Cholesterol metabolism in diabetes. I. The effect of diabetic control on sterol balance.

To evaluate the effect of diabetic control on sterol balance, five subjects (one with fasting chylomicronemia) were studied when they had little control of blood glucose (period I) and, continuously, when increased insulin dosage improved diabetic control (period II). The four subjects with no chylomicronemia showed a diminished fecal bile acid (FBA) excretion. Although fecal neutral steroid excretion increased variably, the total steroid balance was unchanged. The results support the concept that good control of diabetes shifts the fecal steroid excretion towards diminished FBA, but steroid balance methods did not reveal an effect of insulin on total steroid balance.


Hypomagnesemia, a risk factor in diabetic retinopathy.

The serum magnesium concentration was measured in 71 insulin-treated diabetic outpatients who had had the disease for 10 to 20 years. The patients were divided into two subgroups according to the severity of their retinopathy. As a whole the patients exhibited a definite hypomagnesemia (P less than 0.001) that was most pronounced in the subgroup having the severest degree of retinopathy (P less than 0.01). The subgroups were comparable regarding known risk factors implicated in diabetic retinopathy. Thus, hypomagnesemia appears to be an additional risk factor in the development and progress of this complication.


Protective effects of ketogenic diets on signs of hypoglycemia.

The effects of diet-induced ketosis on the signs of hypoglycemia were investigated. Lard, medium chain triglycerides, or 1,3-butylene glycol comprised 43% of the diet fed to mice. The diet containing lard or medium chain triglycerides greatly protected the animals from the manifestations of acute insulin-induced hypoglycemia. Furthermore, both diets protected the animals from the effects of repeated insulin injections (every eight hours) for 10 days. In contrast, 1,3-butylene glycol had no protective effects. These experiments suggest that ketogenic diets may be of value in the treatment of recurrent hypoglycemic conditions.


Immunopathology of juvenile-onset diabetes mellitus. I. IgA deficiency and juvenile diabetes.

There is an increased prevalence (P less than 0.001) of IgA deficiency in children with juvenile-onset insulin-dependent diabetes mellitus (9/366) but not in adults with insulin-dependent diabetes (0/421). The juvenile diabetics with IgA deficiency have other immune-associated diseases, such as thyroiditis and chronic active hepatitis, and have a history of infections. Four of the nine IgA-deficient diabetics we studied have autoantibodies to endocrine organs. Seven of eight have the HLA-B8, a proportion significantly (P less than 0.05) greater than control populations. Based on the clinical findings of IgA deficiency and multiple autoantibodies in patients with ataxia-telangiectasia and chronic mucocutaneous candidiasis, diseases associated with thymus deficiency, we suspect that thymus deficiency and autoimmunity may play a role in the pathogenesis of some types of juvenile-onset diabetes mellitus. In addition, an excess morbidity of the IgA-deficient juvenile diabetic population may explain the lack of IgA deficiency in older insulin-dependent diabetic individuals.


Antibodies to nucleic acids in juvenile-onset diabetes.

Antibodies to single stranded (SS-) and double stranded (DS-) DNA and RNA were determined by a passive microhemagglutination assay in sera from 80 children with juvenile-onset diabetes mellitus (JDM) and 129 children with asthma. The latter group was chosen for comparison with the JDM group because of their increased susceptibility to viral infection and the nonautoimmune nature of the disease. We found that JDM patients had increased titers of antibodies to SS-DNA (61.3%), synthetic polyadenylicpolyuridylic acid (Poly A-U) (78.8%), synthetic polyinosinicpolycytidylic acid (Poly I-C) (62.5%), and DS-RNA of statolon virus (51.3%) and reovirus (27.3%), respectively, in contrast to asthmatics (15.5, 34.9, 3.9, 20.2, and 2.3%, respectively) or to healthy controls. The difference of the incidence of antibodies among the groups is statistically significant (P less than 0.001). Presence of SS-DNA antibody found in two thirds of cases of JDM further support the increased prevalence of autoimmune phenomenon in that disease. Furthermore, the increased prevalence of DS-RNA antibodies in patients with JDM, found especially in cases of recent onset, is suggestive of an active immune response against the underlying viral replications that may have led to beta cell injury in islets of pancreas.


Assessment of methods for estimating autonomic nervous control of the heart in patients with diabetes mellitus.

A comparison of the cardiac responses to a variety of maneuvers that modify cardiac vagal tone was made in nondiabetic and diabetic subjects. We concluded that assessment of heart rate variability by reference to standard deviation of R-R intervals is unhelpful; that a single deep breath is a more potent stimulus for heart rate change than repeated deep breaths in diabetic subjects; and that measurement of this response together with the bradycardia evoked by the Valsalva maneuver obviate the need to perform invasive investigations, such as the estimation of baroreflex sensitivity, or tedious procedures, such as apneic face immersion. In a small number of subjects, heart responses to lower body, negative pressure provided information not forthcoming from other tests.


Comparison of the early time courses of the release of insulin that follow injections of tetragastrin, tolbutamide, xylitol, and glucose into the pancreatic artery of dogs.

The early time courses of insulin release were studied by injecting insulinotropic substances directly into a dog's pancreatic artery. Blood samples from the pancreatic vein were collected every five seconds continuously over 90 seconds and were assayed for their insulin concentrations. Injections were repeated two to five times, with intervals of 30 minutes. Insulin release was stimulated within one minute after injection of each of tetragastrin, tolbutamide, xylitol, and glucose, but the time courses of the release of insulin were different with different stimulants: Tetragastrin and tolbutamide increased insulin release faster than did glucose; xylitol produced a slower insulin release than did glucose. The slower insulin-releasing effects of glucose and xylitol than the other agents would be compatible with the theory that their metabolism is required to cause release of insulin, but it is also possible that the glucoreceptor mechanism may require a longer lag time than the other receptor mechanisms for the perception and transfer of the signal to release insulin.


Aspirin stimulates insulin and glucagon secretion and increases glucose tolerance in normal and diabetic subjects.

Normal subjects and patients with adult-onset diabetes received 10 gm. of aspirin in four days. On the fourth day, the fasting serum glucose and the glucose response to oral glucose were decreased in both groups. These changes were associated with increased levels of serum insulin and pancreatic glucagon, although the glucagon responses to oral glucose were unchanged. In the diabetic patients, aspirin therapy was followed by a decreased glucose response to I.V. glucose and by the appearance of an early insulin peak, which could not be demonstrated before treatment. Aspirin did not affect the I.V. glucose tolerance in normal subjects, although it did enhance the early insulin peak. A decrease in the fasting levels of free fatty acids was noted in both groups, whereas the fasting level of triglycerides decreased only in the diabetic patients. Cholesterolemia did not change in either group. A few preliminary observations indicate that, in normal subjects, ibuprofen and ketoprofen, two other presumed prostaglandin inhibitors, did not affect fasting glycemia, glucose tolerance, or the insulin response to glucose. No changes were noted after the administration of placebo.


Diabetic pregnancy: management of diabetes on the day of delivery.

An insulin regimen for management of the insulin dependent diabetic on the day of delivery is described. Pregnant diabetics were fasted on the day of delivery and infused with 10g glucose per hour throughout labour and after delivery until normal eating was resumed. In the morning a fixed dose of intermediate acting insulin (NPH 24 units) was administered subcutaneously at 8:00 A.M. This dose was found suitable for women whose insulin requirements during pregnancy ranged from 60 to 250 units/day. The regimen worked satisfactorily both under close study conditions and also when used routinely and was equally applicable to the diabetic scheduled for induction or for elective Caesarian section. It was associated with an 8% incidence of foetal distress amongst women who were induced. Neonatal hypoglycaemia affected 19% of all infants, the incidence rising from less than 10% amongst infants of women with the best control to 41% amongst infants of women with the worst control. No cases of maternal hypoglycaemia during or after delivery were recorded.


The metabolic response to norepinephrine in normal versus diabetic man.

Norepinephrine was infused for 60 minutes in high physiological concentration (0.08 microgram/kg/min) into seven insulin dependent diabetic subjects with no demonstrable endogenous insulin secretion and into seven normal subjects. Insulin dependent diabetic subjects had a stable, free insulin concentration of 23 +/- 5 microunits/ml which was unaffected by norepinephrine infusion. In the normal subjects, norepinephrine induced an initial inhibition of insulin secretion which lasted for approximately 20 minutes. Norepinephrine infusion caused a rapid increase in both ketone body and glucose concentrations but this response did not differ between the two groups. In contrast, plasma nonesterified fatty acid and triglyceride concentrations were increased significantly more in the normal than in the diabetic subjects. The increase in plasma glucagon concentrations was similar in the two groups of subjects. The cause of the differential metabolic response to norepinephrine between the normal and diabetic groups was not resolved, but may be related, at least in part, to suppression of endogenous insulin secretion in the normal subjects.


HLA-typing in juvenile diabetics with and without positive family history and in families with one and two diabetic siblings.

HLA-typing was performed in two groups of juvenile-onset diabetics, one with (n = 58) and one without (n = 109) a family history of the disease. The association of this type of diabetes with certain HLA antigens (excess of B8 and B15, shortage of B7) was confirmed. No heterogeneities could be established between the two groups. This suggests that the aetiologic basis in single and familial cases of juvenile diabetes is the same. The hypothesis, that the B8 associated gene is more penetrant than the B15 associated gene, cannot be confirmed. Haplotypes were determined in families with one and two diabetic siblings. The findings of high haplotype concordance among diabetic siblings was confirmed: concordance of 2, 1 and 0 haplotypes in 7, 5 and 3 pairs respectively. There was a low degree of haplotype concordance between diabetics and nonaffected siblings in the families with two diabetics: 2, 1, and 0 haplotypes in 2, 8 and 6 pairs respectively. This led to the hypothesis of negative selection against these HLA-linked "diabetogenic" genes. This tendency was not, however, observed in families with only one diabetic. The report of a high recombination rate in families with juvenile diabetics could not be confirmed.


Cardiovascular effects of insulin: plasma volume changes in diabetics.

The mechanism by which insulin can alter the heart-rate and blood pressure of diabetics has been studied. Insulin decreased the plasma volume of 16 diabetics without complications by an average of 190 ml, a 6% change. Nine diabetics with severe autonomic neuropathy had no significant change in plasma volume after insulin. The basal plasma volume of autonomic neuropathy patients was smaller than that of the uncomplicated diabetics, perhaps accounting for the disparity observed between these two groups of diabetics. The decrease of plasma volume could thus account for the heart rate increase of uncomplicated diabetics, but not for the induction of hypotension in those with autonomic neuropathy.


Lack of gastrointestinal glucagon response to hypoglycaemia in depancreatized dogs.

Fasting (24 h) normal dogs and depancreatized dogs were injected intravenously with highly purified porcine insulin (Actrapid) in the doses of 0.2 U/kg and 0.5 U/kg, respectively. Blood glucose decreased from 152 +/- 41 (SEM) mg/100 ml to 39 +/- 7 mg/100 ml in the depancreatized dog and from 95 +/- 3 mg/100 ml to 42 +/- 4 mg/100 ml in the normal animal. Using a specific antiserum for "pancreatic" glucagon, the circulating level of glucagon immunoreactivity did not rise from the basal value of 247 +/- 31 pg/ml in the depancreatized group whereas it rose significantly from 223 +/- 24 pg/ml to 321 +/- 41 pg/ml in the normal group. In contrast intravenous infusion of 7 g of arginine increased "pancreatic" glucagon immunoreactivity in both groups. Thus, extrapancreatic glucagon of the pancreatic type does not respond to hypoglycaemia but to arginine infusion.


Dual action of mn++ upon the secretion of insulin and glucagon from the isolated, perfused canine pancreas. Possible interactions with ca++.

Since Mn++ apparently interferes with excitation-contraction coupling by both reducing inward movement of Ca++ across the cell membrane and by displacing Ca++ from an intracellular store, studies were performed in the isolated, perfused canine pancreas to elucidate the existence of a similar effect in stimulus-secretion coupling and to draw comparisons with the effect of Mg++, which antagonizes Ca++ at the cell membrane. The results show: 1. than Mn++ (0.05, 0.125, and 0.25 mmol/l) inhibits the release of insulin and glucagon in a dose dependent fashion during the first 3-4 min of infusion followed by a dose-dependent increase in hormone release, the 'escape phase'. 2. The inhibitory action of Mn++ (0.25 mmol/l) upon release of both hormones is progressively counteracted when perfusate calcium is increased from 0.7 to 1.3 to 5.0 mmol/l. 3. Mg++ (5 mmol/l) inhibits the release of both hormones with no sign of an 'escape phase'. 4. Mn++ (0.5 mmol/l) during calcium depletion causes a gradual stimulation of the release of both hormones. The dual action of Mn++ upon hormone release from the endocrine pancreas suggests that Mn++ can cross the cell membrane and can interfere with stimulus-secretion coupling both at the membrane level, by competitively inhibiting the Ca++ influx, and at some intracellular level by releasing calcium from an intracellular store.


Placental enzymes of glycolysis, gluconeogenesis and lipogenesis in the diabetic rat and in starvation. Comparison with maternal and foetal liver.

The activity of several regulatory enzymes representing the pathways of glycolysis, gluconeogenesis, NADPH generation and lipogenesis was measured in rat placenta maternal and foetal livers on the 20th day of gestation. Streptozotocin diabetes, induced on the 12th day of gestation, or 48 h of fasting did not induce adaptive changes in the activity of placental enzymes while producing a typical insulin deficiency pattern in maternal liver. Foetal liver enzyme activities were unaffected by fasting and in diabetes showed changes suggestive of foetal hyperinsulinaemia. A small increase was observed in the activity of placental pyruvate kinase and a small decrease in that of PEP carboxylase in diabetic and in glucocorticoid-treated rats; these changes were reciprocal to those in the maternal liver and were attributed to hyperglycaemia, as was the increase in placental glycogen. Lack of response to insulin deficiency and to other endocrine alterations indicates that placenta is not sensitive to stimuli which induce adaptive alterations in hepatic enzymes. The only consistent change found in placental enzyme activities was a decrease associated with gestational age.


Growth hormone enhances basement membrane thickening in experimental diabetes. A preliminary report.

Injection of porcine growth hormone (200 microgram) or saline 5 days a week for 16 to 20 weeks in streptozotocin-diabetic rats showed that compared to saline growth hormone produced a 2 1/2-fold larger increase in glomerular capillary basement membrane thickness (2p = 0.027). The possible significance of this effect of an elevated level of growth hormone for diabetic microangiopathy is discussed.


Spore differentiation by isolated Dictyostelium discoideum cells, triggered by prior cell contact.

Cells of D. discoideum mutant Fr-17 were allowed to form multicellular aggregates and develop undisturbed through 12 h (out of 18-required for terminal morphogenesis and cytodifferentiation). Then the cells were disaggregated and redeposited at densities so low as to preclude further sustained cell contacts and were incubated in the presence of certain diffusible metabolites. In this condition they transformed into spores and stalk cells with normal timing and, in the case of the spores, in proportions approaching those observed in undisturbed fruiting bodies. In contrast, mutant cells dispersed from aggregates at earlier stages or wild type cells dispersed from aggregates at any stage, remained as amoebae under the same conditions. The completion of cytodifferentiation by the isolated cells was found to require threshold concentrations of diffusible, dialysable metabolites. A part of this requirement could be satisfied by addition of 10 mM NH4Cl particularly in conjunction with an amino acid mixture. At least one metabolite, however, had to be supplied by feeder cells separated from the test cells by a dialysis membrane or by increasing the population density of the test cells themselves.


Stimulation of the clonal growth and differentiation of feeder layer dependent mouse embryonal carcinoma cells by beta-mercaptoethanol.

Embryonal carcinoma cells are the undetermined stem cells of teratocarcinomas. Supplementation of culture medium with beta-mercaptoethanol permits the feeder layer independent clonal growth and differentiation of normally feeder layer dependent embryonal carcinoma cell lines. Differentiated cells within the clones appeared less than 6 days after plating and were distinguished from embryonal carcinoma cells by their morphology, lack of histochemically detectable alkaline phosphatase activity, and secretion of plasminogen activator. Over 70% of the colonies secreted plasminogen activator after 6 days. In comparison, a different embryonal carcinoma cell line which has lost the potential for substantial differentiation, either in vitro or in vivo forms very few clones (less than 1%) which secrete plasminogen activator. Embryonal carcinoma cells derived from the rare clones which secrete plasminogen activator have the same frequency of production of plasminogen activator secreting colonies as the parental cell line.


Human lymphoblastoid cells in culture replicate immune information carried by xenogeneic RNA.

Immune RNA is obtained from lymphoid organs of immunized animals and is reputed to transfer immunological information. Human lymphoblastoid cells in culture, after incubation with sheep Immune RNA produce RNA (Ic-RNA) which carries the same immunological information as the inducing sheep preparation. This Ic-RNA produced in tissue culture is capable of converting 'naive' human lymphocytes to cytotoxic effector cells against tumour target cells, to the same extent as the Is-RNA preparation used for induction of the cell line. The sheep Immune RNA information is present and can be recovered from the lymphoblastoid cells for at least ten weeks after the induction. It is suggested that xenogeneic Immune RNA information is incorporated in a stable fashion by cultured human lymphoblastoid cells, and also that it is replicated during their own replication. This system could be used for studying the incorporation of information carried by exogenous RNA and it might provide insight into some mechanisms underlying the transfer and processing of immunological information.


A scanning electron microscope study of cell shape and cell appendages in the primitive streak region of the rat and chick embryo.

This report provides a scanning electron microscopic account of cell shapes and cell appendages that are observed in the primitive streak region of the rat and chick embryos. Epiblast cells become progressively elongated in the primitive streak region until flask cells predominate medially. The flask cells have a broad basal end directed toward the endoderm. In addition to fine filopodia, broad lamellipodia are found anchoring the flask cells to subjacent cells. The primary mesenchyme cells are at first round in shape and closely packed, but laterally are flattened and more dispersed. The mesenchyme cells are associated with each other by filopodia and lamellipodia and with the epiblast and endoderm by filopodia. On the basis of this description it is suggested that cell movement through the primitive streak occurs by cell extension, attachment by basal lamellipodia, and cell shortening that results in the movement of individual cells in a cell stream.


Some determinants of temporal experience in the retired and its correlates.

The effects of physical health status, attitude toward retirement, and social class on temporal experience were studied in 70 male Ss, aged 52--74. A semistructured interview was utilized, and a content analysis by independent raters was performed on the resulting interview material. In general, it was found that chronic illness had a differential effect on experience, depending upon social class, for certain temporal variables. Among the healthy retirees it was also found that willingness to retire interacted with social class, and that blue collar workers who had resisted retirement resembled the chronically ill in terms of affect and temporal experience. The possibility for adjustment in retirement was linked to variations in temporal experience, and implications were drawn for preretirement intervention with specific social class target populations. Finally, psychological and behavioral consequences of variations in temporal experience were discussed, and the possibility of developing methods of altering temporal experience as a means of helping the elderly to adjust to life transitions was explored.


Multidimensional sources of infant temperament.

Previous research on infant temperament has implicated a variety of prenatal and perinatal conditions, but most studies have investigated a single source of infant variability. This study examined the impact of several prenatal and perinatal factors on infant outcome according to a conceptual system of hypothetical models of influence. Seventy-five couples expecting their first child were recruited and interveiwed in the last trimester of pregnancy, providing demographic data and measures of the pregnancy experience and expectations of parenting. Childbirth information was obtained from hospital records, and infant behaviors were measured at three days of age by the Neonatal Behavioral Assessment Scale. Results indicate that the antecedent variables are themselves intercorrelated in that older, more highly educated, and financially secure couples are more likely to have a satisfying pregnancy and to be confident about childbirth and parenting than their young, more anxious counterparts. Two statistical methods--partial correlation and path analysis--were used to analyze relative relationships with infant behaviors. Results from both methods indicate that most of the antecedent variables (parental characteristics of age and socioeconomics, parental pregnancy orientation, and use of obstetric anesthesia) must be considered sources of infant behaviors. These findings thus demonstrate the imprecision of inferring a single causal pathway of parental or perinatal influence on infant temperament.


[Genetic control of the tissue concentration of serotonin in mice].

Brain stem, stomach and blood serotonin contents were studied in inbred mice of eight strains. The serotonin level in brain and in peripheral tissue is genetically determined. There was no correlation between the serotonin levels of brain, blood and stomach. This suggests a different genetic regulation of serotonin metabolism in the central nervous system and in the gastrointestinal tract.


[Regulator of expression of the brachypodism-H gene in mice].

Extracts were prepared from the whole limb buds of the 11 day-old mouse embryos and from the postaxial or preaxial parts of the 12 day-old embryo limb buds. Effects of these extracts on the growth of the 13 day-old bpH/bpH embryo tibia rudiments were studied in vitro. It was shown that the limb buds of the 11- and 12 day-old mouse embryos contain a factor regulating bpH gene expression in differentiating cartilage cells. This factor is present in the postaxial part of the limb bud and is absent in its preaxial one. When the extract from the limb bud postaxial parts of the 12 day-old +/+ embryos is added to culture medium, the expression of bpH gene is observed in cultured tibia rudiments of the 13 day-old bpH/bpH embryos. The extraxt from the limb bud preaxial parts of the 12 day-old +/+ embryos does not affect the growth of tibia rudiments of mutant embryos in vitro. The regulator factor does not induce bpH gene expression in cultured bone rudiments of the 14 day-old bpH/bpH embryos. It is obvious that bpH locus does not act in cartilage cells of developing tibia after the 14th day of embryogenesis. The sensitivity of the factor regulating bpH gene expression to heating and proteolytic enzymes suggests its protein nature. The molecular weight of this protein is from 15 000 to 25 000. Experiments with actinomycin D show that this factor regulates the expression of bpH at the post-transcriptional level.


[Chromosome aberrations in human lymphocytes induced by exposure to different doses of chronic gamma irradiation in vitro].

Non-stimulated with phytohemagglutinin human blood was chronically gamma-irradiated (226Ra, 99 mg) in vitro at 37 derees C. The dose rates were 8.2 (irradiation doses 8.2, 16.4, 41 and 162.2 rads) and 25.3 (irradiation doses 8.4, 16.9, 42.2, 168.2, 337.3 and 506 rads) rads/hour. Quantitative analysis of different types of structural chromosome aberrations was carried out. The data on aberrant cells and dicentrics were statistically interpreted. The frequency of aberrant cells, observed at both dose rates, was statistically described by the equation y = a + bD, where y = 7.11 (+/- 0.56) + 11.38 (+/- 2.32) . 10(-2) D, and y = 5.23 (+/- 0.23 + 13.20 (+/- 1.11) . 10(-2) D at dose rates 8.2 and 25.3 rads respectively. The dicentrics yield was described by the equation y = alphaD + betaD2 + C, where y = 3.19 (+/- 0.22) . 10(-2) D + 7.0 (+/- 0.46) . 10(-5) D2 + 0.42, and y = 5.05 (+/- 0.38) . 10(-2) D + 7.1 (+/- 0.41) . 10(-5) D2 + 0.42 at 8.2 and 25.3 dose rates. Statistically reliable differences in the dicentric yield in lymphocytes irradiated with different dose rates are observed. The results obtained show that the increase in the dose rate results in the increase of the dicentric yield, originated in one-track process, while the dicentric yield from two-track process remains constant.


[Effect of blood storage and nutrient medium on the frequency of chromosomal cell aberrations after subsequent x-irradiation].

Cytogenetic investigations are carried out in order to study the yield of chromosome aberrations depending on storage conditions of intact and X-irradiated blood and 199 nutrient medium containing calf serum in glass and plexiglas bottles at 20 degrees C within 0, 24, 48 and 72 hours. The yield of chromosome aberrations in blood stored in glass for 24, 48 and 72 hours and then X-irradiated at a dose of 250 r is the same as in freshly irradiated (at the same dose) blood. Statistically significant differences in the yield of chromosome aberrations were observed in blood stored for 24, 48 and 72 hours in plexiglas bottles as compared with freshly irradiated and stored in glass before the irradiation (at a dose of 250 r) blood. No chromosome changes in hereditary structures of lymphocytes were observed in non-irradiated blood, incubated with nutrient medium which was stored for 24, 48 and 72 hours in plexiglas bottles and then irradiated at a dose of 250 r. Non-irradiated blood stored for 24, 48 and 72 hours in glass and plexiglas bottles produced the same chromosome aberration yield as fresh non-irradiated blood. Thus, sensibilization of hereditary lymphocyte structures was observed only in X-irradiated blood stored in plexiglas bottles.


[Dominant lethality and translocations in the sex cells of male rats under low-intensity gamma irradiation].

Adult male rats were given 1300 rad of chronic gamma-irradiation (0.08 rad/min) Dominant lethal rates were found to be high (ranging from 48 to 75%) in irradiated postmeiotic cells and clearly lower (6.8%) in spermatogonia. The chromosome aberration (reciprocal translocation) yields observed with 1300 rad chronic irradiation were comparatively low, averaging 1.6%. Spermatogonia irradiation at low dose rate resulted in a smaller effect as compared to the genetic effects of a single acute exposure.


[Single-strand DNA breaks and chromosome aberrations in the hepatocytes of mice of different ages].

The same damages were found to occur in hepatocyte DNA from old mice of different strains by means of sedimentation in alkaline sucrose concentration gradient. At the same time, the number of hepatocytes with aberrant chromosomes is strongly different in these strains. From these data an assumption is made that some other damages being accumulated with aging are responsible for chromosome aberrations except for single-strand DNA breaks. The number of single-strand breaks registered in hepatocyte DNA of the old animals under gamma-irradiation is two-three times more than that of the young animals, though the rates of repair of the induced single-strand breaks in DNA are the same for mice of different age and strains.


[Mapping new structural genes of phage phi80].

A new set of am and ts-mutants of the phage phi80 was isolated. A series of lambdacI857h80att80int3 prophage deletion strains, extending for various lengths into the region of structural genes was generated and characterized in order to facilitate the mapping of the phi80 am and ts-mutants. Complementation test allowed to find out 5 new genes named 20, 21, 22, 23 and 24. The result of the deletion mapping of structural genes is as follows: 1-2-3-20-4-5-6-21-7-22-9-23-10-8-12-24-13.


[Genetic analysis of the resistance of mouse somatic cells to colchicine].

The genetic nature of the resistance of mouse L cells to 0.06 microgram/ml of colchicine (the first step of selection) was studied. Fluctuation tests showed that the generation of drug-resistant variants in the wild type population was random and did not depend on the action of the selective agent. The rate of spontaneous occurrence of this variants was approximately 2 . 10(-5) per cell per generation. Colchicine resistance proved to be relatively unstable: it was 2--3-fold less in all clones propagated in non-selective conditions for 25--33 days. Two mutagens, ethylmethanesulphonate and N-nitroso-N-methylurea, failed to induce colchicine resistance in conditions when they enhanced the frequency of 8-azaguanine-resistant cells 10-fold.


[Genetic-biochemical analysis of the shuttle-box behavior of 2 inbred strains of mice differing in brain protein S-100 content. I. Neurospecific protein S-100 and learning].

A hybridological analysis of a mode of inheritance of two characters: biochemical (brain S-100 protein level) and behavioral (rate of active avoidance conditioned reflex formation in a shuttle box), in mice of inbred strains DBA/2J and AKR/J characterized by respectively high and low levels of these characters. The high concentration of water soluble S-100 protein in whole brain is a recessive character. The inheritance of total S-100 protein in whole brain and of the level of its water soluble fraction in brain cortex and hippocampus is complex. In all hybrids of a given couple of parents from different strains, dominance and over-dominance of a low rate of the formation of the conditioned reflex takes place. No sex differences in the avoidance level were found. Neurospecific S-100 protein content correlates positively with the rate of active avoidance conditioned reflex formation.


[Case of partial trisomy 4p+ in a child as a result of a balanced translocation in the father].

Clinical and cytogenetic data on the infant with mental retardation, multiple congenital anomalies and trisomy for the short arm of the 4th chromosome (46, XY, der (1) (1;4) (q43; p15) are given. The abnormal chromosome was inherited from the father who had a balanced translocation 46, X; (1, 4) (q43; p15). Clinical features of the patient corresponded to those in the observation of other authors.


Least-squares method for restriction mapping.

A least-squares procedure has been developed to aid in deriving restriction-fragment maps once the order of cutsites has been determined. A computer program which carries out this method can be used to map either linear or circular molecules.


Isolation and insolubilisation of human F VIII by affinity chromatography.

A simple procedure has been developed for the isolation of coagulation factor VIII (F VIII) from plasma in a form which induces a monospecific antibody in rabbits. Amino acid precipitation from plasma was followed by gel filtration on Sepharose 4B and further purification was achieved by affinity chromatography on heparin-Sepharose. The material so isolated was identified by immunoelectrophoresis and lacked coagulant activity. The antiserum produced in rabbits inhibited F VIII coagulant activity and von Willebrand factor activity as measured by ristocetin platelet agglutination. The isolated IgG fraction insolubilised with CNBr-Sepharose 4B retained the ability to complex with F VIII. This complex possessed F VIII coagulant activity which could be removed in 0.6 M NaCl and dissociated in 8 M urea.


Increased level of factor VIII complex in severe arterial hypertension.

Factor VIII complex was studied in patients presenting arterial hypertension. Visceral involvement was quantified using a clinical index calculated from ocular fundus, renal function and left ventricular hypertrophy data. A significant correlation was found between the mean arterial pressure, the visceral involvement and the level of complex VIII. Nevertheless, other data obtained in different patients (Conn's disease) suggest that the visceral involvement (and not the mean arterial pressure) is the main determining factor in the increase of factor VIII complex.


Binding of 14C-ADP to normal human and thrombasthenic platelet membranes. Study of the dissociation of the nucleotide from its receptors.

Normal and thrombasthenic platelet membranes are able to specifically bind 14C-ADP (12). According to the concentration of ADP present in the medium, 'high affinity binding sites' (Ka = 0.5 X 10(6) M-1 and 'low affinity-binding sites' (Ka = 0.05 X 10(6) M-1) can be recognized. In the present study, dissociation of ADP from the 'high affinity binding sites' was measured with six normal and with three thrombasthenic platelet membrane preparations. A 1:100 dilution was used to dissociate the membrane-bound 14C-ADP and the kinetics of the dissociation was determined. The same profile of dissociation (with T 1/2 = 4--10 min at 37 degrees C) was observed using normal or thrombasthenic membranes. With both preparations, the rate of dissociation was increased (up to T 1/2 = 1--3 min) when unlabelled ADP (at concentration higher than 10(-5) M) was added in the diluting medium. The results confirm the presence of normal ADP binding sites on thrombasthenic platelet membrane and possibly suggest the existence of cooperative interactions between the sites on normal as well as on thrombasthenic membranes.


A simplified assay method for platelet factor 4 in plasma and in platelets with a chromogenic substrate.

A simple assay method for platelet factor 4 is described. When factor Xa was added to a system containing antithrombin III in excess and heparin in low concentration, the amount of factor Xa immediately inactivated was found to be a function of the concentration of heparin. When an antiheparin such as platelet factor 4 was added, an increase of the residual activity of factor Xa was observed. The magnitude of this increase was shown to be correlated to the amount of heparin inactivation in the system. Platelet factor 4 could be assayed when the concentrations of antithrombin III, heparin, and factor Xa were maintained at a constant level and in excess. As an indicator of the reaction, factor Xa was measured with the chromogenic substrate benzoyl-Ile-Gou-Gly-Arg-p-nitroanilide (S-2222).


Effect of temperature on short-term preservation of platelets for in vitro tests.

We have evaluated the effect on the response of citrated platelet-rich plasma to aggregating agents of storage at 4 degrees C versus room temperature (21 degrees C) for 2 and 4 h after venipuncture. While there were small decreases in some responses to epinephrine, ADP and collagen attributable to 21 degrees C storage, only in the case of ristocetin-induced aggregation was a profound difference noted. Platelets stored at 4 degrees C for 4 h showed no significant change in response to ristocetin. In contrast, those stored at room temperature showed a marked decrease. This change is not likely to be attributable to a change of pH, although pH rose less with storage at 4 degrees C than at 21 degrees C. It is recommended that PRP for in vitro testing be stored at 4 degrees C.


Urokinase inactivation rate in the rabbit: effect of circulatory isolation of the liver, spleen and kidneys.

After injection of urokinase (UK) in normal rabbits and in rabbits with ligated liver, spleen and kidneys, the inactivation rate constant of UK was evaluated by using the disappearance rate of fibrinolytic activity from plasma. A peripheral intravenous injection of UK in normal rabbits induced significant but transient fibrinolytic activity, with ligated liver, spleen and kidneys, the fibrinolytic activity sustained for a long period, i.e. the inactivation rate constant of UK was 6 times smaller compared with normal rabbits. The implications of these results are discussed.


Locomotion and posture in Ateles geoffroyi and Ateles paniscus.

The locomotor and postural behavior of Ateles geoffroyi and Ateles paniscus was studied in Panama and Surinam. Ateles locomotion can be divided into five patterns on the basis of limb usage: quadrupedal walking and running, suspensory locomotion, climbing, bipedalism and leaping. The first three are commonly used in both locomotion during travel and locomotion during feeding, but climbing (especially 'horizontal climbing') is the most important pattern during feeding. Most Ateles locomotion takes place on twigs and branches, with twigs playing a greater role in feeding than in travel. Feeding postures are mainly suspensory and seated, short resting postures are suspensory, seated and standing, and long resting postures are almost entirely seated and reclining. Twigs are the most important supports in feeding postures, but branches are much more important in resting postures. The results of this study indicate that the quadrumanous climbing, forelimb-dominated locomotion during feeding that FLEAGLE considers the primary hominoid adaptation is also characteristic of Ateles.


[Prevention of recurrent nerve paresis and parathyroid lesions in thyroidectomy].

At present the risk of a post-operative nerve lesion or of hypothyroidism occurring after surgery of the thyroid still exists. Those surgeons who expose the entire length of the nerve are few but they obtain the lowest rate of post-operative vocal cord palsy. In a series of a 100 patients undergoing thyroid surgery, the nerves were visually exposed along their entire length. A nerve stimulator was used to facilitate recognition and identification. During electrical stimulation, spasmodic contractions of the larynx could be observed behind the crico-thyroid muscle, close to the ligatures of the superior thyroid vessels. The lobe was freed as for a total lobectomy. During this procedure, due to their anatomical relations, the parathyroid glands are unendangered as only the vessels which reach the thyroid itself are ligated. The safety of this operative technique was demonstrated by the absence of either nerve lesions or hypoparathyroidism in this series of 100 patients. The ensuing security allows modification of the surgical technique or procedure according to the situation. For all solid cold nodules total lobectomy is unequivocably indicated. In Graves' disease and endemic goitre the classical subtotal thyroidectomy is replaced by total lobectomy on one side and subtotal lobectomy on the other.


[Psychopathology of schizophrenic diseases].

After a short historical review the main symptoms of schizophrenia such as disorders of thought, perception, emotion and motor behavior are discussed. Doing this, the acknowledgements of the classical German psychiatry are displayed. Finally, the Schneiderian first and second rank symptoms (Symptome 1. und 2. Ranges) and the Bleulerian basic symptoms (Grundsymptome) are discussed.


[Significance of environmental factors for the development of schizophrenic psychoses].

Various factors of environment are analyzed by means of literature with regard to their significance for the development of schizophrenic psychoses. These factors are classified as follows: family situation, ecological factors, stress situations, professional situations, transcultural points of view, extraordinary circumstances. Although there are a great number of analyses, they partly come to different, even opposite results. Yet most authors agree in recognizing the influence of factors of environment on the development of schizophrenias.


[Reciprocal relationship between bones, hematopoiesis and kidney with reference to sex hormoses. 2. Endocrine osteopathy and sex hormones].

Interactions and influence between blood and bone-tissue are discussed. In chronic renal insufficiency there is a failure of the kidneys as an endocrine organ with hormones for hemopoiesis and bone-metabolism. This deficit can partly or completely be replaced by an appropriate therapy. The--in the kidney transformed and so activated--vitamine-D-metabolite 1,25(OH)2D3 can be used in the therapy of osteoporosis, the combination with sodium fluoride brings even better results. In cases of postmenopausal osteoporosis and lack of estrogen estrogens are indicated for the treatment and the prophylaxis of osteoporosis.


[Perbronchil a lung biopsy].

The term "exogenic pneumopathology" means a cluster of problems resulting from the still unknown consequences of the exposure of workmen to various industrial noxious agents. Progress is to be expected from advanced methods of examination: Perbronchial lung biopsy is a new chance to solve the problems. With perbronchial biopsy we get lung tissue in about 90% of examined cases. The complication rates are low: pneumothorax developed in about 4% controllable bleedings occurred in 1.2%. Relevant diagnostic results were possible in about 60%. From the tabulated global results after more than 1400 perbronchial lung biopsies, the occupational diseases and the lung fibrosis are especially pointed out and discussed in detail.


[The child between life and death. Child psychiatry in neoplastic diseases].

The highly specialized treatment of the child with a fatal illness confronts the patient, his relatives and the staff with continuous psychological stress. Knowledge of how a child feels about illness, life and death is a prerequisite for the understanding and help of these patients. The participation of a child psychiatrist seems to  be essential in providing optimal psychological support. In the present study, all children were aware of the life-threatening nature of their disease. The maintenance of a meaningful dialogue till the end is of great importance for the patients and their families. The therapist engaged in such a dialogue is forced to face loss and grief.


[Adverse effects of modern inhalation anesthetics. 2. Control of amounts and elimination of escaping anesthesia gases].

This paper presents a review on the pathological effects caused by acute or chronic exposure to the inhalation anesthetics halothane, methoxyflurane, or enflurane. Methoxyflurane has a dose-related nephrotoxicity due to its metabolic degradation with release of fluoride ions whereas suggested pathological renal effects of halothane or enflurane are still under discussion. As to the syndrome of halothane- (or enflurane-, methoxyflurane-) associated hepatitis no dose-dependent hepatotoxicity has been proven but interactions with hypoxia, hypotension, drug-pretreatment, and perhaps genetic abnormalities should be kept in mind. Severe hematologic alterations are effected by prolonged exposure to N2O or halothane and alterations of tumor immunity caused by anesthetic agents are reported, too. From clinical studies and observations of pregnant animals, a correlation between the incidence of miscarriages or malformations and chronic exposure to low doses of inhalation agents may be stated. Nevertheless, an inhalation agent is easy to control because it can be eliminated quickly in the case of complications. Therefore, one would not like to miss these inhalation agents in clinical practice but the immission into the operating room should be limited. Moreover, the best way to keep the operating room clean from waste anesthetic gases is the installation of a scavenging system which is connected to suction.


[Unstable angina pectoris from surgical view (author's transl)].

Between January 1974 and September 1977 37 patients with unstable angina pectoris have been treated (7,6% of the patients operated upon). 49% suffered from an old myocardial infarct, 86% had a 2 or more coronary vessel disease, and only 4 patients showed critical stenoses on the left main stem. We preferred a combined medical and surgical treatment. By means of medical treatment all patients but one became painfree. At the same time coronary angiography had been performed without any complications. 37 patients received 67 vein bypasses (graft-patient-relation of 1,8). The surgical degree of revascularization was 80%. The hospital mortality came to 2,7%, the late mortality to 2,8%. Perioperatively 3 patients underwent a myocardial infarction. 84% of the patients were painfree and clinically improved. 41% went back to work in their old jobs. 84% of the vein bypasses were open. The effective degree of revascularization was 67%. There is no difference between patients with stable and unstable angina referring to coronary morphology, rate of survival and of surgical complications as well as to clinical and objective improvement. We recommend an early but not emergency angiography and we prefer an elective surgical treatment and not an emergency procedure.


[Surgery of congenital acyanotic cardiac malformations (author's transl)].

Congenital heart lesions are found in 0.8% of all newborns; four-fifths of them are correctable. Two thirds of all surgical procedures are done in acyanotic malformations, mainly in septal defects, patent ductus arteriosus, coarctations of the aorta and valvular stenosis. Within the last twenty years corrective repair has been established with good results in these lesions. Therapeutic problems still remain in cases of late diagnosis and in some rare and complex anomalies like malformations of the aortic arch, of the coronary arteries, in some types of aortopulmonary window and atrioventricular canal. Surgery becomes urgent in babies suffering from severe heart disease because of progressive pulmonary hypertension, inadequate growth or severe heart failure (despite intensive medical treatment). For certain lesions corrective repair (patent ductus arteriosus, coarctation) is definitely indicated, for others (ventricular septal defect, atrioventricular canal) urgent palliation or early total repair is debatable. In most patients with uncomplicated lesions treated in time during childhood a low operative mortality below 1% was observed. A higher mortality rate was found (10 to 50%) in patients with pulmonary artery disease or associated pulmonary lesions. A significantly higher mortality could also be observed in the advanced age group (4.7%) and in infants below one year of age (11,5%), underlining the important point of the age at operations. Recurrence of lesions occured in 1% of our patients after closure of ventricular septal defects, reconstructions of mitral valve disease and early corrected coarctations. Nevertheless, most of these patients can expect a normal growth, life span and ability to work.


[Surgery in newborns and infants with cyanotic cardiac malformations: indication and technique of emergency operations and urgent early surgical interventions (author's transl)].

Between April 1974 and September 1977, 368 infants underwent surgery at the German Heart Center. 287 were less than 1 year of age, and 81 were between the ages of one and two years. In 90 patients (= 24.4%) surgery was necessary because of cyanotic lesions. Within this group corrective procedures were performed in 36 infants during the first year of life, and in 33 during the second year of life, while palliative measures were carried out in these age groups in 15 and 6 infants, respectively. Urgent corrective surgery is indicated as a life-saving measure in neonates with total anomalous pulmonary venous connection (TAPVC) since this lesion is not amenable to either medical nor palliative interventions. Of 10 neonates and young infants who underwent corrective surgery for TAPVC, 3 died during the early post-operative period and 1 subsequently. Balloon atrial septostomy palliatively employed for transposition of the great arteries (TGA) may render only temporary improvement in the clinical status of young infants. In these infants, more favourable results can be achieved through early, functionally-corrective surgery (Mustard-Brom procedure). In 7 infants who underwent correction of TGA during the first year of life there was 1 post-operative death. There was no post-operative mortality in 18 infants whose age at the time of operation was between 1 and 2 years. In the presence of TGA combined with ventricular septal defect there were 3 deaths in 8 infants operated on during the first year of life and none in the 3 who underwent surgery during the second year of life. In the same age groups, early correction of tetralogy of Fallot (TOF) was performed in 11 infants (with 2 deaths) and in 10 infants (with one death), respectively. Thus, in the absence of preclusive, complex anomalies, early surgical correction of congenital cyanotic lesions in young infants consistently yields results superior to that of palliation or two-stage procedures.


[Tachyarrhythmias (author's transl)].

Various types of supraventricular and ventricular tachyarrhythmias causing severe clinical symptoms may be refractory to coventional antiarrhythmic therapy. In a large number of cases, electrotherapeutical approaches such as DC-cardioversion and cardiac pacing are effective in controlling ectopic tachycardias. Electrical pacing offers certain advantages over standard DC-cardioversion for the termination of tachycardias: 1. No general anesthesia is required. 2. Digitalis induced arrhythmias may be abolished, a situation in which DC-cardioversion is dangerous and usually ineffective. 3. Pacing can be effected rapidly, simply and repeatedly leaving the pacing catheter in place. At the present time different modes of cardiac pacing techniques are in use in order to suppress supraventricular, junctional and ventricular tachycardias. These are: rapid atrial stimulation, overdrive pacing, coupled stimulation, patient initiated atrial pacing, precisely timed single or multiple premature stimulation, and programmed rate-related stimulation. Rate-related interval stimulation may be useful when applied in drug-resistant junctional and ventricular tachycardias or runs of ventricular extrasystoles as precursors of a tachycardia. DC-cardioversion as well as the pacing techniques proved to be low risk alternative methods for treatment of tachyarrhythmias unresponsive to drug therapy.


[Bradyarrhythmias (author's transl)].

Bradyarrhythmias are due to disturbance of impulse formation and conduction in the heart. The sick sinus syndrome consists of both forms, sinusbradycardia being the most common type of arrhythmia, followed by sinus arrest and sinuatrial block. There is a wide range of the reported frequency of concomitant intermittent supraventricular tachycardia. Most patients have additional atrioventricular conduction disturbances. Diagnostic methods include measurement of the sinus node recovery time and sinoatrial conduction time, but therapy, i.e. pacemaker implantation depends largely on documentation of significant reduction of heart rate with clinical symptoms. The largest group of bradycardias is due to high degree atrioventricular block. As the prognosis of Mobitz Type II block is unfavorable in regard to development of complete distal av-block, differentiation between type I and II is of clinical importance, particularly in patients with additional fascicular block. Although exact localization of conduction disturbance with the Hisbundle-electrogram is possible, proof or exclusion of block distal to the Hisbundle including high frequency testing with atrial stimulation does not give the sole indication for therapeutic measures as follow up studies of patients with intraventricular conduction disturbances with and without distal block have demonstrated, that progression to complete av-block is difficult to predict.


[Therapy of cardiac arrest: cardiopulmonary resuscitation (author's transl)].

Reports of successful attempts at resuscitation have been published for more than 200 years, but systematic analysis of an optimal technique has been undertaken for only the last 20 years. As a result of these experiments and of the many years of experience of resuscitation teams, extensive recommendations were formulated by a conference on cardiopulmonary resuscitation of the "American Heart Association" in May 1973. The superiority of mouth-to-mouth resuscitation in comparison to older methods and the importance of the triple-airway-maneuvre for the maintenance of a patent airway were pointed out. Despite the fact, that an exact numerical relationship of cardiac massage to artificial ventilation is not particularly important, an optimal procedure was established. However, the worldwide spread of cardiopulmonary resuscitation should not lead to this procedure being performed just somehow, since correct execution, if possible without interruptions, is essential for the effectiveness of the remaining circulation and the response to medications and defibrillation. The prognosis varies widely depending on the group of patients being examined. In 1976 34 resuscitations were performed on adult patients of the Cardiothoracic Intensive Care Unit of the German Heart Centre in Munich (5.5% of patients admitted). Seven patients survived primarily. Of these, four patients died within the subsequent twentyfour hours. One patient survived with permanent brain damage, two could eventually be discharged from the hospital without complications.


[Entry into pulmonary artery in complete transposition of the great arteries (author's transl)].

In 91 children with complete transposition of the great arteries investigated by heart catheterization since 1974 the pulmonary artery was probed at the first investigation in 46% and at the second preoperative investigation in 85%. Considering only the last 2 years the pulmonary artery was entered in 93% during the second catheterization. When an additional catheterization was necessary the pulmonary artery was always entered. This was mostly achieved by a flow-directed balloon-catheter preformed before introduction into the vein by alternating application of hot and cold water or in the left atrium by use of a guide wire.


[His bundle electrography in children (author's transl)].

The His bundle electrography has confirmed many earlier hypotheses about the localization of atrioventricular block and the mechanism of tachyarrythmias; beyond this, it has added new information. In this paper, normal values and results of the method during childhood are reviewed. The indication for His bundle electrography as an invasive method is limited in children. An important indication consists of clarification of unclear partial atrioventricular block and of the state of the remaining third fasicle in postoperative bifascicular block.


[Pulmonary hypertension after spontaneous closure of an atrial septal defect in infancy (author's transl)].

Clinical findings and haemodynamic data of an infant with atrial septal defect and hypoplasia of the left ventricle are reported. At the first cardiac catheterization at the age of 3 weeks an interatrial left to right shunt of 55% and a moderately elevated pulmonary artery pressure, but normal pulmonary vascular resistance were found. At repeat cardiac catheterization at the age of 6 month the atrial septal defect had closed spontaneously, however, the pressure in the pulmonary artery had risen to 90/55 mm Hg and pulmonary vascular resistance was elevated with 9.6 Um2. 3 months later pulmonary artery pressure had normalized to 35/15 mm Hg, but pulmonary vascular resistance was still elevated at 7.8 Um2.


[Pulmonary hypertension and cor pulmonale complicating ventricular vascular shunting for hydrocephalus (author's transl)].

Obstructive pulmonary vascular disease and pulmonary hypertension are facts daily encountered by pediatric cardiologists. However longterm thromboembolism, pulmonary vascular obstruction and cor pulmonale are rare conditions in children. The case report of a four years old child treated by a Pudenz ventriculo venous shunt for hydrocephalus is presented. Due to fibrin thromboembolism from the Pudenz shunting tube pulmonary vascular obliteration, pulmonary hypertension and chronic cor pulmonale developed. The autopsy findings are in agreement with the ECG, x-ray, cardiac catheterization data and the angiocardiogram.


[Transposition of the great arteries with horizontal interventricular septum (author's transl)].

Transposition of the great arteries with horizontal interventricular septum is characterized by a superior-inferior relationship of the ventricular chambers in the presence of ventriculo-arterial discordance. Embryologically this very peculiar anatomy can be explained by a rotation of the bulboventricular loop around a sagittal axis. A typical case is reported. The most important anatomical features are described and the embryologic mechanisms leading to this ventricular arrangement are discussed. The significance of this deformity to nomenclature of congenital heart disease is emphasized.


The pulmonary circulation in congenital heart disease. II. Pulmonary hypertension.

In young children with congenital heart disease the pulmonary circulation is exposed to abnormal haemodynamic conditions before it is fully developed. In the newborn infant the persistence or development of pulmonary hypertension rapidly leads to structural change. The speed with which an increase in muscularity can develop has hitherto been underestimated. In most children dying in early infancy with congenital heart disease and pulmonary hypertension the presence of thick walled small arteries is due not to persistence of the high wall thickness of foetal life, but to a rapid postnatal response of the pulmonary circulation to pulmonary hypertension. In older patients with a ventricular septal defect, aged between 3 months and 4 years, the presence of pulmonary hypertension has been shown to interfere with the growth and development of the pulmonary circulation, judging this by reduction in size and multiplication of intra-acinar arteries and an increase in muscularity of both pre and intra-acinar arteries and veins. In these patients elevation of pulmonary vascular resistance was associated with failure of the intra-acinar pulmonary circulation to develop normally and not with obliterative pulmonary vascular disease. Recent studies indicate that growth and development of the peripheral pulmonary circulation can be quantitated in lung biopsies taken from infants and young children with congenital heart disease. It should therefore be possibe to correlate structure and function at a critical period of lung development, before the changes of obliterative pulmonary vascular disease are established.


[Cardiac catheterization of neonates and young infants using a flow-directed balloon catheter (author's transl)].

In cardiac catheterization with the Swan-Ganz-flow-directed balloon catheter the aorta or, in  transposition of the great arteries, the pulmonary artery was entered from the left ventricle with a special heart catheterization technique in 68 neonates and young infants. In the same way selective aortography was performed in 29 of these patients. This catheterization technique has the following advantages: 1. the complete evaluation of complex cardiac anomalies even in neonates, 2. selective aortography avoiding the retrograde arterial catheterization, 3. reducing the risk of cardiac perforation or myocardial staining due to the contrast injection using the usual semirigid catheters. Balloon rupture or knotting are specific but avoidable complications.


[Current status of pacemaker technology (author's transl)].

Since the first cardiac pacemaker was implanted twenty years ago, advances rendered have provided patients with increased reliability and therapeutic efficiency as well as subsequent incrementation in their life expectancy. Technological developments have yielded improvement in the main components such as electrode, the energy source and the electronic circuitry. A variety of leads are available to effect pacing requirements at ventricular and, in part, atrial levels. The introduction of lithium energy sources has prolonged the useful life of pacemakers to more than 8 years. Consumption of current has been reduced by decreasing electrode surface area, shortening of pulse duration and employment of hybrid circuits. Microprocessing of the electronic components have enabled reduced size of pulse generators while providing increased reliability and capabilities for additional functions. Amelioration of electrophysiologic disturbances has been specifically approached through increasing use of atrial and bifocal pacemakers, external programmability and overdrive pacing.


[Transmural and nontransmural myocardial infarction. Clinical course and prognosis (author's transl)].

In a group of 701 patients with acute myocardial infarction treated in the intensive care unit from 1969 to 1976 557 ((79,5%) had a transmural infarction. The clinical course in these patients was significantly more aggravated by haemodynamic complications especially left and right heart failure and cardiogenic shock. The pericarditis appeared with an incidence of 10,4% as complication of transmural myocardial infarction only. Atrioventricular block, supraventricular ectopies, ventricular fibrillation and intraventricular disturbance of conduction occurred more frequently in patients with transmural myocardial infarction. Corresponding to the larger size of infarction the maximal average rise of serum enzymes (SGOT, CPK) was observed in this group. The hospital mortality was 28,2%, compared to 11,2% of the patients with nontransmural infarction.


[Cardio-pulmonary complications, respiratory treatment and PaO2 after open heart surgery (author's transl)].

Despite the almost complete disappearance of the so called "postperfusion lung syndrome" after cardiac surgery with extracorporeal circulation (ECC), there is still a need for respiratory treatment in some cases, primarily for cardio-circulatory or respiratory reasons. In addition postoperative artificial ventilation is provided routinely in many centers for at least a few hours, until stabilization of cardio-circulatory and metabolic state is achieved. In 4 groups (I-IV) with a total of 659 patients (18 to 72 years old) undergoing open cardiac surgery for acquired heart disease (I: aortic valve, II: mitral valve, III: multivalvular disease, IV: coronary artery disease) postoperative cardio-circulatory and pulmonary complication rate, duration of artificial ventilation needed, PaO2 and some influencing factors have been evaluated. Group II and III show the highest rate of complications, 15.5 and 19.8% respectively, versus 7.7 and 8.1% in group I and IV respectively. The mean duration of postoperative respiratory treatment in cases with complications within all groups (133--156 h) is about 6 times the duration of respiratory treatment in the non complicated cases (23--24 h). In all 4 groups mean PaO2 at the time of extubation is lower for the complicated compared with the non complicated cases. Age of patients, severity of disease, preoperative pulmonary function, prolonged duration of ECC and myocardial ischemia have been found to be predisposing factors for postoperative cardio-pulmonary complications, whereas the duration of anesthesia and the type of anesthesia do not show any influence.


[Incidence, natural history and complications of chronic arterial hypertension (author's transl)].

Representative studies in Switzerland and the Federal Republic of Germany show that 12 to 25% of the adult population have elevated blood pressure values of 160/95 mm Hg or above. The incidence of hypertension increases with age. Approximately 2 to 6% of high school students have hypertension whereas 30 to 50% of persons older than 60 years may be found to have elevated blood pressure. In consideration of selected epidemiologic studies, it is apparent that even mild degrees of hypertension increase mortality and the risk of development of cardiovascular disease. The superimposition of hypertension on additional risk factors renders the probability of disease excessively high. However the rationale for antihypertensive treatment is not based on the relation between blood pressure levels and life expectancy or morbidity risk, but on controlled therapeutic trials showing that blood pressure reduction at all levels of hypertension leads to decreased incidence of cardiovascular disease and reduction of mortality.


Hemodynamic characteristics in hypertension.

Recent studies have outlined both the importance and limitations of hemodynamic studies in hypertension. Characterization of any type of hypertension cannot be established in terms of cardiac output or total peripheral resistance alone. It depends more on the way in which various factors (hemodynamics, volume, humoral and neural) interrelate than on disturbances of one factor alone. More studies are needed, not so much of each variable alone as of correlations among those variables, e.g. correlations between humoral factors and hemodynamic characteristics. Further, hemodynamic analyses must be extended beyond calculations of TPR to evaluation of other variables such as magnitude and distribution of intravascular volume, indices of aortic distensibility, of velocity of ventricular ejection and of cardiac performance. Interpretation of the results must also take into account factors such as hemodynamic setting, age of patient, neurogenic stimulation and structural changes amongst others. Careful attention to these variables will allow more accurate conclusions regarding characteristics of different types of hypertension, and patterns of response to therapy. Accurate hemodynamic characterization may help orient diagnosis and a rational choice of treatment in initial stages but specially for evaluation of resistant cases.


[Pathogenetic, pathophysiological and biochemical aspects of essential hypertension (author's transl)].

Hereditary and environmental factors are involved in the pathogenesis of essential hypertension. Obesity, salt intake and stress are predominant among the environmental influences. Autonomous nervous dysfunction, increased contractility of vascular smooth muscle cells and impaired renal handling of sodium are major abnormalities in essential hypertension. At present it cannot be decided if alterations in the activities of systemic or renal hormonal systems reflect primary defects or adaptive changes in the regulation of blood pressure. In any case the kidney is regarded to have a key position in the long term increase of blood pressure in essential hypertension. Recent studies in essential hypertensive patients suggest that renin release decreases as renal vascular resistance increases. Studies from our laboratory have shown that renal prostaglandins are intrinsic to the renin release mechanism from the kidney. Additionally, there is evidence that renal prostaglandin synthesis is disturbed in essential hypertension, either primarily or secondarily, leading to unresponsive renin secretion. Further studies on the interrelationships of other hormonal systems and on hormone-receptor interactions in the vascular wall are necessary to delineate more precisely the mechanisms which are operative in the pathogenesis and manifestation of essential hypertension.


Management of hypertensive encephalopathy.

The hypertensive encephalopathy is a syndrome consisting of a sudden elevation of arterial pressure usually preceded by severe headache and followed by convulsions, coma or a variety of transitory cerebral phenomena. The syndrome may complicate acute glomerulonephritis, toxemia of pregnancy and essential or malignant hypertension. Two syndromes must be differentiated from true hypertensive encephalopathy: 1. acute anxiety state with labile hypertension and 2. acute pulmonary edema due to hypertensive heart disease. At least in patients with acute anxiety states, the use of antihypertensive agents is usually not indicated. Since encephalopathy is always accompanied by increased vascular resistance and since clinical experience has demonstrated clearing of the sensorium, cessation of convulsions and release of vasoconstriction following reduction of blood pressure, the primary aim of therapy should be prompt lowering of arterial pressure. The two agents of choice are diazoxide and sodium nitroprusside. Stroke is differentiated from encephalopathy by the persistence of lateralizing signs. The aggressiveness of antihypertensive therapy in this situation depends on the severity of the hypertensive process. Rapid reduction of blood pressure is indicated in patients found to have accelerated hypertension while a more gradual lowering of pressure appears warranted for patients with chronic arterial hypertension and evidence of generalized arteriosclerosis.


Ecdysone 20-hydroxylase in midgut mitochondria of Manduca sexta (L.).

The conversion of alpha-ecdysone to 20-hydroxyecdysone in the midgut of Manduca sexta (L.) was found to be catalyzed by a mitochondrial, cytochrome P450-mediated monooxygenase. The reaction required oxygen and was inhibited by the presence of carbon monoxide. Tricarboxylic acid cycle intermediates, such as succinate, malate, and isocitrate, supported the hydroxylation as did NADPH, NADH, ATP, and ADP. Temperature and pH optima were 30 degrees C and 8.5, respectively. The apparent Km and V values for the ecdysone 20-hydroxylase were 18.3 +/- 6.8 micronM and 46.6 +/- 14.2 pmol per min per mg protein. The midgut mitochondria were found to contain malate dehydrogenase and NAD(P) transhydrogenase. The presence of these enzymes suggests that the tricarboxylic acid cycle intermediates and NADH support the ecdysone hydroxylation indirectly by providing NADPH for the cytochrome P450 system. The content of cytochromes a + a3, b, c + c1, and P450 in midgut mitochondria was determined.


Effect of phospholipases and lysophosphatides on partially purified steroid hormone receptors.

Treatment with phospholipase A2 of crude or partially purified preparations of the glucocorticoid receptor of rat liver results in an inactivation of the receptor, which cannot be attributed to contaminating proteases. Similar enzymatic treatment of the progesterone receptor of rabbit uterus does not affect its steroid-binding activity. At various stages during purification the preparations of glucocorticoid receptor contain 10 to 50-fold higher concentrations of lipid phosphate than the corresponding preparations of progesterone receptor, suggesting that the effect of phospholipase A2 on the hepatic receptor could be mediated by lysophosphatides produced during hydrolysis of endogeneous phospholipids. In fact, mixing experiments show that in the presence of the glucocorticoid receptor, phospholipase A2 also inactivated the progesterone receptor. Both partially purified receptors are inactivated by similar concentrations of added lysophosphatides but are not affected by incubation with phospholipase C, which does not produce ionic detergents. In addition, the effects of phospholipase A2 and of added lysophosphatides can be overcome by an excess of bovine serum albumin, indicating that free lysophosphatides are involved in receptor inactivation, possibly due to their strong detergent properties.


Transcription of the chicken ovalbumin and conalbumin gene during early secondary induction with estrogens.

Estrogens stimulate the rate of transcription of the ovalbumin and conalbumin gene in the chicken oviduct. The synthesis of ovalbumin and conalbumin mRNA was studied in isolated nuclei. RNA synthesized in vitro was distinguished from preexisting nuclear RNA by affinity labeling the in vitro products with a mercurated nucleotide and subsequent purification of the Hg-RNA on SH-agarose. The content of ovalbumin and conalbumin mRNA sequences in the in vitro transcripts was determined by hybridization to cDNA. After the withdrawal of implanted hormones from chickens, the synthesis of conalbumin and ovalbumin RNA increased 2.5- and at least 20-fold, respectively, by treatment with estrogens. The maximal rate of transcription of the conalbumin gene is achieved within 2 h after estrogen induction, whereas the rate of transcription of the ovalbumin gene becomes maximal after a lag of several hours. These results demonstrate that estrogens affect two genes in the same target cell differently.


[Purification and properties of two chloridazondihydrodiol dehydrogenases from chloridazon degrading bacteria].

A cell-free extract of Chloridazon-degrading soil bacteria catalyzes the conversion of the dihydrodiol derivative of chloridazon to the corresponding catechol derivative. NAD is required as hydrogen acceptor. Chromatography of the crude extract on DEAE-cellulose results in the elution of two different enzymes (enzyme A and enzyme B, respectively) with the same catalytic capacity. Both enzymes were purified to homogeneity in disc-gel electrophoresis and their properties were compared. The molecular weight was found to be 220 000 for both enzymes. Dodecyl sulphate polyacrylamide gel electrophoresis indicated subunits of molecular weight 50 000 in both cases. The synthesis of the enzymes does not seem to be under inductive control. The two dehydrogenases differ in heat-stability, pH-optimum, Km-values for the substrate and in their sensitivity to inhibitors. Enzyme A shows relatively high heat lability, a pH-optimum at pH 9.5, and a Km-value of 0.25 mM for the dihydrodiol derivative of chloridazon. The catalytic activity of enzyme A is not influenced by p-chloromercuribenzoate or by N-bromosuccinimide. In contrast enzyme B is relatively stable at high temperatures, showing a pH-optimum of 7.0, and a Km for the dihydrodiol derivative of chloridazon of 1.0 mM. Enzyme B can be completely inhibited by even small amounts of p-chloromercuribenzoate and by N-bromosuccinimide. Striking differences were found in the substrate specificities of the two dehydrogenases. Whereas enzyme A exhibits a high specificity towards dihydrodiols derived from aromates of the chloridazon or phenazon type, enzyme B is much less specific and is also able to convert the dihydrodiols of benzene, toluene or chlorobenzene into the corresponding catechols. Both enzymes are competitively inhibited by the reaction product, the catechol of chloridazon. Other catechols differed in their inhibitory effect on the two dehydrogenases. These differences are correlated with the different substrate specificities.


Desialylation of glycoconjugates using immobilized vibrio cholerae neuraminidase. Preparation, properties and use of the bound enzyme.

Neuraminidase from Vibrio cholerae was immobilized on Sepharose 4B using the cyanogen bromide technique. The properties of the bound enzyme were found to be similar to those of the soluble form, except for an appreciably improved stability on storage at equivalent dilution and a reduction in recovered activity. Evidence was obtained that the binding of large molecular weight substrates to the bound enzyme is modified due to the immobilized state of the enzyme. The use of the enzyme gel for desialylation of glycoconjugates in a closed circuit system was investigated and optimal conditions delineated using fetuin as a model substrate. The bound enzyme could be used repeatedly with only low loss of activity. The value of the desialylation circuit in the preparation of partially and completely desialylated glycoconjugates is discussed. The use of immobilized neuraminidase for the desialylation of cells is described.


Juvenile hormone activity of some glycosidic juvenogens.

In a search for new hormonogen compounds related to insect juvenile hormones we have prepared and bioassayed several beta-D-glucosides of some selected secondary juvenoid alcohols. Due to localization of the activating enzyme beta-D-glucopyranosidase in the epithelium and in the lumen of the digestive tract, the glycosidic juvenogens exhibit juvenile hormone activity in insects only when ingested. They are completely inactive in topical application as well as when injected into the haemolymph. It is suggested that the highly specific and selective action of the hydrophilic, nonvolatile, glycosidic juvenogens could be of practical importance.


The genome of Calliphora. Analysis by DNA reassociation kinetics.

The size and nucleotide sequence complexity of the Calliphora vicina genome has been determined from the kinetics of reassociation of its DNA. Unique sequence DNA comprises 80% of the genome and the remainder is divided into medium (14%) and highly repetitive sequences (6%), which are repeated roughly 150 times and more. The size of the Calliphora genome was calculated relative to the DNA from T4-phage to be 1.5--1.9 X 10(11) daltons.


Ribosomal RNA synthesis in rat liver cells.

DNA-dependent RNA polymerase A was analyzed in rat liver cells after partial hepatectomy, which is known to enhance the synthesis of ribosomal RNA. In agreement with previous results, it was found that the extractable enzyme activity increased after partial hepatectomy and could be quenched by the subsequent administration of cycloheximide, which suggests that continuous protein synthesis is required for the maintenance of the observed stimulation. However, administration of alpha-amanitin to hepatectomized rats did not quench the enzyme activity. These results cast doubt on the hypothesis that the increased activity of RNA polymerase A observed after partial hepatectomy is mediated by RNA products synthesized by polymerase B. Moreover, data are reported which indicate that ribosomal RNA may be regulated directly, without the obligatory involvement of HnRNA.


The follicle cell epithelium of maturing ovaries of Locusta migratoria: a new biosynthetic tissue for ecdysone.

Follicle cells of maturing ovaries of Locusta migratoria are demonstrated to synthesize the moulting hormone ecdysone (2beta,3beta,14alpha,22R,25-pentahydroxy-5beta-cholest-7-en-6-one). Studies of secretory kinetics under in vitro conditions show that the intensity of hormone secretion is strictly dependent on the stage of maturation of the excised ovaries.


Malignant histiocytosis: a histological and ultrastructural study of lymph nodes in six cases.

A morphological, histological, and ultrastructural investigation was carried out on a series of six cases of malignant histiocytosis observed between 1973 and 1977. All lymph nodes were obtained prior to treatment. The histological findings revealed that the proliferating cell type was in all cases represented by histiocytes of varying degrees of atypia and with consistent phagocytic activity. In four cases, the histiocytic cellular proliferation also showed some degree of cohesiveness and, in two cases, there was capsular invasion. In three cases blood vessel invasion by malignant cells could be seen within the lymph node and in the surrounding tissue. On electron microscopy the tumour cells of malignant histiocytosis appeared to be pleomorphic with three types of cells: undifferentiated cells, histiocytes with variable degrees of differentiation, and cells with intermediate features. In particular, nonphagocytic and actively phagocytic histiocytes could be identified. The histological and ultrastructural data further support the idea that malignant histiocytosis is a disease that is related to the neoplastic proliferation of moderately differentiated histiocytes and their precursors. The latter may undergo various transformations with either apparently benign or definitely atypical morphological features.


Inflammatory fibroid polyp of the gastrointestinal tract.

Details of 13 new cases of inflammatory fibroid polyp of the gastrointestinal tract and of 76 patients recorded in the literature (total 89) are described and analysed. The lesion is always benign, may occur at any age but is commonest in the sixth and seventh decades, and involves the stomach most frequently. Abdominal pain, often related to obstruction, is the principal symptom. Eosinophilia of the peripheral blood does not occur. The lesions are sessile or polypoidal, originate in the gut submucosa, vary greatly in cellularity, and have a wide range of tissue eosinophilia. Some are very vascular, many of the larger vessels having a notably broad zone of connective tissue about them. The aetiology of the condition is discussed and reasons for distinguishing it from eosinophilic gastroenteritis, with which it is frequently confused, are given. The precise nature and aetiology of the inflammatory fibroid polyp remains undetermined.


Host response and tumour biological behaviour in the two histological types of gastric carcinoma.

It appears that there is validity in categorizing gastric carcinoma into two histologic types, intestinal and diffuse. The local host tissue response in 92.5% of cases of the intestinal type of gastric carcinoma was of an exudative nature. Diffuse gastric carcinoma in 70% of cases incited a dense productive fibrosis. Pools of mucin and large number of 'signet-ring' cells were mostly encountered in the intestinal type of carcinoma. Applying Dukes' parameters the tumour was found to be more than three times more invasive in cases of diffuse carcinoma. The prognostic bearing of the two histologic types, different host tissue response, behaviour of the tumour in terms of mucous production and local extension are discussed and it is suggested that diffuse gastric carcinoma carries a worse prognosis than the intestinal type. Study of a larger series of cases and longer follow-up with controlled treatment is essential to confirm this assessment.


Regulation of the synthesis of human chorionic gonadotropin by strains of HeLa cells in culture.

Thirty-seven strains of HeLa cells were examined for their ability to synthesize human chorionic gonadotropin (hCG) and its alpha subunit (hCG-alpha) in culture. Synthesis of hCG-alpha and hCG also was investigated in the presence of sodium butyrate and 5-bromo-2'-deoxyuridine (BrdUrd). All HeLa strains synthetized hCG-alpha in culture. Sodium butyrate increased the synthesis of hCG-alpha in all HeLa cells; BrdUrd increased synthesis in 32 of the 37 strains examined. Although few HeLa strains synthesized hCG in the absence of inducers, hCG was detected in most strains in the presence of sodium butyrate. The synthesis of hCG and its alpha subunit is, therefore, a stable genetic characteristic of HeLa cells.


In vitro cultivation of human renal cell cancer. II. Characterization of cell lines.

Two cell lines derived from primary human renal-cell cancers (RCC) have been established and characterized. Cell line 786-O has been in culture for longer than 1 year and has been subcultured more than 50 times. It has a doubling time of 45 hr and a hypertriploid karyotype and possesses a Y chromosome. Cell line 769-P also has been in culture for longer than 1 year. It has been subcultured 50 times and has a doubling time of 35 hr and a hypodiploid karyotype. Cells from both lines are epithelial, and they produce tumors in the cheek pouches of immunosuppressed hamsters. Neither cell line is contaminated with Mycoplasma. Cells of the two lines can be distinguished from HeLa cells both by their karyotypes and by the mobility patterns of their isoenzymes of glucose-6-phosphate dehydrogenase.


In vitro synthesis and secretion of glycoprotein by human mammary tissue.

Organ cultures of human surgical specimens can be used to investigate glycoprotein production in vitro under conditions in which three-dimensional tissue structures and cell-cell interactions resemble those present in vivo. In this report, an organ-culture system is used to investigate the synthesis, transport and release of glycoprotein by normal and benign hyperplastic human mammary epithelium. Autoradiography of explants pulse-labeled with individual glycoprotein precursors ([3H]glucosamine, [3H]fucose, [3H]acetylmannosamine) and maintained in organ culture for intervals up to 72 hr revealed that glycoprotein is synthesized and then secreted by mammary epithelium. Incorporation of each isotope took place in the Golgi apparatus. Most of the newly synthesized glycoprotein, labeled with each of the three precursors, then was transported to apical cell surfaces and secreted into gland lumina. Observations were indistinguishable in normal and benign hyperplastic glands. Thus nonlactating human mammary epithelium exhibits a glycoprotein secretory activity. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of [3H]glucosamine-labeled macromolecules released into the medium showed a group of glycoproteins with a molecular weight of 48,000 +/- 6,000 daltons plus high-molecular-weight glycosylated components at the top of gels. The nature of gp48 is not known, but similar molecular-weight glycoproteins also are released by surgical specimens of human mammary cancer maintained in organ culture.


Effects of cystine or glutamine restriction on human diploid fibroblasts in culture.

Amino-acid restriction was studied using a strain of human diploid fibroblasts (HDF) isolated from fetal skin. HDF populations were maintained at reduced proliferation rates by lowering cystine or glutamine concentrations of Eagle's MEM. Effects of this treatment on mean cell diameters, total cell protein and specific activity of acid phosphatase were assessed. Threshold levels of cystine required for maintenance were found to be markedly influenced by type and/or batch of serum used irrespective of their free cystine content. A 96-hr exposure of passage 25 cells to medium 0.01 or 0.005 mM in cystine resulted in an increased mean cell diameter and a greater heterogeneity of cell size. This was accompanied by an increase in the total cellular protein. A 48-hr exposure, followed by return to control serial cultivation, induced persistent change in mean cell diameter without affecting the total life span (49 passages over 165 days). The mean size of untreated cells increased with serial passage reaching a size similar to treated cells only at passage 44. Acid-phosphatase specific activities were higher in cells maintained under conditions restrictive in cystine. None of the above changes were observed when glutamine concentrations were reduced to 0.0025 mM, a level required to inhibit division rates. The possible relevance of these findings to the phenomenon of in vitro cell senescence is discussed.


The lymphocyte mediators of delayed hypersensitivity: the early phase cells.

Inbred rats were immunized with living BCG and lymphocytes which mediate tuberculin DTH and anti-tuberculosis immunity were found 10 days later in the draining lymph nodes, thoracic duct, blood, spleen and acute peritoneal exudates. The lymphocytes that mediated DTH incorporated 3HT in vitro, were large in size, sensitive to vinblastine but relatively resistant to irradiation, and had a short effective lifespan in syngeneic recipients. These properties characterize the cells as short-lived, nonrecirculating immunoblasts. In some experimental situations it was possible to dissociate the expression of DTH and immunity following the transfer of sensitized lymphocytes.


Immunobiology of congenitally athymic-asplenic mice.

Congenitally athymic-asplenic mice on an outbred N:NIH(S) background were produced by the mating of nude by hereditarily asplenic (Dh/+)mice. Athymic-asplenic mice survive for up to 9 months, under specific pathogen free conditions, with no evidence for increased risk of spontaneous neoplasia. Although lymphocyte surface markers and sera immunoglobulin levels of athymic-asplenic mice are similar to their nude and asplenic littermates, there are a number of significant differences. In particular, levels of sera IgA are higher than nude, but lower than either nu/+ or Dh/+ mice, related perhaps to the increased histiocytic engorgement of Peyer's patches. Athymic-asplenic mice have normal haematocrit, haemoglobin, and reticulocyte counts, but are markedly leucopenic, have a thrombocytosis and an increased number of bone marrow CFU-C. As expected, the response of the athymic-asplenic mice to the T cell mitogen PHA is markedly reduced. However, levels of Thy 1.2 bearing cells, while reduced compared to either nu/+ or Dh/+ littermates, are significantly higher than nude mice in both Peyer's patches and lymph nodes. Further, they, like their nude littermates, fail to respond to sheep red blood cell immunization. Nonetheless, athymic-asplenic mice appear more immunologically compromised than nude mice. Indeed, there is an elevated rate of growth and a lower inoculated cell threshold needed for successful transplantation of a human malignant melanoma. Finally, there was no evidence for auto-antibody production in mice up to 9 months of age. Congenitally athymic-asplenic mice can be used for a variety of studies in which other immunologically deprived mouse mutants are desired.


The secretory immunological system of the fowl. VI. The effect of chemical bursectomy on immunoglobulin concentration in tears.

The effect of chemical bursectomy (3-5 mg testosterone cypionate injected at 12 days in ovo followed by 4-0 mg cyclophosphamide intraperitoneally at days 1 and 2 post-hatching) on concentration of immunoglobulins in tears and serum of chickens was investigated. Tears and serum samples were collected from bursectomized and normal control birds between days 26 and 120 post-hatching and were assayed for IgA, 7SIg and IgM concentrations using double gel-diffusion and radial immunodiffusion. No immunoglobulins other than passively acquired 7SIg were detected in the sera or tears of 23 out of 30 bursectomized birds throughout the time period. Sera were also assayed for natural agglutinins; normal birds had titres for rabbit erythrocytes which gradually increased from a mean of 1:24 at day 26 to 1:280 at day 120, while bursectomized chickens had titres of less than 1:8 throughout the experimental period. It was concluded that chemical bursectomy effectively abolished the secretory immunoglobulins normally present in tears as well as serum immunoglobulins.


Studies on the control of antibody synthesis. XII. Genetic influences on antibody affinity.

Genetic controls on the concentration and affinity of the anti-dinitrophenyl antibodies produced by different inbred strains of mice in response to immunization with dinitrophenylated bovine gamma globulin in Freund's complete adjuvant were demonstrated. Based upon data on F1 hybrids and backcrosses, it can be concluded that there are genetic controls on antibody affinity which are not linked to the major histocompatibility complex. In addition, the genetic controls on affinity which were studied here appear to be inherited independently of genetic controls on antibody concentration.


Solid phase activation of alternative pathway of complement by beta-1,3-glucans and its possible role for tumour regressing activity.

The efficiency of some anti-tumour polysaccharides, such as lentinan, pachyman, pachymaran, carboxymethylpachymaran and hydroxyethylpachyman to trigger the alternative pathway of complement activation (APC) was investigated in detail, in order to clarify whether solid phase activation of APC by these polysaccharides will occur or not. From the eight polysaccharides tested, all were found to be potent activators of the alternative pathway except for carboxymethylpachymaran, regardless of their potency of inhibition of sarcoma 180 (S 180) transplanted in mice. This activation was observed both for the insoluble as well as the soluble part of the same polysaccharide. The turnover of C3, C5 and factor B showed no difference among these seven active polysaccharides. The polysaccharide particles (PX), isolated after treatment with C4d GPS showed prominent C3 consuming activity, which disappeared during prolonged incubation at 37 degrees. The activity of the decayed enzyme could be regenerated by treatment with the purified factor B. The stability of the particulate enzyme PX was comparable to the zymosan-complex (ZX) previously described.


Induction of contact sensitivity. Selective induction of delayed hypersensitivity by the injection of cells from draining lymph nodes into the footpads of normal recipients.

Cells taken from the draining lymph nodes of mice 1 day after painting with picryl chloride can induce contact hypersensitivity when injected into the footpads of normal recipients. Previous studies have presented evidence to show that this is an immunizing process rather than a transfer of sensitized cells. This study shows that footpad injection of 5 times 10(6) 1-day draining lymph node cells induces a similar degree of hypersensitivity to the original skin painting with picryl chloride but no antibody, as judged by anti-TNP splenic PFC and serum antibody, in contrast to the moderate antibody response found after skin painting. The apparent inability to induce a response did, however, correlate with the finding that the draining lymph nodes of mice painted with picryl chloride had few PFC. Some effect of the cells on antibody was noted in that after mice were challenged on the ear to produce contact sensitivity reactions they produced an antibody response larger than that of mice not injected with cells. This was not a large phenomenon but was unusual because 2-5 times 10(6) cells was more effective than either 10(6) or 5 times 10(6) cells, even though 5 times 10(6) cells produced the largest contact sensitivity reactions. The augmentation was antigen specific and the same dose-response effect could be obtained with irradiated cells (2000 rad). It is suggested that the ability of these cells to induce large contact sensitivity reactions without antibody indicates that they may have an important role in the immunogenicity of contact sensitizing agents, which can induce large delayed-type hypersensitivity reactions accompanied only by moderate antibody responses.


A comparison of the cytotoxic activity of eosinophils and other cells by 51 chromium release and time lapse microcinematography.

Antibody dependent cytotoxicity of chicken erythrocytes by purified rat eosinophils, neutrophils, macrophages and K cells has been compared by 51Cr release and time lapse microcinematography. Techniques have been developed for purifying these effector cell types. Both eosinophils and neutrophils cause rapid release of 51Cr from erythrocytes. Time lapse observations indicated that this was the result of phagocytosis. Eosinophils show rapid membrane movement and repeatedly engulf and regurgitate the erythrocytes. On the other hand, neutrophils become quiescent after phagocytosing erythrocytes, and remain quiescent until the remains of the cell are expelled. Neutrophils presumably have a mechanism for the release of soluble material, as 51Cr is released rapidly. Macrophages show a similar quiescence after phagocytosis, but in these cells there is apparently no rapid mechanism to expel material, as there is no significant 51Cr release over 20 h. K cells appear to damage chicken erythrocytes more slowly than they destroy tumour cells. Mast cells cause antibody-independent cytotoxicity which can be attributed to the release of toxic materials. None of these effector cells produced the type of lysis seen with antibody and complement.


Migration of human lymphocytes. I. A model using the mouse as host.

The distribution of radioactivity after the intravenous injection of 51Cr-labelled human lymphocytes has been examined in normal mice, irradiated mice, mice treated with anti-platelet antiserum and in mice treated with colloidal carbon. Pre-treatment with carbon and anti-platelet antiserum appears to protect the human lymphocytes from uptake by the host's reticuloendothelial system (RES). Comparison of tissue radioactivity in carbon-treated mice after the injection of viable human lymphocytes with that found after the injection of dead cells and soluble or insoluble cell debris showed that radioactivity recovered in the spleen and lymph nodes is primarily due to the migration of viable lymphocytes into these tissues. Thus the measurement of radioactivity in lymph nodes of carbon-treated mice after the injection of 51Cr-labelled human lymphocytes can be used as a model of these lymphocytes' ability to migrate into the lymph nodes during recirculation and to study factors influencing this migration.