinct from, but often associated with, major depression. The relatively few reports on treatment of PLC are primarily with tricyclic antidepressants. We report the effective treatment of PLC due to stroke in three patients with nortriptyline or fluoxetine. The cases also illustrate the broad spectrum of depressive symptoms (from none to a major depression) seen in patients with PLC. We discuss treatment implications and directions for future research.