Mental retardation and congenital malformations associated with a ring chromosome 9. A 46,XY,r(9) (p24q34) complement was observed in a 35-month-old boy with multiple congenital anomalies. The main clinical features included intrauterine growth retardation, dwarfism, microcephaly, peculiar face, undescended testes, seizures and severe psychomotor retardation. It appears that 4 reported cases of r(9) can be divided into two groups. Three of them, including the present case, share clinical features with those of cases with 9p--. On the other hand, one case showed a different combination of malformations.


Fusion of two apparently intact human X chromosomes. Cytological studies have been presented from a 15-year-old girl with short stature and failure of puberty. Buccal mucosa preparations revealed X-chromatin mass approximately double in size of that of a normal female. Leukocyte metaphases suggested a two cell line composition of the patient. One population of cells conformed with 45,X chromosome distribution. The chromosome complement of her other cell line had a modal number of 46. In this cell line a "C" chromosome was replaced by an exceptionally large submetacentric chromosome. This abnormal element exhibited late DNA replicating pattern. G-banding study revealed that the abnormal chromosome was produced as a result of fusion involving telomeric ends of long arms of 2 intact X chromosomes. This translocation X was bearing 2 C-banded areas; one around the centromere and the other at the distal end of the long arm. The distal C-band area did not show any evidence for centromeric function. It appears that a centromere becomes latent in the presence of another centromere in a translocation bearing 2 total chromosomes. Such a change of state in the additional centromere is vital for the stability of the translocation chromosome.


Localization of the human GLO gene locus. Data on the linkage relation between the GLO locus and the HLA, Bf, and PGM3 loci are presented. The family material includes 49 GLO/HLA-B (and/or Bf) segregating matings with 134 children informative on 199 parental meioses. Of phase-known meioses, 3 are recombinants and 75 nonrecombinants; linkage is therefore proven. From the total material a distance of 2.5 cM between GLO and HLA-B/Bf is calculated; and from the segregation in some informative family groups it is shown that GLO is situated between PGM3 and HLA-B/Bf.


Significance of a new type of human fetal hemoglobin carrying a replacement isoleucine replaced by threonine at position 75 )E 19) of the gamma chain. A new type of hemoglobin F, in which isoleucine in position 75 (E 19) of the gamma chain is replaced by a threonine residue, has been found in 29 out of 32 homozygotes for beta thalassemia. The amount of this hemoglobin ranges from traces to 40% of the total Hb F. The same gamma75 Thr chain is also present in the Hb F of 40% of normal newborns and premature infants examined, of one 14-week-old fetus and in one out of 3 patients with aplastic anemia and raised levels of Hb F. Our results strongly suggest that the synthesis of this new chain is under the control of a gamma gene nonallelic with those coding for Agamma and Ggamma chains.


The human leukocyte test system. VIII. DNA synthesis and mitoses in 3-day cultures stimulated with pokeweed mitogen. In human leukocyte cultures set up with Ham's F-10 medium and stimulated with pokeweed mitogen (PWM), DNA synthesis and mitotic indices were analyzed by means of (3H)TdR autoradiography and cell counting. The results show a very similar pattern of DNA synthesis and mitotic indices to that found in cultures set up with TC medium 199 and stimulated with phytohemagglutinin (Obe et al., 1975 a).


Evidence for an association between ABO blood group and goitre. A medical and genetic study on KarKar Island, Papua New Guinea revealed a significant association between ABO blood group status and susceptibility to goitre with O individuals more susceptible than non-O. The association is found in a number of separate villages on the island which indicates that it is not due simply to chance concordance in geographical patterns of genetic and disease variations.


A family with a high risk of segregation for an autosomal unbalanced reciprocal translocation. A family with autosomal reciprocal translocation t(4;13) (q25;a31) with a sibship comprising 2 children with unbalanced karyotypes, der(13) partial trisomy 4q, 1 child with the balanced translocation, and 2 abortions were studied. The segregation risk of unbalanced derivation in reciprocal translocations is discussed. The clinical picture of the 2 children with partial trisomy 4q is compared with similar cases.


Hereditary retinoblastoma: penetrance, expressivity and age of onset. Analyses of family data published in Japan concerning 29 kindred with 2 or more cases of retinoblastoma revealed that, in the children who received the gene from a carrier parent, both penetrance and expressivity increase with increasing degree of expressivity in the parent. The estimate for the average degree of penetrance varies from 0.7 to 0.9, depending upon the method employed. The value will be increased with increasing number of survivors of hereditary retinoblastoma. Data were presented to indicate that in the hereditary form of retinoblastoma onset tends to be later in unilateral than in bilateral affection, though in the non-hereditary form onset will be further delayed. No effect of birth order was detected. It was suggested that suppressor genes at other loci play a significant role in manifestation of the major dominant gene for retinoblastoma. Implications of these findings were discussed.


Inherited congenital normofunctional testicular hyperplasia and mental deficiency. Four 46,XY siblings with congenital bilateral megalorchidia, marcogenitosomia, and severe mental deficiency were investigated. The testicular size was significantly larger than age-matched normal males. A normal hypothalamic-pituitary gonadotropin function was demonstrated by the finding of normal levels of luteinizing and follicle-stimulating hormones in blood samples drawn at frequent intervals and by normal responses to gonadotropin-releasing hormone and testosterone administration. A normal testicular function was shown by the finding of normal (a) plasma testosterone and estradiol levels, (b) gonadal response to human chorionic gonadotropin, (c) sperm analysis, and (d) morphology and cell architecture of the testes. Adrenal function was found to be within normal limits. These results demonstrated the existence of normofunctional testicular hyperplasia. The family studies suggested that this distinct congenital disorders is inherited as an X-linked recessive trait.


Isochromosome X in man: different DNA replication patterns in the long arms. An X isochromosome for the long arm was studied in 3 patients with Turner's syndrome using the BrdUrd-Hoechst 33258-Giemsa method and C-staining. In all 3 patients studied, the long arms of the i(Xq) were asymmetrical with respect to chronology of DNA synthesis. The most striking asynchrony of DNA replication was observed in large early replicating segments adjacent to the centromeric region. Two C bands of similar appearance were observed localized symmetrically in both arms. The data are interpreted in accordance with two possible origins of an abnormal X which is known as i(Xq).


Gene dosage effect in human triploid fibroblasts. The activity of 13 cytoplasmic enzymes has been determined in fibroblast extracts from 9 triploid and 13 control lines. The results show a high activity for 2 X-linked enzymes, glucose 6-phosphate dehydrogenase and phosphoglycerate kinase. These data, together with cytogenetic observations, support the contention that 2 X chromosomes were active in the triploid lines.


Genetic polymorphism of C3 and serum levels of immunoglobulins, C3, C4 components of complement and C3-proactivator in four different populations of Afghanistan. The C3 phenotype distribution was studied in 4 different populations from Afghanistan. The gene frequencies of C3S allele were: Tajiks (0,8547), Pushtoons (0.8812), Hazaras (0.9036) and Osbeks (0.8530). These values were significantly higher than in European populations studied previously. No significant differences were found between the mean serum levels of C3, C4 and C3-proactivator among 4 population groups. A higher concentration of IgG, IgA and IgM was observed in Afghanistan sera than reported for Europeans.


Complex translocation t(9;21)(9;22)(q12p13)(q12q11) in the family of a child with 9p trisomy syndrome. A case of partial trisomy 9 is described in a mentally retarded and dysmorphic child, confirming that this chromosome unbalance results in a characteristic clinical entity. This trisomy arose through aberrant segregation of translocation chromosome during meiosis in the patient's mother, who is a balanced heterozygote for a complex translocation involving chromosomes 9, 21 and 22. The phenotypically normal sister of the proposition is also carrier of the same complex translocation.


Partial trisomy 15q1.

Partial trisomy 15q1. A supernumerary extra chromosome of maternal origin, precisely described from QM- and C-banding patterns, was studied in a mentally defective boy with a severe convulsive disorder. This case is considered to represent a specific phenotype of trisomy 15q1. The suggestion that in cases of partial trisomy 15q different phenotypes are due to the second chromosome involved in interchange is supported by the observation of a tertiary trisomy in 2 sibs. It resulted from a balanced reciprocal translocation in the mother t(8q+15q--) and caused an unusual malformation syndrome (mental deficiency, cleft lip and palate, funnel chest, hypospadias).


rDNA and acrocentric chromosomes in man. I. rDNA levels in a subject carrier of a 8p/13p balanced translocation and in his unbalanced son. A malformed female infant was found to have a 46,XX complement with a chromosome 8 shorter than normal with a secondary constriction and satellites on the short arm. Chromosome studies on the clinically normal father showed a balanced translocation between chromosome 8 and 13, i.e., 46,XY,t(8;13) (p21 p12). The proposita, carrier of the unbalanced form of the translocation, resulted partially monosomic for short arm of chromosome 8 (8p-) and partially trisomic for short arm of chromosome 13. The levels of DNA complementary to rRNA (normal in the father who had 10 NOR and increased in the proposita who had 11 NOR) confirmed our interpretation of the rearrangement.


Investigations on the frequency of chromosome aberrations in bone marrow cells of chinese hamsters after simultaneous application of caffeine and cyclophosphamide. The potentiating effect of caffeine (1,3,7-trimethylxanthine) on chemically induced chromosome aberrations was studied in bone marrow cells of chinese hamsters, exposed to the alkylating agent cyclophosphamide. Four experimental series were performed: In the first two tests caffeine (200 mg/kg) or cyclophosphamide (40 mg/kg), respectively, were administered. A third and fourth test was performed with caffeine plus cyclophosphamide (200 + 40 mg/kg and 35 + 40 mg/kg, respectively) simultaneously. Aberrations induced by cyclophosphamide (40 mg/kg) were strongly potentiated by simultaneous application of caffeine (200 mg/kg) not only additively but even synergistically. This increase of aberrations cannot be found after injection of the lower dose of caffeine (35 mg/kg).


Elimination of spontaneous and chemically induced chromosome aberrations in mice during early embryogenesis. NMRI mice (female female) were treated with 0.25 mg/kg body weight Trenimon (2,3,5-triethyleneiminobenzoquinone-1,4) in the preovulatory phase just before ovulation. Then they were mated with untreated males. The female mice were dissected 45 h after application of this mutagen. The preimplantation embryos, being in a 2-cell stage, were flushed out of the oviduct and cultured in vitro for 60 h. Of the cultured embryos 87.7% reached the blastocysts stage in the control series, whereas only 49.7% did so in the experiments. Some of the females were dissected on the 14th day post conception (p.c.) and the number of dead and living implants was determined. Furthermore, the 9.5- and 13.5-day-old embryos were cytologically investigated, to determine the frequency of chromosomal aberrations. Of the unfertilized oocytes 76.2% deriving from mice treated with 0.25 mg/kg Trenimon, were aberrant in the stage of metaphase II (Röhrborn and Hansmann, 1971). Comparing Röhrborn's and Hansmann's results (1971) to our own findings a continuous elimination of chromosome aberration is clearly to be seen during early embryogenesis. The biological selection takes place in the pre- as well as in the early and late postimplantative phase.


The cytogenetics of 90 patients with idiopathic mental retardation/malformation syndromes and of 90 normal subjects. A cytogenetic study, done on randomized coded slides, of 90 patients with idiopathic mental retardation and at least 3 other developmentally independent congenital anomalies and of 90 normal subjects is reported. Audiatorography, Q-banding and C-staining were used in the analysis of chromosomally abnormal cases. Eight patients were found to have chromosome abnormalities. Four had substantial chromosome aberrations that would be expected to cause abnormal phenotype. These were CD165 (46,18q-); CD25 (46,18q+) (partial trisomy of 10q); CD175 (46,4q+) and CD95 (46,mar22). In addition, 4 patients were found to have chromosomal anomalies that could not account for their conditions. Three of these were considered to have heterochromatic variants. Patient CD167 had an 9qh+ chromosome which had been inherited from her mother. Case CD137 had a No. 19 chromosome with additional centric heterochromatin. A similar chromosome was found in her mother, maternal grandmother and 2 of 3 half sibs. In patient CD125 a telocentric No. 13 was found. In addition, CD80 was shown to have an XYY constitution. In the normal subjects, no unbalanced chromosome rearrangements were found. Four persons, however, had minor chromosome anomalies. Three were considered to have heterochromatic variants. These were CD54 (46,22p+); CD149 (46,21p+) and CD19 (46,tel22). One normal subject (CD51) was found to be a balanced t(13q14q) carrier. The translocation chromosome had been inherited from his father.


Partial trisomy 4q due to familial 2/4 translocation. The case of a 5-year-old boy with partial trisomy for the long arm of chromosome No. 4 is described. The pattern of abnormal development in this and in 12 previously reported cases is similar, but the phenotype is not as characteristic as that associated with some other types of chromosomal imbalance. The most consistent features are: growth and mental retardation, small head with narrow forehead, short philtrum, relatively large ears with incomplete differentiation of the pinnae, cryptorchidism, oedema of the hands and/or feet, and renal anomalies. Abnormal development of the thumb was present in 4 of 13 cases. Eleven of the 13 families had balanced translocation carriers whose future offspring would be at increased risk for a mental retardation syndrome.


Two cases of trisomy 4p with translocation t(4p-,7q+) in several members of one family. Report of a family with 7 cases of balanced translocation t(4p-,7q+), resulting in partial trisomy in 2 children descending from parents being brother and sister. Description of the clinical cases, family history, and cytogenetic findings followed by a short discussion of phenotypical differences of the two probands.


The red blood cell esterase D polymorphism in Europe and Asia. Several regional series from Britain and 3 Asian series were typed for the Esterase D polymorphism. It was found that haemolysates up to 5 years old could be reliably typed when prepared from washed anticoagulated red blood cells. Lysates prepared from blood clots do not retain Esterase D activity quite as well. The Manx population has higher Esterase D 2 gene frequencies than neighbouring populations. A Nepalese population exhibits the highest Esterase D 2 gene frequency so far recorded. The other series presented supplement or confirm results already published.


The occurrence of Hb E Saskatoon in Scotland. The finding of several examples of Hb E Saskatoon in the Orkney Islands, in Edinburgh and in individuals of Scottish descent in Canada but nowhere else, suggests that the original mutation occurred in Scotland, perhaps in the Orkneys.


Parental origin of a ring 13 chromosome in a female with multiple anomalies. A ring chromosome No. 13 was found in a 21-year-old female with multiple anomalies suggestive of 13q--syndrome. Chromosomes of the girl and her parents, studied by quinacrine staining, revealed the ring to be of paternal origin. Detailed study of the quinacrine banding pattern of the ring indicated loss of the most distal band of the long arm (13q34) and possible partial loss of the next adjacent long arm band (13q33). The short arm (13q11) was present but the stalk (13p12) and satellite (13p13) regions appeared to be missing.


Ring chromosome 15 in child with a minor dysmorphism of phenotype. The analysis of a karyotype of a girl with slight mental retardation, without significant dysmorphism, showed the presence of a ring chromosome in group 13-15. By the application of G technique it was discovered that in this case it was an aberrant chromosome 15. Besides retardation in growth and a slight mental backwardness in this case, it was confirmed that in cases of ring 15 syndrome no preponderant change appears in phenotype.


Brachydactylia with symphalangism, probably autosomal recessive. Association, in one patient, of the following malformations: brachydactylia of all segments but terminal phalanges; proximal symphalangism of many fingers and toes; abnormalities of carpal and tarsal bones; partial duplication of both big toes; mild hypertelorism. Genetic transmission seems to be recessive autosomal.


Generalized dermal perifollicular fibromas with polyps of the colon. The cases of 2 siblings with a rare, generalized genodermatosis have been reported, the most conspicuous feature being multiple perifollicular fibromas. In this type of dermal hamartomas, an apparent autosomal dominant trait was noted as well as the association with a small number of colon polyps in one of the patients. The author assumes a distinct dermo-intestinal syndrome not reported hitherto, which can be differentiated from Gardner's syndrome.


Applications of a health planning model in Morocco. It is argued in this paper that public health planning should be guided by the principle of output maximization. The objective of the health sector should be specified, and measurable forms of output should be derived from these statements of purpose. Knowledge of the contributions which given combinations of inputs make toward output thus defined allow, in principle, calculation of the particular deployment of the avilable inputs which will maximize output. There is a discussion of the objectives or forms of output in a public health system, both humanitarian and economic. A verbal model of such a system for an underdeveloped country is constructed which identifies the relationships which must be known if spending decisions are to suceed in maximizing output. An attempt is then made, in the context of the Moroccan public health system, to show that the model is not merely a theoretical exercise, but is potentially useful as a planning instrument. The respective contributions of general hospitals and of mass vaccination programs toward the objective of reducing mortality are estimated. On the whole, the preventive activities (the mass vaccinations) are found to be a much a cheaper way of saving lives than are the curative activities (the general hospitals).


Alternative methods for determining resource requirements: the Chile example. Many more or less attractive techniques have been proposed for statistical analyses involving multiple sources of variation, for example in examing the possible contributors to differential patterns of health services utilization and expenditure. A large scale investigation of such patterns among 10,000 household in Chile provided a useful basis for comparison of alternative analytical approaches. The multiple regression, Automatic Interaction Detection, and Multisort techniques were applied to the survey data deparately and in combination and results were compared. The Multisort technique was found to be the single most useful and convenient approach, but the most meaningful results were obtained from the systematic application of the three approaches combined.


Magement education for health services.

Magement education for health services. This paper examines the implications of the recent emergence in the United States of three major factors for management education in health services. The factors are: new organizational forms for delivery of services, increased emphasis on public accountability, and the proliferation of agencies intended to monitor and coordinate health services providers. Several questions are considered, including the degree to which training for various managerial careers within health services should be differentiated; the degree to which professional education should occur in the academic setting as distinct from the work setting; and, most importantly, the appropriate content of graduate education. It is argued that formal education for health services management should place substantial emphasis on the development of a student's analytic skills, with particular reference to quantitative methods. While these technical skills are not likely to become the dominant ingredient of successful and effective management, they do provide the manager with the ability to identify courses of action which will benefit the organization, and strengthen his hand in dealing with groups that are necessarily in conflict with its goals. It is stressed that training in this area should be oriented toward the needs of the prospective manager rather than the quantitative methods specialist.


Women's emancipation and socialsm: the case of the People's Republic of Poland. Determinants of occupational position in Poland, as elsewhere, include the socialization process, access to education, and the employment structure. The socialization process includes the domestic pattern of division of labor, occupational models encountered in person and in the various media, and parental and social pressures, including vocational counseling. Ecuational access is a critical determinant of the extent and type of participation in the labor force as well as attitudes toward work. Although Poland has made major attempts to improve the socialization process and acces by type of program, disparties are still encountered in pay received for similar work, and for work in positions that cannot be explained by differences in productivity or education. Employment policies being undertaken or considered include measures to improve working conditions and occupational position, to socialize a larger number of "domestic" tasks, and to provide more flexibility via part-time work and longer maternity leaves.


Regulation and control of the medical profession in Great Britain. Regulation and control of the medical profession are evaluated in the light of recent inquiry into the British General Medical Council. The Report of the Committee of Inquiry into Regulation of the Medical Profession is examined and its worldwide applications are discussed.


The recent history of parasitic disease in China: the case of schistosomiasis, some public health and economic aspects. This paper examines the extent to which the prevalence of schistosomiasis may have increased during the period 1958-1964. Certain hypotheses are examined, mainly dealing with irrigation and water conservancy construction. The probable economic and demographic effects of schistosomiasis are also examined. The article concludes that schistosomiasis prevalence probably did increase, but that the economic-demographic effects of this were probably minimal.


Quality control and the community physician in England: an American perspective. The quality of health care is becoming an issue of increasing public importance in both England and the United States. As the government role in providing health care grows and citizen demands increase, the effective and efficient use of health care resources and their equitable distribution become crucial. Although government responsibilities, particulary for health care, differ in both countries, as do traditions of quality control, cross-national comparisons are nonetheless useful. An examination of the role of the new English community medicine specialist and his potential for quality control may indicate what tools and powers should be introduced into a health planning and quality control system in the United State. The study concludes that at the district level of the National Health Service, where the basic planning, monitoring, and evaluation of services are to take place, the District Community Physician has very limited tools to carry out his quality control function. Although he has formal position in the unified decision-making structure, it is unlikely that he will be able to effect any substantial reallocation of resource without the voluntary support and copperation of the consultants, general practitioners, and other health providers.


Social theory and medicine.

Social theory and medicine. Three sociolgists-Talcott Parson, Eliot Freidson, and Mechanic-have explained medical phneomena within a broader theoretical framework. Although all three have made significant contributions, their conclusions remain incomplete on the theoretical level and seldom have been helpful for workers concerned with ongoing problems of health care. Our purpose here is to summarize some of the strengths and weakness of each theoretical position. Parsons has elucidated the sick role as a deviant role in society, the function of physicians as agents of social control, and the normative patterns governing the doctor-patient relationship. The principal problems in Parsons' analysis center on an uncritical acceptance of physicians' social control functions, his inattention tot the ways in which physicians' behavior may inhibit change in society, and overoptimism about the medical profession's ability to regulate itself and to prevent the exploitation of patients. Viewing medical phenomena within a broader theory of the professions in general, Freidson has formulated w wide ranging critique of the medical profession and professional dominance. On the other hand, Freidson's work neglects the full political implications of bringing professional autonomy under control. Mechanic's coceptual approach emphasizes the social psychologic factors, rather than the institutional conditions, which are involved in the genesis of illness behavior. Mechanic also overlooks the ways in which illness behavior, by permitting a controllable from of deviance, fosters institutional stability. In conclusion, we present a breif overview of a theoretical framework whose general orientation is that of Marixian analysis. Several themes recur in this framework: illness as a source of exploitation, the sick role as a conservative mechanism fostering social stability, stratification in medicine, and the imperialsm of large medical institutions and health-related industries.


Health care: an international comparison of perceived morbidity, health services resources, and use. Selected summary findings from the World Health Organization/International Collaborative Study of Medical Care Utilization are presented, based on data collected during a twelve-month period in 1968-1969 in twelve study areas in seven countries in the Americas and Europe. A household interview survey of almost 48,000 persons, representing a total population of about 15 million, elicited information on demographic characteristics, on perceptions of illness, its severity and character, and on attitudes toward and use of major components of health services. Information was also collected on the prevailing health care systems and resources available to the study population, as well as on socioeconomic characteristics of the study areas. Standardized rates for those defined as "healthy" and "functionally healthy" are quite similar across the twelve study areas, as are the rates for persons who reported being sick within two weeks. Rates for the volume of sick days within two weeks vary widely, and levels of chronicity with disability are much higher in the four continental European study areas. Rates for volume of physician contacts within two weeks vary considerably across study areas, but rates for persons with contacts are more stable, although for persons with perceived morbidity of high severity, the corresponding rates are lower in the four continental European study areas. By contrast, the rates for persons with an administrative reason for their most recent physical examination within twelve months are substantially higher in the latter. Where unmet need for a physician contact is greatest, the volume of hospital nights used is also greatest; a direct relationship between these two measures is evident without regard to the ratio of hospital beds available to the population. Wide differences are observed between the extremes of the measures of need, resources, and use employed in the study, raising questions about the ways in which resources are organized to provide services and about the effectiveness and efficiency of these services.


The doctor's role in rural health care.

The doctor's role in rural health care. A new pattern of health care in developing countries promises to meet the needs of rural people and still provide reasonable gratification for health workers. The service must have mutually strengthening linkages between all levels of the health care system. Reallocating roles in the health team requires turning routine medical care over to auxiliaries so that professionals can concentrate on more complex problems, such as community diagnosis and therapy. Young doctors are reasonable and willing to undertake a rural rotation early in their medical careers. This will help to identify those few who will provide leadership in improving rural services.


Medical brain drain revisited.

Medical brain drain revisited. There is increasing pressure for the training of greater numbers of doctors. This pressure stems from the growing demand for higher education for the children of an expanding middle class, and from the desire to create more "satisfactory" doctor/population ratios. But, in fact, the middle classes produce doctors primarily to serve their own class. Since the training of doctors is geared to the values and requirements of those with money incomes sufficient to purchase private medical care, it is very expensive. These costs are such that the level of effective economic demand of most of the population cannot possibly meet the expectations and requirements of the medical graduates, who then "overflow" into those parts of the world where demand is greater than the current supply of doctors.


Foreign intervention in medical education: a case study of the Rockefeller Foundation's involvement in a Thai medical school. A case study of the process of foreign intervention in medical education in the developing world is presented. Material collected from the Rockefeller Foundation Archives on a Foundation program in Thailand is used to analyze the conditions under which foreign agencies and their personnel intervene in the development of medical professionals in the Third World and to study the problems that may occur as a result of such intervention. The importance of value consensus and the competitive advantage foreigners have in the marketing of professional models are highlighted as reasons for the diffusion of Western models of medical education throughout the developing world.


An analysis of the medical supply industries. Medical supply industries are dominated by widely diversified multinational companies that produce chemicals, pharmaceuticals, computers, cosmetics, and electronic equipment. Of these products, the most profitable group is prescription drugs. This article contains a description of the general structure of the pharmaceutical industry worldwide and the specific details of drug operations in the United Kingdom. The United Kingdom is of special interest because of its long-standing and partially successful attempt to regulate drug prices. The government's inability to achieve total control is related to the competitive structure of capitalist economy, to the patent system that grants monopoly privileges to drug firms, and to the duplication of research efforts and waste of resources that push up drug costs. The pharmaceutical industry serves the needs of people poorly in developed countries; its impact on underdeveloped countries is much worse. In the Third World, nascent national companies and small local producers of drugs cannot compete with the huge multinationals; the patent system proves to be an imperfect mechanism for the transfer of medical science and technology; and the high cost of imported drugs determines the amount of health care governments can provide for the population. The multinational corporations are now global enterprises that integrate the production of chemicals for many different uses-drugs for human and animal consumption, fertilizers, pesticides, and food additives. Thus the multinationals affect agricultural production and animal husbandry in underdeveloped countries and thereby nutrition as well as the treatment of disease.


Support for the medical profession among the aged. National survey data are utilized to delineate areas of confidence among the aged in the medical profession. Four key specifying variables were used in the analysis-race, sex, socioeconomic status, and size of community. Findings indicate that confidence in medical leaders is lowest among that group which in past studies has been found to visit the doctor most often: the elderly of low socioeconomic status. This finding suggests that improvement in the medical care received by the aged could be an important first step in restoring the elderly's confidence in medical leaders.


Unions and strikes in the National Health Service in Britain. This article outlines the origins of the main manual and white-collar trade unions in the British Health Service, traces their growth after the establishment of the National Health Service in 1949, and examines the wave of industrial action in British hospitals in the seventies. It is argued that although strike action inside hospitals in the early seventies was a novel tactic adopted as a last resort by manual workers pressing for wage increases, industrial action over a wide range of political and medical issues has now been taken by all types of hospital worker in Britain and plays a central part in the national debate over the future of the National Health Service.


An overview of primary health care.

An overview of primary health care. Primary health care has become a focus of interest from the World Health Organization down. The hopes that more emphasis on primary care will lead to less expensive and better care will not be realized unless a more critical analysis of its problems is undertaken and some of its defects and deficiencies put right. Its roles must be better defined and the work shared within a team; training and education must be more related to its needs; and much sharper research is required to decide what is useful and what is useless.


Nutrition and the future of mankind.

Nutrition and the future of mankind. Malnutrition is primarily due to poverty, a manifestation of social injustice with inadequate distribution of resources and services within and between countries. By limiting the capability of poor people to improve their economical and social status, malnutrition helps to perpetuate this situation. A change in developmental policies taking more into account the improvement of living conditions of the poor is needed to correct this social problem.


Assisted suicide: some ethical considerations. When we die, it is only very rarely that we do so without days, weeks, or months of illness in which the suffering may be very great, sometimes from pain, often from breathlessness, impairment of consciousness, depression, anxiety, vomiting, bedsores, and incontinence. If we were able to choose our own time to die, there would be no need to suffer any of this. There should be a "right to die". It should be ethically and legally possible for the doctor attending a terminally ill patient, who asks him for help to take his own life, to put the means within his reach.


Photography of the corneal endothelium.

Photography of the corneal endothelium. Excellent photographs of corneal endothelial cells may be obtained during clinical examinations with the specular microscope. Endothelial photographs are extremely useful in documenting the corneal effects of ocular trauma, aging, inflammation, and surgery. An objective appraisal of various ocular surgical techniques and their effect on the corneal endothelium is possible. This new photographic technique provides information that can improve both the diagnosis and the therapy of corneal diseases.


Ocular fundus photography.

Ocular fundus photography. This chapter is a review of fundus photography techniques, with particular emphasis on the important parameters of producing high quality fundus photographs. The role of fundus photography has extended beyond that of a documentary service to one with specific diagnostic value. Thus, ocular fundus photography relates directly to patient care and is an essential part of the sophisticated armamentarium of any clinical ophthalmological unit.


Use of the astigmatism correction device on the Zeiss fundus camera for peripheral retinal photography. High quality photographs of the peripheral retina are made possible by the proper positioning of the astigmatism correction device on the Zeiss fundus camera. Using a plus cylinder, axis perpendicular or a minus cylinder, axis parallel to that around which the eye is rotated will eliminate the astigmatism induced by viewing the retina obliquely through the optical surfaces of the eye, resulting in a sharply focused image at the film plane. Proper use of this instrument can be helpful in evaluating and diagnosing retinal lesions that occur in the peripheral fundus.


Spectral reflectance photography.

Spectral reflectance photography. It can be seen that the technique of using properly selected filters to provide rigidly defined monochromatic bands with which to observe the fundus presents interesting and challenging information that is as yet mainly untapped. The applications quoted present only a small part of the areas that can be investigated. The technique is basically standard, but advances can still be made in optimizing filters. The question of what band width to use for a given application is by no means solved and presents a challenging avenue of inquiry. It should be pointed out that the use of color film with interference filters offers no advantage. The only dimension being recorded at each point in the film is reflectivity of the structure at the wavelength of the filter being used. Documenting the color of this wavelength by the use of color film is a fruitless exercise.


Application of an implantable stimulator in the rehabilitation of paraplegic patients. The surgical problems of implantable systems for functional electrical stimulation in the rehabilitation of plegic patients have been discussed. The "Ljubljana implant" was developed through experiments on animals and later with two volunteers. It has a typical electrode configuration, acceptable miniaturization and reduces the amount of surgery necessary. This system was tested in 14 patients, primarily as a part of an implantable peroneal brace. For five years the system has been reliable and safe. It may be possible to apply this implant as part of a multi-channel control system.


Effect of intraocular surgery on the tension of the other eye: preliminary report. Thirty-one cases of glaucoma and cataract were studied to determine if intraocular surgery in one eye could affect the ocular tension in the fellow eye. Twenty-seven patients showed varying degrees of change in the untreated eye. Possible factors causing the change have been discussed.


Dynamic studies with radionuclides.

Dynamic studies with radionuclides. Scintigraphy, the visual display of radioactivity, shows the size, shape and structure of the organ being studied. This information should be complemented with dynamic studies which will indicate the distribution of the radioactivity in the organ in relation to time. Dynamic studies must be performed with external detectors and the gamma camera. Circulation (systemic, pulmonary or cerebrospinal fluid) can be studied depending on the method of administration and the radionuclide used. The indicators are the same as for arteriography. Regional distribution of ventilation can be studied using radioactive gases. Regional distribution of ventilation of the lungs and mucociliary clearance can also be studied using inhaled particles. Dynamic studies do not replace but only supplement scintigraphy. They should be quantitated to obtain objective information.


Treatment of antral and duodenal bleeding ulcers by Guevara's catheter. The catheter is based on the principle of compression and tamponage, assuring and guaranteeing hemostasis at the base of the ulcer. This method is suitable for permanently controlling an acute hemorrhage in the event medical treatment fails and surgery is contraindicated. Emergency surgery is changed to elective surgery with all its advantages.


[Variations in the behavior in chronic hospitalized schizophrenics under treatment with EMD 16, 139, a benzoquinolizine derivative]. A group of hospitalized chronic schizophrenic patients was treated with EMD 16 139 - a benzochinolizin derivate - for 4 weeks in a placebo-controlled trial. Changes of behavior were measured using a rating scale. The results suggest an increase of activity and initiative during treatment. Problems concerning some neuroleptic effects are discussed.


Ovarian metastases from carcinoma of the bilharzial urinary bladder. A pathologic study of 135 cases of carcinoma of the bilharzial urinary bladder treated with radical anterior pelvic exenteration, including 60 cases examined by subserial sections of both ovaries, did not reveal a single incidence of ovarian metastases from bladder carcinoma. The same observation has been reported by some investigators examining the more aggressive forms of bladder carcinoma seen in Western countries. Based on these findings, we recommend that at least one ovary, the one away from the tumors, should be retained with an intact blood supply to avoid the distressing symptoms of menopausal syndrome. This is especially advisable in our patients where carcinoma of the bladder occurs at a younger age.


Acute lithium effects on rat brain glucose metabolism - in vivo. Administration of LiCl to rats was found to affect brain glucose metabolism in the following ways. The concentrations of brain glucose, brain lactate and brain glycogen were increased, and the concentration of brain glutamate was decreased. The incorporation of (14)C from U-(14)C D-glucose, administered intraperitoneally to the rats, was increased in brain glucose and brain lactate, and decreased in brain glutamate. The results were explained by a lithium-induced increase in brain glucose uptake and an increased rate of glycolysis, and a slight inhibition of the oxidative decarboxylation of the Krebs cycle.


Serotonin in the portal vein after acidification. To test whether serotonin release from the argentaffin cells of the intestinal tract can elicit peptic ulcer, rats were given intraduodenal infusions of N/10 and N/20 hydrochloric acid. Serotonin measured in the portal venous blood of rats which had had an intraduodenal infusion of N/20 HCl for five minutes was significantly higher than in the portal (P less than 0.05) or systemic (P less than 0.01) blood of control animals. After longer intervals serotonin release tapered off and measurements obtained 30 minutes after an infusion of N/10 HCl did not differ significantly from those in the controls.


Medical electronics in surgery.

Medical electronics in surgery. I have described the results of a telemetering radio capsule which we used in the clinical assessment of digestive disease. This method has many merits which we have never found with other methods. This is one example of the clinical use of medical electronics. Medical electronics provides surgeons with many useful aids to improve diagnosis and treatment of their patients. Medical electronic technics should be used more often.


Kinematic analysis of spinal fusions.

Kinematic analysis of spinal fusions. Two cases with clinical suspicion of incompletely healed anterior fusion between L5 and S1 were examined by means of a roentgen stereophotogrammetric method. In both cases a pseudarthrosis was found. The method makes it possible to disclose rotations and translations between veretebrae with an accuracy of about 0.2degree and 30-120 mum, respectively.


Considerations of 201T1 as a myocardial radionuclide imaging agent in man. Recent reports have suggested the use of intravenous 201T1 (thallium-201) for myocardial imaging with the gamma scintillation camera. In order to better appreciate the possible utility of this agent in humans we examined its distribution and kinetics in 13 patients and in six mongrel dogs, three with experimental coronary artery occlusion. In addition, 201T1 was compared to 86Rb (rubidium-86) in 84 rats. In the rat heart, the concentration of 201T1 was 30% higher than that of 86Rb ten minutes after injection. Moreover, myocardium-to-blood ratios for 201T1 averaged 51:1, but only 32:1 for 86Rb ten minutes after administration. In the dog heart, the distribution of 201T1 paralleled that of radioiodinated (131I) albumin particles injected into the left atrium and, thus, appears to be related to regional blood flow. Its concentration in ischemic regions decreased to 32.3% of the normally perfused myocardium. In the patients with a recent or old myocardial infarction, areas of decreased 201T1 uptake were easily identified and corresponded in location to that by ECG. Repeat scans 24 hours after the initial injection showed a significant retention of 201T1 by the myocardium. 201T1 blood levels in humans 15 minutes after injection were low (averaging 1.06% +/- 0.41% SD of the total dose per liter) and these levels decreased with a biological half-life of 3.1 +/- 0.7 days. Twenty-four hour urinary excretion rates ranged from 0.6 to 6.5% of the total dose and appeared related to urinary flow and the concentation of 201T1 in blood. Because of the higher target to background ratios, 201T1 compares favorably with radioactive rubidium. 201T1 in diagnostic doses remained without detectable adverse effects and appears promising as an agent for visualizing abnormal regional myocardial perfusion in patients with coronary artery disease.


An automated fluorescent excitation analysis system for medical applications. The use of stable tracers assayed by x-ray fluorescent excitation analysis has proven advantageous over other stable or radioisotopic techniques in a number of clinical and investigative situations. An automated fluorescent excitation analysis system for medical application has developed. Its design parameters and performance are described.


Metrizamide in experimental urography. V. Renal excretion mechanism of a non-ionic contrast medium in rabbit and cat. The excretion mechanisms of the non-ionic contrast medium, metrizamide, and the ionic, sodium diatrizoate, are compared to investigate the potential usefulness of metrizamide in clinical urography. A mixture of 125I-labeled metrizamide and 131I-labeled diatrizoate was injected intravenously to rabbits or cats. Urine, bile and blood were analyzed for their concentration of iodine. From these concentrations the renal and total clearance was calculated. In the rabbit the excretion of metrizamide was also compared with that of 3H-inulin with or without influence of p-aminohippurate or probenecid. The earlier reported relatively low urinary iodine concentrations after intravenous injection to rabbits of low doses were explained by the following findings: In the rabbit the volume of distribution, the renal clearance and the total clearance of metrizamide were smaller than those measured for diatrizoate and inulin. The biological half-life in serum measured 30-150 min after injection was the same for all three compounds. No indication of tubular secretion was found. The excretion mechanism of the contrast media exhibits species differences as no differences between metrizamide and diatrizoate in the parameters mentioned above could be measured in the cat.


Sequential feline esophageal nutrient blood flow: perfusion measurements in vivo. The utilization of a catheter semiconductor beta detector (CASRAD) to perform in vivo, sequential, esophageal nutrient blood flow distribution studies in cats is described. A  diffusable radioisotope, Rubidium 86 (86Rb), was injected intravenously and the CASRAD placed within the esophageal lumen. The distribution of 86Rb remained stable within the feline esophagus for sufficient time to allow for counting at 1.5 cm levels in the esophagus. The accuracy limitations of the CASRAD system were assessed by comparing the in vivo, recorded distribution of 86Rb with the esophageal distribution of 86Rb as determined by a well-type scintillation counter. The distribution throughout most of the esophagus was similar by both techniques. Sequential esophageal studies performed with the CASRAD showed less variability than existed in the biological differences between cats and the methodology of obtaining and counting tissue by well-type scintillation counter (mean coefficient of variation 11.6% versus coefficient of variation 23.1%).


The use of Compton scattered gamma rays for tomography. A method of tomographic imaging of soft tissues by the use of Compton scattering of gamma rays is described. A highly collimated source (800 Ci of 60Co) and collimated detectors are used. Spatial resolutions of the order of 0.5 cm or better are achieved, with a density resoution of 2.0% to 4%. Experimental tests with dogs have shown internal organs in sagittal, coronal and transverse section. No contrast or radioactive material is required. Tests have shown that the regional dose for humans will be about 0.25 to 1 rad for one scan.


Syngeneic and allogeneic mouse lymphoma antisera: specificity, reaction with fetal antigen and protective capacity. Vaccination with modified lymphoma cells produced highly specific antisera in syngeneic murine hosts. These were C3H/HeJ anti-6C3HED and BALB/cJ anti-P1798. These antisera gave positive membrane immunofluorescence tests with the corresponding tumor cells as well as with drug-resistant cells derived from the parental line. Immune BALB/cJ, but not immune C3H/HeJ, antiserum was cytotoxic in the presence of complement. The antisera did not cross-react with the opposite tumor, Moloney virus-induced YAC lymphoma cells, or normal splenocytes from either mouse strain. Both immune and nonimmune sera gave a positive cytotoxic test with Gross virus-induced lymphoma cells, indicating exposure of all the animals to the virus. Mice periodically given booster injections served repeatedly as serum donors; BALB/cJ mice not boosted for 42 weeks after tumor rejection still had circulating anti-P1798 antibodies. Allogeneic C57BL/KsJ anti-P1798 gave immunofluorescence tests with P1798, 6C3HED and normal BALB/cJ lymphocytes; it was cytotoxic for P1798 but not for normal lymphocytes. After absorption with normal BALB/cJ tissues, the serum became highly specific for P1798 but lost it cytotoxicity. Syngeneic and absorbed allogeneic anti-P1798 inhibited fetal liver colony formation on the spleens of  irradiated BALB/c mice, indicating reaction with fetal antigen, but 6C3H/HeJ anti-6C3HED did not give similar inhibition. The latter antiserum was used successfully for passive immunization as long as there was excess antibody; BALB/c anti-P1798 did not protect, while C57BL/KsJ anti-P1798 was only marginally protective.


Protective serum effects in tumor immunity. Administration of serum presumed to contain tumor-specific antibodies supported the rejection in immunized mice of syngeneic fibrosarcoma implants which receded after an initial period of s.c. growth. Passive transfer of immune serum to unsensitized mice, sublethally radiated and injected with normal lymph node cells, protected the recipients against i.v. but not against s.c. implantation of syngeneic mammary carcinoma cells. Injection of immune serum assisted the recovery of mice in a state of tumor-induced specific immune depression induced by a large. s.c. mammary carcinoma implant and maintained after surgical cure by injections of serum presumed to contain soluble tumor antigen.


[Quantitative study of nonsegmented and segmented neutrophilic granulocytes in newborn]. Serial white blood cell counts were studied in 20 healthy full-term babies and 252 newborn babies of different birthweights (61 of them without and 191 with perinatal risks). Nonsegmented (band form) and segmented neutrophils participate in roughly equal quantities in the physiological postnatal neutrophil reaction, which begins 1 hour after birth (8100/mm3 +/- 2600), reaches the peak after 9 hours (15 500/mm3 +/- 4000), and drops to the initial level within 42 hours. During the first 3 days the shift to the left with the relative and absolute increase of the band forms is more significant for a perinatal infection than the rise of total neutrophil count, which can remain within the normal range. However, these changes are not specific for infectious diseases. In the period the white blood count has only a diagnostic value in relation with the age of the newborn in hours and with short term follow-ups. Newborns of low birth weight (under 2500 g) show lower absolute counts and less significant changes than newborns of normal birth weight.


Tumor-specific immune responsiveness of the tumor-bearing host. In vitro lymphocyte stimulation by mitomycin-C-blocked tumor cells has been used to demonstrate tumor-specific antigens in methylcholanthrene-induced sarcomas and in syngeneic murine systems, and to follow the evolution of tumor immunity in the tumor-bearing state. Lymphocytes from normal mice, from mice bearing small methylcholanthrene-induced tumors (less than 1 cm in diameter) and from tumor-immunized mice (which had been sensitized by tumor cell inoculation and subsequent tumor (removal) were stimulated by mitomycin-C-blocked tumor cells to undergo increased DNA synthesis in culture. However, lymph node cells from mice with large methylcholanthrene-induced tumors (greater than 1 cm in diameter) had quite different characteristics. The background DNA-synthetic activity of lymph node cells from tumor-bearing mice was much higher than that of lymph node cells from normal mice or from preimmunized, non-tumor-bearing mice, and progressively increased with the duration of tumor-bearing and the size of the tumor. Lymph node cells from mice bearing large tumours appeared to be maximally stimulated by the tumor in vivo and were incapable of further stimulation by the same tumor cells in vitro, but exhibited normal responses to other antigens and nonspecific mitogens. Lymph node cells from mice bearing large tumors depleted of the adherent cells had lower background levels of DNA synthetic activity per 10(6) cells and underwent stimulation similarly to lymphoid cells from preimmunized, non-tumor-bearing mice. Spleen cells from mice bearing large tumors also had increased background levels of DNA synthetic activity, but contrary to the observations made with the lymph node cells, they were able to undergo further stimulation when cultured with the same tumor cells. Studies on the background incorporation of tritiated thymidine by lymph node cells from tumor-bearing mice revealed that the spontaneous uptake of reconstituted populations was nearly that of the original population and more than twice that of the arithmetical sum of the nonadherent and the adherent subpopulations. This was not found with normal lymph node cells or with spleen cells from normal or tumor-bearing mice. The differential effects observed with lymph node cells compared to spleen cells from tumor-bearing mice are emphasized and possible explanations for these findings are discussed.


Monitoring of nonspecific cell-mediated immunity in cancer patients. I. Frequent dissociation between the responses of skin tests to recall antigens and in vitro lymphocyte transformation. No correlation was found between in vivo delayed hypersensitivity responses in cancer patients and in vitro lymphocyte transformation by mitogens or antigens, even when the same antigen [purified protein derivative of tuberculin (PPD)] was used for both the in vivo and in vitro testing. However, there was a good correlation between the in vitro lymphocyte transformation tests with PPD and with the mitogens phytohemagglutinin and pokeweed mitogen.


[Blood picture in the early diagnosis of neonatal septicemia]. In the search of a fast and simple laboratory test for the diagnosis of neonatal septicemia the blood pictures of 29 cases of septicemia were compared with normal values derived from 390 healthy newborns. In each case the leucocyte count, the neutrophil count, the band count and its percentage, the ratio of band forms to segmented neutrophils and the platelet count were analysed in the blood smear taken on the day of clinical suspicion of septicemia. The leucocyte count, the neutrophil count and the band count are within the pathological range in 70% of the cases. The percentage of band forms and the ratio of bands forms to segmented neutrophils are, with one exception, always abnormally elevated. Thrombocytopenia is present in only 60% of the cases. Among the different criteria the percentage of band forms is evidently the most practical and most significant one. Considering our normal values, the pathological range for this percentage is above 20% on the first day of life, above 15% on the second day and above 8% from the third day on.


Milk casein polymorphism in man.

Milk casein polymorphism in man. Urea-starch-gel electrophoresis was used to examine 175 casein samples, 130 collected at random from women from the urban area of Turin, and 45 from women resident in villages in the Sardinian hinterland. Two polymorphic systems controlling alpha- and beta-casein were demonstrated in both groups, together with similar gene frequencies for individual alleles. In addition, a rare variant was discovered in the Sardinian group.


[Myocardial infarct following embolism in a newborn]. A case of myocardial infarction in a newborn, most probably consecutive to air embolism, is described. The acute episode occurred immediately after the removal of a venous umbilical catheter. The infant survived, without clinical evidence of cardiac impairment 14 months later. However, he developed signs of a spastic cerebral palsy.


Renin-angiotensin system in an infant with malignant renovascular hypertension. A one-year-old girl with malignant renovascular hypertension had increased levels of plasma renin activity and angiotensin II concentration in peripheral blood and in blood from the affected kidneys as compared with that from the contralateral kidney. Unilateral nephrectomy was followed by resolution of the hypertension and normalization of the activity of the renin-angiotensin system.


Galactosemia with endogenous production of galactose-1-phosphate and with cystic fibrosis-like appearance at autopsy. In an infant with galactosemia high levels of galactose-1-phosphate in red blood cells and of blood galactose were observed under a "galactose-free'' diet. The child did not thrive and developed a liver cirrhosis. At the age of 5 months he died unexpectedly. Post mortem examination revealed in the pancreas and the small intestine changes suggestive of a cystic fibrosis. Since the exogenous administration of galactose by diet could be excluded the endogenous production of significant amounts of galactose-1-phosphate has to be considered.


[The aglossia-adactylia syndrome].

[The aglossia-adactylia syndrome]. We present two own cases of the aglossy-adactyly syndrome and a review of 25 cases of the literature. Our experience concernes two girls. One was followed from birth until 4 1/2 years, the other from 5 to 9 years. This helped us to obtain a good knowledge of the development of these patients. Malformations of the mouth and of the limbs with a normal intelligence characterize the aglossy-adactyly syndrome. The most important features are: shortness of the tongue of variable degree, anomaly of the teeth, hypoplasia of the mandible and ectromelia of different extension with a peripheric predilection and often with an asymmetry. The etiology is unknown. All the known cases are sporadic. The differential diagnosis of the aglossy-adactyly syndrome includes the ankyloglossia superior, the Hanhart syndrome and the oro-farcio-digital syndrome I. Even when the mouth malformations are of a great degree, the functional limitations of the patients with aglossy-adactyly syndrome are very small. This is important in determining the prognosis, in consulting the patients and their parents and for decisions about corrective operations.


Increased densities and calcifications in the finger bones of children. A feature of irregular calcifications and increased densities in the metaphyseal region of the fingers of the hand in adolescent children, occurring mostly in males, is described. These changes become evident at puberty and disappear with the closure of the epiphyses. The etiology of this feature does not appear to be related to a specific hormone. It may be the result of an imbalance between those hormones which cause the pubertal spurt, possibly combined with an irregularity of testosterone secretion.


Microspectrophotometry of mitochondrial cytochrome P-450 in single adrenal cells. The cytochrome P-450 is known to be a key enzymic component in steroid hydroxylation. Biochemically it is localized in adrenal cells, both in the mitochondrial and in the microsomal fractions. Owing to its characteristic light absorptivity, attempts were made at its localization and measurement in a microspectrophotometric system. Specific difference spectra were obtained in the cytoplasm of some cells from an adrenal cell suspension before and after saturation with carbon monoxide. Scanning at 450 nm showed slender absorption maxima after CO saturation randomyl distributed in the cytoplasm. These may be attributed to mitochondria or larger cytoplasmic functional units including mitochondria.


Hepatocyte population dynamics during hydrocortisone and thioacetamide treatment. The orderly organization in a number of discrete classes of weight persists in the hepatocytes during acute and chronic poisoning with thioacetamide and during a prolonged treatment with hydrocortisone, though many striking cytological and structural changes occur in the liver. The number of hepatocyte classes decreases under hydrocortisone treatment and during acute and chronic thioacetamide poisoning, and increases during recovery after acute thioacetamide poisoning and during the late phases of chronic thioacetamide poisoning. This is due to decrements and increments in dry mass of the hepatocytes, which occur by steps, through repeated losses and additions of a constant amount of solids substantially corresponding to the class period. Such a mechanism is similar to that acting in the hepatocyte atrophy due to starvation and in the hepatocyte enlargement occurring during postnatal development. Therefore, the increment and the decrement in dry mass by defined steps takes place in the hepatocytes in both physiological and pathological conditions.


Uptake and localization of mercury in the brain of rats after prolonged oral feeding with mercuric chloride. Uptake and localization of mercury was studied in rats orally intoxicated with inorganic mercury. By atomic absorption spectrophotometry large quantitative differences were found between test and control animals, particularly relating to blood, kidney and brain. By histochemical demonstration of heavy metals the uptake in the CNS was shown to occur particularly within the cytoplasm of large neurons in the cortex, pons and basal ganglia but also in other neurons, to some extent in the choroid plexus and the vessel walls, and least in the white matter. No lesions were detectable by light microscopy. The mercury was mostly in the methylated form, something that may be explained by gastrointestinal methylation by bacteria. A similar mechanism can be expected in human chronic inorganic mercury poisoning.


Cryosurgical treatment of cancerous and noncancerous diseases of dogs, horses, and cats. Cryosurgery was used to treat a variety of cancerous and noncancerous diseases in dogs, horses, and cats. Follow-up evaluation on 52 animals revealed an overall "no recurrence" rate of 61%. Among the animals with no recurrence were 12 of 17 with cutaneous lesions and 5 of 8 (horses) with sarcoids. Seven of 10 dogs with anal fistulas healed after cryosurgery, but 2 had recurrence of the disease. Treatment of invasive neoplasms of the oral and nasal cavities was not successful. Side effects and complications were minimal.


Myodegeneration and suspected selenium/vitamin E deficiency in horses. The clinical, macroscopic, and microscopic features of 10 isolated cases of myodegeneration in foals were compared. Low values for selenium and vitamin E content were found in the hay and oats from one breeding stable. Serum selenium concentrations in mares at this stable were also low. Creatinine phosphokinase and serum glutamic oxaloacetic transaminase activities were increased in 2 young foals at this stable; in 1 of these foals, both enzymatic activities were markedly reduced after treatment with vitamin E and selenium. Nutritional myodegeneration was suggested as a diagnosis in this stable, on the basis of the histologic findings, feed analyses, serum selenium values, response to treatment, and enzymatic determinations. Nine other isolated cases of nutritional myodegeneration were tentatively diagnosed on the basis of macroscopic and microscopic findings and the young age of the animal. The gross lesions included pale areas in the myocardium and skeletal muscle masses. Histologically, lesions were characterized by fragmentation and hyaline and granular changes in swollen muscle fibers in widely distributed skeletal muscle masses.


Necrotizing myelopathy secondary to embolization of herniated intervertebral disk material in the dog. Seven dogs (3 Great Danes, 2 German Shepherd Dogs, 1 Weimaraner, and 1 Boxer) ranging in age from 1 1/2 to 9 years were examined because of acute neurologic signs involving the limbs. All dogs were nonambulatory--3 tetraparetic and 4 paraparetic. In each case, treatment was unsuccessful or not advised, and each dog was euthanatized. Necropsy revealed hemorrhagic infarcts of the gray and white matter as a result of fibrocartilaginous embolization in leptomeningeal and parenchymal vessels of the spinal cord. The emboli were derived from disk material herniated into the vertebral venous sinuses.


Culture method for detection of Salmonella in dried active yeast: collaborative study. A method for detecting Salmonella in dried active yeast was subjected to collaborative study. This method employs trypticase soy broth as the pre-enrichment medium, a sample-to-broth ratio of 1:10, and subsequent transfers to lauryl sulfate tryptose broth and tetrathionate before streaking onto selective agars. Each collaborating analyst received ten 25 g samples of dried active yeast. Duplicate 25 g samples were each inoculated with Salmonella oranienburg at a low level (28 cells) and a high level (107 cells). Similarly, duplicate 25 g samples were each inoculated with S. senftenberg at a low level (30 cells) and a high level (114 cells). The remaining 2 of 10 samples were not inoculated. Results from 12 of 13 collaborators were evaluated. Only 2 (8.2%) of the 24 low level S. oranienburg samples were reported incorrectly as negative. Twelve of the analysts detected S. senftenberg at both levels and S. oranienburg at the high level in the inoculated samples. Results from 12 collaborators used in the final evaluation show that 117 of 119 (98.3%) collaborative determinations are in agreement. The official final action method for the detection and identification of Salmonella, 46.013-46.026, has been revised official first action to include applicability to dried active yeast.


Biological parameters and the acute LD50 test. The acute LD50 is an inadequate index of toxicity because the catastrophe of death obscures the mechanisms and sites of action. Thus, nonlethal toxicity is not evaluated, and the LD50 is not extrapolated to the possible effects of low level exposures for long periods of time. Collaborative studies should be undertaken which would develop methods to reasonably permit such evaluation and extrapolation.


Gas-liquid chromatography and infrared spectroscopy of resmethrin in nonaqueous aerosols. Two rapid and precise methods have been developed for the determination of resmethrin in nonaqueous aerosol formulations. The propellents are evaporated, the residue is dissolved in carbon disulfide, and the resulting solution is analyzed by gas-liquid chromatography or infrared spectroscopy. The accuracies of the methods were confirmed by a collaborative study.


Rapid screening procedure for the determination of preservatives in ground beef: sulfites, benzoates, sorbates, and ascorbates. A procedure is described for the examination of large numbers of ground beef samples for the 4 most commonly used preservatives. A single sample solution is prepared and aliquots are taken for the various tests. Sulfite is determined colorimetrically with acid-bleached prosaniline. Ascorbic acid is titrated with 2,6-dichloroindophenol. Benzoic and sorbic acids are measured by ultraviolet absorption. Negative samples are rapidly sorted out in this procedure and positive samples are completed for quantitative determination of the preservative. Recoveries are 95% for sodium sulfite, 103% for sodium benzoate, 90% for potassium sorbate, and 81% expected recovery for sodium ascorbate. The limit of detection is 0.005% for potassium sorbate, and 0.001% for the 3 other perservatives.


Nitrite in meat products determined by fluorescence quenching of p-aminobenzoate ion. A direct fluorometric method is presented for determining nitrites in meat products by means of quenching. The extracted sodium nitrite is consumed in a diazotization reaction with a measured excess of the fluorescent reagent p-aminobenzoic acid (PABA) in boiling water and at pH less than or equal to 1.4. The amount of decrease in fluorescence (quenching) of PABA, in alkaline medium (pH 11.0) with excitation at 265 nm and fluorescence at 339 nm, is directly related to the amount of nitrite present. The slope for that standard curve is 1% decrease in relative fluorescence intensity per 2.76 ppm NaNO2. Results obtained for a series of 20 meat samples analyzed by this fluorometric method are in good agreement with results obtained by a colorimetric method with an average difference of +/- 6.1 ppm NaNO2.


Colorimetric assay of reserpine in formulations and biological fluids. Two colorimetric methods are presented for determining reserpine. In the first method, an iron hydroxamate complex is formed through the ester group in position 16 in the reserpine molecule. The color is measured at 535 nm (0.5-6 mg/25 ml). This method is useful for routine and control analyses of reserpine formulations. In the second method the tertiary amino group of reserpine reacts with 2% citric acid in acetic anhydride to form a red-violet complex which is measured at 505 nm (5-400 mug/10 ml). This method could be useful in measuring trace amounts of reserpine present in biological fluids.


Colorimetric determination of aconitine in galenicals and in biological samples. A sensitive method is presented for determining aconitine. Aconitine is complexed with Co2+, the aconitine-cobalt complex is extracted with chloroform, and the absorbance is measured at 320 nm. The sensitivity of the method ranged between 0.06 and 3 mg/25 ml, and the color was stable for 6 hr. The method was successfully applied for the quantitative determination of aconitine in animal tissues.


Ion-pair extraction method for quantitation of a bisquaternary ammonium compound, pancuronium bromide. Pancuronium bromide (PCBr), a neuro-muscular blocking agent, was determined quantitatively in aqueous solution by ion-pair extraction. Separate determination of PCBr and degradation products was possible after thin layer chromatography. The procedure was developed by using a theoretical approach. Favorable conditions were calculated from the ion-pair extraction constant. The drug was determined with bromothymol blue at pH 9.0, using one extraction in the direct procedure and 2 successive extractions in the combined elution-extraction process after thin layer chromatography. In the direct method, 0.100 mg PCBr was determined with a reproducibility of +/- 1.0%.


Collaborative study of the spectrophotometric determination of procainamide hydrochloride. The USP analysis for procainamide-HCl is titrimetric and relatively nonspecific, capsule and tablet dyes may interfere, and the method is not applicable to coated tablets. In the spectrophotofluorometric method the sample deteriorates when exposed to  a xenon source. In the ultraviolet spectrophotometric method reported here, the sample is dispersed in acid medium, possible interferences are extracted in chloroform, base is added, procainamide is extracted in chloroform, the residue is dissolved in sodium hydroxide, the compound is measured by absorption at 272 nm and comparison with a standard. Recoveries of standards added to capsule, tablet, and injection composites ranged from 99.3 to 102%. Twelve collaborators reported duplicate assay results for all 3 dosage forms with per cent standard deviations for 5 samples ranging from 1.01 to 1.27%. The method has been adopted as official first action.


Chemical confirmation of diethylstillbestrol residues in beef livers. A simple chemical technique was developed to confirm the presence of diethylstillbestrol (DES) residues in beef tissues at 2 ppb. The DES-trifluoroacetate (TFA) from the previously published method is hydrolyzed in water-methanol at 55 degrees C for 20 min to free DES which is then extracted into benzene. Trimethylamine and a small amount of heptaafluorobutyric (HFB) anhydride are added to effect the smooth conversion of DES to its di-HFB at either room temperature or 60 degrees C. DES-HFB is determined by gas-liquid chromatography with electron capture detection on a 6' x 4 mm id column of 3% OV-210 at 190 degrees C. This procedure yields 2 peaks for DES-HFB (retention times 2.7 and 4.8 min for the cis and trans, respectively) which are resolved from the 2 DES-TFA peaks (retention times 2.3 and 3.3 min for cis and trans, respectively). The sensitivity of detection of DES-HFB is increased by a factor of 4-5 over that for DES-TFA. This chemical technique was successfully applied to purified extracts of beef liver fortified with DES at 2-10 ppb with recoveries from 60 to 110%.


Gas-liquid chromatographic determination of diethylstilbestrol at low levels in mixed feeds. A gas-liquid chromatographic method for the determination of diethylstilbestrol (DES) at 2 ppb in mixed feeds and ingredients is presented. The DES is extracted into ethanol, the solvent is evaporated, and the residue is redissolved in chloroform. The extract is purified by washing the chloroform solution with carbonate buffer and transferring the DES to sodium hydroxide. The sodium hydroxide is washed with chloroform, the pH is adjusted to 10.3, and the DES is transferred to chloroform. The extract is derivatized with hepatafluorobutyric anhydride, chromatographed on an SE-30 glass column, and measured with a 3H electron capture detector. The method has been used for routine testing of a wide variety of feeds and ingredients.


Collaborative study of the extraction of light filth from canned crabmeat. Canned carbmeat is boiled with mineral oil in a Wildman trap flask. The trappings are transferred to a Corning percolator and cycled at least 3 times. Average recoveries from 7 collaborators were 82.7% for rodent hairs and 98.0% for flies. The proposed method has been adopted as official first action.


Collaborative study of a method for the extraction of light filth from ground mace and ground caraway seed. A new method has been developed for the extraction of light filth from ground mace and ground caraway seed. The method uses a 2-step chloroform-isopropanol pretreatment followed by separation of the light filth from 40% isopropanol with mineral oil. The collaborative study resulted in clean filter papers with more reproducible recoveries of light filth elements than the official first action method, 44.116 (b). The method has been adopted as official first action.


Colorimetric determination of zirconium in antiperspirant aerosols. A rapid direct dilution procedure for the estimation of soluble zirconium and a fusion procedure for the determination of total zirconium (soluble and insoluble forms) in cream base concentrates prepared from antiperspirant aerosols are described. The direct dilution procedure involves extraction of soluble zirconium with HCl (55 + 45). The filtered extract is reacted with alizarin red S to form a stable colored complex which is measured spectrophotometrically. The fusion procedure involves ashing the aerosol concentrate followed by fusion of the ash with potassium pyrosulfate to form an acid-soluble melt. Zirconium is precipitated from solution as the hydroxide and washed to eliminate interfering ions, particularly sulfate. After redissolving in HCl (55 + 45) and reacting with alizarin red S, total zirconium is measured. Zirconyl chloride octahydrate, assayed gravimetrically by hydroxide precipitation and conversion to the oxide, is used as the zirconium reference standard. Concentration range of zirconium measured was 200-500 mug/100 ml. Recoveries of standard zirconium added to commercial aerosols labeled to contain aluminum and zirconyl hydroxychlorides ranged from 97 to 101% by the fusion procedure. Analysis of these aerosols by direct dilution gave generally slightly lower results than by fusion. It is recommended that the procedures be collaboratively studied after further testing of their general applicability to a variety of drugs and cosmetics.


Gas-liquid chromatographic determination of 3-trifluoromethyl-4-nitrophenol in natural waters. A procedure for the analysis of 3-trifluoromethyl-4-nitrophenol (TFM) in natural waters is described. The lampricide is extracted from acidified water samples on the macroreticular resin XAD-7 and eluted from the column with ethyl ether. The ether extract is dried, concentrated, and partitioned with potassium carbonate. TFM is acetylated in the aqueous alkaline solution and the acetate derivative is extracted into benzene for analysis by electron capture gas-liquid chromatography. Recoveries of TFM from natural waters exceeded 90% and as little as 0.01 mug TFM can be quantitated in a 1 L sample.


Selenium in foods: evaluation of atomic absorption spectrometric techniques involving hydrogen selenide generation and carbon furnace atomization. The performance of hydrogen selenide generation- and carbon furnace atomization-atomic absorption spectrometry, with a semiautomated trace metal accessory and a carbon rod atomizer, respectively, was evaluated for the determination of selenium in foods. Samples were digested with nitric, perchloric, and sulfuric acids for both procedures. Hydrogen selenide was generated with stannous chloride/potassium iodide/zinc from 20 ml aliquots in a hydrochloric-sulfuric acid medium and directed into an argon-hydrogen-entrained air flame. Sample matrix interferences in the carbon furnace technique were minimized by isolating selenium by precipitation with ascorbic acid and redissolution in nitric-perchloric acid prior to taking 5 mul aliquots for estimation; precision was significantly improved by incorporating 5000 mug nickel/ml into analytical solutions. For the hydrogen selenide and carbon furnace techniques, respectively, the following data were obtained for untreated standard solutions: sensitivity, 0.13 and 10.0 ng/ml; absolute sensitivity, 2.6 and 0.05 ng; detection limit, 0.4 and 90 ng/ml; absolute detection limit, 7 and 0.45 ng. The detection limit and absolute detection limit for samples were 2.5 ng/ml and 50 ng, respectively, for the hydrogen selenide method, and 25 ng/ml and 0.13 ng, respectively, for the carbon furnace method. Taking into consideration these figures and the practical aspects of both methods, the overall performance of the hydrogen selenide method was superior.


Studies on the subsite structure of amylases. IV. Tryptophan residues of glucoamylase from Rhizopus niveus studied by chemical modification with N-bromosuccinimide. Chemical modification of glucoamylase [EC 3.2.1.3] from Rhizopus niveus by N-bromosuccinimide was carried out to investigate the role of tryptophan residues in the enzyme-catalyzed reaction and their location in the enzyme subsites. Of the ten tryptophan residues of the enzyme four could be modified. The two more reactive residues were confirmed not be essential for the catalytic activity for the hydrolysis of maltodextrin and phenyl alpha-maltoside. Complete loss of the catalytic activity, however, was brought about by modifying the two less reactive residues, and the modification of these residues was prevented by the substrates. The characteristic difference spectrum produced by maltose (7) disappeared in parallel with the loss of the catalytic activity. These results suggest that the tryptophan residue(s) responsible for the maltose-induced difference spectrum may be located at one of the subsite near the catalytic site and plays an important role in the catalytic activity of the enzyme.


Dispersion of fibrin using cationic detergent. By treating fibrin with cationic detergent in a medium containing 5M urea, a fibrincationic detergent complex was formed. The complex was soluble in distilled water, and was observed to be in a dispersed state by electron microscopy. The complex was precipitated and resolubilized in the presence of salt. This behavior of the complex was due to adsorption of the salt anions onto the complex. When an aqueous solution of the complex was incubated with fresh serum, the complex soon aggregated and then was converted into a firm clot which was not soluble in distilled water.


Biochemical studies of pigments from a pathogenic fungus Microsporum cookei. III. Comparison of the effects of xanthomegnin and O-methylxanthomegnin on the oxidative phosphorylation of rat liver mitochondria. The effects of xanthomegnin and O-methylxanthomegnin on the oxidative phosphorylation of rat liver mitochondria were compared. The n-octanol/water partition coefficient of xanthomegnin was markedly enhanced by O-methylation, but O-methylation of xanthomegnin reduced the uncoupling effect on the respiratory system of mitochondria. Analogous results were obtained in the uncoupling action of 5-hydroxy-1, 4-naphthoquinone (juglone) and 5-methoxy-1, 4-naphthoquinone (O-methyljuglone) on the oxidative phosphorylation of rat liver mitochondria. These data indicate that the phenolic hydroxyl groups of xanthomegnin might contribute to its uncoupling action on the oxidative phosphorylation of mitochondria. Bovine serum albumin (BSA) improved the efficiency of oxidative phosphorylation of mitochondria which were uncoupled by xanthomegnin. Spectroscopic observations revealed that xanthomegnin interacted with BSA by means of hydrophobic and ionic forces but O-methylxanthomegnin showed only hydrophobic interaction. Analogous interactions between mitochondria and xanthomegnin or O-methylxanthomegnin were observed. These results indicate that the uncoupling action of xanthomegnin on the respiratory system in mitochondria might involve ionic interaction of xanthomegnin with cationic residues in the hydrophobic region of mitochondrial membrane proteins.


Pyruvate kinase isozymes in various tissues of rat, and increase of spleen-type pyruvate kinase in liver by injecting chromatins from spleen and tumor. Pyruvate kinase [EC 2.7.1.40] in various tissues of rats was separable into seven kinds of pI-isozymes by isoelectric separation with Ampholine carrier ampholytes; pI 5.4-isozyme, pI 5.6-isozyme, pI 6.2-isozyme (2 kinds), pI 6.6-isozyme, pI 7.4-isozyme, and pI 7.8-isozyme. Some of these pI-isozymes contained bound fructose 1,6-diphosphate (FDP). The bound FDP was completely dissociated when the pI-isozymes were salted out with ammonium sulfate. In the FDP-free form, pyruvate kinase was classified into three types, liver-type (type L) of pI 6.2, muscle-type (type M) of pI 7.4, and spleen-type (type M2) of pI 7.8. The liver-type isoenzyme had two kinds of FDP-binding sites; the pI 5.6-isozyme and pI 5.4-isozyme were obtained when one and two kinds of sites were bound with FDP, respectively. The association and dissociation of FDP at both sites were reversible in the presence and absence of 0.15 M KC1 (high ionic strength). The muscle-type isoenzyme had no FDP-binding site. The spleen-type isoenzyme had two kinds of FDP-binding sites, like the liver-type isoenzyme. When the ionic strength of solutions containing the enzyme and FDP was sufficiently low, one and two kinds of the sites could bind with FDP, converting the enzyme into pI 6.6-isozyme and pI 6.2-isozyme, respectively. FDP bound with one kind of site (the 2nd site) was easily dissociable, but FDP bound with the other kind of site (the 1st site) was not. Provided that the 1st site carried bound FDP, the 2nd site was associable at high ionic strength. The liver-type isoenzyme free of FDP and the spleen-type isoenzyme bound with FDP at both sites had similar pI values of 6.2 and were not separable by isoelectric separation. Some properties of these pI-isozymes were compared. When Rhodamine sarcoma was transplanted in rats, the content of spleen-type isoenzyme in the livers increased. When rats were injected with chromatin prepared from either Rhodamine sarcoma or spleen, the content of spleen-type isoenzyme in the livers again increased. This was not observed on the injection of chromatin prepared from liver, indicating that the factor capable of controlling the gene expression was present in chromatins of sarcoma and spleen but barely or not at all in chromatin of liver.


Immunochemical studies on fluctuation of phenylalanine ammonia-lyase activity in sweet potato in response to cut injury. Antibody toward phenylalanine ammonia-lyase (PAL) [EC 4.3.1.5] was obtained by immunization of a rabbit with highly purified PAL. The antibody reacted specifically with RAL, as demonstrated by the Ouchterlony double diffusion test, immunoelectrophoresis, and SDS polyacrylamide gel electrophoresis of the immunoprecipitate. Experiments using anti-PAL showed that PAL was not present in fresh sweet potato tissue, but appeared in response to cut injury, reaching a maximum, and then decreasing, in parallel with PAL activity. The results suggest that the development of PAL activity was due to de novo synthesis of PAL and that the decrease of PAL activity after reaching a maximum was due to proteolytic degradation of PAL.


Molecular-size-dependent degradation of liver cytosolic proteins in vitro. Degradation of rat liver cytosolic proteins at a neutral pH in the presence of 0.1% SDS was demonstrated by SDS-acrylamide gel electrophoresis. This proteolysis in vitro mimics molecular-size-dependent proteolysis in vivo; larger proteins were degraded more rapidly than smaller ones. Evidence is presented that the proteolysis is not due to contaminating lysosomal cathepsins in the cytosol.


Identification of tryptophan 62 as an ozonization-sensitive residue in hen egg-white lysozyme. The position of a single N'-formylkynurenine residue in ozone-inactivated hen egg-white lysozyme [EC 3.2.1.17] was determined by two methods. One involved identification of an amino-terminus of the C-peptide obtained by selective cleavage with hydrazine of the kynurenyl peptide linkage in oxidized lysozyme. The other was to analyze a tryptic peptide containing kynurenine in the modified enzyme. Both methods showed that tryptophan 62 in lysozyme was so sensitive to ozone as to be selectively oxidized to N'-formylkynurenine with concomitant loss of the lytic activity.


Enzyme coupled immunoassay of insulin using a novel coupling reagent. A novel coupling reagent, meta-maleimidobenzoyl N-hydroxysuccinimide ester was synthesized. Using this reagent, insulin was conjugated very easily with beta-D-galactosidase [EC 3.2.1.23] in neutral, aqueous solution. No reduction of the enzyme activity was observed during the coupling procedure. The competitive bindings of the conjugate and insulin to anti-insulin serum were tested. The results indicated that the conjugate has enough immune reactivity for use in enzyme coupled immunoassay. Using this assay 20-800 pg of insulin were detectable.


Studies on an alpha-amylase from a thermophilic bacterium. I. Purification and characterization. An amylase-producing thermophilic bacterium was isolated from a Japanese hot spring. The thermophilic cells were gram-negative, nonsporulating, nonpigmented rods and were motile with flagella. Alpha-Amylase [EC 3.2.1.1) purified from the thermophile was studied. The enzyme was more heat-stable than the corresponding enzymes from mesophilic sources, and 50% loss of activity was observed after incubation for 1 hr at 90 degrees. The thermophilic enzyme resembled the corresponding mesophilic enzymes in many respects, such as kinetic parameters, physicochemical properties, and amino acid composition. The molecular weight of the enzyme was 50,000 and the enzyme contained 2 moles of half-cystine residues per mole of protein, but there were no disulfide crosslinkages. The alpha-helix content of the enzyme was estimated to be about 20% from CD spectra, a value similar to those of other alpha-amylases. The isoelectric point of the enzyme was at pH 9.2.


Limited hydrolysis of the polypeptide chain elongation factor Tu by trypsin. Isolation and characterization of the polypeptide fragments. The digestion of EF-Tu-GDP (or EF-Tu-GTP) by trypsin [EC 3.4.21.4] under native conditions has been shown to proceed through two different and characteristic stages. 1. In the first phase, the protein is transformed into a fragment (Fragment A) with a molecular weight of 39,000 by exposure to trypsin for a relatively short period of time. Fragment A is unable to catalyze the binding of aminoacyl-tRNA to ribosomes. The ability to promote two partial steps of the binding reaction, i.e., formation of the aminoacyl-tRNA-EF-Tu-GTP ternary complex as well as the methanol-stimulated, ribosome dependent GTPase reaction, was rapidly destroyed. On the other hand, the ability to interact with guanine nucleotides as well as EF-Ts survived well during prolonged digestion. 2. In the second phase of digestion, a nick is introduced in Fragment A to yield two subfragments (Fragments B and C). These two fragments exist as a hybrid molecule which migrates as a single peak on a Sephadex G-75 column, and which dissociates into Fragments B and C only in the presence of 6 M guanidine hydrochloride or 5% sodium dodecyl sulfate. The molecular weights of Fragments B and C, as determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate, were 22,000 and 12,000 respectively. The hybrid molecule still retained one mole of bound guanine nucleotide and was resistant to further tryptic digestion. 3. Three sulfhydryl groups of EF-Tu were found to be present in Fragment B, both by amino acid analysis of the purified fragments and also by electrophoresis of tryptic digests labeled with N-ethyl[14C]maleimide. 4. The tryptic digestion of EF-Tu-GDP (or EF-Tu-GTP) labeled with N-(1-anilinonaphthyl-4)maleimide (ANM) at SH2 (the second SH), caused a 30% decrease in the fluorescence emission during the first rapid phase of digestion. This indicates that destruction of the hydrophobic environment near SH2 of EF-Tu occurred in the early phase of tryptic digestion. 5. The kinetic studies on the reaction of ANM with EF-Tu before and after tryptic digestion indicated that both Fragment A and the hybrid molecule reacted with ANM in the presence of GTP three to four times more rapidly than in the presence of GDP. Thus, it appears that the ability to induce conformational transition near SH2 by a change of nucleotide ligands is still retained in the hybrid molecule consisting of Fragments B and C.


Surgery for rheumatic tricuspid valve disease in children. Rheumatic valvular disease in children is common in underprivileged countries and often damages the tricuspid valve (in addition to the mitral and aortic valves). Fifteen children aged 12 to 16 years underwent tricuspid valve surgery. Fourteen were graded as Class IV disability; five were operated during rheumatic activity. The tricuspid valve was replaced in ten patients, four had annuloplastic procedures and one underwent tricuspid commissurotomy. There was one operative death and four late deaths. Eight of the ten long-term survivors are in Class I and the remainder in Class II functional ability. It may be concluded that in children who can be protected from additional bouts of carditis and thromboembolism, the surgical treatment of advanced multivalvular disease including the tricuspid valve is most rewarding, and dramatic clinical improvement with return to normal or near-normal hemodynamics may be expected.


Suppression of the progress of necrosis after coronary artery ligation in the dog by pharmacologic interventions. A study was carried out of a therapy supporting the anaerobic glycolysis and coronary perfusion of ischemic myocardium and preserving its potassium and magnesium contents, which consisted in combined administration of hyaluronidase, glucose, insulin, Tris, methoxamine, and potassium and magnesium aspartate. The drugs were administered to Beagle dogs between 30 minutes and 20 hours after the ligation of the left anterior descending coronary artery. The size of infarction was determined by the Nachlas method, which is based on the detection of activities of dehydrogenases in heart slices. Treated animals showed a reduced infarction size (p less than 0.001). The evidence of the favourable effect of the therapy used was brought also by hemodynamic measurements. The heart rate was slower (p less than 0.02) and the mean arterial blood pressure was higher (p less than 0.001) in treated animals than in control ones (as evaluated at the end of the experimental period). Significant correlation between the infarction size and the heart rate on the one hand and the mean arterial pressure on the other hand was found (r = 0.59, p less than 0.01; r=--0.47, p less than 0.05, respectively).


The role of pulmonary embolectomy in venous thromboembolism. Embolectomy was performed by the Trendelenburg method on one patient and with cardiopulmonary bypass on 10 patients during the period 1961 to 1975. The use of cardiopulmonary bypass permitted preoperative resuscitation, cardiorespiratory support during the operation, complete embolectomies to be performed and resulted in the survival of 4 of the 10 patients. There were 5 patients who suffered cardiac arrest prior to embolectomy. Three died intraoperatively, of which two died of left ventricular failure, and two others died postoperatively of brain damage indicating the need to proceed rapidly with the accurate diagnosis and treatment of massive pulmonary embolism. Following embolectomy, partial interruption of the inferior vena cava was performed and prevented recurrent pulmonary emboli and significant post-thrombotic sequelae in four patients. Another patient underwent caval ligation with significant sequelae.


Kinetics and regulation of synthesis of the major polypeptides of thylakoid membranes in Chlamydomonas reinhardtii y-1 at elevated temperatures. Etiolated cells of Chlamydomonas reinhardtii y-1 exhibit rapid and linear initial kinetics of greening when exposed to light at 38 degrees C. The initial rate of chlorophyll accumulation under these conditions is greater than the maximal rate during greening at 25 degrees C. Synthesis of the major polypeptides of thylakoid membranes within intact cells was assayed during greening by the incorporation of [3H]leucine and the subsequent electrophoresis of total cellular protein on polyacrylamide gels in the presence of sodium dodecyl sulfate. At 38 degrees C the major membrane polypeptides (about 28,000 and 24,000 daltons in mass) were synthesized at a linear rate after exposure of the cells to light, with no evidence of a lag period. A 1-2 h preincubation in the dark at the higher temperature was necessary to achieve linear initial kinetics. Actinomycin D inhibited synthesis of the membrane polypeptides if added at the beginning of a 2 h dark preincubation, but not when added near the end. These results suggested that transcription of the messenger RNA for the membrane polypeptides occurred during the dark period at 38 degrees C. But the major membrane polypeptides were not made by y-1 cells in the dark. The wavelengths of light most effective in eliciting production of the membrane polypeptides were the same as those allowing chlorophyll synthesis. In contrast, wild type cells, which are capable of chlorophyll synthesis in the dark, also make the membrane polypeptides in the dark. The data indicate that at elevated temperatures synthesis of the major thylakoid membrane polypeptides is controlled at a posttranscriptional step, and that this reaction normally proceeds only under conditions which permit reduction of protochlorophyllide.